uu.seUppsala University Publications
1 - 55 of 55
rss atomLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
  • Public defence: 2017-11-23 13:00 B42, Uppsala
    Zhao, Yani
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Systemic RNAi Relies on the Endomembrane System in Caenorhabditis elegans2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The membrane system of a eukaryotic cell is a large and complex system handling the transport, exchange and degradation of many kinds of material. Recent research shows that double-stranded RNA (dsRNA) mediated gene silencing (RNA interference) is a membrane related process. After long dsRNA is processed to small interfering RNA (siRNA) by Dicer, the guide strand and passenger strand are separated in the RNA induced silencing complex (RISC) by Argonaute. The process of loading siRNA into RISC has been suggested to occur at the rough Endoplasmic Reticulum (rER).The components of RISC also associate with late endosomes/multivesicular bodies (MVBs). Furthermore, disturbing the balance between late endosomes/MVBs and lysosomes has been shown to affect the efficiency of silencing.

    We use the nematode Caenorhabditis elegans as our model organism to study two questions: how does membrane transport affect RNAi and spreading of RNAi from the recipient cells to other tissues (systemic RNAi); and how does RNA transport contribute to the multigenerational silencing induced by dsRNA (RNAi inheritance)? Using SID-5, a protein required for efficient systemic RNAi, as bait in a yeast two-hybrid (Y2H) screen, we got 32 SID-5 interacting candidate proteins. Two of these are the SNARE protein SEC-22 and the putative RNA binding protein C12D8.1. In two additional Y2H screens, we found that SID-5 interacts with multiple syntaxin SNAREs, including SYX-6, whereas SEC-22 only interacts with SYX-6. SNAREs usually function in vesicle fusion processes. We found the two SNARE proteins SEC-22 and SYX-6 to be negative regulators of RNAi and to localize to late endosomes/MVBs. In addition, loss of sid-5 leads to an endosome maturation defect. Finally, we found that the putative RNA binding protein C12D8.1 negatively regulates RNAi inheritance and that C12D8.1 mutant animals show impaired RNAi upon targeting a new gene. Taken together, the results presented in this thesis provide us with more evidence for the connection of the membrane transport system and RNAi. The identification of a putative negative regulator of RNAi inheritance further enriches this research field.

    List of papers
    1. The conserved SNARE SEC-22 localizes to late endosomes and negatively regulates RNA interference in Caenorhabditis elegans
    Open this publication in new window or tab >>The conserved SNARE SEC-22 localizes to late endosomes and negatively regulates RNA interference in Caenorhabditis elegans
    2017 (English)In: RNA, ISSN 1355-8382, Vol. 23, no 3, 297-307 p.Article in journal (Refereed) Published
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-321388 (URN)10.1261/rna.058438.116 (DOI)
    Available from: 2017-05-04 Created: 2017-05-04 Last updated: 2017-10-13
    2. RNA Transport Protein SID-5 Interacts with Multiple SNAREs and Affects Membrane Trafficking in C. elegans Intestinal Cells
    Open this publication in new window or tab >>RNA Transport Protein SID-5 Interacts with Multiple SNAREs and Affects Membrane Trafficking in C. elegans Intestinal Cells
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-320894 (URN)
    Available from: 2017-04-26 Created: 2017-04-26 Last updated: 2017-10-13
    3. Putative RNA-Binding Protein C12D8.1 Negatively Regulates Inheritance of RNAi in Caenorhabditis elegans
    Open this publication in new window or tab >>Putative RNA-Binding Protein C12D8.1 Negatively Regulates Inheritance of RNAi in Caenorhabditis elegans
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-320895 (URN)
    Available from: 2017-04-26 Created: 2017-04-26 Last updated: 2017-10-13
  • Public defence: 2017-11-24 09:00 A1:111a, Uppsala
    Thulin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mechanisms and Dynamics of Mecillinam Resistance in Escherichia coli2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The introduction of antibiotics in healthcare is one of the most important medical achievements with regard to reducing human morbidity and mortality. However, bacterial pathogens have acquired antibiotic resistance at an increasing rate, and due to a high prevalence of resistance to some antibiotics they can no longer be used therapeutically. The antibiotic mecillinam, which inhibits the penicillin-binding protein PBP2, however, is an exception since mecillinam resistance (MecR) prevalence has remained low. This is particularly interesting since laboratory experiments have shown that bacteria can rapidly acquire MecR mutations by a multitude of different types of mutations.

    In this thesis, I examined mechanisms and dynamics of mecillinam resistance in clinical and laboratory isolates of Escherichia coli. Only one type of MecR mutations (cysB) was found in the clinical strains, even though laboratory experiments demonstrate that more than 100 genes can confer resistance Fitness assays showed that cysB mutants have higher fitness than most other MecR mutants, which is likely to contribute to their dominance in clinical settings.

    To determine if the mecillinam resistant strains could compensate for their fitness cost, six different MecR mutants (cysB, mrdA, spoT, ppa, aspS and ubiE) were evolved for 200-400 generations. All evolved mutants showed increased fitness, but the compensation was associated with loss of resistance in the majority of cases. This will also contribute to the rarity of clinical MecR isolates with chromosomal resistance mutations.

    How MecR is mediated by cysB mutations was previously unclear, but in this thesis I propose and test a model for the mechanism of resistance. Thus, inactivation of CysB results in cellular depletion of cysteine that triggers an oxidative stress response. The response alters the intracellular levels of 450 proteins, and MecR is achieved by the increase of two of these, the LpoB and PBP1B proteins, which rescue the cells with a mecillinam-inhibited PBP2.

    Mecillinam is used for UTI treatments and to investigate mecillinam resistance in a more host-like milieu, MecR strains were grown in urine and resistance was examined. Interestingly, this study showed that neither laboratory, nor clinical cysB mutants are resistant in urine, most likely because the cysteine present in the urine phenotypically reverts the bacteria to susceptibility. These findings suggest that mecillinam can be used to treat also those clinical strains that are identified as MecR in standard laboratory tests, and that testing of mecillinam susceptibility in the laboratory ought to be performed in media that mimics urine to obtain clinically relevant results.

    In summary, the work described in this thesis has increased ourgeneral knowledge of mecillinam resistance and its evolution. Hopefully this knowledge can be put to good use in clinical settings to reduce the negative impact of antibiotic resistance.

    List of papers
    1. Amdinocillin (Mecillinam) Resistance Mutations in Clinical Isolates and Laboratory-Selected Mutants of Escherichia coli
    Open this publication in new window or tab >>Amdinocillin (Mecillinam) Resistance Mutations in Clinical Isolates and Laboratory-Selected Mutants of Escherichia coli
    2015 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, no 3, 1723-1732 p.Article in journal (Refereed) Published
    Abstract [en]

    Amdinocillin (mecillinam) is a beta-lactam antibiotic that is used mainly for the treatment of uncomplicated urinary tract infections. The objectives of this study were to identify mutations that confer amdinocillin resistance on laboratory-isolated mutants and clinical isolates of Escherichia coli and to determine why amdinocillin resistance remains rare clinically even though resistance is easily selected in the laboratory. Under laboratory selection, frequencies of mutation to amdinocillin resistance varied from 8 x 10(-8) to 2 x 10(-5) per cell, depending on the concentration of amdinocillin used during selection. Several genes have been demonstrated to give amdinocillin resistance, but here eight novel genes previously unknown to be involved in amdinocillin resistance were identified. These genes encode functions involved in the respiratory chain, the ribosome, cysteine biosynthesis, tRNA synthesis, and pyrophosphate metabolism. The clinical isolates exhibited significantly greater fitness than the laboratory-isolated mutants and a different mutation spectrum. The cysB gene was mutated (inactivated) in all of the clinical isolates, in contrast to the laboratory-isolated mutants, where mainly other types of more costly mutations were found. Our results suggest that the frequency of mutation to amdinocillin resistance is high because of the large mutational target (at least 38 genes). However, the majority of these resistant mutants have a low growth rate, reducing the probability that they are stably maintained in the bladder. Inactivation of the cysB gene and a resulting loss of cysteine biosynthesis are the major mechanism of amdinocillin resistance in clinical isolates of E. coli.

    National Category
    Microbiology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-252716 (URN)10.1128/AAC.04819-14 (DOI)000352550000043 ()25583718 (PubMedID)
    Available from: 2015-05-11 Created: 2015-05-11 Last updated: 2017-10-05Bibliographically approved
    2. Compensatory evolution in mecillinam resistant Escherichia coli
    Open this publication in new window or tab >>Compensatory evolution in mecillinam resistant Escherichia coli
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Antibiotic resistance mutations typically have pleiotropic effects that reduce bacterial fitness, but secondary compensatory mutations may ameliorate these fitness costs. Mecillinam is a b-lactam antibiotic that is used for treatment of Urinary Tract Infections (UTIs) and in a previous screen of mecillinam resistant (MecR) clinical isolates of Escherichia coli mutations in the cysB gene were shown to be the main cause of MecR.  This is unexpected since over 100 different genes are known to confer MecR in laboratory settings. Mutations in cysB are less costly than most other types of MecR, which is likely to be a contributing factor to only cysB mutations being found in clinical MecR isolates.

    To examine if the fitness costs associated with MecR can be compensated by second-site mutations, we performed a serial passage evolution experiment where six different MecR mutants (mrdA, ppa, ubiE, aspS, spoT and cysB) were grown without mecillinam for 200-400 generations. All evolved lineages showed increased fitness as compared to the parental MecR strain. Increase of fitness was associated with loss of resistance in all compensated mutants except in the mrdA mutant lineages. Our results show that compensation of the fitness cost of MecR mutations involved either a small mutational target or acquisition of several mutations. These factors are likely to contribute to the low frequency of MecR clinical isolates.

    National Category
    Medical and Health Sciences
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:uu:diva-330816 (URN)
    Funder
    Swedish Research Council
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-05
    3. An oxidative stress-induced bypass mechanism confers antibiotic resistance in Escherichia coli
    Open this publication in new window or tab >>An oxidative stress-induced bypass mechanism confers antibiotic resistance in Escherichia coli
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Mecillinam is a beta-lactam antibiotic that specifically inhibits the essential penicillin binding protein PBP2. Mutations in >100 genes can confer resistance to mecillinam but in clinical isolates of Escherichia coli from urinary tract infections, mutations in the cysB gene are the major cause of resistance. However, how cysB mutations confer resistance is unknown. We used a combination of proteomics and genetic analysis to examine the mechanism of resistance. Results show that cysB mutations cause an oxidative stress response and change expression of more than 450 genes, among them the PBP1B, LpoB and FtsZ proteins, which show increased levels. Addition of reducing agents to a cysB mutant converted it to full susceptibility, with an associated down-regulation of PBP1B, LpoB and FtsZ. Artificial over-expression of either PBP1B or LpoB in a wild type E. coli conferred mecillinam resistance, and conversely, inactivation of either the mrcB (encodes PBP1B) or lpoB gene, made cysB mutants susceptible. These results together show that expression of the proteins PBP1B and LpoB is both necessary and sufficient to confer mecillinam resistance.

    We propose a model whereby cysB mutants confer mecillinam resistance by inducing an oxidative stress response that causes an up-regulation of the PBP1B and LpoB proteins. These two proteins can then together substitute for the function of the mecillinam-sensitive PBP2 protein. Our results provide new insights into how antibiotic resistance can be conferred by a bypass mechanism that is induced by changed redox state and gene expression.

