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  • Public defence: 2018-04-26 13:15 Rosénsalen, Ing 95/96, Uppsala
    Liljeström, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Birth asphyxia: Fetal scalp blood sampling and risk factors for hypoxic ischemic encephalopathy2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Preventing birth asphyxia is a major challenge in delivery care. The aims of this thesis were to evaluate fetal scalp blood sampling (FBS) and explore risk factors for moderate to severe neonatal hypoxic ischemic encephalopathy (HIE).

    In a study of 241 deliveries monitored by FBS, a discrepancy between pH and lactate (one abnormal and one normal value) was common (55%) in combined FBS. We found that the frequency of operative deliveries for fetal distress (ODFD) was lower when both pH and lactate were analysed in FBS compared with analysis of only pH or lactate, without affecting neonatal outcome. (Study I)

    In a questionnaire study, women (n = 51) monitored by FBS generally tolerated the test well. Women without epidural, with higher body mass index (BMI), and with less cervical dilatation had higher pain ratings compared with their counterparts. The obstetricians that performed the test generally experienced the test as easy to perform, but more complicated with high maternal BMI, less cervical dilatation, and higher station of the fetal head. (Study II)

    In a national cohort of 692 428 live births ≥ 36 weeks, risk factors for moderate to severe HIE were identified. We found a linear association between increasing maternal BMI and decreasing maternal height and risk of HIE. Compared with non-short (≥156 cm) and normal weight (BMI<25 kg/m2) women, short and overweight women had a threefold risk of HIE. (Study III)

    Obstetric emergencies occurred in 29% of HIE cases, more commonly in parous (37%) than in nulliparous (21%) women. Among nulliparous women, shoulder dystocia was most common, with the strongest association to HIE. In parous women without previous caesarean, shoulder dystocia was most common, but placental abruption had the strongest association to HIE. Among parous women with previous caesarean, uterine rupture was the most prevalent, with the strongest association to HIE. (Study IV)

    Conclusions: Combined FBS might decrease the frequency of ODFD. FBS is well tolerated in women and generally uncomplicated for the obstetrician to perform. Women with short stature and overweight have increased risk of having an infant with HIE. Obstetric emergencies are common underlying causes of HIE, especially in parous women.

    List of papers
    1. Evaluation of the discrepancy between pH and lactate in combined fetal scalp blood sampling
    Open this publication in new window or tab >>Evaluation of the discrepancy between pH and lactate in combined fetal scalp blood sampling
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    2011 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 90, no 10, p. 1088-1093Article in journal (Refereed) Published
    Abstract [en]

    Objective. To evaluate the rate of discrepancy between pH and lactate values in fetal blood sampling (FBS). To evaluate differences in obstetric management in response to combined tests (pH and lactate) and single tests (pH or lactate).

    Design. Descriptive study.

    Setting. Uppsala University Hospital, Sweden. Population. Labors monitored by FBS during one year (n=241).

    Methods. Discrepancy in the combined tests was defined as a test having one abnormal and one normal value. Abnormal pH was defined as 7.24 or lower and abnormal lactate as 4.2 or higher. The results were categorized according to whether the test was normal or abnormal and according to whether it was a combined or single analysis. Main outcome measures. Discrepancy between pH and lactate values in combined tests. Frequency of operative delivery for fetal distress (ODFD). Time interval from the last FBS to ODFD.

    Results. In the combined tests with abnormality, a discrepancy between pH and lactate values occurred in 55%. The mean time interval from the last FBS to ODFD was longer in combined tests with one abnormal compared with two abnormal test results, 75 vs. 37 minutes (p<0.05). Operative delivery for fetal distress was performed less often after combined tests than after single tests: 41/62 (66%) vs. 19/20 (95%) (p<0.05).

    Conclusion. In the combined test, discrepancies were common and occurred in half of the samples with an abnormality. Obstetric management was influenced by the discrepancy between test results with respect to ODFD rates and the time interval from the last FBS to delivery.

    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-159948 (URN)10.1111/j.1600-0412.2011.01228.x (DOI)000295595100005 ()21707554 (PubMedID)
    Available from: 2011-10-12 Created: 2011-10-12 Last updated: 2018-02-17Bibliographically approved
    2. Experience of fetal scalp blood sampling during labor
    Open this publication in new window or tab >>Experience of fetal scalp blood sampling during labor
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    2014 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 93, no 1, p. 113-117Article in journal (Refereed) Published
    Abstract [en]

    Fetal scalp blood sampling (FBS) is often claimed to be painful for women in labor and difficult for obstetricians to perform. Our aim was to assess women's experience of pain during FBS and obstetricians' experience of difficulty in performing the test. At a tertiary centre in Sweden, a questionnaire with answers on a ten-point scale was completed by 51 women and by the obstetricians performing the test. Women's experience of pain had a median of 3.5. FBS was well tolerated in women who had epidural analgesia, but might be associated with pain in women without. Higher maternal body mass index and less cervical dilatation were associated with higher pain ratings. Obstetricians did not generally experience scalp sampling as difficult to perform (median score 3.0). However, the sampling procedure can be more complicated in situations with higher maternal body mass, less cervical dilatation, and a higher station of the fetal head. 

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-209534 (URN)10.1111/aogs.12271 (DOI)000328435300017 ()24116986 (PubMedID)
    Available from: 2013-10-21 Created: 2013-10-21 Last updated: 2018-02-17Bibliographically approved
    3. Antepartum risk factors for moderate to severe neonatal hypoxic ischemic encephalopathy: a Swedish national cohort study
    Open this publication in new window or tab >>Antepartum risk factors for moderate to severe neonatal hypoxic ischemic encephalopathy: a Swedish national cohort study
    (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412Article in journal (Refereed) Epub ahead of print
    Keyword
    Asphyxia, body mass index, hypoxic ischemic encephalopathy, maternal height, overweight, risk factors, short stature, therapeutic hypothermia
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Research subject
    Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-341926 (URN)
    Available from: 2018-02-16 Created: 2018-02-16 Last updated: 2018-02-17
    4. Obstetric emergencies as antecedents to neonatal hypoxic ischemic encephalopathy, does parity matter?: : a Swedish national cohort study
    Open this publication in new window or tab >>Obstetric emergencies as antecedents to neonatal hypoxic ischemic encephalopathy, does parity matter?: : a Swedish national cohort study
    (English)Manuscript (preprint) (Other academic)
    Keyword
    Asphyxia, hypoxic ischemic encephalopathy, obstetric emergencies, parity, risk factors, therapeutic hypothermia
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Research subject
    Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-341718 (URN)
    Available from: 2018-02-13 Created: 2018-02-13 Last updated: 2018-02-17
  • Public defence: 2018-04-27 09:00 Gunnesalen, Uppsala
    Westerberg, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Environmental Factors of Importance in Myasthenia Gravis: Emphasis on Physical Activity2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Myasthenia Gravis (MG) is an autoimmune disease caused by antibodies directed against proteins at the neuromuscular junction (NMJ). The disturbed neuromuscular transmission induces fatigable weakness in skeletal muscles. The severity of MG ranges from purely ocular symptoms to extensive weakness with, at worst, respiratory failure and need of intensive care. Due to different pathogenic antibodies, as well as varying phenotypes there is a classification into MG subgroups.

    As lifestyle disorders are common conditions they occur also in MG patients. It is unknown whether there are any lifestyle factors associated with MG or MG subgroups. However, medication side effects and disability due to disease could contribute to higher risks for lifestyle related diseases. General treatment guidelines are not suitable to MG patients, since various medications are known to affect the disease negatively and as the tolerance and effects of physical activity in MG is unknown.

    In this thesis the occurrence of lifestyle related environmental factors in MG patients were investigated. MG epidemiology, subgroup differences and the presence of lifestyle related risks in MG patients were evaluated in Jönköping county in Southern Sweden. The findings were compared to a similar evaluation in a region of Estonia. We found that MG patients in the late-onset disease subgroup had a more disadvantageous pattern of life-style related risk factors, with a higher rate of obesity, smoking and physical inactivity and a lower rate of fish consumption in comparison to matched population controls. Furthermore, we found that despite comparable clinical muscle fatigue status, Estonian MG patients subjectively scored fatigue and disease severity higher than Swedish MG patients. More Estonian patients were physically inactive. The tolerance and effects of physical exercise was further evaluated in two intervention studies, where MG patients with stable disease performed a 12-week-training-program according to general exercise recommendations to healthy adults. We found that physical exercise was well tolerated by the MG patients and that they had a beneficial skeletal muscle response to physical exercise.

    List of papers
    1. Diversity in mental fatigue and social profile of patients with myasthenia gravis in two different Northern European countries
    Open this publication in new window or tab >>Diversity in mental fatigue and social profile of patients with myasthenia gravis in two different Northern European countries
    2017 (English)In: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 7, no 4, article id e00653Article in journal (Refereed) Published
    Abstract [en]

    Tntroduction: Self-estimated health can be used for comparison of different diseases between countries. It is important to elaborate on whether disparities in self-estimated health are due to disease-specific parameters or socioeconomic differences. In this study, we aimed at evaluating clinical and social similarities and differences in myasthenia gravis (MG) patients between comparable regions in two Baltic Sea countries, Estonia and Sweden. Methods: This cross-sectional study included southern counties in Sweden and Estonia of comparable size. All patients with a confirmed MG diagnosis were asked to answer two questionnaires including demographic and disease-specific data, lifestyle issues, and mental fatigue (Fatigue Severity Scale [FSS]). Clinical fatigue was assessed objectively through the Quantitative Myasthenia Gravis Score (QMG). Results: Thirty-six of 92 identified patients in Estonia and 40 of 70 identified MG patients in Sweden chose to participate in the study. The demographic characteristics and symptoms reported by the patients were similar. QMG score did not differ; however, the Estonian patients scored their current subjective disease severity significantly higher (5.6 +/- 2.8) compared to the Swedish patients (3.4 +/- 2.3, p=.0005). Estonian patients also had significantly higher FSS scores (5.0 +/- 1.7) than Swedish patients (3.5 +/- 1.6; p=.001). Swedish patients were more active and performed physical activity more regularly (29.1% in Estonia and 74.2% in Sweden, p=.004). Conclusions: Although, the patients had comparable clinical fatigue, Estonian patients evaluated their health state as being more severe and reported more mental fatigue than Swedish patients. These data indicate large regional differences in disease perception of MG, which is important to consider in international studies.

    Place, publisher, year, edition, pages
    WILEY, 2017
    Keyword
    Estonia, fatigue, myasthenia gravis, Sweden
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-322219 (URN)10.1002/brb3.653 (DOI)000399452500009 ()28413704 (PubMedID)
    Funder
    Swedish Research Council, VR-523-2014-2048
    Available from: 2017-05-17 Created: 2017-05-17 Last updated: 2018-03-08Bibliographically approved
    2. Lifestyle factors and gender-related differences in clinical subgroups of Myasthenia Gravis in southern Sweden
    Open this publication in new window or tab >>Lifestyle factors and gender-related differences in clinical subgroups of Myasthenia Gravis in southern Sweden
    (English)In: BMC Neurology, ISSN 1471-2377, E-ISSN 1471-2377Article in journal (Refereed) Submitted
    Abstract [en]

    Background: Based on the need for further regional and global epidemiological knowledge on Myasthenia Gravis (MG) and MG subgroups, we conducted a questionnaire-based epidemiological survey in a medium-sized health care region in southern Sweden. The primary aims were to investigate disease-specific items and lifestyle related factors between MG subgroups and matched population controls.

    Methods: All MG patients (n=70) in Jönköping County were invited to participate in a survey, using a standardized disease-specific questionnaire, previously developed by an expert group. This questionnaire contains three parts, including demographic and disease-specific data, lifestyle and health-related aspects as well as co-morbidity and mental fatigue. The patients were clinically evaluated. Four hundred age- and gender matched randomly selected population controls excluding MG were invited to answer the non-disease-specific part of the questionnaire. Statistical tests included student t-test (for parametric data) or Mann–Whitney U test (for nonparametric data) and Chi-square test and Fisher’s exact test for evaluations between MG subgroups. In the case-control analysis conditional logistic regression was used to estimate the adjusted Odds Ratios.

    Results: Forty of the 70 identified MG patients and 188 of the 400 age-and gender matched population controls participated in the study (response rate 57.1%). In the late onset MG (LOMG; N=18) subgroup, the male predominance was higher than previously reported. In the early onset MG (EOMG; N=17) group, time to diagnosis was longer and bulbar weakness was the dominant symptom (65%). EOMG patients had higher fatigue compared to LOMG. Compared to their matched population controls, LOMG patients were obese more often, ate ess fish, smoked more, had a lower educational level and were employed as manual laborers more often. Mental health problems and sickness benefits were more common among MG patients than in controls and MG patients were less regularly doing focused physical activity.

    Conclusions: These findings highlight lifestyle and gender related differences between the EOMG and LOMG subgroups and between MG patients and population controls. Importantly, these lifestyle issues such as cardiovascular risk factors and physical inactivity, as well as mental health problems should be addressed intensively in the clinical follow-up of MG patients.

    Keyword
    Myasthenia Gravis, late onset MG, early onset MG, lifestyle, fatigue
    National Category
    Neurology
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-344665 (URN)
    Funder
    Swedish Research Council, VR-523-2014-2048Futurum - Academy for Health and Care, Jönköping County Council, Sweden, 488501
    Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-03-08
    3. Physical exercise in Myasthenia Gravis is safe and improves neuromuscular parameters and physical performance-based measures: A pilot study
    Open this publication in new window or tab >>Physical exercise in Myasthenia Gravis is safe and improves neuromuscular parameters and physical performance-based measures: A pilot study
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    2017 (English)In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 56, no 2, p. 207-214Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: Due to the shortage of exercise-related research in Myasthenia Gravis (MG), there are no consensus guidelines on physical exercise for MG patients.

    METHODS: In this prospective pilot study, 10 MG patients with mild disease performed supervised aerobic and resistance training twice weekly for 12 weeks. The Myasthenia Gravis Composite (MGC) score, compound motor action potential (CMAP), repetitive nerve stimulation, muscle force, physical performance-based measures, serum levels of interleukin-6, muscle enzymes as well as immuno-microRNAs miR-150-5p and miR-21-5p were assessed before and after the training period.

    RESULTS: Physical exercise was well tolerated, and the MGC score was unchanged. Muscle resistance weights and CMAP amplitudes increased for biceps brachii and rectus femoris muscles, and physical performance-based measures improved. Muscle enzymes remained normal, whereas disease-specific microRNAs miR-150-5p and miR-21-5p were reduced after the training period.

    CONCLUSIONS: We propose that general recommendations regarding physical exercise safely can be applied to well-regulated MG patients.