    Keyword
    Antibiotic resistance, mecillinam, Escherichia coli, penicillin binding protein, cell wall, cysB, lpoB, ftsZ, cysteine, redox state
    National Category
    Medical and Health Sciences
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:uu:diva-330815 (URN)
    Funder
    Swedish Research Council
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-05
    4. Reversion of High-level Mecillinam Resistance to Susceptibility in Escherichia coli During Growth in Urine.
    Open this publication in new window or tab >>Reversion of High-level Mecillinam Resistance to Susceptibility in Escherichia coli During Growth in Urine.
    2017 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 23, 111-118 p., S2352-3964(17)30338-9Article in journal (Refereed) Published
    Abstract [en]

    Mecillinam (amdinocillin) is a β-lactam antibiotic used to treat uncomplicated urinary tract infections (UTIs). We have previously shown that inactivation of the Escherichia coli cysB gene is the major cause of mecillinam resistance (Mec(R)) in clinical isolates. In this study, we used different E. coli strains (laboratory and clinical isolates) that were Mec(R) due to cysB mutations to determine how mecillinam susceptibility was affected during growth in urine compared to growth in the commonly used growth medium Mueller Hinton (MHB). We also examined mecillinam susceptibility when bacteria were grown in urine obtained from 48 different healthy volunteers. Metabolome analysis was done on the urine samples and the association between the mecillinam susceptibility patterns of the bacteria and urine metabolite levels was studied. Two major findings with clinical significance are reported. First, Mec(R)E. coli cysB mutant strains (both laboratory and clinical isolates) were always more susceptible to mecillinam when grown in urine as compared to laboratory medium, with many strains showing complete phenotypic susceptibility in urine. Second, the degree of reversion to susceptibility varied between urine samples obtained from different individuals. This difference was correlated with osmolality such that in urine with low osmolality the Mec(R) mutants were more susceptible to mecillinam than in urine with high osmolality. This is the first example describing conditional resistance where a genetically stable antibiotic resistance can be phenotypically reverted to susceptibility by metabolites present in urine. These findings have several important clinical implications regarding the use of mecillinam to treat UTIs. First, they suggest that mecillinam can be used to treat also those clinical strains that are identified as Mec(R) in standard laboratory tests. Second, the results suggest that testing of mecillinam susceptibility in the laboratory ought to be performed in media that mimics urine to obtain clinically relevant susceptibility testing results. Third, these findings imply that changes in patient behavior, such as increased water intake or use of diuretics to reduce urine osmolality and increased intake of cysteine, might induce antibiotic susceptibility in an infecting Mec(R)E. coli strain and thereby increase treatment efficiency.

    Keyword
    Conditional resistance, Escherichia coli, Mecillinam, Metabolomics, Urinary tract infection, Urine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-330802 (URN)10.1016/j.ebiom.2017.08.021 (DOI)28855073 (PubMedID)
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-05
  • Public defence: 2017-11-24 09:15 Sal IV, Uppsala
    Thunander Sundbom, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The influence of gender and depression on drug utilization: Pharmacoepidemiological research in Sweden2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Drug use has increased over recent decades, and is especially great among women and among people with mental health problems. To take advantage of the full potential of drugs and to avoid drug-related problems, drug prescription needs to be correct and the drugs need to be taken according to the prescribed regimens. Research on drug utilization is thus important to the public health.

    Aim To study the influence of gender and depression on drug utilization, prescription of drugs and self-reported use of drugs, i.e. adherence.

    Methods The thesis included two population-based questionnaires and data from the Swedish Prescribed Drug Register (SPDR) covering Swedish citizens 18-84 years. The questionnaire in Study I and II included items on prescription drug use and adherence to treatment regimens; Study II also included the Hospital Anxiety and Depression Scale (HADS) for self-estimation of anxiety/depression. The questionnaire in Study III included the HADS and data from the SPDR on prescribed antidepressants. Study IV included data from the SPDR on all types of prescribed drugs.

    Results Men and women differed in non-adherent behaviours and reasons for non-adherence, for example, men were more likely to report forgetting to take the drug, while women were more likely to report adverse drug reactions (ADRs) as a reason for non-adherence. Further, both anxiety and depression were associated with non-adherence and with ADRs as a reason for non-adherence. In addition, men reported depression to a greater extent than women did but used antidepressants to a lesser extent, while women used antidepressants without reporting depression more often than men did, which may be a sign of under-treatment among men and over-treatment among women. Moreover, the associations between antidepressants and other types of drugs differed by gender; they were often specific, or stronger, in women than in men, which may be a sign of a gender difference in comorbidity between depression and other conditions.

    Conclusions Although the cross-sectional study design prevented confirmation of causality, the thesis found that gender and depression influence both prescription of drugs and adherence, and are thus important to pay attention to in clinical practice as well as research.

    List of papers
    1. Women and men report different behaviours in, and reasons for medication non-adherence: a nationwide Swedish survey
    Open this publication in new window or tab >>Women and men report different behaviours in, and reasons for medication non-adherence: a nationwide Swedish survey
    2012 (English)In: Pharmacy Practice, ISSN 1885-642X, E-ISSN 1886-3655, Vol. 10, no 4, 207-221 p.Article in journal (Refereed) Published
    Abstract [en]

    Objectives

    The aim of the present study was to analyse gender differences in self-reported non-adherence (NA) to prescribed medication in the Swedish general population. We aimed to study unintentional and intentional NA as well as the reasons given for NA.

    Methods

    A questionnaire was mailed to a cross-sectional, random, national sample of people aged 18-84 years in Sweden (n=7985). The response rate was 61.1% (n=4875). The questionnaire covered use of prescription drugs, NA behaviourand reasons for NA.

    Results

    Use of prescription drugs was reported by 59.5% (n=2802) of the participants, and 66.4% (n=1860) of these participants did not adhere to the prescribed regimen. No overall gender differences in reporting NA were found. However, when analysing the various types of NA behaviour and the reasons for NA, different gender patterns emerged. Men were more likely to report forgetting [OR 0.77 (95% CI 0.65:0.92)], changing the dosage [OR 0.64 (95% CI 0.52:0.79)] and that they had recovered [14.3%, (OR 0.71 (95% CI 0.56:0.90)] as a reason. In contrast, more women than men reported filling the prescription but not taking the drug [OR 1.25 (95% CI 1.02:1.54)] and reported the development of adverse drug reactions (ADRs) [OR 1.89 (95% CI 1.37:2.59)] as a reason more commonly. The gender differences remained, in most cases, after controlling for confounders such as age, socioeconomic factors, medical problems and attitudes toward drugs.

    Conclusions

    Women and men have different patterns of NA behaviour and different reasons for NA. Therefore, if adherence is to be improved, a wide knowledge of all the reasons for NA is required, along with an understanding of the impact of gender on the outcomes.

     

    Keyword
    Medication Adherence, Health knowledge, Attitudes, Practice, Health care surveys, Sweden
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmacoepidemiology
    Identifiers
    urn:nbn:se:uu:diva-193611 (URN)
    Available from: 2013-02-05 Created: 2013-02-05 Last updated: 2017-10-04Bibliographically approved
    2. The influence of symptoms of anxiety and depression on medication nonadherence and its causes: a population based survey of prescription drug users in Sweden
    Open this publication in new window or tab >>The influence of symptoms of anxiety and depression on medication nonadherence and its causes: a population based survey of prescription drug users in Sweden
    2013 (English)In: Patient Preference and Adherence, ISSN 1177-889X, Vol. 7, 805-811 p.Article in journal (Refereed) Published
    Abstract [en]

    Purpose: The purpose of this study was to evaluate the associations between self-reported symptoms of anxiety and/or depression, nonadherent (NA) behaviors, and reasons for NA to medication regimens.

    Methods: A population based cross-sectional study with questionnaire was performed in the general Swedish population. The participants were 2802 prescription drug users aged 18-84 years. The questionnaire covered use of prescription drugs, symptoms of anxiety and/or depression, based on the Hospital Anxiety and Depression Scale (HADS), various NA behavior types, intentional and unintentional, and various reasons for NA.

    Results: Symptoms of anxiety and depression, independently and in combination, were associated with unintentional and intentional NA, with a stronger association with intentional NA. Regarding the reasons given for NA, for example anxiety, independently or in combination with depression, was associated with a fear of developing adverse drug reactions (ADRs). Depression, independently or in combination with anxiety, on the other hand, was associated with the actual development of ADRs.

    Conclusion: A cross-sectional design such as this does not allow assessment of causality derived from the results. However, the results indicate that patients experiencing symptoms of psychological distress are at increased risk of NA, especially intentional NA, and could therefore benefit from extra attention from the health care professional. Patients with symptoms of anxiety and/or depression should be identified and monitored for the development and/or fear of ADRs, in order to improve adherence to medication regimens.

    Keyword
    Medication Adherence, Anxiety symptoms, Depression symptoms, Reasons
    National Category
    Medical and Health Sciences
    Research subject
    Pharmacoepidemiology
    Identifiers
    urn:nbn:se:uu:diva-205574 (URN)10.2147/PPA.S50055 (DOI)000323147600001 ()
    Available from: 2013-08-20 Created: 2013-08-20 Last updated: 2017-10-04Bibliographically approved
    3. Are men under-treated and women over-treated with antidepressants?: Findings from a cross-sectional survey in Sweden
    Open this publication in new window or tab >>Are men under-treated and women over-treated with antidepressants?: Findings from a cross-sectional survey in Sweden
    2017 (English)In: BJPsych bulletin, ISSN 2056-4694, E-ISSN 2056-4708, Vol. 41, no 3, 145-150 p.Article in journal (Refereed) Published
    Abstract [en]

    Aims and method To examine gender differences in self-reported depression and prescribed antidepressants (ADs). The Hospital Anxiety and Depression Scale was used to assess depression, and information on prescribed ADs was obtained from the Swedish Prescribed Drug Register.

    Results Depression was reported by 11.7% of the participants (12.3% men and 11.2% women). ADs were prescribed for 7.6% of the participants (5.3% men, 9.8% women). Among men, 1.8% reported depression and used ADs, 10.5% reported depression but did not use ADs, and 3.6% used ADs but did not report depression. The corresponding figures for women were 2.6%, 8.6% and 7.2%.

    Clinical implications Men report depression to a greater extent than women but are prescribed ADs to a lesser extent, possibly a sign of under-treatment. Women are prescribed ADs without reporting depression more often than men, possibly a sign of over-treatment. Although the causes remain unclear, diagnostic and treatment guidelines should benefit from considering gender differences in these respects.

    Keyword
    Self-reported depression, Antidepressants, Gender differences, Over-treatment, Under-treatment
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmacoepidemiology
    Identifiers
    urn:nbn:se:uu:diva-310328 (URN)10.1192/pb.bp.116.054270 (DOI)000407961600004 ()28584650 (PubMedID)
    Available from: 2016-12-14 Created: 2016-12-14 Last updated: 2017-10-30Bibliographically approved
    4. Gender differences in the association between prescribed antidepressants and other prescribed drugs: a nationwide register-based study in Sweden
    Open this publication in new window or tab >>Gender differences in the association between prescribed antidepressants and other prescribed drugs: a nationwide register-based study in Sweden
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: People with depression are prescribed more drugs than people in general, partly due to comorbidity with other conditions. However, little research has been done on depression-related drug use from a gender perspective.

    Aim: Examine gender differences in the association between antidepressants, other drugs, and polypharmacy.

    Methods: Data on drugs dispensed October to December 2016 to all Swedish citizens aged 18-84 years were collected from the Swedish prescribed drug register. Logistic regression analyses were performed to examine gender differences in the associations between antidepressants and other drugs.

    Results: For both men and women, associations were found between antidepressants and drugs for alimentary tract problems, respiratory problems, drugs for the blood, and drugs for the nervous system, analgesics, and polypharmacy. For many of the drugs, for example those for respiratory problems and analgesics, the association was stronger in women than in men. However, concerning drugs for the nervous system and polypharmacy, the association was stronger in men than in women. Furthermore, for women, but not men, associations were found for drugs for diabetes, musculoskeletal problems, dermatological problems, and systemic hormones.

    Conclusions: Many of the associations between antidepressants and other drugs were found to be specific, or stronger, among women than among men. In some cases, however, the associations were stronger in men. Whether this indicates that men and women differ in comorbidity between depression and other conditions cannot be concluded based on this cross-sectional study. However, physicians should be aware that possible gender differences in comorbidity exist, and because comorbidity between depression and other conditions impairs the possibility of recovery, and decreases adherence, screening for depression could be valuable.

    Keyword
    Gender, Antidepressants, Prescribed drugs, Polypharmacy
    National Category
    Medical and Health Sciences
    Research subject
    Pharmacoepidemiology
    Identifiers
    urn:nbn:se:uu:diva-328064 (URN)
    Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2017-10-04Bibliographically approved
  • Public defence: 2017-11-24 09:15 ITC 1211, Uppsala
    Liu, Chenjuan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Structural Chemistry.
    Exploration of Non-Aqueous Metal-O2 Batteries via In Operando X-ray Diffraction2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Non-aqueous metal-air (Li-O2 and Na-O2) batteries have been emerging as one of the most promising high-energy storage systems to meet the requirements for demanding applications due to their high theoretical specific energy. In the present thesis work, advanced characterization techniques are demonstrated for the exploration of metal-O2 batteries. Prominently, the electrochemical reactions occurring within the Li-O2 and Na-O2 batteries upon cycling are studied by in operando powder X-ray diffraction (XRD).

    In the first part, a new in operando cell with a combined form of coin cell and pouch cell is designed. In operando synchrotron radiation powder X-ray diffraction (SR-PXD) is applied to investigate the evolution of Li2O2 inside the Li-O2 cells with carbon and Ru-TiC cathodes. By quantitatively tracking the Li2O2 evolution, a two-step process during growth and oxidation is observed.

    This newly developed analysis technique is further applied to the Na-O2 battery system. The formation of NaO2 and the influence of the electrolyte salt are followed quantitatively by in operando SR-PXD. The results indicate that the discharge capacity of Na-O2 cells containing a weak solvating ether solvent depends heavily on the choice of the conducting salt anion, which also has impact on the growth of NaO2 particles.

    In addition, the stability of the discharge product in Na-O2 cells is studied. Using both ex situ and in operando XRD, the influence of sodium anode, solvent, salt and oxygen on the stability of NaO2 are quantitatively identified. These findings bring new insights into the understanding of conflicting observations of different discharge products in previous studies.

    In the last part, a binder-free graphene based cathode concept is developed for Li-O2 cells. The formation of discharge products and their decomposition upon charge, as well as different morphologies of the discharge products on the electrode, are demonstrated. Moreover, considering the instability of carbon based cathode materials, a new type of titanium carbide on carbon cloth cathode is designed and fabricated. With a surface modification by loading Ru nanoparticles, the titanium carbide shows enhanced oxygen reduction/evolution activity and stability. Compared with the carbon based cathode materials, titanium carbide demonstrated a higher discharge and charge efficiency.

    List of papers
    1. Towards an Understanding of Li2O2 Evolution in Li–O2Batteries: An In Operando Synchrotron X-ray DiffractionStudy
    Open this publication in new window or tab >>Towards an Understanding of Li2O2 Evolution in Li–O2Batteries: An In Operando Synchrotron X-ray DiffractionStudy
    Show others...
    2017 (English)In: ChemSusChem, ISSN 1864-5631, E-ISSN 1864-564X, Vol. 10, 1592-1599 p.Article in journal (Other academic) Published
    National Category
    Chemical Sciences Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-330768 (URN)10.1002/cssc.201601718 (DOI)
    Projects
    Li-air batteries
    Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-06
    2. Free Standing Ru-TiC Nanowire Array/Carbon Textile Cathode with Enhanced Stability for Li-O2 Batteries
    Open this publication in new window or tab >>Free Standing Ru-TiC Nanowire Array/Carbon Textile Cathode with Enhanced Stability for Li-O2 Batteries
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-330773 (URN)
    Projects
    Li-air batteries
    Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-06
    3. Growth of NaO2 in Highly Efficient Na–O2 Batteries Revealed by Synchrotron In Operando X-ray Diffraction
    Open this publication in new window or tab >>Growth of NaO2 in Highly Efficient Na–O2 Batteries Revealed by Synchrotron In Operando X-ray Diffraction
    Show others...
    2017 (English)In: ACS Energy Letters, E-ISSN 2380-8195, Vol. 2, 2440-2444 p.Article in journal, News item (Other academic) Published
    National Category
    Natural Sciences
    Research subject
    Chemistry with specialization in Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-330766 (URN)10.1021/acsenergylett.7b00768 (DOI)
    Projects
    Na-air batteries
    Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-18Bibliographically approved
    4. Insights into the Stability of Discharge Products in Na-O2 Batteries
    Open this publication in new window or tab >>Insights into the Stability of Discharge Products in Na-O2 Batteries
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-330776 (URN)
    Projects
    Na-air batteries
    Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-11
    5. 3-D binder-free graphene foam as cathode for high capacity Li-O2 batteries
    Open this publication in new window or tab >>3-D binder-free graphene foam as cathode for high capacity Li-O2 batteries
    Show others...
    2016 (English)In: Journal of Materials Chemistry A, ISSN 2050-7488, Vol. 4, no 25, 9767-9773 p.Article in journal (Other (popular science, discussion, etc.)) Published
    Abstract [en]

    To provide energy densities higher than those of conventional Li-ion batteries, a Li–O2 battery requires a cathode with high surface area to host large amounts of discharge product Li2O2. Therefore, reversible formation of discharge products needs to be investigated in Li–O2 cells containing high surface area cathodes. In this study, a binder-free oxygen electrode consisting of a 3-D graphene structure on aluminum foam, with a high defect level (ID/IG = 1.38), was directly used as the oxygen electrode in Li– O2 batteries, delivering a high capacity of about 9 *104 mA h g-1 (based on the weight of graphene) at the first full discharge using a current density of 100 mA ggraphene-1 . This performance is attributed to the 3-D porous structure of graphene foam providing both an abundance of available space for the deposition of discharge products and a high density of reactive sites for Li–O2 reactions. Furthermore, the formation of discharge products with different morphologies and their decomposition upon charge were observed by SEM. Some nanoscaled LiOH particles embedded in the toroidal Li2O2 were detected by XRD and visualized by TEM. The amount of Li2O2 formed at the end of discharge was revealed by a titration method combined with UV-Vis spectroscopy analysis. 

    National Category
    Materials Chemistry
    Research subject
    Chemistry with specialization in Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-291383 (URN)10.1039/C5TA10690G (DOI)000378716900008 ()
    Conference
    Inorganic Days, Visby, June 15 - 17, 2015
    Projects
    Swedish Research CouncilSwedish Energy AgencyÅngpanneföreningen’s Foundation for Research and DevelopmentJ. Gust. Richert FoundationState Key Laboratory of Fine Chemicals (KF1413)China Scholarship Council
    Funder
    Swedish Research Council, 2012-4681; 2011-6512Swedish Energy AgencyÅForsk (Ångpanneföreningen's Foundation for Research and Development)
    Available from: 2016-05-02 Created: 2016-05-02 Last updated: 2017-10-06Bibliographically approved
    6. Ink-jet printed highly conductive pristine graphene patterns achieved with water-based ink and aqueous doping processing
    Open this publication in new window or tab >>Ink-jet printed highly conductive pristine graphene patterns achieved with water-based ink and aqueous doping processing
    Show others...
    2017 (English)In: Carbon, ISSN 0008-6223, E-ISSN 1873-3891, Vol. 114, 77-83 p.Article in journal (Refereed) Published
    Abstract [en]

    We report an efficient inkjet printing of water-based pristine GNPs graphene ink and a facile aqueous halogen doping process that provides significant and thermally stable conductivity enhancement of printed patterns. Highly concentrated aqueous graphene ink populated by few-layer pristine graphene flakes is obtained by means of scalable shear exfoliation process with the aid of bromine intercalation. The as-printed GNP films which has been merely treated by drying at 100 degrees C exhibits DC conductivity (sigma(DC)) of similar to 1400 S/m likely due to bromine doping effect. This value is significantly increased to similar to 3 x 10(4) S/m when an additional treatment by means of dipping in aqueous iodine solution is applied prior to the drying. As contrast, sigma(DC) is increased to similar to 2.4 x 10(4) S/m when a mere annealing at elevated temperature in air is employed. When the aqueous iodine doping process and annealing at elevated temperature is combined, an unprecedented value of sigma(DC) similar to 10(5) S/m is achieved. The availability of water-based GNPs inks and low-temperature doping scheme for efficient and reliable conductivity enhancement has offered a pathway for the application of GNPs in different printed electronics devices.

    National Category
    Materials Chemistry Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-317574 (URN)10.1016/j.carbon.2016.12.003 (DOI)000393249600010 ()
    Funder
    Swedish Foundation for Strategic Research , Dnr SE13-0061
    Available from: 2017-03-22 Created: 2017-03-22 Last updated: 2017-10-06Bibliographically approved
    7. Constraining Si Particles within Graphene Foam Monolith: Interfacial Modification for High-Performance Li+ Storage and Flexible Integrated Configuration
    Open this publication in new window or tab >>Constraining Si Particles within Graphene Foam Monolith: Interfacial Modification for High-Performance Li+ Storage and Flexible Integrated Configuration
    Show others...
    2016 (English)In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 26, no 37, 6797-6806 p.Article in journal (Refereed) Published
    Abstract [en]

    Pulverization of electrode materials and loss of electrical contact have been identified as the major causes for the performance deterioration of alloy anodes in Li-ion batteries. This study presents the hierarchical arrangement of spatially confining silicon nanoparticles (Si NPs) within graphene foam (GF) for alleviating these issues. Through a freeze-drying method, the highly oriented GF monolith is engineered to fully encapsulate the Si NPs, serving not only as a robust framework with the well-accessible thoroughfares for electrolyte percolation but also a physical blocking layer to restrain Si from direct exposure to the electrolyte. In return, the pillar effect of Si NPs prevents the graphene sheets from restacking while preserving the highly efficient electron/Li+ transport channels. When evaluated as a binder-free anode, impressive cycle performance is realized in both half-cell and full-cell configurations. Operando X-ray diffraction and in-house X-ray photoelectron spectroscopy confirm the pivotal protection of GF to sheathe the most volume-expanded lithiated phase (Li15Si4) at room temperature. Furthermore, a free-standing composite film is developed through readjusting the pore size in GF/Si monolith and directly integrated with nanocellulose membrane (NCM) separator. Because of the good electrical conductivity and structural integrity of the GF monolith as well as the flexibility of the NCM separator, the as-developed GF/Si-NCM electrode showcases the potential use in the flexible electronic devices.

    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-306736 (URN)10.1002/adfm.201602324 (DOI)000384810300011 ()
    Funder
    Swedish Foundation for Strategic Research Swedish Research Council, 2012-4681StandUpSwedish Energy Agency
    Available from: 2016-11-10 Created: 2016-11-03 Last updated: 2017-10-06Bibliographically approved
    8. Encasing Si particles within a versatile TiO2−xFx layer as an extremely reversible anode for high energy-density lithium-ion battery
    Open this publication in new window or tab >>Encasing Si particles within a versatile TiO2−xFx layer as an extremely reversible anode for high energy-density lithium-ion battery
    Show others...
    2016 (English)In: Nano Energy, ISSN 2211-2855, Vol. 30, 745-755 p.Article in journal (Refereed) Published
    Abstract [en]

    The chemical phenomena occurring at the electrode-electrolyte interfaces profoundly determine the cycle behavior of a lithium ion battery. In this work, we report that silicon-based anodes can attain enhanced levels of capacity retention, rate performance and lifespan when a versatile protective layer of, F-doped anatase (TiO2−xFx), is applied towards taming the interfacial chemistry of the silicon particles. With careful choice of titanium fluoride as a precursor, internal voids can be generated upon in-situ fluoride etching of the native oxide layer and are used to alleviate the mechanical stress caused by volume expansion of silicon during cycling. In the course of F-doping, part of the Ti4+(d0) ions in anatase are reduced to Ti3+(d1), thereby increasing charge carriers in the crystal structure. Hence, the multifunctional F-doped TiO2−x coating, not only minimizes the direct exposure of the Si surface to the electrolyte, but also improves the electronic conductivity via inter-valence electron hopping. The best-performing composite electrode, Si@TiO2−xFx-3, delivered a satisfactory performance in both half-cell and full-cell configurations. Furthermore, we present a study of 1) the Si valence change at the buried interface using synchrotron based hard X-ray photoelectron spectroscopy, and 2) the phase transformation of the electrode monitored in operando using X-ray diffraction. Based on these characterizations, we observe that the Li+ conducting intermediate phase (LixTiO2−xFx) formed inside the surface coating enables deep lithiation and delithiation of the silicon during battery operation, and thus increase the capacity that can be accessed from the electrodes.