    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-314678 (URN)10.1002/mus.25493 (DOI)000406875000009 ()27935072 (PubMedID)
    Funder
    Swedish Research Council, 2014-02048Futurum - Academy for Health and Care, Jönköping County Council, Sweden, 520281, 520411Swedish Society of Medicine, SLS-499271
    Available from: 2017-02-04 Created: 2017-02-04 Last updated: 2018-03-08Bibliographically approved
    4. The impact of physical exercise on functional muscle measures in Myasthenia Gravis patients – a single subject design study
    Open this publication in new window or tab >>The impact of physical exercise on functional muscle measures in Myasthenia Gravis patients – a single subject design study
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    (English)In: Medicine®, ISSN 0025-7974Article in journal (Refereed) Submitted
    Abstract [en]

    There is a need for tailored exercise recommendations to patients with Myasthenia Gravis (MG). A few pilot studies have recently shown that physical exercise in accordance with general recommendations to healthy adults can be applied safely to patients with mild MG symptoms. How physical exercise affects muscle parameters and risk factors for life-style diseases in patients with MG is, however, only poorly known. We evaluated functional skeletal muscle parameters in 11 MG patients, before and after conducting a 12-week supervised physical therapy regimen of aerobic and high-resistance strength training. After the training program, parameters of the proximal leg muscle rectus femoris improved: compound motor action potential (from 4.5 ± 2.6 to 5.3 ± 2.8 mV, p=0.016), isometric muscle force (from 25.2 ± 4.4 to 30.2 ± 3.8 kg; p=0.014) and ultrasound muscle thickness (from 19.6 ± 5.6 to 23.0 ± 3.9 mm, p=0.0098) all increased. Further, physical performance-based measures improved, including the 30-Second Chair Stand Test (median change +2, p=0.0039) as well as the clinical MG composite score (from 3[2-5] to 2 [0-4], p=0.043). These findings indicate that MG patients can improve their functional muscle status as a result of aerobic and high-resistance strength training, especially in proximal leg muscles. This is important knowledge when physical therapy is considered for this patient group, for whom no guidelines on physical exercise currently exist.

    Keyword
    Myasthenia Gravis, physical exercise, neuromuscular, CMAP, resistance training
    National Category
    Neurology
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-344666 (URN)
    Funder
    Swedish Research Council, VR-523-2014-2048
    Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-03-08
  • Public defence: 2018-04-27 09:00 Hambergssalen, Uppsala
    Xu, Jingying
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Remediation of mercury contaminated soil and biological mercury methylation in the landscape2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Accumulation of mercury (Hg) in soil originating from both natural and anthropogenic sources poses a major hazard to environmental and human health. Inorganic Hg(II) in soil can be transformed to highly toxic methylmercury (MeHg) mainly via methylating microorganisms. Although MeHg constitutes less than 2% of total Hg in soil, it enters aquatic systems through runoff and can be subsequently bioaccumulated along the food chain, thereby causing severe harm to humans.

    Current major remediation techniques to control soil Hg contamination were reviewed. Organic matter, clay/minerals and complexation ligands within soil are principal factors influencing Hg mobility that is crucial for evaluating and optimising remedial techniques. The potential of soil washing to treat soil Hg contamination was evaluated. The studied soil was fractionated from fine to coarse particles to assess the effectiveness of physical separation. Batch leaching and pH-static titration tests were performed using (1) water, (2) EDTA, (3) NaOH, (4) HCl, (5) acidic leachates from biodegradable wastes, and (6) alkaline leachates from fly/bottom ashes, to estimate the efficiency of chemical extraction. Less than 1.5% of the total Hg could be mobilised after combined treatments, implying very tight binding of Hg to soil particles, thereby hampering soil washing as a strategy for the studied soil.

    Hg(II) methylation in boreal soils and lake sediments can have major consequences for MeHg inputs to downstream aquatic systems. It is therefore important to understand the biogeochemical mechanisms involved in MeHg formation in these landscapes. The microbes involved in Hg(II) methylation in sediments and boreal forests and wetlands were investigated by high-throughput 16S rRNA and hgcA sequencing with molecular barcoding. In all three environments, hgcA sequences were distributed among Proteobacteria, Firmicutes and Euryarchaeota, and Deltaproteobacteria, particularly Geobacteraceae, appeared to play a predominant role. Ruminococcaceae were also abundant Hg(II) methylators in soils from one forest and all the wetlands. The boreal forest survey provided some first insights about the possible link between MeHg formation and non-Hg(II) methylating bacterial communities that likely support the growth and activity of Hg(II) methylating members. Results from wetlands pointed out nutrient status as an important factor shaping Hg(II) methylating communities across the four wetlands, and highlighted a significant role of water content and iron in controlling the distribution of Hg(II) methylators within individual wetlands. Furthermore, the interactions between Hg(II) methylating groups revealed that the more anaerobic and productive conditions seemed to favour the activity of Methanoregulaceae and hamper the growth of Ruminococcaceae. Results from lake sediments supported that Geobacteraceae have an important role in Hg(II) methylation under ferruginous geochemical conditions. Our findings provide a better understanding of Hg(II) methylating communities in the landscape.

    List of papers
    1. Sources and remediation techniques for mercury contaminated soil
    Open this publication in new window or tab >>Sources and remediation techniques for mercury contaminated soil
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    2015 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 74, p. 42-53Article, review/survey (Refereed) Published
    Abstract [en]

    Mercury (Hg) in soils has increased by a factor of 3 to 10 in recent times mainly due to combustion of fossil fuels combined with long-range atmospheric transport processes. Other sources as chlor-alkali plants, gold mining and cement production can also be significant, at least locally. This paper summarizes the natural and anthropogenic sources that have contributed to the increase of Hg concentration in soil and reviews major remediation techniques and their applications to control soil Hg contamination. The focus is on soil washing, stabilisation/solidification, thermal treatment and biological techniques; but also the factors that influence Hg mobilisation in soil and therefore are crucial for evaluating and optimizing remediation techniques are discussed. Further research on bioremediation is encouraged and future study should focus on the implementation of different remediation techniques under field conditions.

    Place, publisher, year, edition, pages
    Elsevier, 2015
    Keyword
    Mercury contaminated soil, Mobility, Remediation, Soil washing, Stabilisation/solidification
    National Category
    Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-242480 (URN)10.1016/j.envint.2014.09.007 (DOI)000346681700006 ()
    Funder
    Swedish Research Council, D0697801
    Available from: 2015-01-26 Created: 2015-01-26 Last updated: 2018-03-15Bibliographically approved
    2. Influence of particle size distribution, organic carbon, pH and chlorides on washing of mercury contaminated soil
    Open this publication in new window or tab >>Influence of particle size distribution, organic carbon, pH and chlorides on washing of mercury contaminated soil
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    2014 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 109, p. 99-105Article in journal (Refereed) Published
    Abstract [en]

    Feasibility of soil washing to remediate Hg contaminated soil was studied. Dry sieving was performed to evaluate Hg distribution in soil particle size fractions. The influence of dissolved organic matter and chlo- rides on Hg dissolution was assessed by batch leaching tests. Mercury mobilization in the pH range of 3– 11 was studied by pH-static titration. Results showed infeasibility of physical separation via dry sieving, as the least contaminated fraction exceeded the Swedish generic guideline value for Hg in soils. Soluble Hg did not correlate with dissolved organic carbon in the water leachate. The highest Hg dissolution was achieved at pH 5 and 11, reaching up to 0.3% of the total Hg. The pH adjustment was therefore not suf- ficient for the Hg removal to acceptable levels. Chlorides did not facilitate Hg mobilization under acidic pH either. Mercury was firmly bound in the studied soil thus soil washing might be insufficient method to treat the studied soil. 

    Keyword
    Organic matter, Mobilization pH-dependent, dissolution, Soil remediation
    National Category
    Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-224367 (URN)10.1016/j.chemosphere.2014.02.058 (DOI)
    Available from: 2014-05-09 Created: 2014-05-09 Last updated: 2018-03-15Bibliographically approved
    3. Mercury methylating microbial communities of boreal forest soils
    Open this publication in new window or tab >>Mercury methylating microbial communities of boreal forest soils
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The formation of the potent neurotoxic methylmercury (MeHg) is a microbially mediated process that has raised much concern because MeHg poses threats to wildlife and human health. Since boreal forest soils can be a source of MeHg in aquatic networks, it is crucial to understand the biogeochemical processes involved in the formation of this pollutant. High-throughput sequencing of 16S rRNA and the mercury methyltransferase, hgcA, combined with geochemical characterisation of soils, were used to determine the microbial populations contributing to MeHg formation in forest soils across Sweden. The hgcA sequences obtained were distributed among diverse clades, including Proteobacteria, Firmicutes, and Methanomicrobia, with Deltaproteobacteria, particularly Geobacteraceae, dominating the libraries across all soils examined. Our results also suggest that MeHg formation is linked to the composition of also non-mercury methylating bacterial communities, likely providing growth substrate (e.g. acetate) for the hgcA-carrying microorganisms responsible for the actual methylation process. While previous research focused on mercury methylating microbial communities of wetlands, this study provides some first insights into the diversity of mercury methylating microorganisms in boreal forest soils.

    National Category
    Natural Sciences
    Research subject
    Biology with specialization in Limnology
    Identifiers
    urn:nbn:se:uu:diva-346175 (URN)
    Available from: 2018-03-15 Created: 2018-03-15 Last updated: 2018-03-15
    4. Mercury methylating microbial communities in boreal wetlands
    Open this publication in new window or tab >>Mercury methylating microbial communities in boreal wetlands
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Understanding the formation of the potent neurotoxic methylmercury (MeHg) is a major concern due to its threats to wildlife and human health. As boreal wetlands play a crucial role for Hg cycling on a global scale, it is crucial to understand the biogeochemical processes involved in MeHg formation in this landscape. A strategy combining high-throughput hgcA amplicon sequencing with molecular barcoding was used to revealed diverse clades of Hg(II) methylators in a wide range of wetland soils. Our results confirms a predominant role of Deltaproteobacteria, and in particular Geobacteraceae, as important Hg(II) methylators in boreal wetland soils. Firmicutes, and in particular Ruminococcaceae, were also abundant members of the Hg(II) methylating microbial communities. Our survey highlight the importance of nutrient status for the shaping of Hg(II) methylating communities across the four wetlands and reveal that water content and prevailing redox states are key factors determining the local variation in Hg(II) methylating community composition within individual wetlands. Also, our study suggests that high nutrient levels linked to low redox potential seemed to favour Hg(II) methylating methanogens within the Methanoregulaceae. Our findings expand the current knowledge on the Hg(II) methylating microbial community composition in wetland soils and the geochemical factors underpinning spatial heterogeity in such communities.  

    Keyword
    Wetlands, Methylmercury, Mercury methylation, hgcA, Community composition, Bacteria
    National Category
    Genetics
    Research subject
    Biology with specialization in Limnology
    Identifiers
    urn:nbn:se:uu:diva-346177 (URN)
    Available from: 2018-03-15 Created: 2018-03-15 Last updated: 2018-03-15Bibliographically approved
    5. Geobacteraceae are important members of mercury-methylating microbial communities of sediments impacted by wastewater releases
    Open this publication in new window or tab >>Geobacteraceae are important members of mercury-methylating microbial communities of sediments impacted by wastewater releases
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    (English)In: The ISME Journal, ISSN 1751-7362, E-ISSN 1751-7370Article in journal (Refereed) Accepted
    National Category
    Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-335005 (URN)
    Available from: 2017-11-29 Created: 2017-11-29 Last updated: 2018-03-15
  • Public defence: 2018-04-27 09:15 C8:301, Uppsala
    Zan, Yanjun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Understanding the genetic basis of complex traits2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Recent advances in genetics and genomics have provided numerous opportunities to study the genetic basis of complex traits. Nevertheless, dissecting the genetic basis of complex traits is still challenged by the complex genetic architecture, in which many genes are involved, and many have small contributions to phenotypic variation, interactions with other genes or environmental factors. The aim of this thesis is to evaluate the genetic basis of the complex traits by exploring available genomic resources and analytical approaches. Four studies included in this thesis explore: the genetic basis of global transcriptome variation in natural population (Study I); the genetic basis of 8-week body weight in artificial selected chicken lines (Study II); the genetic basis of flowering time variation for Arabidopsis thaliana sampled from a wide range of ecological conditions (Study III and Study IV). Findings from this thesis show that the genetic architecture of complex traits involves many polymorphisms with variable effect sizes. Some of those polymorphisms are multi-allelic and have interactions with each other and environmental factors at the same time. The presence of many alleles with minor contributions to phenotypic variation in natural and artificially selected population demonstrates that response to natural and artificial selection has been achieved by polygenic adaptation. Furthermore, population-specific large-effect loci with long-range LD to QTL in functionally related pathways indicate that emergence and fixation of loci with large effects and co-evolution of loci in the related pathway is contributing to the local adaptation of Arabidopsis thaliana. Overall, this thesis shows the complexity of complex trait genetics and provides a few insights into study designs and analysis approaches for understanding the genetic basis of complex traits.

    List of papers
    1. Artificial Selection Response due to Polygenic Adaptation from a Multilocus, Multiallelic Genetic Architecture.
    Open this publication in new window or tab >>Artificial Selection Response due to Polygenic Adaptation from a Multilocus, Multiallelic Genetic Architecture.
    Show others...
    2017 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 34, no 10, p. 2678-2689Article in journal (Refereed) Published
    Abstract [en]

    The ability of a population to adapt to changes in their living conditions, whether in nature or captivity, often depends on polymorphisms in multiple genes across the genome. In-depth studies of such polygenic adaptations are difficult in natural populations, but can be approached using the resources provided by artificial selection experiments. Here, we dissect the genetic mechanisms involved in long-term selection responses of the Virginia chicken lines, populations that after 40 generations of divergent selection for 56-day body weight display a 9-fold difference in the selected trait. In the F15 generation of an intercross between the divergent lines, 20 loci explained >60% of the additive genetic variance for the selected trait. We focused particularly on fine-mapping seven major QTL that replicated in this population and found that only two fine-mapped to single, bi-allelic loci; the other five contained linked loci, multiple alleles or were epistatic. This detailed dissection of the polygenic adaptations in the Virginia lines provides a deeper understanding of the range of different genome-wide mechanisms that have been involved in these long-term selection responses. The results illustrate that the genetic architecture of a highly polygenic trait can involve a broad range of genetic mechanisms, and that this can be the case even in a small population bred from founders with limited genetic diversity.

    Keyword
    epistasis, genetic architecture, genetic variation, multiallelic, multilocus, polygenic adaptation
    National Category
    Natural Sciences Genetics
    Identifiers
    urn:nbn:se:uu:diva-332731 (URN)10.1093/molbev/msx194 (DOI)000411814800019 ()28957504 (PubMedID)
    Funder
    Swedish Research Council, 2012-4634Swedish Research Council Formas, 2010-643, 2013-450
    Available from: 2017-11-01 Created: 2017-11-01 Last updated: 2018-02-26
    2. Genetic Regulation of Transcriptional Variation in Natural Arabidopsis thaliana Accessions
    Open this publication in new window or tab >>Genetic Regulation of Transcriptional Variation in Natural Arabidopsis thaliana Accessions
    2016 (English)In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 6, no 8, p. 2319-2328Article in journal (Refereed) Published
    Abstract [en]

    An increased knowledge of the genetic regulation of expression in Arabidopsis thaliana is likely to provide important insights about the basis of the plant's extensive phenotypic variation. Here, we reanalysed two publicly available datasets with genome-wide data on genetic and transcript variation in large collections of natural A. thaliana accessions. Transcripts from more than half of all genes were detected in the leaf of all accessions, and from nearly all annotated genes in at least one accession. Thousands of genes had high transcript levels in some accessions but no transcripts at all in others and this pattern was correlated with the genome-wide genotype. In total, 2,669 eQTL were mapped in the largest population, and 717 of them were replicated in the other population. 646 cis-eQTLs regulated genes that lacked detectable transcripts in some accessions, and for 159 of these we identified one, or several, common structural variants in the populations that were shown to be likely contributors to the lack of detectable RNA-transcripts for these genes. This study thus provides new insights on the overall genetic regulation of global gene-expression diversity in the leaf of natural A. thaliana accessions. Further, it also shows that strong cis-acting polymorphisms, many of which are likely to be structural variations, make important contributions to the transcriptional variation in the worldwide A. thaliana population.