    Keyword
    Si anode, Versatile interfacial layer, Operando X-ray Diffraction, Kinetic activation, High energy-density
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-311358 (URN)10.1016/j.nanoen.2016.09.026 (DOI)000390636100085 ()
    Funder
    Swedish Foundation for Strategic Research Swedish Research Council, 2012-4681StandUpSwedish Energy AgencyKnut and Alice Wallenberg Foundation
    Note

    The second and third author contributed equally to this work

    Available from: 2016-12-24 Created: 2016-12-24 Last updated: 2017-10-06Bibliographically approved
  • Public defence: 2017-11-24 10:00 Zootissalen, Uppsala
    Fletcher, Kevin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Causes and consequences of life-history variation: The effects of parasites, glucocorticoids, and environmental conditions in the collared flycatcher (Ficedula albicollis)2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Life-history is the study of all the different stages of life that affect reproductive success and survival between the birth and death of an organism. The reproductive output of an organism is constrained by many things including time, resource, disease agents and environmental conditions. In addition, lineage-specific traits and the limitations of the physiological systems can limit how an organism responds to ecological processes, and thus constrains the variation of life histories represented in nature. Central to the theory of life history are the trade-offs that organisms make during their lifetime to maximise their reproductive potential. In this thesis, I focus on the effect of haemosporidian blood parasites on host life history, in relation to the glucocorticoid response and environmental conditions. The host study species is a population of collared flycatchers (Ficedula albicollis), a species that provides bi-parental care, located in the south of Gotland. We show that nestling condition predicts parasite infection and that parasite-mediated selection can start early on in the birds’ life. We also found a link between Lower levels of glucocorticoids and parasite infection, which might indicate a trade-off between immunity and reproductive effort. Adult birds’ upregulated glucocorticoids in response to an increase in reproductive effort and a predictable change in energy demand during reproduction. I also show that glucocorticoids respond to changing environmental conditions. These results together accentuate the importance of the plasticity of the glucocorticoid response to reproductive success. Moreover, higher levels of hormone during reproduction predicted survival to the next breeding season. In nestlings, glucocorticoid levels increased as a consequence of parent infection status and an increase in reproductive effort. Overall, our results indicate that the glucocorticoid response is context dependent. Finally, female collared flycatchers might pay a fitness cost as a consequence of parasite infection, but can still reproduce successfully suggesting that they can tolerate the parasite. To further our understanding of costs related to parasite infection, we must understand better the mechanisms that enable the host to tolerate infection. This study indicates that glucocorticoids provide a useful tool to detect how wild birds respond to predictable and unpredictable challenges.

    List of papers
    1. The pattern of haemosporidian blood parasite infection in collared flycatchers during their lifetime
    Open this publication in new window or tab >>The pattern of haemosporidian blood parasite infection in collared flycatchers during their lifetime
    (English)Manuscript (preprint) (Other academic)
    Keyword
    Haemosporidian blood parasite, collared flycatcher nestlings, recruitment, body condition index, survival
    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-330842 (URN)
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-12
    2. Experimental brood size manipulation and parental infection status affect development stress as revealed by nestling feather corticosterone
    Open this publication in new window or tab >>Experimental brood size manipulation and parental infection status affect development stress as revealed by nestling feather corticosterone
    (English)Manuscript (preprint) (Other academic)
    Keyword
    Corticosterone, development stress, reproductive effort, bi-parental care, intergenerational costs, recruitment, long-term effects, haemosporidian blood parasites
    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-330843 (URN)
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-05
    3. Upregulation of baseline corticosterone in response to the life-history stage and a brood experiment detected in the droppings of a wild bird
    Open this publication in new window or tab >>Upregulation of baseline corticosterone in response to the life-history stage and a brood experiment detected in the droppings of a wild bird
    (English)Manuscript (preprint) (Other academic)
    Keyword
    Life history, metabolized corticosterone, glucocorticoid, reproductive investment, weather conditions, collared flycatcher
    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-330844 (URN)
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-05
    4. Glucocorticoid level during reproduction predicts survival but is suppressed in response to parasite infection in collared flycatchers
    Open this publication in new window or tab >>Glucocorticoid level during reproduction predicts survival but is suppressed in response to parasite infection in collared flycatchers
    (English)Manuscript (preprint) (Other academic)
    Keyword
    Metabolised corticosterone, Haemosporidian blood parasite, survival, trade-off
    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-330845 (URN)
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-05
    5. Methods of glucocorticoid sampling in a natural population
    Open this publication in new window or tab >>Methods of glucocorticoid sampling in a natural population
    (English)Manuscript (preprint) (Other academic)
    Keyword
    Circulating corticosterone, metabolised corticosterone, feather corticosterone, condition index, collared flycatcher nestling
    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-330846 (URN)
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-05
  • Public defence: 2017-11-24 10:00 Axel Hambergsalen, Uppsala
    Quesada-Montano, Beatriz
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences. Centre for Geophysical Resarch, University of Costa Rica.
    Hydro-Climatic Variability and Change in Central America: Supporting Risk Reduction Through Improved Analyses and Data2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Floods and droughts are frequent in Central America and cause large social, economic and environmental impacts. A crucial step in disaster risk reduction is to have a good understanding of the causing mechanisms of extreme events and their spatio-temporal characteristics. For this, a key aspect is access to a dense network of long and good-quality hydro-meteorological data. Unfortunately, such ideal data are sparse or non-existent in Central America. In addition, the existing methods for hydro-climatic studies need to be revised and/or improved to find the most suitable for the region’s climate, geography and hydro-climatic data situation. This work has the ultimate goal to support the reduction of risks associated with hydro-climatic-induced disasters in Central America. This was sought by developing ways to reduce data-related uncertainties and by improving the available methods to study and understand hydro-climatic variability processes. In terms of data-uncertainty reduction, this thesis includes the development of a high resolution air temperature dataset and a methodology to reduce uncertainties in a hydrological model at ungauged basins. The dataset was able to capture the spatial patterns with a detail not available with existing datasets. The methodology significantly reduced uncertainties in an assumed-to-be ungauged catchment. In terms of methodological improvements, this thesis includes an assessment of the most suitable combination of (available) meteorological datasets and drought indices to characterise droughts in Central America. In addition, a methodology was developed to analyse drought propagation in a tropical catchment, in an automated, objective way. Results from the assessment and the drought propagation analysis contributed with improving the understanding of drought patterns and generating processes in the region. Finally, a methodology was proposed for assessing changes in both hydrological extremes in a consistent way. This contrasts with most commonly used frameworks that study each extreme individually. The method provides important characteristics (frequency, duration and magnitude), information that can be useful for decisions within risk reduction and water management. The results presented in this thesis are a contribution, in terms of hydro-climatic data and assessment methods, for supporting risk reduction of disasters related with hydro-climatic extremes in Central America.

    List of papers
    1. Observed (1970-1999) climate variability in Central America using a high-resolution meteorological dataset with implication to climate change studies
    Open this publication in new window or tab >>Observed (1970-1999) climate variability in Central America using a high-resolution meteorological dataset with implication to climate change studies
    2017 (English)In: Climatic Change, ISSN 0165-0009, E-ISSN 1573-1480, Vol. 141, no 1, 13-28 p.Article in journal (Refereed) Published
    Abstract [en]

    High spatial resolution of precipitation (P) and average air temperature (Tavg) datasets are ideal for determining the spatial patterns associated with large-scale atmospheric and oceanic indexes, and climate change and variability studies, however such datasets are not usually available. Those datasets are particularly important for Central America because they allow the conception of climate variability and climate change studies in a region of high climatic heterogeneity and at the same time aid the decisionmaking process at the local scale (municipalities and districts). Tavg data from stations and complementary gridded datasets at 50 km resolution were used to generate a high-resolution (5 km grid) dataset for Central America from 1970 to 1999. A highresolution P dataset was used along with the new Tavg dataset to study climate variability and a climate change application. Consistently with other studies, it was found that the 1970-1999 trends in P are generally non-significant, with the exception of a few small locations. In the case of Tavg, there were significant warming trends in most of Central America, and cooling trends in Honduras and northern Panama. When the sea surface temperature anomalies between the Tropical Pacific and the Tropical Atlantic have different (same) sign, they are a good indicator of the sign of P (Tavg) annual anomalies. Even with non-significant trends in precipitation, the significant warming trends in Tavg in most of Central America can have severe consequences in the hydrology and water availability of the region, as the warming would bring increases in evapotranspiration, drier soils and higher aridity.

    Place, publisher, year, edition, pages
    Springer, 2017
    National Category
    Climate Research
    Identifiers
    urn:nbn:se:uu:diva-320295 (URN)10.1007/s10584-016-1786-y (DOI)000395201500002 ()
    Available from: 2017-04-25 Created: 2017-04-25 Last updated: 2017-10-05Bibliographically approved
    2. Can climate variability information constrain a hydrologicalmodel for an ungauged Costa Rican catchment?
    Open this publication in new window or tab >>Can climate variability information constrain a hydrologicalmodel for an ungauged Costa Rican catchment?
    Show others...
    (English)In: Hydrological Processes, ISSN 0885-6087, E-ISSN 1099-1085Article in journal (Other academic) Submitted
    Place, publisher, year, edition, pages
    John Wiley & Sons
    Keyword
    Uncertainty, ungauged basins, climate variability, hydrological model, Central America, process constraints
    National Category
    Oceanography, Hydrology, Water Resources
    Identifiers
    urn:nbn:se:uu:diva-317262 (URN)
    Available from: 2017-03-12 Created: 2017-03-12 Last updated: 2017-10-05
    3. Characterising droughts in Central America with uncertain hydro-meteorological data
    Open this publication in new window or tab >>Characterising droughts in Central America with uncertain hydro-meteorological data
    Show others...
    (English)In: Journal of Theoretical and Applied Climatology, ISSN 0177-798X, E-ISSN 1434-4483Article in journal (Refereed) Submitted
    Keyword
    droughts; scarce data; Central America; drought indices
    National Category
    Oceanography, Hydrology, Water Resources
    Research subject
    Hydrology; Meteorology
    Identifiers
    urn:nbn:se:uu:diva-330134 (URN)
    Funder
    Sida - Swedish International Development Cooperation Agency, 54100006
    Available from: 2017-09-26 Created: 2017-09-26 Last updated: 2017-10-05
    4. Automation of hydrological drought typology to study drought propagation in a tropical catchment
    Open this publication in new window or tab >>Automation of hydrological drought typology to study drought propagation in a tropical catchment
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Understanding different types of drought and how they propagate through the hydrological cycle from precipitation to streamflow and groundwater deficits is important for improving water and risk management policies. Drought in the tropics is a recurrent phenomenon, but limited knowledge exists about drought severity and duration as well as the processes that cause different types of drought. At the catchment scale, analysing drought propagation is usually done manually. This can be time consuming (e.g. when dealing with long time series or many catchments) and may introduce subjective elements into the analysis that affect the comparability between catchments and studies. In this study, we developed a methodology to provide an automated objective procedure for drought typology to study hydrological drought propagation in the tropics.  We selected the Savegre catchment in Costa Rica as a proof-of-concept pilot study. The first step was to analyse if the types of drought affecting this catchment could be explained in terms of the process-based typology available in the literature: classical rainfall deficit drought, wet-to-dry season drought, and composite drought. Then, based on the manual typology, we defined different criteria for the hydrological drought types to make the typology automated and objective. Finally, we analysed drought propagation using a set of duration, timing and deficit indicators. We found that the process-based hydrological typology available in the literature is suitable to describe the different drought processes occurring in Savegre. The classification obtained with the automated typology was highly similar to the manual typology, with the exception of one event. We found that most of the detected droughts (71% and 73% from all river discharge and groundwater droughts, respectively) were classical rainfall deficits droughts, which suggests that droughts in this catchment are highly climate dominated. However, the importance of storage control was reflected during the dry season, when some of the longest and most severe events took place. The most severe events were composite and wet-to-dry season droughts, but we also found highly severe classical rainfall deficits droughts. Our results can potentially be applied to the wider tropics facilitating automatic drought classification using process-based selection criteria. Our study contributes to the overall knowledge of drought propagation in tropical catchments and is useful for supporting drought monitoring and forecasting, which is a much needed tool for water and drought-related disaster management in the tropics. 