    Keyword
    eQTL mapping; RNA sequencing; gene expression; Arabidopsis thaliana; structural variation
    National Category
    Genetics
    Identifiers
    urn:nbn:se:uu:diva-298144 (URN)10.1534/g3.116.030874 (DOI)000381282300008 ()27226169 (PubMedID)
    Available from: 2016-06-30 Created: 2016-06-30 Last updated: 2018-02-26Bibliographically approved
    3. A multi-locus association analysis method integrating phenotype and expression data reveals multiple novel associations to flowering time variation in wild-collected Arabidopsis thaliana.
    Open this publication in new window or tab >>A multi-locus association analysis method integrating phenotype and expression data reveals multiple novel associations to flowering time variation in wild-collected Arabidopsis thaliana.
    2018 (English)In: Molecular Ecology Resources, ISSN 1755-098X, E-ISSN 1755-0998Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    The adaptation to a new habitat often results in a confounding between genome-wide genotype and beneficial alleles. When the confounding is strong, or the allelic effects weak, it is a major statistical challenge to detect the adaptive polymorphisms. We describe a novel approach to dissect polygenic traits in natural populations. First, candidate adaptive loci are identified by screening for loci directly associated with the adaptive trait or the expression of genes known to affect it. Then, a multi-locus genetic architecture is inferred using a backward elimination association analysis across all candidate loci with an adaptive false discovery rate based threshold. Effects of population stratification are controlled by accounting for genomic kinship in both steps of the analysis and also by simultaneously testing all candidate loci in the multi locus model. We illustrate the method by exploring the polygenic basis of an important adaptive trait, flowering time in Arabidopsis thaliana, using public data from the 1,001 genomes project. We revealed associations between 33 (29) loci and flowering time at 10 (16)°C in this collection of natural accessions, where standard genome wide association analysis methods detected 5 (3) loci. The 33 (29) loci explained approximately 55.1 (48.7)% of the total phenotypic variance of the respective traits. Our work illustrates how the genetic basis of highly polygenic adaptive traits in natural populations can be explored in much greater detail by using new multi-locus mapping approaches taking advantage of prior biological information, genome and transcriptome data. This article is protected by copyright. All rights reserved.

    Keyword
    Arabidopsis thaliana, Expression QTL, Flowering, Genome wide association analysis, Polygenic
    National Category
    Natural Sciences
    Research subject
    Bioinformatics
    Identifiers
    urn:nbn:se:uu:diva-340301 (URN)10.1111/1755-0998.12757 (DOI)29356396 (PubMedID)
    Funder
    Swedish Research Council Formas, 2013-450
    Available from: 2018-01-29 Created: 2018-01-29 Last updated: 2018-02-26
  • Public defence: 2018-04-27 10:00 Häggsalen, Å10132, Uppsala
    Apelfröjd, Rikke
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Signals and Systems Group.
    Channel Estimation and Prediction for 5G Applications2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Accurate channel state information (CSI) is important for many candidate techniques of future wireless communication systems. However, acquiring CSI can sometimes be difficult, especially if the user equipment is mobile in which case the future channel realisations must be estimated/predicted. In realistic settings the predictability of radio channels is limited due to measurement noise, limited model orders and since the fading statistics must be modelled based on a set of limited and noisy training data.

    In this thesis, the limits of predictability for the radio channel are investigated. Results show that the predictability is limited primarily due to limitations in the training data, while the model order provides a second order limitation effect and the measurement noise comes in as a third order effect.

    Then, a Kalman-based linear filter is studied for potential 5G technologies:

    Coherent coordinated multipoint joint transmission, where channel predictions and the covariance matrix of the prediction error are used to design a robust linear precoder, evaluated in a three base station system. Results show that prediction improves the CSI for the pedestrian users such that system delays of 10 ms are acceptable. The use of the covariance matrix is important for difficult user groups, but of less importance with a simple user grouping system proposed.

    Massive multiple-input multiple-output (MIMO) in frequency division duplex (FDD) systems were a reduced, suboptimal, Kalman filter is suggested to estimate channels based on non-orthogonal pilots. By introducing a fixed grid of beams, the system generates sparsity in the channel vectors seen by each user, which then estimates its most relevant channels based on unique pilot codes for each beam. Results show that there is a 5 dB loss compared to orthogonal pilots.

    Downlink time division duplex (TDD) channels are estimated based on uplink pilots. By using a predictor antenna, which scouts the channel in advance, the desired downlink channel can be estimated using pilot-based estimates of the channels before and after it (in space). Results indicate that, with the help of Kalman smoothing, predictor antennas can enable accurate CSI for TDD downlinks at vehicular velocities of 80 km/h.

    List of papers
    1. Kalman predictions for multipoint OFDM downlink channels
    Open this publication in new window or tab >>Kalman predictions for multipoint OFDM downlink channels
    2014 (English)Report (Other academic)
    National Category
    Engineering and Technology
    Research subject
    Electrical Engineering with specialization in Signal Processing
    Identifiers
    urn:nbn:se:uu:diva-235010 (URN)
    Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2018-03-07
    2. Design and measurement based evaluation of coherent JT CoMP: A study of precoding, user grouping and resource allocation using predicted CSI
    Open this publication in new window or tab >>Design and measurement based evaluation of coherent JT CoMP: A study of precoding, user grouping and resource allocation using predicted CSI
    2014 (English)In: EURASIP Journal on Wireless Communications and Networking, ISSN 1687-1472, E-ISSN 1687-1499, Vol. 100Article in journal (Refereed) Published
    National Category
    Engineering and Technology
    Research subject
    Electrical Engineering with specialization in Signal Processing
    Identifiers
    urn:nbn:se:uu:diva-235014 (URN)DOI:10.1186/1687-1499-2014-100 (DOI)
    Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2018-03-07
    3. Robust linear precoder for coordinated multipoint joint transmission under limited backhaul with imperfect CSI
    Open this publication in new window or tab >>Robust linear precoder for coordinated multipoint joint transmission under limited backhaul with imperfect CSI
    2014 (English)In: 2014 11TH INTERNATIONAL SYMPOSIUM ON WIRELESS COMMUNICATIONS SYSTEMS (ISWCS), 2014, p. 138-143Conference paper, Published paper (Refereed)
    Abstract [en]

    Coordinated Multipoint (COMP) transmission provides high theoretic gains in spectral efficiency, in particular with coherent linear Joint Transmission (JT) to multiple users. However, this requires high backhaul capacity. If the backhaul requirement cannot be met by the system, then CoNIP gains decrease as the linear precoder matrix must be adjusted to include zeros. To minimize the loss of CoMP gains, all elements in the precoder should be adjusted as zeros are added to the precoder. We here propose a low complexity method for adjusting a precoder matrix when some elements are required to be zero, with respect to a robust MSE criterion. This is done by introducing penalties on specific precoder matrix elements. This generalized MSE criterion can then be used as a low complexity tool for optimizing e.g. with respect to sum-rate. Results show that this does indeed provide a better solution than if zeros are added separately. It is especially beneficial for cell edge users, i.e. for the same users that can gain the most from JT CoNIP.

    National Category
    Engineering and Technology
    Research subject
    Electrical Engineering with specialization in Signal Processing
    Identifiers
    urn:nbn:se:uu:diva-235007 (URN)000363906500027 ()978-1-4799-5863-4 (ISBN)
    Conference
    International Symposium on Wireless Communication Systems ISWCS, Barcelona, Spanien, 25-29 Augusti
    Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2018-03-07Bibliographically approved
    4. Joint reference signal design and Kalman/Wiener channel estimation for FDD massive MIMO. Extended Report Version.
    Open this publication in new window or tab >>Joint reference signal design and Kalman/Wiener channel estimation for FDD massive MIMO. Extended Report Version.
    2017 (English)Report (Other academic)
    Place, publisher, year, edition, pages
    Uppsala: Signals and Systems, Uppsala University, 2017
    Series
    Report r1701
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-330705 (URN)
    Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2018-03-07
    5. Kalman smoothing for irregular pilot patterns; A case study for predictor antennas in TDD systems
    Open this publication in new window or tab >>Kalman smoothing for irregular pilot patterns; A case study for predictor antennas in TDD systems
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    For future large-scale multi-antenna systems, channel orthogonal downlink pilots are not feasible due to extensive overhead requirements. Instead, channel reciprocity can be utilized in time division duplex (TDD) systems so that the downlink channel estimates can be based on pilots transmitted during the uplink. User mobility affects the reciprocity and makes the channel state information outdated for high velocities and/or long downlink subframe durations. Channel extrapolation, e.g. through Kalman prediction, can reduce the problem but is also limited by high velocities and long downlink subframes. An alternative solution has been proposed where channel predictions are made with the help of an extra antenna, e.g. on the roof of a car, so called predictor antenna, with the primary objective to measure the channel at a position that is later encountered by the rearward antenna(s). The predictor antenna is not directly limited by high velocities and allows the channel in the downlinks to be interpolated rather than extrapolated. One remaining challenge here is to obtain a good interpolation of the uplink channel estimate, since a sequence of uplink reference signals (pilots) will be interrupted by downlink subframes. We here evaluate a Kalman smoothing estimate of the downlink channels and compare it to a cubic spline interpolation. These results are compared to results where uplink channels are estimated through Kalman filters and predictors. Results are based on measured channels and show that with Kalman smoothing, predictor antennas can enable accurate channel estimates for a longer downlink period at vehicular velocities.

    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-344267 (URN)
    Available from: 2018-03-06 Created: 2018-03-06 Last updated: 2018-03-07
  • Public defence: 2018-04-27 10:15 Sal IX, Universitetshuset, Uppsala
    Jacobsson, Linus
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Permanent Establishment through Related Persons: A Study on the Treatment of Related Persons under Article 5 of the OECD Model Tax Convention2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Globalization, changed business practices and the developments in information technology have put pressure on the PE concept. This thesis deals with related persons and the PE concept, and the increasing tension between them.

    The main objective of the thesis is to analyze and define the scope of the PE concept, when applied to related persons. To meet this objective, the thesis is focused on three research questions. Initially, a theoretical foundation regarding the PE concept is established. It is concluded that the PE concept’s underlying principles are the notions of source, equity and basic neutrality.

    The first research question deals with the scope of the “related company clause” in Article 5(7) of the OECD MTC. To answer this, the history and underlying principles and theories of the related person PE are analyzed. It is concluded that the related person PE should be understood as including two distinct taxpayers and that the “related company clause” has no substantive scope.

    The second research question deals with the application of the PE concept to situations with related persons. It is established that the central question is whose business is being conducted. It is argued that this is a substance-over-form assessment and that guidance should be had from the dependency test in the agency clause, i.e. legal control and economic relationship.

    The third research question concerns what function the PE concept has, and should have, when it comes to preventing tax avoidance. It is argued that applying substance-over-form, not inherent to a specific PE condition, should be limited to preventing abuse. To determine if a situation is abusive, one should compare the outcome with the PE concept’s underlying principles. If the result is unintended and contrary to the underlying principles, it is an abuse of the PE concept, provided that this is achieved intentionally by the taxpayer.

  • Public defence: 2018-04-27 10:15 Ihresalen, Engelska parken, Uppsala
    Landolsi, Houda
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Languages, Department of Modern Languages, Romance Languages.
    L’exemplification et ses marqueurs2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This thesis deals with exemplification and example markers in contemporary French. Earlier research has focused mainly on the rhetorical aspect and showed less interest in syntax and semantics.

    The current study is based on several written corpora; the data are provided by C-ParlEur (Corpus of European Parliament discourse), by a corpus composed of non-academic humanities texts, and by a third one consisting of twenty contemporary French novels.

    The first part of the thesis focuses on the identification of the example in written text. Emphasis is given to the study of exemplification as a relation between two segments that are pragmatically linked. The analysis leads us to propose two main categories: the example-sample and the example-model. While the first represents the example as a non-specific and arbitrarily chosen element of the paradigm, the second shows the example as a particular and typical element.

    The second and third parts of the study are devoted to a detailed analysis of the characteristics and functions of three markers par exemple, comme and notamment – not only from a semantic and pragmatic viewpoint, but also from a rhetorical perspective. This account includes a thorough description of their functions and of the different constructions in which the markers appear. It also embraces a detailed analysis of the intersection between the example markers and the segment they introduce, as well as between the exemplifying unit and the sentence in its entirety.

    Even though par exemple, comme and notamment have several distinctive properties, they also have many common characteristics. Our analyses lead to the result that the segment these markers introduce is an intermediate link in the argumentative chain and thus entails a re-evaluation of the traditional definition, which recognizes only that the example’s role is to provide the mental imagery needed to overcome the difficulty of shaping an object or understanding a concept. The study of example and exemplification as a linguistic phenomenon allows us to refine the rhetorical definition of examples as inductive arguments, to propose a multi-dimensional description that aims to identify the examples’ main textual, topical and argumentative roles, and to reveal exemplification as a complex strategy in the negotiation of meaning.

  • Public defence: 2018-04-27 13:00 Hambergsalen, Uppsala
    Rasmusson, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Residual and Solubility trapping during Geological CO2 storage: Numerical and Experimental studies2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Geological storage of carbon dioxide (CO2) in deep saline aquifers mitigates atmospheric release of greenhouse gases. To estimate storage capacity and evaluate storage safety, knowledge of the trapping mechanisms that retain CO2 within geological formations, and the factors affecting these is fundamental. The objective of this thesis is to study residual and solubility trapping mechanisms (the latter enhanced by density-driven convective mixing), specifically in regard to their dependency on aquifer characteristics, and to investigate and develop methods for quantification of CO2 trapping in the field. The work includes implementation of existing numerical simulators and inverse modeling, as well as the development of new models and experimental methods for the study and quantification of CO2 trapping.

    A comparison of well-test designs in regard to their abilities to estimate the in-situ residual gas saturation (that determines the residual trapping of CO2) is presented, as well as a novel indicator-tracer approach to obtain residual gas saturation conditions in a formation. The results can aid in the planning of well-tests for estimation of trapping potential during site characterization.

    Pore-network modeling simulations were conducted to study the effects of co-contaminant sulphur dioxide and formation thermodynamic and salinity conditions on residual CO2 trapping.

    Furthermore, an analysis tool was developed and used to study the prerequisites for density-driven instability and convective mixing over broad geological storage conditions, including the relative influences of formation characteristics on factors controlling the convective process. The results show which conditions favour or disfavour residual and solubility trapping, knowledge useful for long-term predictions of the fate of injected CO2, and safety assessments during site selection.

    An optical experimental method, the refractive-light-transmission (RLT) technique, and an analogue system design were developed for studying density-driven flow in porous media. The method exploits changes in light refraction to visualize convective flow, and incorporates a calibration procedure and an image post-processing scheme that enable quantification of solute concentration, density and viscosity within porous media. The experimental setup was used to study the dynamics of convective mixing, and to derive scaling laws for the onset time and mass flux of convection.

    List of papers
    1. Analysis of alternative push-pull-test-designs for determining in situ residual trapping of carbon dioxide
    Open this publication in new window or tab >>Analysis of alternative push-pull-test-designs for determining in situ residual trapping of carbon dioxide
    Show others...
    2014 (English)In: International Journal of Greenhouse Gas Control, ISSN 1750-5836, E-ISSN 1878-0148, Vol. 27, p. 155-168Article in journal (Refereed) Published
    Abstract [en]

    Carbon dioxide storage in deep saline aquifers is a promising technique to reduce direct emissions of greenhouse gas to the atmosphere. To ensure safe storage the in situ trapping mechanisms, residual trapping being one of them, need to be characterized. This study aims to compare three alternative single-well carbon dioxide push-pull test sequences for their ability to quantify residual gas trapping. The three tests are based on the proposed test sequence by Zhang et al. (2011) for estimating residual gas saturation. A new alternative way to create residual gas conditions in situ incorporating withdrawal and a novel indicator-tracer approach has been investigated. Further the value of additional pressure measurements from a nearby passive observation well was evaluated. The iTOUGH2 simulator with the EOS7C module was used for sensitivity analysis and parameter estimation. Results show that the indicator-tracer approach could be used to create residual conditions without increasing estimation uncertainty of S-gr. Additional pressure measurements from a passive observation well would reduce the uncertainty in the S-gr estimate. The findings of the study can be used to develop field experiments for site characterization.

    Keyword
    CO2, CCS, Site characterization, Field test, Residual saturation, Single-well test
    National Category
    Energy Systems
    Identifiers
    urn:nbn:se:uu:diva-232013 (URN)10.1016/j.ijggc.2014.05.008 (DOI)000340319600012 ()
    Available from: 2014-09-12 Created: 2014-09-12 Last updated: 2018-03-03Bibliographically approved
    2. The impact of SO2 as a co-contaminant on the residual trapping of CO2 during geological storage
    Open this publication in new window or tab >>The impact of SO2 as a co-contaminant on the residual trapping of CO2 during geological storage
    Show others...
    (English)In: Article in journal (Other academic) Submitted
    Place, publisher, year, edition, pages
    Uppsala:
    National Category
    Earth and Related Environmental Sciences
    Research subject
    Hydrology
    Identifiers
    urn:nbn:se:uu:diva-343502 (URN)
    Available from: 2018-02-27 Created: 2018-02-27 Last updated: 2018-03-03
    3. Prerequisites for density-driven instabilities and convective mixing under broad geological CO2 storage conditions
    Open this publication in new window or tab >>Prerequisites for density-driven instabilities and convective mixing under broad geological CO2 storage conditions
    Show others...
    2015 (English)In: Advances in Water Resources, ISSN 0309-1708, E-ISSN 1872-9657, Vol. 84, p. 136-151Article in journal (Refereed) Published
    Abstract [en]

    Direct atmospheric greenhouse gas emissions can be greatly reduced by CO2 sequestration in deep saline aquifers. One of the most secure and important mechanisms of CO2 trapping over large time scales is solubility trapping. In addition, the CO2 dissolution rate is greatly enhanced if density-driven convective mixing occurs. We present a systematic analysis of the prerequisites for density-driven instability and convective mixing over the broad temperature, pressure, salinity and permeability conditions that are found in geological CO2 storage. The onset of instability (Rayleigh-Darcy number, Ra), the onset time of instability and the steady convective flux are comprehensively calculated using a newly developed analysis tool that accounts for the thermodynamic and salinity dependence on solutally and thermally induced density change, viscosity, molecular and thermal diffusivity. Additionally, the relative influences of field characteristics are analysed through local and global sensitivity analyses. The results help to elucidate the trends of the Ra, onset time of instability and steady convective flux under field conditions. The impacts of storage depth and basin type (geothermal gradient) are also explored and the conditions that favour or hinder enhanced solubility trapping are identified. Contrary to previous studies, we conclude that the geothermal gradient has a non-negligible effect on density-driven instability and convective mixing when considering both direct and indirect thermal effects because cold basin conditions, for instance, render higher Ra compared to warm basin conditions. We also show that the largest Ra is obtained for conditions that correspond to relatively shallow depths, measuring approximately 800 m, indicating that CO2 storage at such depths favours the onset of density-driven instability and reduces onset times. However, shallow depths do not necessarily provide conditions that generate the largest steady convective fluxes; the salinity determines the storage depth at which the largest steady convective fluxes occur. Furthermore, we present a straight-forward and efficient procedure to estimate site-specific solutal Ra that accounts for thermodynamic and salinity dependence.

    Keyword
    Carbon dioxide, CCS, Density-driven flow, Density instability, Double-diffusive convection, Porous media
    National Category
    Oceanography, Hydrology and Water Resources
    Identifiers
    urn:nbn:se:uu:diva-265827 (URN)10.1016/j.advwatres.2015.08.009 (DOI)000362305900012 ()
    Funder
    Swedish Research Council
    Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2018-03-03Bibliographically approved
    4. Refractive-Light-Transmission Technique Applied to Density-Driven Convective Mixing in Porous Media With Implications for Geological CO2 Storage
    Open this publication in new window or tab >>Refractive-Light-Transmission Technique Applied to Density-Driven Convective Mixing in Porous Media With Implications for Geological CO2 Storage
    Show others...
    2017 (English)In: Water resources research, ISSN 0043-1397, E-ISSN 1944-7973, Vol. 53, no 11, p. 8760-8780Article in journal (Refereed) Published
    Abstract [en]

    Density-driven convection has been identified to accelerate the rate of CO2 solubility trapping during geological CO2 storage in deep saline aquifers. In this paper, we present an experimental method using the refractive properties of fluids (their impact on light transmission), and an analogous system design, which enables the study of transport mechanisms in saturated porous media. The method is used to investigate solutally induced density-driven convective mixing under conditions relevant to geological CO2 storage. The analogous system design allows us by choice of initial solute concentration and bead size to duplicate a wide range of conditions (Ra-values), making it possible to study the convective process in general, and as a laboratory analogue for systems found in the field. We show that the method accurately determines the solute concentration in the system with high spatial and temporal resolution. The onset time of convection (t(c)), mass flux (F), and flow dynamics are quantified and compared with experimental and numerical findings in the literature. Our data yield a scaling law for tc which gives new insight into its dependence on Ra, indicating t(c) to be more sensitive to large Ra than previously thought. Furthermore, our data show and explain why F is described equally well by a Ra-dependent or a Ra-independent scaling law. These findings improve the understanding of the physical process of convective mixing in saturated porous media in general and help to assess the CO2 solubility trapping rate under certain field conditions.

    Place, publisher, year, edition, pages
    American Geophysical Union (AGU), 2017
    Keyword
    carbon dioxide, CCS, density-driven convection, experiment, refraction, solubility trapping
    National Category
    Environmental Sciences Oceanography, Hydrology and Water Resources
    Identifiers
    urn:nbn:se:uu:diva-339703 (URN)10.1002/2017WR020730 (DOI)000418736700007 ()
    Available from: 2018-01-26 Created: 2018-01-26 Last updated: 2018-03-03Bibliographically approved
  • Public defence: 2018-04-28 10:15 Ihresalen, Engelska parken, Humanistiskt centrum, Uppsala
    Palumbo, Alessandro
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Languages, Department of Scandinavian Languages.
    Skriftsystem i förändring: en grafematisk och paleografisk studie av de svenska medeltida runinskrifterna2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The aim of this dissertation is to study the development of Swedish runic writing during the Middle Ages in terms of runic shapes and orthography. It comprises three related investigations. A preparatory investigation surveys the runic shapes employed during the Middle Ages in Sweden. The second investigation aims to identify the graphematic distinctions used and developed during the Middle Ages, the chronological and geographical patterns evident in the use of the system of runic writing as well as the phonological conclusions which can be drawn from the graphematic analysis. The third and final section of the dissertation focuses on the use of certain long-branch and short-twig runes from a palaeographic perspective.

    The Swedish runic writing system changed during the course of the Middle Ages and varied in accordance with different factors, including chronology as well as local traditions. Västergötland, especially the area of Falbygden, appears the most prominent Swedish centre of innovation. As regards to the vowel system, the new grapheme <æ> was consistently used there in the 12th century, whereas not even in the 13th century was it completely established in Uppland. The grapheme <ø> instead was introduced only in the beginning of the 13th century and does not appear to have ever been consistently employed in any province. The analysis of the vowel system, in particular as regards to the unrounded front vowels, has also revealed several graphematic changes that can be explained phonologically and attest to ongoing dialectal developments.

    Even though no dotted graph type for consonants is used without exception and the double marking of long consonants is employed in less than a third of the attestations of long consonants, greater consistency in the use of both practices can be observed during the 13th century than during earlier periods. Also in this case, the development proceeded more rapidly in Västergötland than in Uppland. Among other provinces, several new features also occur in Småland. Also the inscriptions in Östergötland attest to an advanced use of writing, but the mediaeval innovations there seem to be younger than in Västergötland and western Småland, which indicates that they spread to more easterly areas at a later stage.

    Medieval innovations such as dotted runes with a consonantal value seem to have their origin and focus in East Scandinavia. Many of the earliest attestations occur on coins minted in Lund, and it is possible that they spread from there to Småland and Västergötland. In other cases, for example as regards the dotted f-rune, these Swedish areas may themselves have acted as centres of innovation. Here, closer contact between carvers and the Church and the introduction of the Roman script may have contributed to creating a more dynamic writing culture.

    As regards the alleged existence of a "completely dotted runic alphabet", the analyses in this dissertation have shown that there was no uniform use of those features which are often maintained to be characteristic of the completely dotted rune row. These results make it clear that the introduction of innovations could not have occurred via a reform and confirm that no completely dotted rune row was ever established.

  • Public defence: 2018-05-03 13:15 Polhemssalen, Ångströmlaboratoriet, Uppsala
    Akansel, Serkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Magnetization Dynamics in Ferromagnetic Thin Films: Evaluation of Different Contributions to Damping in Co2FeAl and FeCo Film Structures2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Static and dynamic magnetic properties of Co2FeAl and Fe65Co35 alloys have been investigated. Co2FeAl films were deposited at different temperatures and the deposition parameters were optimized with respect to structural and magnetic properties. As a result, a film with B2 crystalline phase was obtained without any post-annealing process. A lowest magnetic damping parameter of  was obtained for the film deposited at 573K. This obtained low value is comparable to the lowest values reported in research literature.  After optimizing the deposition parameters of this alloy, different seed layers and capping layers were added adjacent to the Co2FeAl layer and the effect of these layers on the magnetic relaxation was investigated. In addition to adding nonmagnetic layers to Co2FeAl, the dependence of the magnetic damping parameter with respect to the thickness of Co2FeAl was investigated by depositing films with different thicknesses. A temperature dependent study of the magnetic damping parameter was also performed and the measured damping parameters were compared with theoretically calculated intrinsic Gilbert damping parameters. Different extrinsic contributions to the magnetic damping, such as two magnon scattering, spin pumping, eddy-current damping and radiative damping, were identified and subtracted from the experimentally obtained damping parameter. Hence, it was possible to obtain the intrinsic damping parameter, that is called the Gilbert damping parameter.

    In the second part of the thesis, Fe65Co35 alloys were investigated in terms of static and dynamic magnetic properties. Fe65Co35 films were deposited without and with different seed layers in order to first understand the effect of the seed layer on static magnetic properties of the films, such as the coercivity of the films. Then the films with seed layers yielding the lowest coercivity were investigated in terms of dynamic magnetic properties. Fe65Co35 films with different rhenium dopant concentrations and with ruthenium as the seed and capping layer were also investigated. The purpose of this study was to increase the damping parameter of the films and an increase of about ~230% was obtained by adding the dopant to the structure. This study was performed at different temperatures and after subtraction of the extrinsic contributions to the damping, the experimental values were compared with theoretically calculated values of the Gilbert damping parameter. During the thesis work, magnetic looper and superconducting quantum interference device magnetometers set-ups were used for static magnetic measurements and cavity, broadband in-plane and broadband out-of-plane ferromagnetic resonance set-ups were used for dynamic measurements.

    List of papers
    1. Thickness dependent enhancement of damping in Co2FeAl/β-Ta thin films
    Open this publication in new window or tab >>Thickness dependent enhancement of damping in Co2FeAl/β-Ta thin films
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In the present work Co2FeAl (CFA) thin films were deposited by ion beam sputtering on Si (100) substrates at the optimized deposition temperature of 300°C. A series of CFA films with different thickness (tCFA ); 8, 10, 12, 14, 16, 18 and 20 nm were prepared and all samples were capped with a 5 nm thick b-Ta layer. The thickness dependent static and dynamic properties of the films were studied by SQUID magnetometry, in-plane as well as out-of-plane broadband VNA-FMR measurements and angle dependent cavity FMR measurements. The saturation magnetization and the coercive field were found to be weakly thickness dependent and lie in the range 900 – 950 kA/m and 0.53 – 0.87 kA/m, respectively. The effective damping parameter ( αeff) extracted from in-plane and out-of-plane FMR results reveal a 1/tCFA dependence, the values for the in-plane αeff being larger due to two-magnon scattering (TMS). The origin of the αeff thickness dependence is spin pumping into the non-magnetic b-Ta layer and in case of the in-plane  αeff also a thickness dependent TMS contribution. From the out-of-plane FMR results, it was possible to disentangle the different contributions to αeff   and to the extract values for the intrinsic Gilbert damping (αG ) and the effective spin-mixing conductance (g_eff^↑↓ ) of the CFA/ b-Ta interface, yielding αG=1.1X10-3 and g_eff^↑↓=2.90x1019 m-2.

    Keyword
    Magnetization dynamics, magnetic thin films, Gilbert damping, ferromagnetic resonance
    National Category
    Condensed Matter Physics
    Research subject
    Physics with spec. in Atomic, Molecular and Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-345848 (URN)
    Funder
    Knut and Alice Wallenberg Foundation, 2012.0031
    Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2018-03-12
    2. Enhanched Gilbert Damping in Re doped FeCo Films: A combined experimental and theoretical study
    Open this publication in new window or tab >>Enhanched Gilbert Damping in Re doped FeCo Films: A combined experimental and theoretical study
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The effects of rhenium doping in the range 0 – 10 at% on the static and dynamic magnetic properties of Fe65Co35 thin films have been studied experimentally as well as with first principles electronic structure calculations focussing on the change of the saturation magnetization (Ms ) and the Gilbert damping parameter (α ). Both experimental and theoretical results show that Ms decreases with increasing Re doping level, while at the same time α increases.  The experimental low temperature saturation magnetic induction exhibits a 29% decrease, from 2.31T to 1.64T, in the investigated doping concentration range, which is more than predicted by the theoretical calculations. The room temperature value of the damping parameter obtained from ferromagnetic resonance measurements, correcting for extrinsic contributions to the damping, is for the undoped sample 2.7X103, which is close to the Gilbert damping parameter extracted from the theoretical calculations. The room temperature experimental value for the damping parameter increases to  9X103 when doping with 10 at% Re; the corresponding increase of the Gilbert damping parameter obtained from theoretical calculations is 7.3X103. Both experimental and theoretical values for the damping parameter weakly decrease with decreasing temperature.