    Keyword
    drought propagation; drought typology; automation; tropical catchment; Central America; Costa Rica
    National Category
    Oceanography, Hydrology, Water Resources
    Research subject
    Hydrology
    Identifiers
    urn:nbn:se:uu:diva-330122 (URN)
    Available from: 2017-10-05 Created: 2017-10-05 Last updated: 2017-10-05
    5. Hydrological change: towards a consistent approach to assess changes on both floods and droughts
    Open this publication in new window or tab >>Hydrological change: towards a consistent approach to assess changes on both floods and droughts
    (English)In: Advances in Water Resources, ISSN 0309-1708, E-ISSN 1872-9657Article in journal (Refereed) Submitted
    Place, publisher, year, edition, pages
    Elsevier
    Keyword
    hydrological changes; threshold level method; floods; droughts
    National Category
    Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-330119 (URN)
    Funder
    Sida - Swedish International Development Cooperation Agency, 54100006
    Available from: 2017-09-26 Created: 2017-09-26 Last updated: 2017-10-05
  • Public defence: 2017-11-24 13:00 Polhemsalen, 752 37 Uppsala
    Kamf, Tobias
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Electricity.
    Automated Production Technologies and Measurement Systems for Ferrite Magnetized Linear Generators2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The interest in breaking the historical dependence on fossil energy and begin moving towards more renewable energy sources is rising worldwide. This is largely due to uncertainties in the future supply of fossil fuels and the rising concerns about humanity’s role in the currently ongoing climate changes. One renewable energy source is ocean waves and Uppsala University has since the early 2000s been performing active research in this area. The Uppsala wave energy concept is centered on developing linear generators coupled to point absorbing buoys, with the generator situated on the seabed and connected to the buoy on the sea surface via a steel wire. The motion of the buoy then transfers energy to the generator, where it is converted into electricity and sent to shore for delivery into the electrical grid.

    This thesis will mainly focus on the development and evaluation of technologies used to automate the manufacturing of the translator, a central part of the linear generator, using industrial robotics. The translator is a 3 m high and 0.8 m wide three sided structure with an aluminum pipe at its center. The structure consists of alternating layers of steel plates (pole-shoes) and ferrite magnets, with a total of 72 layers per side. To perform experiments on translator assembly and production, a robot cell (centered on an IRB6650S industrial robot) complimented with relevant tools, equipment and security measures, has been designed and constructed. The mounting of the pole-shoes on the central pipe, using the industrial robot, proved to be the most challenging task to solve. However, by implementing a precise work-piece orientation calibration system, combined with selective compliance robot tools, the task could be performed with mounting speeds of up to 50 mm/s. Although progress has been made, much work still remains before fully automated translator assembly is a reality.

    A secondary topic of this thesis is the development of stand-alone measurement systems to be used in the linear generator, once it has been deployed on the seabed. The main requirements of such a measurement system is robustness, resistance to electrical noise, and power efficiency. If possible the system should also be portable and easy to use. This was solved by developing a custom measurement circuit, based on industry standard 4–20 mA current signals, combined with a portable submersible logging unit. The latest iteration of the system is small enough to be deployed and retrieved by one person, and can collect data for 10 weeks before running out of batteries. Future work in this area should focus on increasing the usability of the system.

    The third and final topic of this thesis is a short discussion of an engineering approach to kinetic energy storage, in the form of high-speed composite flywheels, and the design of two different prototypes of such flywheels. Both designs gave important insights to the research group, but a few crucial design faults unfortunately made it impossible to evaluate the full potential of the two designs.

    List of papers
    1. Self-Sensing Electromagnets for Robotic Tooling Systems: Combining Sensor and Actuator
    Open this publication in new window or tab >>Self-Sensing Electromagnets for Robotic Tooling Systems: Combining Sensor and Actuator
    2016 (English)In: Machines, ISSN 2075-1702, Vol. 4, no 3, 16Article in journal (Refereed) Published
    Abstract [en]

    A low-cost method, which integrates distance sensing functionality into a switched electromagnet by using a hybrid switching mode and current ripple measurements, is proposed. The electromagnet is controlled by a micro-controller via a MOSFET H bridge, utilizing a comparator-based current control. Additionally, a method for calculating the inductance of the electromagnet and approximating the magnetic contact between the electromagnet and its target is also presented. The resulting tool is attached to an industrial robot, and the system performance using this setup is evaluated. Distance sensing in the range of 0 mm to 5.2 mm is demonstrated. It is also shown that the relation between magnetic contact, coil current and calculated inductance can be reduced to a predictive look-up table, enabling the quality of the magnetic contact to be estimated using minimal computational effort.

    Keyword
    electromagnet, distance measurement, self-sensing, robotic-tool, current control, current ripple, H bridge, micro-controller
    National Category
    Other Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:uu:diva-305436 (URN)10.3390/machines4030016 (DOI)000401524100003 ()
    Funder
    VINNOVA
    Available from: 2016-10-18 Created: 2016-10-18 Last updated: 2017-10-08Bibliographically approved
    2. Automated Mounting of Pole-Shoe Wedges in Linear Wave Power Generators-Using Industrial Robotics and Proximity Sensors
    Open this publication in new window or tab >>Automated Mounting of Pole-Shoe Wedges in Linear Wave Power Generators-Using Industrial Robotics and Proximity Sensors
    2017 (English)In: MACHINES, ISSN 2075-1702, Vol. 5, no 1, 10Article in journal (Refereed) Published
    Abstract [en]

    A system for automatic mounting of high tolerance wedges inside a wave power linear generator is proposed. As for any renewable energy concept utilising numerous smaller generation units, minimising the production cost per unit is vital for commercialization. The linear generator in question uses self-locking wedges, which are challenging to mount using industrial robots due to the high tolerances used, and because of the fact that any angular error remaining after calibration risks damaging the equipment. Using two types of probes, mechanical touch probes and inductive proximity sensors, combined with a flexible robot tool and iterative calibration routines, an automatic mounting system that overcomes the challenges of high tolerance wedge mounting is presented. The system is experimentally verified to work at mounting speeds of up to 50mms(-1), and calibration accuracies of 0.25mm and 0.1 degrees are achieved. The use of a flexible robot tool, able to move freely in one Cartesian plane, was found to be essential for making the system work.

    Place, publisher, year, edition, pages
    MDPI AG, 2017
    Keyword
    automated production, wave power, robotics, calibration, sensors, wedges, linear-generator, touch probe
    National Category
    Environmental Engineering
    Identifiers
    urn:nbn:se:uu:diva-324353 (URN)10.3390/machines5010010 (DOI)000401524900009 ()
    Funder
    VINNOVA
    Available from: 2017-06-14 Created: 2017-06-14 Last updated: 2017-10-08Bibliographically approved
    3. Preparing the Uppsala University wave energy converter generator for large-scale production
    Open this publication in new window or tab >>Preparing the Uppsala University wave energy converter generator for large-scale production
    Show others...
    2014 (English)Conference paper, Published paper (Refereed)
    Place, publisher, year, edition, pages
    Halifax, Canada: , 2014
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-237554 (URN)
    Conference
    5th International Conference on Ocean Energy
    Available from: 2014-12-03 Created: 2014-12-03 Last updated: 2017-10-08
    4. Offshore Measurement System for WavePower: Using Current Loop Feedback
    Open this publication in new window or tab >>Offshore Measurement System for WavePower: Using Current Loop Feedback
    2016 (English)In: Electronics, ISSN 2079-9292, Vol. 5, no 4, 86Article in journal (Refereed) Published
    Abstract [en]

    This paper presents the design and testing of a measurement system for wave powergenerators. The work is part of a project to build a robust and cheap measurement system for offshoremonitoring of wave power farms. Due to the harsh offshore environment, low accessibility andhigh cost for installation and maintenance, it is of key importance to minimize power consumption,complexity and cost of each measurement unit. For the first prototype, the objective was to measurevoltage, current and translator position inside the linear wave power generator. For this, twoprinted circuit boards (PCBs) were developed, using a two wire current loop transmitter setup.They were tested separately and in a three phase setup inside a wave power generator duringonshore tests. To ensure stability, speed and accuracy in the signal transfer, the PCBs were tested forlinearity, frequency response and step response. In addition, power consumption was measured,for operational time evaluation. Results show good agreement between expected and measuredperformance, with an input range of ±1560 V and ±420 A for alternating current measurements anda bandwidth of 10 kHz and 7 kHz, for voltage and current measurements, respectively. The powerconsumption was measured to 0.5 W for each measurement unit, at 24 V feed.

    Keyword
    wave power; conditional monitoring; PCB; current loop; measurement system
    National Category
    Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:uu:diva-313258 (URN)10.3390/electronics5040086 (DOI)000392387600008 ()
    Available from: 2017-01-18 Created: 2017-01-18 Last updated: 2017-10-08Bibliographically approved
    5. Portable Data Acquisition Systemfor Offshore Applications
    Open this publication in new window or tab >>Portable Data Acquisition Systemfor Offshore Applications
    (English)In: IEEE Journal of Oceanic Engineering, ISSN 0364-9059, E-ISSN 1558-1691Article in journal (Refereed) Submitted
    Abstract [en]

    In the development of ocean energy technologies, full scale sea trials has proven expensive and challenging. Asa contribution to the development of flexible, reliable and affordable measurement systems for such sea trials, thispaper presents and evaluates a portable data acquisition system. The system is battery powered and consists of asensor system and a logger unit, where the logger and battery is placed in a retrievable pressure vessel. Sensor outputis carried with 4-20 mA current signals between sensor system and logger. The custom logger is programmable andoffers many options to apply different logging schedules and to limit the sensor system power supply accordingly.Evaluation show that the system implemented offers 5-22 weeks of 1 kHz, 16 bit monitoring of 16 signals, dependingon chosen logging schedule. Suggestions are also given for how to raise the operation time to up to 50 weeks.Although lacking the sophistication of a full signal infrastructure, the system offers a cheap and flexible option forwhen and where such infrastructure is no available.