    Keyword
    Magnetization dynamics, magnetic thin films, Gilbert damping, ferromagnetic resonance
    National Category
    Condensed Matter Physics
    Research subject
    Physics with spec. in Atomic, Molecular and Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-345854 (URN)
    Funder
    Knut and Alice Wallenberg Foundation, 2012.0031
    Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2018-03-12
    3. Effect of seed layers on dynamic and static magnetic properties of Fe65Co35 thin films
    Open this publication in new window or tab >>Effect of seed layers on dynamic and static magnetic properties of Fe65Co35 thin films
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Fe65Co35 thin films have been deposited on SiO2 substrates using sputtering technique with different choices of seed layer; Ru, Ni82.5Fe17.5, Rh, Y and Zr. Best soft magnetic properties were observed with seed layers of Ru, Ni82.5Fe17.5 and Rh. Adding these seed layers, the coercivity of the Fe65Co35 films decreased to values of around 1.5 mT, which can be compared to the value of 12.5 mT obtained for films deposited without seed layer. Further investigations were performed on samples with these three seed layers in terms of dynamic magnetic properties, both on as prepared and annealed samples, using constant frequency cavity and broadband ferromagnetic resonance measurements. Damping parameters of around 8.0X10-3 and 4.5X10-3 were obtained from in-plane and out-of-plane measurements, respectively, for as prepared samples, values that were reduced to 6.5X10-3 and 4.0X10-3 for annealed samples.

    Keyword
    Magnetization dynamics, magnetic thin films, Gilbert damping, ferromagnetic resonance
    National Category
    Condensed Matter Physics
    Research subject
    Physics with spec. in Atomic, Molecular and Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-345853 (URN)
    Funder
    Knut and Alice Wallenberg Foundation, 2012.0031
    Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2018-03-12
    4. Growth of Co2FeAl Heusler alloy thin films on Si(100) having very small Gilbert damping by Ion beam sputtering
    Open this publication in new window or tab >>Growth of Co2FeAl Heusler alloy thin films on Si(100) having very small Gilbert damping by Ion beam sputtering
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    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 28692Article in journal (Refereed) Published
    Abstract [en]

    The influence of growth temperature T-s (300-773 K) on the structural phase ordering, static and dynamic magnetization behaviour has been investigated in ion beam sputtered full Heusler alloy Co2FeAl (CFA) thin films on industrially important Si(100) substrate. The B2 type magnetic ordering is established in these films based on the clear observation of the (200) diffraction peak. These ion beam sputtered CFA films possess very small surface roughness of the order of subatomic dimensions (<3 angstrom) as determined from the fitting of XRR spectra and also by AFM imaging. This is supported by the occurrence of distinct Kiessig fringes spanning over the whole scanning range (similar to 4 degrees) in the x-ray reflectivity (XRR) spectra. The Gilbert damping constant alpha and effective magnetization 4 pi M-eff are found to vary from 0.0053 +/- 0.0002 to 0.0015 +/- 0.0001 and 13.45 +/- 00.03 kG to 14.03 +/- 0.04 kG, respectively. These Co2FeAl films possess saturation magnetization ranging from 4.82 +/- 0.09 to 5.22 +/- 0.10 mu(B)/f.u. consistent with the bulk L2(1)-type ordering. A record low alpha-value of 0.0015 is obtained for Co2FeAl films deposited on Si substrate at T-s similar to 573 K.

    National Category
    Other Physics Topics Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-299867 (URN)10.1038/srep28692 (DOI)000378783900001 ()27357004 (PubMedID)
    Available from: 2016-07-28 Created: 2016-07-28 Last updated: 2018-03-12Bibliographically approved
    5. Static and dynamic properties of Co2FeAl thin films: Effect of MgO and Ta as capping layers
    Open this publication in new window or tab >>Static and dynamic properties of Co2FeAl thin films: Effect of MgO and Ta as capping layers
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    2017 (English)In: 61ST DAE-SOLID STATE PHYSICS SYMPOSIUM, 2017, Vol. 1832, article id 080007-1Conference paper, Published paper (Refereed)
    Abstract [en]

    The influence of MgO and Ta capping layers on the static and dynamic magnetic properties of Co2FeAl (CFA) Heusler alloy thin films has been investigated. It is observed that the CFA film deposited with MgO capping layer is preeminent compared to the uncapped or Ta capped CFA film. In particular, the magnetic inhomogeneity contribution to the ferromagnetic resonance line broadening and damping constant are found to be minimal for the MgO capped CFA thin film i.e., 0.12±0.01 Oe and 0.0074±0.00014, respectively. The saturationmagnetization was found to be 960±25emu/cc.

    Series
    AIP Conference Proceedings, ISSN 0094-243X
    Keyword
    Heusler alloy, MgO, Gilbert damping
    National Category
    Physical Sciences Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-332482 (URN)10.1063/1.4980467 (DOI)000412824400289 ()978-0-7354-1500-3 (ISBN)
    Conference
    61st DAE-Solid State Physics Symposium, DEC 26-30, 2016, KIIT Univ, Bhubaneswar, INDIA
    Projects
    Knut and Alice Wallenberg (KAW) Foundation, Grant No. KAW 2012.0031.
    Available from: 2017-10-27 Created: 2017-10-27 Last updated: 2018-03-29Bibliographically approved
    6. Temperature-dependent Gilbert damping of Co2FeAl thin films with different degree of atomic order
    Open this publication in new window or tab >>Temperature-dependent Gilbert damping of Co2FeAl thin films with different degree of atomic order
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    2017 (English)In: Physical Review B, ISSN 2469-9950, E-ISSN 2469-9969, Vol. 96, no 224425Article in journal (Refereed) Published
    Abstract [en]

    Half-metallicity and low magnetic damping are perpetually sought for spintronics materials, and full Heusler compounds in this respect provide outstanding properties. However, it is challenging to obtain the well-ordered half-metallic phase in as-deposited full Heusler compound thin films, and theory has struggled to establish a fundamental understanding of the temperature-dependent Gilbert damping in these systems. Here we present a study of the temperature-dependent Gilbert damping of differently ordered as-deposited Co2FeAl full Heusler compound thin films. The sum of inter- and intraband electron scattering in conjunction with the finite electron lifetime in Bloch states governs the Gilbert damping for the well-ordered phase, in contrast to the damping of partially ordered and disordered phases which is governed by interband electronic scattering alone. These results, especially the ultralow room-temperature intrinsic damping observed for the well-ordered phase, provide fundamental insights into the physical origin of the Gilbert damping in full Heusler compound thin films.

    Place, publisher, year, edition, pages
    American Physical Society, 2017
    Keyword
    Gilbert damping, full Heusler compound, Temperature Dependent Gilbert damping, Thin Films, Density of states
    National Category
    Condensed Matter Physics Engineering and Technology
    Research subject
    Engineering Science with specialization in Solid State Physics
    Identifiers
    urn:nbn:se:uu:diva-337305 (URN)10.1103/PhysRevB.96.224425 (DOI)000418572700007 ()
    Funder
    Knut and Alice Wallenberg Foundation, KAW 2012.0031Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology, GGS1403ASwedish National Infrastructure for Computing (SNIC)
    Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-03-12
  • Public defence: 2018-05-04 09:00 Häggsalen, Uppsala
    Binda, Federico
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Liquid scintillators as neutron diagnostic tools for fusion plasmas: System characterization and data analysis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The neutrons produced in fusion devices carry information about various properties of the ions that are reacting in the machine. Measurements of the neutron flux and energy distribution can therefore be used to study the behaviour of the plasma ions under different experimental conditions.

    Several neutron detection techniques are available, each having advantages and disadvantages compared to the others. In this thesis we study neutron measurements performed with NE213 liquid scintillators. One advantage of NE213s compared to other neutron detection techniques is that they are simple to use, small and cheap. On the other hand, their response to neutrons makes the extraction of information about the neutron energy less precise.

    In the thesis we present the development of methods for the characterization and the data analysis of NE213 detectors. The work was performed using two instruments installed at the Joint European Torus (JET) tokamak in the UK: the “Afterburner” detector, which is an NE213 installed on a tangential line of sight, and the neutron camera, which is a system composed of 19 NE213 detectors installed on different lines of sight (10 horizontal and 9 vertical).The analysis of data from the Afterburner detector was focused on resolving different features of the neutron energy spectra which are related to different properties of the ion velocity distribution.

    The analysis of data from the neutron camera was directed towards the investigation of the spatial distribution of ions in the plasma. However, the individual characterization of the camera detectors allowed the inclusion of information about the energy distribution of the ions in the analysis.

    The outcomes of the studies performed indicate that the methods developed give reliable results and can therefore be applied to extract information about the plasma ions. In particular, the possibility of performing neutron emission spectroscopy analysis in each line of sight of a neutron camera is of great value for future studies.

    List of papers
    1. Generation of the neutron response function of an NE213 scintillator for fusion applications
    Open this publication in new window or tab >>Generation of the neutron response function of an NE213 scintillator for fusion applications
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    2017 (English)In: Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, ISSN 0168-9002, E-ISSN 1872-9576, Vol. 866, p. 222-229Article in journal (Refereed) Published
    Abstract [en]

    In this work we present a method to evaluate the neutron response function of an NE213 liquid scintillator. This method is particularly useful when the proton light yield function of the detector has not been measured, since it is based on a proton light yield function taken from literature, MCNPX simulations, measurements of gammarays from a calibration source and measurements of neutrons from fusion experiments with ohmic plasmas. The inclusion of the latter improves the description of the proton light yield function in the energy range of interest (around 2.46 MeV). We apply this method to an NE213 detector installed at JET, inside the radiation shielding of the magnetic proton recoil (MPRu) spectrometer, and present the results from the calibration along with some examples of application of the response function to perform neutron emission spectroscopy (NES) of fusion plasmas. We also investigate how the choice of the proton light yield function affects the NES analysis, finding that the result does not change significantly. This points to the fact that the method for the evaluation of the neutron response function is robust and gives reliable results.

    Keyword
    NE213 scintillator, Neutron spectroscopy, Response function, Proton light yield
    National Category
    Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:uu:diva-330537 (URN)10.1016/j.nima.2017.04.023 (DOI)000407863700029 ()
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2018-04-23Bibliographically approved
    2. Forward fitting of experimental data from a NE213 neutron detector installed with the magnetic proton recoil upgraded spectrometer at JET
    Open this publication in new window or tab >>Forward fitting of experimental data from a NE213 neutron detector installed with the magnetic proton recoil upgraded spectrometer at JET
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    2014 (English)In: Review of Scientific Instruments, ISSN 0034-6748, E-ISSN 1089-7623, Vol. 85, no 11, p. 11E123-Article in journal (Refereed) Published
    Abstract [en]

    In this paper, we present the results obtained from the data analysis of neutron spectra measured with a NE213 liquid scintillator at JET. We calculated the neutron response matrix of the instrument combining MCNPX simulations, a generic proton light output function measured with another detector and the fit of data from ohmic pulses. For the analysis, we selected a set of pulses with neutral beam injection heating (NBI) only and we applied a forward fitting procedure of modeled spectral components to extract the fraction of thermal neutron emission. The results showed the same trend of the ones obtained with the dedicated spectrometer TOFOR, even though the values from the NE213 analysis were systematically higher. This discrepancy is probably due to the different lines of sight of the two spectrometers (tangential for the NE213, vertical for TOFOR). The uncertainties on the thermal fraction estimates were from 4 to 7 times higher than the ones from the TOFOR analysis.

    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-240136 (URN)10.1063/1.4895565 (DOI)000345646000143 ()25430302 (PubMedID)
    Available from: 2015-01-07 Created: 2015-01-05 Last updated: 2018-04-23
    3. Dual sightline measurements of MeV range deuterons with neutron and gamma-ray spectroscopy at JET
    Open this publication in new window or tab >>Dual sightline measurements of MeV range deuterons with neutron and gamma-ray spectroscopy at JET
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    2015 (English)In: Nuclear Fusion, ISSN 0029-5515, E-ISSN 1741-4326, Vol. 55, no 12, article id 123026Article in journal (Refereed) Published
    Abstract [en]

    Observations made in a JET experiment aimed at accelerating deuterons to the MeV range by third harmonic radio-frequency (RF) heating coupled into a deuterium beam are reported. Measurements are based on a set of advanced neutron and gamma-ray spectrometers that, for the first time, observe the plasma simultaneously along vertical and oblique lines of sight. Parameters of the fast ion energy distribution, such as the high energy cut-off of the deuteron distribution function and the RF coupling constant, are determined from data within a uniform analysis framework for neutron and gamma-ray spectroscopy based on a one-dimensional model and by a consistency check among the individual measurement techniques. A systematic difference is seen between the two lines of sight and is interpreted to originate from the sensitivity of the oblique detectors to the pitch-angle structure of the distribution around the resonance, which is not correctly portrayed within the adopted one dimensional model. A framework to calculate neutron and gamma-ray emission from a spatially resolved, two-dimensional deuteron distribution specified by energy/pitch is thus developed and used for a first comparison with predictions from ab initio models of RF heating at multiple harmonics.

    The results presented in this paper are of relevance for the development of advanced diagnostic techniques for MeV range ions in high performance fusion plasmas, with applications to the experimental validation of RF heating codes and, more generally, to studies of the energy distribution of ions in the MeV range in high performance deuterium and deuterium-tritium plasmas.

    Keyword
    fusion, tokamak, fast ions, neutron spectrometry, gamma-ray spectroscopy
    National Category
    Fusion, Plasma and Space Physics
    Research subject
    Physics with specialization in Applied Nuclear Physics
    Identifiers
    urn:nbn:se:uu:diva-247990 (URN)10.1088/0029-5515/55/12/123026 (DOI)000366534500028 ()
    Available from: 2015-03-25 Created: 2015-03-25 Last updated: 2018-04-23Bibliographically approved
    4. Absolute calibration of the JET neutron profile monitor
    Open this publication in new window or tab >>Absolute calibration of the JET neutron profile monitor
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    (English)In: Review of Scientific Instruments, ISSN 0034-6748, E-ISSN 1089-7623Article in journal (Refereed) Submitted
    National Category
    Fusion, Plasma and Space Physics
    Identifiers
    urn:nbn:se:uu:diva-345980 (URN)
    Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13
    5. Calculation of the profile-dependent neutron backscatter matrix for the JET neutron camera system
    Open this publication in new window or tab >>Calculation of the profile-dependent neutron backscatter matrix for the JET neutron camera system
    2017 (English)In: Fusion engineering and design, ISSN 0920-3796, E-ISSN 1873-7196, Vol. 123, p. 865-868Article in journal (Refereed) Published
    Abstract [en]

    We investigated the dependence of the backscatter component of the neutron spectrum on the emissivity profile. We did so for the JET neutron camera system, by calculating a profile-dependent backscatter matrix for each of the 19 camera channels using a MCNP model of the JET tokamak. We found that, when using a low minimum energy for the summation of the counts in the neutron pulse height spectrum, the backscatter contribution can depend significantly on the emissivity profile. The maximum variation in the backscatter level was 24% (8.0% when compared to the total emission). This effect needs to be considered when a correction for the backscatter contribution is applied to the measured profile.

    Place, publisher, year, edition, pages
    ELSEVIER SCIENCE SA, 2017
    Keyword
    Neutron, Profile monitor, Backscatter, mcnp
    National Category
    Subatomic Physics
    Identifiers
    urn:nbn:se:uu:diva-341822 (URN)10.1016/j.fusengdes.2017.03.124 (DOI)000418992000181 ()
    Conference
    29th Symposium on Fusion Technology (SOFT), SEP 05-09, 2016, Prague, CZECH REPUBLIC
    Available from: 2018-02-15 Created: 2018-02-15 Last updated: 2018-03-13Bibliographically approved
    6. Study of the energy-dependent fast ion redistribution during sawtooth oscillations with the neutron camera at JET
    Open this publication in new window or tab >>Study of the energy-dependent fast ion redistribution during sawtooth oscillations with the neutron camera at JET
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Fusion, Plasma and Space Physics
    Identifiers
    urn:nbn:se:uu:diva-345982 (URN)
    Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-04-23
  • Public defence: 2018-05-04 09:00 Rudbecksalen, Uppsala
    Rendo, Verónica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Targeting allelic loss in colorectal cancer2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Targeted cancer therapy exploits molecular differences between tumor and normal cells to selectively kill cancer cells. Whereas targeting of activated oncogenes has proved clinically useful, few current therapies exploit loss-of-function mutations in tumor suppressor genes or in the genome at large. This thesis explores the consequences of allelic loss affecting tumor suppressor genes and passenger genes in colorectal cancer (CRC), aiming to identify vulnerabilities that can be exploited for therapy. 

    In Paper I we used genome editing to model inactivation of PRDM2 and showed that PRDM2 loss impacts cell growth and invasiveness, potentially mediated by genes involved in epithelial-to-mesenchymal transition. We confirmed the role of PRDM2 as a tumor suppressor gene in CRC and proved that c.4467delA inactivating mutations constitute a driver event in CRC.

    In Paper II we investigated whether the reduced allelic diversity resulting from loss of heterozygosity (LOH) in cancers could be exploited for therapy. We identified target genes by mapping prevalent alleles frequently lost in cancer and investigated NAT2 loss in CRC. Drug discovery efforts identified a compound selectively toxic to tumor cells with reduced NAT2 activity, providing proof of concept for LOH targeting by small molecule drugs.

    In Paper III, we aimed to widen the cohort of CRC patients eligible for NAT2 allele-selective chemotherapy. We determined NAT2 slow acetylator frequencies and LOH events in two independent cohorts by next-generation sequencing and genomic arrays. Next, we demonstrated enhanced response to allele-selective chemotherapy of tumor cells encoding additional prevalent NAT2 slow acetylator alleles, and developed a method for detection of NAT2 allelic loss suitable for clinical use.

    In Paper IV, we extended the search of therapeutic target genes by mining loss-of-function (LoF) alleles retained in tumors after LOH. This effort identified a prevalent splice site disruption in CYP2D6 as a putative target and motivated the development of cell model systems to identify compounds targeting CYP2D6 loss in cancer cells.

    In Paper V we characterized a set of 56 microsatellite stable CRCs by whole-genome sequencing in an attempt to understand the genetic causes leading to genomic instability and colorectal tumorigenesis. We confirmed the mutation frequencies of known CRC genes and identified for the first time the contribution of an unknown mutational process in 10% of the analyzed tumors.

    List of papers
    1. Somatic PRDM2 c.4467delA mutations in colorectal cancers control histone methylation and tumor growth
    Open this publication in new window or tab >>Somatic PRDM2 c.4467delA mutations in colorectal cancers control histone methylation and tumor growth
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    2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 58, p. 98646-98659Article in journal (Refereed) Published
    Abstract [en]

    The chromatin modifier PRDM2/RIZ1 is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C-terminal region of PRDM2, affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat. We then engineered isogenic cell systems where the PRDM2 c.4467delA mutation in human HCT116 colorectal cancer cells was corrected to wild-type by genome editing. Restored PRDM2 increased global histone 3 lysine 9 dimethylation and reduced migration, anchorage-independent growth and tumor growth in vivo. Gene set enrichment analysis revealed regulation of several hallmark cancer pathways, particularly of epithelial-to-mesenchymal transition (EMT), with VIM being the most significantly regulated gene. These observations provide direct evidence that PRDM2 c.4467delA is a driver mutation in colorectal cancer and confirms PRDM2 as a cancer gene, pointing to regulation of EMT as a central aspect of its tumor suppressive action.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-345974 (URN)10.18632/oncotarget.21713 (DOI)000419392300074000419392300074 ()
    Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-16Bibliographically approved
    2. Exploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy
    Open this publication in new window or tab >>Exploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-345963 (URN)
    Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13
    3. Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
    Open this publication in new window or tab >>Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-345964 (URN)
    Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13
    4. Exploiting allelic loss in cancer therapy: Identification of CYP2D6 as a potential target
    Open this publication in new window or tab >>Exploiting allelic loss in cancer therapy: Identification of CYP2D6 as a potential target
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-345966 (URN)
    Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13
    5. Characterization of colorectal cancers by whole genome sequencing
    Open this publication in new window or tab >>Characterization of colorectal cancers by whole genome sequencing
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-345967 (URN)
    Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13
  • Public defence: 2018-05-04 09:15 Siegbahnsalen, Uppsala
    Föhlinger, Jens
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Shining Light on Molecules: Electron Transfer Processes in Model Systems for Solar Energy Conversion Investigated by Transient Absorption Spectroscopy2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the recent years, solar energy conversion has attracted a huge research interest due to the potential application for limiting the greenhouse effect. In many solar cells and solar fuel cells, understanding of charge transfer (CT) and recombination is important for future improvement of the overall efficiency. One important tool for that is transient absorption spectroscopy (TAS).

    Mesoporous nickel oxide films were investigated due to their potential application in p-type dye-sensitized solar cells (DSSCs), tandem DSSCs and dye sensitized solar fuel cells (DSSFC:s). Firstly, it was found that the hole generated by band gap excitation is trapped on an ultrafast time scale by Ni3+ states. It was possible to observe a direct signal from the holes by transient mid-IR absorption spectroscopy allowing for direct detection of hole injection and trapping. On a ns time scale, the trapped holes relaxed to much less reactive holes which favored long lived NiO-dye charge separation (CS).

    A series of perylene monoimide (PMI) dyes with different anchoring groups was studied. Differences in binding affinity and stability were found. Nevertheless, all PMIs showed ultrafast charge separation and similar recombination kinetics. Furthermore, the effect of MLCT localization of ruthenium polypyridyl complexes was investigated. All those dyes showed slow or no hole injection. At the same time, a self-quenching process was found for all compounds that limited the photoconversion efficiency.

    Furthermore, a new core-shell structure of p-type DSSCs was proposed and investigated. Here, the liquid electrolyte was replaced by a layer of TiO2. That system was found to undergo both injection and regeneration of the dye on an ultrafast time scale (below 1 ps). Furthermore, the CS state did not show any decay within 2 ns making this structure interesting for application in DSSCs.

    A pentad consisting of a known Ru-based (electro)chemical water oxidation catalyst (WOC) linked to two zinc-porphyrin-fullerene dyads (ZnP-C60) was investigated. The charge transfer processes leading to the first oxidation of the WOC were understood. Low levels of water oxidation were detected in presence of a sacrificial electron acceptor.

    The gained understanding of the CT dynamics and recombination processes thus allows new strategies to improve the efficiency in molecular systems for solar energy conversion.

    List of papers
    1. Unveiling hole trapping and surface dynamics of NiO nanoparticles
    Open this publication in new window or tab >>Unveiling hole trapping and surface dynamics of NiO nanoparticles
    2018 (English)In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 9, no 1, p. 223-230Article in journal (Refereed) Published
    Abstract [en]

    The research effort in mesoporous p-type semiconductors is increasing due to their potential application in photoelectrochemical energy conversion devices. In this paper an electron-hole pair is created by band-gap excitation of NiO nanoparticles and the dynamics of the electron and the hole is followed until their recombination. By spectroscopic characterization it was found that surface Ni3+ states work as traps for both electrons and holes. The trapped electron was assigned to a N2+ state and the trapped hole to a Ni4+ state. The recombination kinetics of these traps was studied and related with the concept of hole relaxation suggested before.The timescale of the hole relaxation was foundto be in the order of tens of ns. Finally the spectrosc opic evidence of this relaxation is presented in a sensitized film.

    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-320185 (URN)10.1039/C7SC03442C (DOI)000418376400025 ()
    Funder
    Swedish Energy Agency, 43599-1
    Available from: 2017-04-17 Created: 2017-04-17 Last updated: 2018-03-14Bibliographically approved
    2. Direct Spectroscopic Observation of Hole Trapping in Dye-Sensitized NiO films by Transient mid-IR Absorption Spectroscopy
    Open this publication in new window or tab >>Direct Spectroscopic Observation of Hole Trapping in Dye-Sensitized NiO films by Transient mid-IR Absorption Spectroscopy
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-343483 (URN)
    Available from: 2018-03-14 Created: 2018-03-14 Last updated: 2018-03-14
    3. A Comparative Investigation about the Role of Anchoring group on Perylene Monoimide Dyes in NiO Based Dye-Sensitized Solar Cells
    Open this publication in new window or tab >>A Comparative Investigation about the Role of Anchoring group on Perylene Monoimide Dyes in NiO Based Dye-Sensitized Solar Cells
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-346015 (URN)
    Available from: 2018-03-14 Created: 2018-03-14 Last updated: 2018-03-14
    4. Self-quenching and Slow Hole Injection May Limit the Efficiency in NiO-based Dye-Sensitized Solar Cells
    Open this publication in new window or tab >>Self-quenching and Slow Hole Injection May Limit the Efficiency in NiO-based Dye-Sensitized Solar Cells
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    (English)In: Article in journal (Refereed) Submitted
    National Category
    Physical Chemistry
    Research subject
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-343442 (URN)
    Available from: 2018-03-14 Created: 2018-03-14 Last updated: 2018-03-14
    5. Ultrafast dye regeneration in a core-shell NiO-dye-TiO2 mesoporous film
    Open this publication in new window or tab >>Ultrafast dye regeneration in a core-shell NiO-dye-TiO2 mesoporous film
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    2018 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 20, no 1, p. 36-40Article in journal (Refereed) Published
    Abstract [en]

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

    Place, publisher, year, edition, pages
    The Royal Society of Chemistry, 2018
    National Category
    Natural Sciences Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-335974 (URN)10.1039/C7CP07088H (DOI)000418374800002 ()
    Funder
    Knut and Alice Wallenberg Foundation, 2011.0067Swedish Energy Agency, 43599-1
    Available from: 2017-12-11 Created: 2017-12-11 Last updated: 2018-03-14Bibliographically approved
    6. A Ruthenium Complex–Porphyrin–Fullerene-Linked Molecular Pentad as an Integrative Photosynthetic Model
    Open this publication in new window or tab >>A Ruthenium Complex–Porphyrin–Fullerene-Linked Molecular Pentad as an Integrative Photosynthetic Model
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    2017 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 56, no 12, p. 3329-3333Article in journal (Refereed) Published
    Abstract [en]

    A ruthenium complex, porphyrin sensitizer, fullerene acceptor molecular pentad has been synthesized and a long-lived hole–electron pair was achieved in aqueous solution by photoinduced multistep electron transfer: Upon irradiation by visible light, the excited-state of a zinc porphyrin (1ZnP*) was quenched by fullerene (C60) to afford a radical ion pair, 1,3(ZnP.+-C60.−). This was followed by the subsequent electron transfer from a water oxidation catalyst unit (RuII) to ZnP.+ to give the long-lived charge-separated state, RuIII-ZnP-C60.−, with a lifetime of 14 μs. The ZnP worked as a visible-light-harvesting antenna, while the C60 acted as an excellent electron acceptor. As a consequence, visible-light-driven water oxidation by this integrated photosynthetic model compound was achieved in the presence of sacrificial oxidant and redox mediator.

    Keyword
    artificial photosynthesis, fullerenes, molecular pentads, photoinduced electron transfer, porphyrins, ruthenium
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-336548 (URN)10.1002/anie.201612456 (DOI)000397329300037 ()
    Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2018-03-14Bibliographically approved
  • Public defence: 2018-05-04 09:15 B:42, BMC, Uppsala
    Hansson, Annelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Science.
    Structural Determination of Drug Metabolites from Doping Classed Compounds Using Mass Spectrometry2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Doping control in equine sports is important for a fair competition, but also to ensure the integrity of the betting system, as well as for animal welfare reasons. To detect the use of illicit compounds, screening for the parent compound is common. However, by using a metabolite as the analytical target instead, the detection time can be prolonged. For some compounds, the use of a metabolite is a necessity since the parent drug may not be detected at all.

    The metabolites of the selective androgen receptor modulators (SARM) S1, S4 and S22 were investigated in horse urine and plasma. The unchanged parent compounds had the longest detection time in plasma, but were not detected at all in urine. Instead, the longest detection time was measured for the metabolites 2-amino-5-nitro-4-(trifluoromethyl)phenyl hydrogen sulfate (SARMs S1 and S4) and 2-amino-5-cyano-4-(trifluoromethyl)phenyl hydrogen sulfate (SARM S22). These metabolites were thus suggested as analytical targets for doping control in urine while the parent compounds were suggested for plasma samples. 2-amino-5-nitro-4-(trifluoromethyl)phenyl hydrogen sulfate could also be produced in large quantities by the fungus Cunninghamella elegans to potentially be used as reference compound.

    The horse metabolites of the SARM LGD-4033 were also studied in urine and plasma. The formate adduct of LGD-4033 had the longest detection time in plasma and in urine after hydrolysis with β-glucuronidase. In non-hydrolyzed urine, the glucuronidated LGD-4033 was detected instead.

    Different in vitro models were used to predict in vivo metabolites of roxadustat, a hypoxia-inducible factor stabilizer. Cunninghamella elegans was successful in producing more metabolites compared to human and equine liver microsomes and human hepatocytes.

    The metabolite detection and identification in all experiments were accomplished using a UHPLC-Q-TOF MS instrument, where the high-resolution MS data was vital in determining which metabolites were formed.

    The thesis shows the benefits of investigating the metabolites of doping substances to allow for a successful doping control method in horse urine and plasma by prolonging the detection time. It also highlights the usefulness of Cunninghamella elegans as an alternative to the more commonly used in vitro models for both predicting and producing metabolites.