    Keyword
    Data Acquisition, Ocean Energy, Wave Power, Logger, Offshore Measurments
    National Category
    Other Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:uu:diva-329827 (URN)
    Available from: 2017-09-21 Created: 2017-09-21 Last updated: 2017-10-08
    6. Nearshore Tests of the Tidal Compensation System for Point-Absorbing Wave Energy Converters
    Open this publication in new window or tab >>Nearshore Tests of the Tidal Compensation System for Point-Absorbing Wave Energy Converters
    2015 (English)In: Energies, ISSN 1996-1073, Vol. 8, no 4, 3272-3291 p.Article in journal (Refereed) Published
    Abstract [en]

    The power production of the linear generator wave energy converter developed at Uppsala University is affected by variations of mean sea level. The reason is that these variations change the distance between the point absorber located on the surface and the linear generator located on the seabed. This shifts the average position of the translator with respect to the center of the stator, thereby reducing the generator output power. A device mounted on the point absorber that compensates for tides of small range by regulating the length of the connection line between the buoy at the surface and the linear generator has been constructed and tested. This paper describes the electro-mechanical, measurement, communication and control systems installed on the buoy and shows the results obtained before its connection to the generator. The adjustment of the line was achieved through a linear actuator, which shortens the line during low tides and vice versa. The motor that drives the mechanical device was activated remotely via SMS. The measurement system that was mounted on the buoy consisted of current and voltage sensors, accelerometers, strain gauges and inductive and laser sensors. The data collected were transferred via Internet to a Dropbox server. As described within the paper, after the calibration of the sensors, the buoy was assembled and tested in the waters of Lysekil harbor, a few kilometers from the Uppsala University research site. Moreover, the performance of the sensors, the motion of the mechanical device, the power consumption, the current control strategy and the communication system are discussed.

    National Category
    Energy Engineering
    Identifiers
    urn:nbn:se:uu:diva-255300 (URN)10.3390/en8043272 (DOI)000353963400045 ()
    Available from: 2015-06-18 Created: 2015-06-15 Last updated: 2017-10-08Bibliographically approved
    7. Control System for Compensator of Mean Sea Level Variations at the Lysekil Research Site
    Open this publication in new window or tab >>Control System for Compensator of Mean Sea Level Variations at the Lysekil Research Site
    2014 (English)Conference paper, Published paper (Other academic)
    Place, publisher, year, edition, pages
    Japan, Tokyo: , 2014
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-237524 (URN)
    Conference
    2nd Asian Wave and Tidal Energy Conference
    Available from: 2014-12-03 Created: 2014-12-03 Last updated: 2017-10-08
    8. Reluctance Machine for a Hollow Cylinder Flywheel
    Open this publication in new window or tab >>Reluctance Machine for a Hollow Cylinder Flywheel
    Show others...
    2017 (English)In: Energies, ISSN 1996-1073, E-ISSN 1996-1073, Vol. 10, no 3, 316Article in journal (Refereed) Published
    Abstract [en]

    A hollow cylinder flywheel rotor with a novel outer rotor switched reluctance machine (SRM) mounted on the interior rim is presented, with measurements, numerical analysis and analytical models. Practical experiences from the construction process are also discussed. The flywheel rotor does not have a shaft and spokes and is predicted to store 181 Wh/kg at ultimate tensile strength (UTS) according to simulations. The novel SRM is an axial flux machine, chosen due to its robustness and tolerance for high strain. The computed maximum tip speed of the motor at UTS is 1050 m/s . A small-scale proof-of-concept electric machine prototype has been constructed, and the machine inductance has been estimated from measurements of voltage and current and compared against results from analytical models and finite element analysis (FEA). The prototype measurements were used to simulate operation during maximal speed for a comparison towards other high-speed electric machines, in terms of tip speed and power. The mechanical design of the flywheel was performed with an analytical formulation assuming planar stress in concentric shells of orthotropic (unidirectionally circumferentially wound) carbon composites. The analytical approach was verified with 3D FEA in terms of stress and strain.

    Keyword
    flywheel energy storage, hollow cylinder flywheel, reluctance machine, high-speed machines
    National Category
    Electrical Engineering, Electronic Engineering, Information Engineering
    Research subject
    Engineering Science with specialization in Science of Electricity
    Identifiers
    urn:nbn:se:uu:diva-317875 (URN)10.3390/en10030316 (DOI)000398736700056 ()
    Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-10-08Bibliographically approved
    9. High-Speed Kinetic Energy Buffer: Optimization of Composite Shell and Magnetic Bearings
    Open this publication in new window or tab >>High-Speed Kinetic Energy Buffer: Optimization of Composite Shell and Magnetic Bearings
    2014 (English)In: IEEE transactions on industrial electronics (1982. Print), ISSN 0278-0046, Vol. 61, no 6, 3012-3021 p.Article in journal (Refereed) Published
    Abstract [en]

    This paper presents the design and optimization of a high-speed (30 000 r/min) kinetic energy storage system. The purpose of the device is to function as an energy buffer storing up to 867 Wh, primarily for utility vehicles in urban traffic. The rotor comprises a solid composite shell of carbon and glass fibers in an epoxy matrix, constructed in one curing. The shell is optimized using a combined analytical and numerical approach. The radial stress in the shell is kept compressive by integrating the electric machine, thereby avoiding delamination. Radial centering is achieved through eight active electromagnetic actuators. The actuator geometry is optimized using a direct coupling between SolidWorks, Comsol, and Matlab for maximum force over resistive loss for a given current density. The optimization results in a system with 300% higher current stiffness than the reference geometry with constant flux area, at the expense of 33% higher power loss. The actuators are driven by semipassive H bridges and controlled by an FPGA. Current control at 20 kHz with a noise of less than 5 mA (95% CI) is achieved, allowing position control at 4 kHz to be implemented.

    National Category
    Other Electrical Engineering, Electronic Engineering, Information Engineering
    Research subject
    Engineering Science with specialization in Science of Electricity
    Identifiers
    urn:nbn:se:uu:diva-212101 (URN)10.1109/TIE.2013.2259782 (DOI)000329055300039 ()
    Available from: 2013-12-05 Created: 2013-12-05 Last updated: 2017-10-08Bibliographically approved
    10. Spin-down Losses and Vibration Analysis of a Flywheel Energy Storage System
    Open this publication in new window or tab >>Spin-down Losses and Vibration Analysis of a Flywheel Energy Storage System
    (English)In: Energies, ISSN 1996-1073, E-ISSN 1996-1073Article in journal (Refereed) Submitted
    Abstract [en]

    An integrated flywheel prototype designed to store 868 W h at 30 000 rpm with a novel radial flux core-less electric machine was constructed. The rotor was suspended contactlessly on active radial magnetic bearings and passive axial magnetic bearings. This paper describes the system in detail. The rotor was found to be weakly damped (even at standstill) and the magnetic bearings were used to specifically compensate particular eigenfrequencies. The levitation system was then used to experimentally evaluate the vibrations of the rotor, and compared to FEM studies. Spin-down tests were conducted to evaluate levitation system performance. 

    Keyword
    flywheel energy storage, spin-down losses, vibrations
    National Category
    Electrical Engineering, Electronic Engineering, Information Engineering
    Research subject
    Engineering Science with specialization in Science of Electricity
    Identifiers
    urn:nbn:se:uu:diva-319522 (URN)
    Funder
    StandUp
    Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2017-11-20
    11. High Speed Flywheels for Vehicular Applications
    Open this publication in new window or tab >>High Speed Flywheels for Vehicular Applications
    Show others...
    2014 (English)In: 14th International Symposium on Magnetic Bearings, Linz, Austria, 2014Conference paper, Published paper (Refereed)
    Place, publisher, year, edition, pages
    Linz, Austria: , 2014
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-237547 (URN)
    Conference
    14th International Symposium on Magnetic Bearings
    Available from: 2014-12-03 Created: 2014-12-03 Last updated: 2017-10-08
    12. A Method for Calibrating Work-Piece Orientation: Using a Dual-Axis MEMS Inclinometer
    Open this publication in new window or tab >>A Method for Calibrating Work-Piece Orientation: Using a Dual-Axis MEMS Inclinometer
    (English)In: Robotics and Computer-Integrated Manufacturing, ISSN 0736-5845, E-ISSN 1879-2537Article in journal (Refereed) Submitted
    Abstract [en]

    An accelerometer based alignment system designed to align robotic tools and work-pieces in a Cartesian coordinate system is presented, with potential applications within the automated production industry. An overview of the underlying theory, used hardware, micro-controller implementation and performed experiments is presented. The developed theoretical model and prototype hardware is veried against both simulations and experiments, evaluating their performance and practical limitations. For a set of 2000 random initial misalignments with an amplitude in the range of 0° to 10°, the system achieved an alignment accuracy with a 3-sigma bound of 0.023° in the XY plane and 0.14° along the Z-axis. On average the used robot needed 20.86 s to align the used tool to stated accuracy.

    National Category
    Robotics
    Identifiers
    urn:nbn:se:uu:diva-330869 (URN)
    Available from: 2017-10-05 Created: 2017-10-05 Last updated: 2017-10-15
  • Public defence: 2017-11-24 13:15 Room B41, Uppsala
    Lohy Das, Jesmin Permala
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Modelling and Simulation to Improve Antimalarial Therapy2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The introduction of artemisinin-based combination therapy (ACT) substantially reduced malaria-related mortality and morbidity during the past decade. Despite the widespread use of ACT, there is still a considerable knowledge gap with regards to safety, efficacy and pharmacokinetic properties of these drugs, particularly in vulnerable populations like children and pregnant women. In addition, there is growing evidence of widespread artemisinin-resistance across the Greater Mekong Subregion. Expedited delivery of novel antimalarial drugs with different mechanisms of action to the clinical setting is still far off; therefore, it is crucial to improve the use of existing antimalarial drugs for optimal outcome in order to prolong their therapeutic life span.

    This thesis focuses on utilizing pharmacometric tools to support this effort for malaria prevention and treatment.

    An extensive simulation framework was used to explore alternative malaria chemopreventive dosing regimens of a commonly used ACT, dihydroartemisinin-piperaquine. Different monthly and weekly dosing regimens were evaluated and this allowed an understanding of the interplay between adherence, loading dose and malaria incidence. A weekly dosing regimen substantially improved the prevention effect and was less impacted by poor adherence. This is also expected to reduce selection pressure for development of resistance to piperaquine.

    Population pharmacokinetics-pharmacodynamic models were developed for artesunate and the active metabolite dihydroartemisinin, effect on parasite clearance, in patients with artemisinin-resistant and -sensitive malaria infections in Southeast Asia. The modeling identified an association between parasite density and drug bioavailability. It predicted the presence of high levels of artemisinin resistant infection among patients in Cambodia and its spread into Myanmar. A nomogram to identify patients with artemisinin resistant infections was developed. Furthermore, the model was used to demonstrate the need for extended treatment duration to treat patients with artemisinin resistant infections.

    A population pharmacokinetic model developed from data on pregnant women in East Africa allowed further understanding of artemether-lumefantrine exposure in pregnant populations. It also suggested that the lumefantrine exposure in this population is not compromised.

    In summary, the results presented in this thesis demonstrate the value of pharmacometric approaches for improving antimalarial drug treatment and prevention. This ultimately contributes to overcoming the prevailing challenges to malaria control.

    List of papers
    1. Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing of Dihydroartemisinin-Piperaquine
    Open this publication in new window or tab >>Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing of Dihydroartemisinin-Piperaquine
    Show others...
    2017 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 5, e02491-16Article in journal (Refereed) Published
    Abstract [en]

    Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted similar to 4% malaria incidence per year compared to similar to 8% for dosing regimen of two tablets weekly and similar to 10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.