    List of papers
    1. Characterization of equine urinary metabolites of selective androgen receptor modulators (SARMs) S1, S4 and S22 for doping control purposes
    Open this publication in new window or tab >>Characterization of equine urinary metabolites of selective androgen receptor modulators (SARMs) S1, S4 and S22 for doping control purposes
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    2015 (English)In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 7, no 8, p. 673-683Article in journal (Refereed) Published
    Abstract [en]

    Selective androgen receptor modulators, SARMs, constitute a class of compounds with anabolic properties but with few androgenic side-effects. This makes them possible substances of abuse and the World Anti-Doping Agency (WADA) has banned the entire class of substances. There have been several cases of illicit use of aryl propionamide SARMs in human sports and in 2013, 13 cases were reported. These substances have been found to be extensively metabolized in humans, making detection of metabolites necessary for doping control. SARMs are also of great interest to equine doping control, but the in vivo metabolite pattern and thus possible analytical targets have not been previously studied in this species. In this study, the urinary metabolites of the SARMs S1, S4, and S22 in horses were studied after intravenous injection, using ultra high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QToF-MS). Eight different metabolites were found for SARM S1, nine for SARM S4, and seven for SARM S22. The equine urinary metabolite profiles differed significantly from those of humans. The parent compounds were only detected for SARMs S4 and S22 and only at the first sampling time point at 3h post administration, making them unsuitable as target compounds. For all three SARMs tested, the metabolite yielding the highest response had undergone amide hydrolysis, hydroxylation and sulfonation. The resulting phase II metabolites (4-nitro-3-trifluoro-methyl-phenylamine sulfate for SARMs S1 and S4 and 4-cyano-3-trifluoro-methyl-phenylamine sulfate for SARM S22) are proposed as analytical targets for use in equine doping control.

    Keyword
    selective androgen receptor modulators, SARM, metabolite, equine, horse
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-261969 (URN)10.1002/dta.1768 (DOI)000359603700003 ()25560998 (PubMedID)
    Available from: 2015-09-08 Created: 2015-09-07 Last updated: 2018-03-14Bibliographically approved
    2. Investigation of the selective androgen receptor modulators S1, S4 and S22 and their metabolites in equine plasma using high-resolution mass spectrometry
    Open this publication in new window or tab >>Investigation of the selective androgen receptor modulators S1, S4 and S22 and their metabolites in equine plasma using high-resolution mass spectrometry
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    2016 (English)In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 30, no 7, p. 833-842Article in journal (Refereed) Published
    Abstract [en]

    RationaleSelective androgen receptor modulators (SARMs) are prohibited in sports due to their performance enhancing ability. It is important to investigate the metabolism to determine appropriate targets for doping control. This is the first study where the equine metabolites of SARMs S1, S4 (Andarine) and S22 (Ostarine) have been studied in plasma. MethodsEach SARM was administered to three horses as an intravenous bolus dose and plasma samples were collected. The samples were pretreated with protein precipitation using cold acetonitrile before separation by liquid chromatography. The mass spectrometric analysis was performed using negative electrospray, quadrupole time-of-flight mass spectrometry operated in MSE mode and triple-quadrupole mass spectrometry operated in selected reaction monitoring mode. For the quantification of SARM S1, a deuterated analogue was used as internal standard. ResultsThe numbers of observed metabolites were eight, nine and four for the SARMs S1, S4 and S22, respectively. The major metabolite was formed by the same metabolic reactions for all three SARMs, namely amide hydrolysis, hydroxylation and sulfonation. The values of the determined maximum plasma concentrations were in the range of 97-170 ng/mL for SARM S1, 95-115 ng/mL for SARM S4 and 92-147 ng/mL for SARM S22 and the compounds could be detected for 96 h, 12 h and 18 h, respectively. ConclusionsThe maximum plasma concentration of SARMs S1, S4 and S22 was measured in the first sample (5 min) after administration and they were eliminated fast from plasma. The proposed targets to be used in equine doping control are the parent compounds for all three SARMs, but with the metabolite yielding the highest response as a complementary target. 

    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-286622 (URN)10.1002/rcm.7512 (DOI)000372508100006 ()26969924 (PubMedID)
    Available from: 2016-04-28 Created: 2016-04-21 Last updated: 2018-03-14Bibliographically approved
    3. Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites.
    Open this publication in new window or tab >>Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites.
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    2018 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 1074-1075, p. 91-98, article id S1570-0232(17)31848-2Article in journal (Refereed) Published
    Abstract [en]

    LGD-4033 has been found in human doping control samples and has the potential for illicit use in racehorses as well. It belongs to the pharmacological class of selective androgen receptor modulators (SARMs) and can stimulate muscle growth, much like anabolic steroids. However, SARMs have shown superior side effect profiles compared to anabolic steroids, which arguably makes them attractive for use by individuals seeking an unfair advantage over their competitors. The purpose of this study was to investigate the metabolites formed from LGD-4033 in the horse in order to find suitable analytical targets for doping controls. LGD-4033 was administered to three horses after which plasma and urine samples were collected and analyzed for metabolites using ultra high performance liquid chromatography coupled to a high resolution mass spectrometer. In horse urine, eight metabolites, both phase I and phase II, were observed most of which had not been described in other metabolic systems. Six of these were also detected in plasma. The parent compound was detected in plasma, but not in non-hydrolyzed urine. The longest detection times were observed for unchanged LGD-4033 in plasma and in urine hydrolyzed with β-glucuronidase and is thus suggested as the analytical target for doping control in the horse. The metabolite profile determined in the horse samples was also compared to those of human urine and fungal incubate from Cunninghamella elegans. The main human metabolite, dihydroxylated LGD-4033, was detected in the horse samples and was also produced by the fungus. However, it was a not a major metabolite for horse and fungus, which highlights the importance of performing metabolism studies in the species of interest.

    Keyword
    Doping, LGD-4033, Horse, Mass Spectrometry, Metabolite, SARM, Selective Androgen Receptor Modulator
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-344303 (URN)10.1016/j.jchromb.2017.12.010 (DOI)29334634 (PubMedID)
    Available from: 2018-03-06 Created: 2018-03-06 Last updated: 2018-03-14
    4. Investigation of the metabolites of the HIF stabilizer FG-4592 (roxadustat) in five different in vitro models and in a human doping control sample using high resolution mass spectrometry
    Open this publication in new window or tab >>Investigation of the metabolites of the HIF stabilizer FG-4592 (roxadustat) in five different in vitro models and in a human doping control sample using high resolution mass spectrometry
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    2017 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 134, p. 228-236Article in journal (Refereed) Published
    Abstract [en]

    FG-4592 is a hypoxia-inducible factor (HIF) stabilizer, which can increase the number of red blood cells in the body. It has not been approved by regulatory authorities, but is available for purchase on the Internet. Due to its ability to improve the oxygen transportation mechanism in the body, FG-4592 is of interest for doping control laboratories, but prior to this study, little information about its metabolism was available. In this study, the metabolism of FG-4592 was investigated in a human doping control sample and in five in vitro models: human hepatocytes and liver microsomes, equine liver microsomes and S9 fraction and the fungus Cunninghamella elegans. By using liquid chromatography coupled to a Q-TOF mass spectrometer operated in MSE and MSMS modes, twelve different metabolites were observed for FG-4592. One monohydroxylated metabolite was detected in both the human and equine liver microsome incubations. For the fungus Cunninghamella elegans eleven different metabolites were observed of which the identical monohydroxylated metabolite had the highest response. This rich metabolic profile and the higher levels of metabolites produced by Cunninghamella elegans demonstrates its usefulness as a metabolite producing medium. In the doping control urine sample, one metabolite, which was the result of a direct glucuronidation, was observed. No metabolites were detected in neither the human hepatocyte nor in the equine liver S9 fraction incubates.

    Keyword
    FG-4592, Drug metabolism, High resolution mass spectrometry
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-317588 (URN)10.1016/j.jpba.2016.11.041 (DOI)000392909900029 ()27918992 (PubMedID)
    Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2018-03-14Bibliographically approved
  • Public defence: 2018-05-04 10:15 Geijersalen, Uppsala
    Baral, Anna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Cultural Anthropology and Ethnology.
    Bad Guys, Good Life: An Ethnography of Morality and Change in Kisekka Market (Kampala, Uganda)2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Based on ethnographic data gathered over a period of almost three years, this dissertation scrutinizes the everyday lives of informal workers selling auto parts in Kisekka Market, central Kampala. Its ambition is to understand how the workers navigated a highly moralized environment in today’s Uganda, where the supposed moral deterioration of society is passionately discussed in public and in private.

    Analytically the dissertation focuses on three “moral landscapes,” or moral discourses of different geographical scales, that intersected in the workers’ lives: first, the Ugandan nation or the country; second, the Buganda kingdom with its cultural institutions to which the majority of the workers professed allegiance; and third, the capital city Kampala. Materializing in Kisekka Market, each landscape posed moral demands that the workers navigated daily as they struggled to balance norms with lived practices.

    The workers were perceived by external observers as morally ambiguous for their supposed instrumentality in riots and violent crimes in Kampala. Their notoriousness increased for the fact that they were men, often uneducated, and therefore, in public discourse, potentially threatening. Consequently, they were referred to as bayaaye, translated as hooligans or bad guys, and this label defined their relations with customers from all parts of Kampala and Uganda.

    In exploring the implications of the three moral landscapes, particular attention is paid to the in-between. Rather than focusing on mediatized events like riots and crimes, the dissertation investigates and locates the workers’ agency in the mundane processes of care and getting by and the tentative paths to a good life that unfolded daily in Kisekka Market, regardless of larger political tensions in Kampala and beyond. The city’s development plan to replace Kisekka Market with a fancy shopping mall rendered the workers’ situation increasingly exposed and their lives increasingly vulnerable. In the workers’ quest for some degree of control and self-worth, the label of bayaaye refracted into its multiple dimensions – proudly appropriated or painfully rejected by the workers themselves – attesting  to the complexities of everyday ethics, in Kampala as elsewhere. Consequently, the ethnography of this dissertation problematizes the dominant yet fraught narrative around young men in urban Africa.

  • Public defence: 2018-05-04 13:15 University Main Building, Room IX, Uppsala
    Bååth, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Sociology.
    Production in a State of Abundance: Valuation and Practice in the Swedish Meat Supply Chain2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This thesis is a sociological contribution to the study of abundance. It discusses the case of Swedish meat producers and how they persist in producing pork and beef despite a lack of demand and competitive disadvantages compared with foreign suppliers. In doing so, this study answers how abundance is perpetuated in the production of a foodstuff in over-supply. This monograph further adds new empirical and theoretical knowledge to the fields of food studies, economic sociology, and the social sciences studying problems of abundance.

    The study explores how Swedish meat producers deal with problems stemming from supplying more than demanded volumes of food. The inquiry into this topic combines pragmatism, economic sociology, and qualitative fieldwork. The empirical materials mainly consist of in-depth interviews with 41 informants and more than one month of participatory observations from the Swedish meat supply chain.

    The evidence supplied shows how farmers, meat processors, and retailers continue supplying an abundant foodstuff by studying the valuations used in their production practice. The conclusion is that meat is not supplied to meet the consumers’ demand for food. Instead, this foodstuff is supplied as a marketing tool to meet the producers’ demand for commerce as an aesthetic of market exchange, or sustained production in line with Swedish agrifood policy, distinguished by high animal welfare and low antibiotics use. It is further argued that abundance is perpetuated because these producers rely on valuations which distinguish certain qualities of a good, rather than sufficient quantity of supply. Without using a quantitative, commensurable measure, it is not possible to limit the supply. This study contrasts existing theories of abundance by stating that problems thereof depend on how sufficiency is valuated, not the existence of some excess. These findings further support the argument that supply chains must be granted more attention in food studies primarily preoccupied with consumers. They also suggest further investigations into the relationships between markets in supply chains, and the role of production sites in economic life, would benefit economic sociology.

  • Public defence: 2018-05-04 13:15 B21, Uppsala
    Mihajlica, Nebojsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pericyte Influence on Drug Delivery Across the Blood-Brain Barrier: Implications for Therapy of Neurodegenerative Diseases2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The blood-brain barrier (BBB) represents a complex interface between the brain parenchyma and systemic blood circulation, strictly controlling exchange of substances between the two sites. Pericytes are mural cells located on the abluminal membrane of the brain endothelium, involved in BBB formation and maintenance. Previous studies have implied that pericyte-deficiency causes alterations in BBB integrity for larger molecules, mainly by upregulated transcytosis pathways.

     The aim of the thesis was to examine the role of pericytes for small-molecular drug transport across the BBB, by providing a closer insight into different aspects of transport in a pericyte-deficient state. PDGF-B retention motif knockout mice were used as a well-established pericyte-deficient model. Small-molecular drugs, namely diazepam, digoxin, imatinib, levofloxacin, oxycodone and paliperidone were selected based on utilization of different BBB transport mechanisms. Surprisingly, the extent of BBB transport expressed as the unbound brain-to-unbound plasma partition coefficients indicated no difference between pericyte-deficient and control mice for all tested drugs. In addition, no difference was observed in the rate of BBB transport estimated by trans-cardiac in situ brain perfusion experiments. These results imply preserved BBB features in terms of tight junctions that limit para-cellular transport, as well as unaltered transporter functionality and expression. Thus, BBB aspects relevant for small-molecular drug transport seem to be maintained regardless of pericyte presence at the BBB. In addition, data from proteome and transcriptome analysis of the brain microvasculature fragments were in line with these findings, showing no difference in major transporter expressions at the BBB in pericyte-deficient mice. Finally, experiments with tyrosine kinase (TK) inhibitors suggested a potential relevance of the imatinib-like TK target profiles for the stabilization of compromised BBB integrity in pericyte-deficiency.

     In conclusion, the present thesis work provided comprehensive insight into pharmacokinetics of small-molecular drugs in a pericyte-deficient state. It represents an important initial platform for future extensive investigations of BBB transport in pericyte-deficiency, towards the ultimate goal of developing novel therapeutics for the treatment of different neurodegenerative diseases.

    List of papers
    1. Pharmacokinetics of Pericyte Involvement in Small-Molecular Drug Transport Across the Blood-Brain Barrier
    Open this publication in new window or tab >>Pharmacokinetics of Pericyte Involvement in Small-Molecular Drug Transport Across the Blood-Brain Barrier
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-345932 (URN)
    Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13
    2. Rate of Small-Molecular Drug Transport Across the Blood-Brain Barrier in a Pericyte-Deficient State
    Open this publication in new window or tab >>Rate of Small-Molecular Drug Transport Across the Blood-Brain Barrier in a Pericyte-Deficient State
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-345939 (URN)
    Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13
    3. The Role of Pericytes at the Blood-Brain Barrier - Comparative Transcriptome and Proteome Analysis
    Open this publication in new window or tab >>The Role of Pericytes at the Blood-Brain Barrier - Comparative Transcriptome and Proteome Analysis
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-345941 (URN)
    Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13
    4. Tyrosine Kinase Inhibitors as Potential Therapeutics for the Improvement of Blood-Brain Barrier Integrity in a Pericyte-Deficient State
    Open this publication in new window or tab >>Tyrosine Kinase Inhibitors as Potential Therapeutics for the Improvement of Blood-Brain Barrier Integrity in a Pericyte-Deficient State
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-345946 (URN)
    Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13
  • Public defence: 2018-05-04 13:15 Häggsalen, Ångströmlaboratoriet, Uppsala
    Tian, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Magnetic Nanoparticle Based Biosensors for Pathogen Detection and Cancer Diagnostics2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes several magnetic nanoparticle (MNP)-based biosensing strategies which take advantage of different magnetic sensors, molecular tools and nanotechnologies. Proposed biosensors can be classified into three groups, i.e., immunoassay-based, molecular amplification-based, and nanoparticle assembly-based. The principal motivation is to develop and optimize biosensors for out-of-lab and point-of-care testing.