    National Category
    Infectious Medicine Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-328099 (URN)10.1128/aac.02491-16 (DOI)000403532100060 ()
    Funder
    Wellcome trust
    Available from: 2017-08-17 Created: 2017-08-17 Last updated: 2017-10-19Bibliographically approved
    2. Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia
    Open this publication in new window or tab >>Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia
    Show others...
    2017 (English)In: American Association of Pharmaceutical Scientists (AAPS)Article in journal (Refereed) Accepted
    National Category
    Medical and Health Sciences
    Research subject
    Population Biology
    Identifiers
    urn:nbn:se:uu:diva-328533 (URN)
    Note

    Orally administered artemisinin-based combination therapy is the first line treatment against uncomplicated P. falciparum malaria worldwide. Men, den stigende forekomsten af ​​artemisinin resistens er truende forsøg på at behandle og eliminere malaria i Southeast Asia. Deze studie was gericht op het karakteriseren van de blootstelling-respons-relatie van artesunate bij patiënten met artemisinine-gevoelige en resistente malaria-infecties. Patients were recruited in Pailin, Cambodia (n = 39) and Wang Pa, Thailand (n = 40), and either received 2 mg / kg / day of artesunate monotherapy for 7 consecutive days or 4 mg / kg / day of artesunate monotherapy. 3 consecutive days followed by mefloquine 15 mg / kg and 10 mg / kg for 2 consecutive days. Plasma concentrations of artesunate and its active metabolite, dihydroarthemisinin, And microscopy-based parasitic densities were measured and evaluated using nonlinear mixed-effect models. All treatments were well tolerated with minor and transient adverse reactions. Patients in Cambodia had significantly slower parasite clearance compared to Thailand patients. The pharmacokinetic properties of artesunate and dihydroartemisin were well described by transit compartment absorption followed by one-compartment disposition models. Parasite density was asignificant covariate and higher parasitic densities were associated with increased absorption. Dihydroartemisinin-dependent parasite killing was described by a delayed sigmoidal Emax model, and a mixing function was implemented to differentiate between sensitive and resistant infections. This predicted that 84% and 16% of infections in Cambodia and Thailand, respectively, Were artemisinin resistant. The final model was used to develop a simple diagnostic nomogram to identify patients with artemisinin resistant infections. The nomogram showed> 80% specificity and sensitivity and outperformed the current practice of day 3 positivity rate.

    Available from: 2017-08-25 Created: 2017-08-25 Last updated: 2017-10-16
    3. Population Pharmacokinetic and Pharmacodynamic Properties of Artesunate in Patients with Artemisinin Resistant Infections in Southern Myanmar
    Open this publication in new window or tab >>Population Pharmacokinetic and Pharmacodynamic Properties of Artesunate in Patients with Artemisinin Resistant Infections in Southern Myanmar
    Show others...
    (English)In: The AAPS JournalArticle in journal (Refereed) Submitted
    Abstract [en]

    Artemisinins are the most effective antimalarial drugs for uncomplicated and severe Plasmodium falciparum malaria. However, widespread artemisinin resistance in the Greater Mekong Region of Southeast Asia is threatening our ability to control and eliminate malaria. This work was aimed at evaluating the pharmacokinetic and pharmacodynamic properties of artesunate and its active metabolite, dihydroarthemisinin, in patients with sensitive and resistant P. falciparummalaria infections in southern myanmar In addition, a simple nomogram previously developed to identify artemisinin resistant malaria infections was evaluated. Fifty-three (n = 53) patients were recruited and received daily oral artesunate monotherapy (4 mg / kg) for 7 days. Frequent artesunate and dihydroartemisinin plasma concentration measurements and parasite microscopy counts were obtained and evaluated using nonlinear mixed-effect models. The absorption of artesunate was best characterized by a transit compartment (n = 3) model, followed by one-compartment disposition models for artesunate and dihydroartemisinin. The drug-dependent parasite killing effect of dihydroarthemisin was described using an Emax function, with a mixture model discriminating between artemisinin sensitive and resistant parasites. Overalls, 56% of the studied population was predicted to have resistant malaria infections. Application of the proposed nomogram to identify artemisinin-resistant malaria infections demonstrated an overall sensitivity of 90% compared to 55% with the traditional day-3 positivity test. In conclusion, the pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to distinguish between drug-sensitive and resistant infections in these patients. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. Application of the proposed nomogram to identify artemisinin-resistant malaria infections demonstrated an overall sensitivity of 90% compared to 55% with the traditional day-3 positivity test. In conclusion, the pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to distinguish between drug-sensitive and resistant infections in these patients. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. Application of the proposed nomogram to identify artemisinin-resistant malaria infections demonstrated an overall sensitivity of 90% compared to 55% with the traditional day-3 positivity test. In conclusion, the pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to distinguish between drug-sensitive and resistant infections in these patients. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. The pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to distinguish between drug-sensitive and resistant infections in these patients. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. The pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to distinguish between drug-sensitive and resistant infections in these patients. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. 

    Keyword
    malaria – resistance – parasite clearance – artemisinin – pharmacokinetics – pharmacodynamics – nonlinear mixed-effects modelling
    National Category
    Infectious Medicine
    Research subject
    Medical Pharmacology
    Identifiers
    urn:nbn:se:uu:diva-329952 (URN)
    Funder
    Wellcome trust
    Available from: 2017-09-22 Created: 2017-09-22 Last updated: 2017-10-16
    4. Population Pharmacokinetics of Artemether and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated  Plasmodium Falciparum  Malaria.
    Open this publication in new window or tab >>Population Pharmacokinetics of Artemether and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated  Plasmodium Falciparum  Malaria.
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Artemisinin-based combination therapy (artemether-lumefantrine) is commonly used in pregnant malaria patients. Men, effekten af ​​svangerskabsrelaterede ændringer på eksponering er uklar og svangerskabet har været forbundet med reduceret effektivitet i tidligere studier. Denne undersøgelse har som mål at karakterisere befolkningen af ​​artemether farmakokinetik, dets aktive metabolit dihydroarthemisinin og lumefantrin hos toogtyve rwandiske gravide kvinder i anden og tredje trimester med ukompliceret Plasmodium falciparum malaria.

    These patients were enrolled from Rwamagana district hospital and received the standard fixed oral dose combi­nation of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Venous plasma concentrations were quantified for all three analytes using liquid chro­matography coupled to tandem mass spectroscopy and analysed using nonlinear mixed-effects modelling. Lumefantrine pharmacokinetics was described by a flexible but highly variable absorption, with a mean absorption time of 4.04 hours, followed by a bi-phasic dis­position model. The median AUC0-∞was 641 μmg / L. Model-based simulations indicated that 11.7% of patients did not reach the target day 7 plasma concentration (280 ng / ml), a threshold associated with increased risk of recrudescence. The pharmacokinetics of artemether were time dependent and the autoinduction of its clearance was described using an enzyme turnover model. The turnover half-life was predicted to be 30.4 hours and the oral clearance of ARM at opportunity 1, increased 1.43 fold, compared at occasion 6. While lumefantrine pharmacokinetic target attainment appeared reassuring in Rwandan pregnant women, especially compared to target achievement in Southeast Asia , larger cohorts will be required to confirm this finding. 

    National Category
    Infectious Medicine
    Research subject
    Biopharmaceutics; Pharmacokinetics and Drug Therapy
    Identifiers
    urn:nbn:se:uu:diva-330111 (URN)
    Available from: 2017-09-26 Created: 2017-09-26 Last updated: 2017-10-16
  • Public defence: 2017-11-24 13:15 Fåhraeussalen, Uppsala
    Barazeghi, Elham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Studies of epigenetic deregulation in parathyroid tumors and small intestinal neuroendocrine tumors2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Deregulation of the epigenome is associated with the initiation and progression of various types of human cancers. Here we investigated the level of 5-hydroxymethylcytosine (5hmC), expression and function of TET1 and TET2, and DNA methylation in parathyroid tumors and small intestinal neuroendocrine tumors (SI-NETs).

    In Paper I, an undetectable/very low level of 5hmC in parathyroid carcinomas (PCs) compared to parathyroid adenomas with positive staining, suggested that 5hmC may represent a novel biomarker for parathyroid malignancy. Immunohistochemistry revealed that increased tumor weight in adenomas was associated with a more aberrant staining pattern of 5hmC and TET1. A growth regulatory role of TET1 was demonstrated in parathyroid tumor cells.

    Paper II revealed that the expression of TET2 was also deregulated in PCs, and promoter hypermethylation was detected in PCs when compared to normal parathyroid tissues. 5-aza-2′-deoxycytidine treatment of a primary PC cell culture induced TET2 expression and further supported involvement of promoter hypermethylation in TET2 gene repression. TET2 knockout demonstrated a role for TET2 in cell growth and migration, and as a candidate tumor suppressor gene.

    In Paper III, variable levels of 5hmC, and aberrant expression of TET1 and TET2 were observed in SI-NETs. We demonstrated a growth regulatory role for TET1, and cytoplasmic expression with absent nuclear localization for TET2 in SI-NETs. In vitro experiments supported the involvement of exportin-1 in TET2 mislocalization, and suggested that KPT-330/selinexor, an orally bioavailable selective inhibitor of exportin-1 and nuclear export, with anti-cancer effects, could be further investigated as a therapeutic option in patients with SI-NETs.

    In Paper IV, DNA methylation was compared between SI-NET primary tumors and metastases by reduced representation bisulfite sequencing. Three differentially methylated regions (DMR) on chromosome 18 were detected and chosen for further analyses. The PTPRM gene, at 18p11, displayed low expression in SI-NETs with high levels of methylation in the presumed CpG island shores, and in the DMR rather than the promoter region or exon 1/intron 1 boundary. PTPRM overexpression resulted in inhibition of cell growth, proliferation, and induction of apoptosis in SI-NET cells, suggesting a role for PTPRM as an epigenetically deregulated candidate tumor suppressor gene in SI-NETs.  

    List of papers
    1. 5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma
    Open this publication in new window or tab >>5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma
    Show others...
    2016 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 8, 31Article in journal (Refereed) Published
    Abstract [en]

    Background: Primary hyperparathyroidism is characterized by enlarged parathyroid glands due to an adenoma (80-85 %) or multiglandular disease (similar to 15 %) causing hypersecretion of parathyroid hormone (PTH) and generally hypercalcemia. Parathyroid cancer is rare (<1-5 %). The epigenetic mark 5-hydroxymethylcytosine (5hmC) is reduced in various cancers, and this may involve reduced expression of the ten-eleven translocation 1 (TET1) enzyme. Here, we have performed novel experiments to determine the 5hmC level and TET1 protein expression in 43 parathyroid adenomas (PAs) and 17 parathyroid carcinomas (PCs) from patients who had local invasion or metastases and to address a potential growth regulatory role of TET1. Results: The global 5hmC level was determined by a semi-quantitative DNA immune-dot blot assay in a smaller number of tumors. The global 5hmC level was reduced in nine PCs and 15 PAs compared to four normal tissue samples (p < 0.05), and it was most severely reduced in the PCs. By immunohistochemistry, all 17 PCs stained negatively for 5hmC and TET1 showed negative or variably heterogeneous staining for the majority. All 43 PAs displayed positive 5hmC staining, and a similar aberrant staining pattern of 5hmC and TET1 was seen in about half of the PAs. Western blotting analysis of two PCs and nine PAs showed variable TET1 protein expression levels. A significantly higher tumor weight was associated to PAs displaying a more severe aberrant staining pattern of 5hmC and TET1. Overexpression of TET1 in a colony forming assay inhibited parathyroid tumor cell growth. Conclusions: 5hmC can discriminate between PAs and PCs. Whether 5hmC represents a novel marker for malignancy warrants further analysis in additional parathyroid tumor cohorts. The results support a growth regulatory role of TET1 in parathyroid tissue.