    Immunoassay-based biosensors described in this thesis employ antibodies as the bio-recognition element for the detection of bacteria cells/fragments or proteins. Two typical immunoassay formats, i.e., direct and competitive format, are studied and compared for bacteria detection. In addition, in the protein biomarker detection, MNP chains are formed in the presence of target analytes as well as in the external rotating magnetic field. The high shape/magnetic anisotropy of the chains provides better optomagnetic performance.

    Two different molecular amplification methods, i.e., rolling circle amplification (RCA) and loop-mediated isothermal amplification (LAMP), are described under the topic of molecular amplification-based biosensors. In RCA-based biosensors, DNA probe modified MNPs bind to the amplicons after amplification. In LAMP-based biosensors, MNPs are either modified with primers that keep growing during the amplification, or are co-precipitated with the by-product (Mg2P2O7) of the amplification.

    The design of the nanoparticle assembly-based biosensors described in this thesis is based on duplex-specific nuclease (DSN)-assisted target recycling and core-satellite magnetic superstructures. In the presence of target microRNA, DSN cuts the DNA scaffold of the core-satellite assembly, releasing MNP satellites that can be quantified by the sensor.

    Different kinds of target analytes, i.e., pathogens or cancer biomarkers, are detected at the aiming for rapid, low-cost and user-friendly diagnostics.

    List of papers
    1. Blu-ray optomagnetic measurement based competitive immunoassay for Salmonella detection
    Open this publication in new window or tab >>Blu-ray optomagnetic measurement based competitive immunoassay for Salmonella detection
    2016 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 77, p. 32-39Article in journal (Refereed) Published
    Abstract [en]

    A turn-on competitive immunoassay using a low-cost Blu-ray optomagnetic setup and two differently sized magnetic particles (micron-sized particles acting as capture particles and nano-sized particles acting as detection particles) is here presented. For Salmonella detection, a limit of detection of 8 x 10(4) CFU/mL is achieved within a total assay time of 3 h. The combination of a competitive strategy and an optomagnetic setup not only enables a turn-on read-out format, but also results in a sensitivity limit about a factor of 20 times lower than of volumetric magnetic stray field detection device based immunoassays. The improvement of sensitivity is enabled by the formation of immuno-magnetic aggregates providing steric hindrance protecting the interior binding sites from interaction with the magnetic nanoparticle labels. The formation of immuno-magnetic aggregates is confirmed by fluorescence microscopy. The system exhibits no visible cross-reaction with other common pathogenic bacteria, even at concentrations as high as 10 CFU/mL. Furthermore, we present results when using the setup for a qualitative and homogeneous biplex immunoassay of Escherichia coli and Salmonella typhimurium.

    Keyword
    Biosensors; Immunoassays; Magnetic particles; Magneto-optics
    National Category
    Engineering and Technology
    Research subject
    Engineering Science with specialization in Solid State Physics
    Identifiers
    urn:nbn:se:uu:diva-264720 (URN)10.1016/j.bios.2015.08.070 (DOI)000366766900006 ()
    Funder
    Swedish Research Council Formas, 221-2012-444
    Available from: 2015-10-15 Created: 2015-10-15 Last updated: 2018-03-13Bibliographically approved
    2. Shape anisotropy enhanced optomagnetic measurement for prostate-specific antigen detection via magnetic chain formation
    Open this publication in new window or tab >>Shape anisotropy enhanced optomagnetic measurement for prostate-specific antigen detection via magnetic chain formation
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    2017 (Swedish)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 98, p. 285-291Article in journal (Refereed) Published
    Abstract [en]

    We demonstrate a homogeneous biosensor for the detection of multivalent targets by combination of magnetic nanoparticle (MNP) chains and a low-cost 405 nm laser-based optomagnetic system. The MNP chains are assembled in a rotating magnetic field and stabilized by multivalent target molecules. The number of chains remaining in zero field is proportional to the target concentration, and can be quantified by optomagnetic measurements. The shape anisotropy of the MNP chains enhances the biosensor system in terms of providing efficient mixing, reduction of depletion effects (via magnetic shape anisotropy), and directly increasing the optomagnetic signal (via optical shape anisotropy). We achieve a limit of detection (LOD) of 5.5 pM (0.82 ng/mL) for the detection of a model multivalent molecule, biotinylated anti-streptavidin, in PBS. For the measurements of prostate-specific antigen (PSA) in 50% serum using the proposed method, we achieve an LOD of 21.6 pM (0.65 ng/mL) and a dynamic detection range up to 66.7 nM (2 µg/mL) with a sample-to-result time of approximately 20 min. The performance for PSA detection therefore well meets the clinical requirements in terms of LOD (the threshold PSA level in blood is 4 ng/mL) and detection range (PSA levels span from < 0.1–104 ng/mL in blood), thus showing great promise for routine PSA diagnostics and for other in-situ applications.

    Keyword
    Magnetic nanoparticles, Magnetic chains, Rotating magnetic field, Brownian relaxation, Optomagnetic biosensor, Prostate-specific antigen
    National Category
    Nano Technology
    Research subject
    Engineering Science with specialization in Solid State Physics
    Identifiers
    urn:nbn:se:uu:diva-330181 (URN)10.1016/j.bios.2017.06.062 (DOI)000407538300039 ()28689114 (PubMedID)
    Funder
    Swedish Research Council Formas, 221-2012-444Swedish Research Council Formas, 221-2014-574Swedish Research Council Formas, 2011-1692EU, FP7, Seventh Framework Programme, Grant No. 604448-NanoMag
    Available from: 2017-09-27 Created: 2017-09-27 Last updated: 2018-03-14Bibliographically approved
    3. Multi-scale magnetic nanoparticle based optomagnetic bioassay for sensitive DNA and bacteria detection
    Open this publication in new window or tab >>Multi-scale magnetic nanoparticle based optomagnetic bioassay for sensitive DNA and bacteria detection
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    2016 (English)In: Analytical Methods, ISSN 1759-9660, E-ISSN 1759-9679, Vol. 8, no 25, p. 5009-5016Article in journal (Refereed) Published
    Abstract [en]

    Benefiting from their rapid readout, highly flexible devices and low-cost portable systems, optomagnetic biosensors have drawn increased attention in recent years as bioassay technologies for small molecules, biomarkers, DNA, and bacteria. Herein, an optomagnetic bioassay strategy suitable for point-of-care diagnostics, utilizing functionalized magnetic nanoparticles (100 nm) with Brownian relaxation behavior is optimized in order to obtain higher detection sensitivity for DNA molecules and bacteria. Presence of target DNA sequences or bacteria changes the dynamic behavior of the magnetic nanoparticles (binding to the target) and thus the optomagnetic response of the sample, which is measured by an optomagnetic setup including a 405 nm laser and a photodetector. The limit of detection is mainly set by the lowest measurable concentration of magnetic nanoparticles. Herein, as new results compared to previous work, we systematically optimize the concentration of 100 nm magnetic nanoparticles to increase the assay sensitivity and lower the limit of detection. To enable biplex detection, we perform this optimization in the presence of larger 250 nm magnetic nanoparticles that do not interact with the target. We show that the optimization and lowering of the 100 nm magnetic nanoparticle concentration result in a limit of detection of 780 fM of DNA coils formed by rolling circle amplification (size of about 1 mu m) and 10(5) CFU per mL Salmonella (for immunoassay). These values are 15 times lower than those reported previously for this readout principle. Finally, we show that the 250 nm magnetic nanoparticles can serve as a second detection label for qualitative biplex detection of DNA coils formed by rolling circle amplification from V. cholerae and E. coli DNA coils using 100 nm and 250 nm magnetic detection nanoparticles, respectively.

    National Category
    Bioprocess Technology
    Identifiers
    urn:nbn:se:uu:diva-300098 (URN)10.1039/c6ay00721j (DOI)000378941500005 ()
    Funder
    Swedish Research Council Formas, 221-2012-444 221-2014-574 2011-1692Swedish Foundation for Strategic Research
    Available from: 2016-08-02 Created: 2016-08-02 Last updated: 2018-03-14Bibliographically approved
    4. Rapid Newcastle Disease Virus Detection based on Loop-Mediated Isothermal Amplification and Optomagnetic Readout
    Open this publication in new window or tab >>Rapid Newcastle Disease Virus Detection based on Loop-Mediated Isothermal Amplification and Optomagnetic Readout
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    2016 (English)In: ACS Sensors, ISSN 2379-3694, Vol. 1, no 10, p. 1228-1234Article in journal (Refereed) Published
    Abstract [en]

    Rapid and sensitive diagnostic methods based on isothermal amplification are ideal substitutes for PCR in out-of-lab settings. However, there are bottlenecks in terms of establishing low-cost and user-friendly readout methods for isothermal amplification schemes. Combining the high amplification efficiency of loop-mediated isothermal amplification (LAMP) with an optomagnetic' nanoparticle-based readout system, we demonstrate ultrasensitive and rapid detection of Newcastle disease virus RNA. Biotinylated amplicons of LAMP and reverse transcription LAMP (RT-LAMP) bind to streptavidin-coated magnetic nanoparticles (MNPs) resulting in a dramatical increase in the hydrodynamic size of the MNPs. This increase was measured by an optomagnetic readout system and provided quantitative information on the amount of LAMP target sequence. Our assay resulted in a limit of detection of 10 aM of target sequence with a total assay time of 30 min. The assay has also been tested on clinical samples (vaccine and tissue specimens) with a performance comparable to real-time RT-PCR By changing the LAMP primers, this strategy can serve as a general method for the detection of other DNA/RNA targets with high specificity and sensitivity.

    Keyword
    out-of-lab diagnostics, Newcastle disease virus, loop-mediated isothermal amplification, optomagnetic bioassay, magnetic nanoparticles
    National Category
    Medical Laboratory and Measurements Technologies Physical Sciences
    Research subject
    Engineering Science with specialization in Solid State Physics
    Identifiers
    urn:nbn:se:uu:diva-305174 (URN)10.1021/acssensors.6b00379 (DOI)000386747600012 ()
    Funder
    Swedish Research Council Formas, 221-2012-444Swedish Research Council Formas, 221-2014-574Swedish Research Council Formas, 2011-1692
    Available from: 2016-10-12 Created: 2016-10-12 Last updated: 2018-03-13Bibliographically approved
    5. Attomolar Zika virus oligonucleotide detection based on loop-mediated isothermal amplification and AC susceptometry
    Open this publication in new window or tab >>Attomolar Zika virus oligonucleotide detection based on loop-mediated isothermal amplification and AC susceptometry
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    2016 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 86, p. 420-425Article in journal (Refereed) Published
    Abstract [en]

    Because of the serological cross-reactivity among the flaviviruses, molecular detection methods, such as reverse-transcription polymerase chain reaction (RT-PCR), play an important role in the recent Zika outbreak. However, due to the limited sensitivity, the detection window of RT-PCR for Zika viremia is only about one week after symptom onset. By combining loop-mediated isothermal amplification (LAMP) and AC susceptometry, we demonstrate a rapid and homogeneous detection system for the Zika virus oligonucleotide. Streptavidin-magnetic nanoparticles (streptavidin-MNPs) are premixed with LAMP reagents including the analyte and biotinylated primers, and their hydrodynamic volumes are dramatically increased after a successful LAMP reaction. Analyzed by a portable AC susceptometer, the changes of the hydrodynamic volume are probed as Brownian relaxation frequency shifts, which can be used to quantify the Zika virus oligonucleotide. The proposed detection system can recognize 1 aM synthetic Zika virus oligonucleotide in 20% serum with a total assay time of 27 min, which can hopefully widen the detection window for Zika viremia and is therefore promising in worldwide Zika fever control.

    Keyword
    Zika virus, Loop-mediated isothermal amplification, Magnetic nanoparticles, Brownian relaxation, AC susceptometer
    National Category
    Biophysics Medical Biotechnology
    Identifiers
    urn:nbn:se:uu:diva-307258 (URN)10.1016/j.bios.2016.06.085 (DOI)000384853300057 ()
    Funder
    Swedish Research Council Formas, 221-2012-444 221-2014-574 2011-1692
    Available from: 2016-11-14 Created: 2016-11-11 Last updated: 2018-03-13Bibliographically approved
    6. Ferromagnetic Resonance Biosensor for Homogeneous and Volumetric Detection of DNA
    Open this publication in new window or tab >>Ferromagnetic Resonance Biosensor for Homogeneous and Volumetric Detection of DNA
    2017 (English)In: Article in journal (Refereed) Submitted
    National Category
    Engineering and Technology
    Research subject
    Engineering Science with specialization in Solid State Physics
    Identifiers
    urn:nbn:se:uu:diva-345595 (URN)
    Funder
    Swedish Research Council Formas, 221-2012-444
    Available from: 2018-03-09 Created: 2018-03-09 Last updated: 2018-03-14
    7. Optomagnetic Detection of MicroRNA Based on Duplex-Specific Nuclease-Assisted Target Recycling and Multilayer Core-Satellite Magnetic Superstructures
    Open this publication in new window or tab >>Optomagnetic Detection of MicroRNA Based on Duplex-Specific Nuclease-Assisted Target Recycling and Multilayer Core-Satellite Magnetic Superstructures
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    2017 (English)In: ACS Nano, ISSN 1936-0851, E-ISSN 1936-086X, Vol. 11, no 2, p. 1798-1806Article in journal (Refereed) Published
    Abstract [en]

    Superstructural assembly of magnetic nanoparticles enables approaches to biosensing by combining specially tailored properties of superstructures and the particular advantages associated with a magnetic or optomagnetic read-out such as low background signal, easy manipulation, cost-efficiency, and potential for bioresponsive multiplexing. Herein, we demonstrate a sensitive and rapid miRNA detection method based on optomagnetic read-out, duplex-specific nuclease (DSN)-assisted target recycling, and the use of multilayer core-satellite magnetic superstructures. Triggered by the presence of target miRNA and DSN-assisted target recycling, the core-satellite magnetic superstructures release their "satellites" to the suspension, which subsequently can be quantified accurately in a lowcost and user-friendly optomagnetic setup. Target miRNAs are preserved in the cleaving reaction and can thereby trigger more cleavage and release of "satellites". For singleplex detection of let-7b, a linear detection range between 10 fM and 10 nM was observed, and a detection limit of 4.8 fM was obtained within a total assay time of 70 min. Multiplexing was achieved by releasing nanoparticles of different sizes in the presence of different miRNAs. The proposed method also has the advantages of single-nucleotide mismatch discrimination and the ability of quantification in a clinical sample matrix, thus holding great promise for miRNA routine multiplex diagnostics.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2017
    Keyword
    miRNA detection, duplex-specific nuclease, magnetic nanoparticles, core-satellite superstructures, optomagnetic bioassay
    National Category
    Biomaterials Science Nano Technology
    Research subject
    Engineering Science with specialization in Nanotechnology and Functional Materials
    Identifiers
    urn:nbn:se:uu:diva-319101 (URN)10.1021/acsnano.6b07763 (DOI)000395357300073 ()28177611 (PubMedID)