    Keyword
    5-hydroxymethylcytosine, 5hmC, Parathyroid cancer, Primary hyperparathyroidism, TET1
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-282795 (URN)10.1186/s13148-016-0197-2 (DOI)000371782000002 ()26973719 (PubMedID)
    Funder
    Swedish Cancer Society
    Available from: 2016-04-14 Created: 2016-04-07 Last updated: 2017-10-04Bibliographically approved
    2. A role for TET2 in parathyroid carcinoma
    Open this publication in new window or tab >>A role for TET2 in parathyroid carcinoma
    Show others...
    2017 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 7, 329-338 p.Article in journal (Refereed) Published
    Abstract [en]

    Primary hyperparathyroidism (pHPT) is rarely caused by parathyroid carcinoma (PC, <1-5% of pHPT cases). The TET proteins oxidize the epigenetic mark 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and inactivation by mutation or epigenetic deregulation of TET1 and TET2 play important roles in various cancers. Recently, we found that 5hmC was severely reduced in all of the analyzed PCs and with deranged expression of TET1 for the majority of PCs. Here, we have examined the expression of the TET2 protein in 15 5hmC-negative PCs from patients who had local invasion or metastases. Cell growth and cell migratory roles for TET2 as well as epigenetic deregulated expression were addressed. Immunohistochemistry revealed very low/undetectable expression of TET2 in all PCs and verified for two PCs that were available for western blotting analysis. Knockdown of TET2 in the parathyroid cell line sHPT-1 resulted in increased cell growth and increased cell migration. DNA sequencing of TET2 in PCs revealed two common variants and no obvious inactivating mutations. Quantitative bisulfite pyrosequencing analysis of the TET2 promoter CpG island revealed higher CpG methylation level in the PCs compared to that in normal tissues and treatment of a PC primary cell culture with the DNA methylation inhibitor 5-aza-2'-deoxycytidine caused increased expression of the methylated TET2 gene. Hence, the data suggest that deregulated expression of TET2 by DNA hypermethylation may contribute to the aberrantly low level of 5hmC in PCs and further that TET2 plays a cell growth and cell migratory regulatory role and may constitute a parathyroid tumor suppressor gene.

    National Category
    Medical and Health Sciences Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-330515 (URN)10.1530/ERC-17-0009 (DOI)
    Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-04
    3. Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors
    Open this publication in new window or tab >>Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Cancer and Oncology Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-330575 (URN)
    Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-04
    4. Reduced representation bisulfite sequencing of small intestinal neuroendocrine tumors identifies PTPRM as a novel candidate tumor suppressor gene
    Open this publication in new window or tab >>Reduced representation bisulfite sequencing of small intestinal neuroendocrine tumors identifies PTPRM as a novel candidate tumor suppressor gene
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Cancer and Oncology Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-330794 (URN)
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-04
  • Public defence: 2017-11-24 13:15 Hörsal 2, Ekonomikum, Uppsala
    Norén, Anna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Caring, Sharing, and Childbearing: Essays on Labor Supply, Infant Health, and Family Policies2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Essay I: I study the consequences on labor market outcomes and sick leave of having an elderly parent in need of care. Caring for an elderly parent may be associated with opportunity costs such as productivity loss on the labor market if informal caregivers are of working age. Using Swedish register data I compare the labor market outcome trajectories of adult children before and after their parent suffer a health shock. I find that employment and income of adult children are slightly reduced in the years leading up to the demise of their parent, but that the size of the impact is largest in the year, and the year after, parental demise. I also find that daughter's sick leave absence increases in the year that the parent dies. No effects on labor market outcomes are found from having a parent suffering stroke. Furthermore, I find no clear gender differences between sons and daughters in the impact of having a parent with increased care demand. Taken together, the results suggest that the opportunity costs of parental care need in the form of adverse labor market impacts are small.

  • Public defence: 2017-11-24 14:15 University Main Building, Hall IX, Uppsala
    Sundqvist, Josephine
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Theology, Uppsala Religion and Society Research Centre.
    Beyond an instrumental approach to religion and development: Challenges for church-based healthcare in Tanzania2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This dissertation serves as a contribution to the larger ongoing debate on the role of religion in development in an effort to move beyond an instrumental approach. The aim is to study the role of religious agents in development through the prism of contractual partnerships between church organisations and the Tanzanian state in healthcare delivery. Three Christian denominations are included in the study: the Roman Catholic Church in Tanzania (Tanzania Episcopal Conference), the Evangelical Lutheran Church in Tanzania and the Free Pentecostal Church of Tanzania.

    Three theoretical perspectives are applied to the study of religion and development: (1) an instrumental perspective; (2) a bottom-up perspective and (3) an integral perspective. In order to operationalise the three theoretical perspectives to function adequately for health sector development research, three analytical concepts are included in the framework, namely resource dependency, linking social capital and intangible religious health assets. The methodology is based on an abductive qualitative approach with the use of case studies on the three church organisations (Catholic, Protestant and Pentecostal). Three key methods have been used for collecting data: policy analysis, semi-structured interviews and participant observation. Each organisation is analysed in terms of their Public Private Partnership (PPP) agreements and collaborative models, their relation towards the state, their internal health policies and their motives for delivering health services. Moreover, by including one local hospital per organisation (Turiani, Selian and Mchukwi), it is also possible to integrate the local implementation level into the study. In order to capture the views of public authorities, interviewees from the national Ministry of Health and local Council Health Management Teams have also been included.

    By entering into PPP health agreements, church organisations have moved to centre stage and gained more influence following the latest political and economic reforms. Their attraction as service providers follows from their existing infrastructure and previous experience and capacity in the health sector. The analysis shows that faith is a key motivator and a central factor in the running of church health services. However, the fact that church organisations are becoming increasingly dependent on the state has implications in terms of their role as a critical voice in the public debate and could potentially threaten their independence as faith-driven civil society actors. Church organisations are also becoming more vulnerable financially, as they are not compensated according to the PPP contracts. The current situation where church organisations are dominating the PPPs in health has implications on both the Tanzanian model of secularism, with its emphasis on Muslim and Christians being treated equally, and the local governments’ strive towards national ownership with their favouring of public healthcare over private alternatives. It is therefore necessary to further study the role of religion beyond an instrumental approach in order to get a deeper understanding of the religious dynamics in the PPPs in health in Tanzania.

  • Public defence: 2017-11-28 09:15 Polhemssalen, Ångströmlaboratoriet, Uppsala
    Stopfel, Henry
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Physics.
    Tailoring the magnetic order in mesoscopic spin systems2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mesoscopic spin systems can be designed and fabricated using modern nano-fabrication techniques. These systems can contain large numbers of patterned ferromagnetic elements, for which the shape will generally determine their effective mesospin dimensionality. The lateral arrangement of these mesospins can be further used to tune the interactions between them.

    With an appropriate choice of material, it is possible to define a temperature range where thermal fluctuations of these mesospins are experimentally accessible. To actively define this range, we use δ-doped Palladium, a three-layer system of Palladium—Iron—Palladium, for which the Curie-temperature scales with the Iron layer thickness. The patterned mesoscopic elements used in this work have a stadium-like shape that promotes a single magnetic domain state, thus making these islands behave as one-dimensional Ising-like mesospins that can be observed using magnetic imaging techniques.

    We investigate the impact on the magnetic order resulting from modifications of the square spin ice geometry. By adding, removing and merging elements in the square artificial spin ice architecture, energy-landscape variations can be realized. Firstly, an added interaction modifier is used to equilibrate the interactions between the mesospins at the vertex level, which can restore the degenerate ground state of the square spin ice model. Secondly, the removal of elements can lead to topologically frustrated spin systems, as not all building blocks can simultaneously be in their lowest energy state. Furthermore, the merging results in multiple element sizes in the mesospin system. As the magnetization reversal barrier is dependent on the element size, these mesospin systems have different energy barriers. The thermal ordering process in such a system differs from a single-size element system with its unique energy barrier. Using reciprocal space analysis tools like the magnetic spin structure factor we show that systems with multiple element sizes achieve a higher short-range order then their single-size element references. The magnetic order in mesoscopic spin systems could successfully be tailored by modifications of the lattice geometry.

    List of papers
    1. A new look on the two-dimensional Ising model: thermal artificial spins
    Open this publication in new window or tab >>A new look on the two-dimensional Ising model: thermal artificial spins
    Show others...
    2016 (English)In: New Journal of Physics, ISSN 1367-2630, E-ISSN 1367-2630, Vol. 18, 023008Article in journal (Refereed) Published
    Abstract [en]

    We present a direct experimental investigation of the thermal ordering in an artificial analogue of an asymmetric two-dimensional Ising system composed of a rectangular array of nano-fabricated magnetostatically interacting islands. During fabrication and below a critical thickness of the magnetic material the islands are thermally fluctuating and thus the system is able to explore its phase space. Above the critical thickness the islands freeze-in resulting in an arrested thermalized state for the array. Determining the magnetic state we demonstrate a genuine artificial two-dimensional Ising system which can be analyzed in the context of nearest neighbor interactions.

    Keyword
    magnetic ordering, artificial spins, Ising model
    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-288634 (URN)10.1088/1367-2630/18/2/023008 (DOI)000372453700002 ()
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research CouncilThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
    Available from: 2016-05-04 Created: 2016-04-28 Last updated: 2017-10-10Bibliographically approved
    2. Thermally induced magnetic relaxation in square artificial spin ice
    Open this publication in new window or tab >>Thermally induced magnetic relaxation in square artificial spin ice
    Show others...
    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 37097Article in journal (Refereed) Published
    Abstract [en]

    The properties of natural and artificial assemblies of interacting elements, ranging from Quarks to Galaxies, are at the heart of Physics. The collective response and dynamics of such assemblies are dictated by the intrinsic dynamical properties of the building blocks, the nature of their interactions and topological constraints. Here we report on the relaxation dynamics of the magnetization of artificial assemblies of mesoscopic spins. In our model nano-magnetic system - square artificial spin ice - we are able to control the geometrical arrangement and interaction strength between the magnetically interacting building blocks by means of nano-lithography. Using time resolved magnetometry we show that the relaxation process can be described using the Kohlrausch law and that the extracted temperature dependent relaxation times of the assemblies follow the Vogel-Fulcher law. The results provide insight into the relaxation dynamics of mesoscopic nano-magnetic model systems, with adjustable energy and time scales, and demonstrates that these can serve as an ideal playground for the studies of collective dynamics and relaxations.

    National Category
    Physical Sciences Materials Engineering
    Identifiers
    urn:nbn:se:uu:diva-315927 (URN)10.1038/srep37097 (DOI)000392061500001 ()27883013 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research CouncilGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
    Available from: 2017-02-22 Created: 2017-02-22 Last updated: 2017-10-10Bibliographically approved
    3. The importance of the weak: Interaction modiers in articial spin ices
    Open this publication in new window or tab >>The importance of the weak: Interaction modiers in articial spin ices
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Condensed Matter Physics Nano Technology
    Identifiers
    urn:nbn:se:uu:diva-328864 (URN)
    Available from: 2017-10-10 Created: 2017-10-10 Last updated: 2017-10-10
    4. Magnetic order and energy-scale hierarchy in articial spin ice
    Open this publication in new window or tab >>Magnetic order and energy-scale hierarchy in articial spin ice
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keyword
    artificial spin ice, magnetic nano-structures, mesoscopic spin systems, mesospins, model systems, Shakti, engineering of energy-landscape, multiple energy-scales
    National Category
    Condensed Matter Physics Nano Technology
    Research subject
    Physics
    Identifiers
    urn:nbn:se:uu:diva-329016 (URN)
    Available from: 2017-10-10 Created: 2017-10-10 Last updated: 2017-10-10
  • Public defence: 2017-11-30 09:00 Room 2001, Uppsala
    Marcusson, Birger
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Electricity.
    Magnetic Leakage Fields and End Region Eddy Current Power Losses in Synchronous Generators2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The conversion of mechanical energy to electrical energy is done mainly with synchronous generators. They are used in hydropower generators and nuclear plants that presently account for about 80% of the electric energy production in Sweden. Because of the dominating role of the synchronous generators, it is important to minimize the power losses for efficient use of natural resources and for the economies of the electric power companies and their customers. For a synchronous machine, power loss means undesired heat production. In electric machines, there are power losses due to windage, friction in bearings, resistance in windings, remagnetization of ferromagnetic materials, and induced voltages in windings, shields and parts that are conductive but ideally should be non-conductive.

    The subject of this thesis is prediction of end region magnetic leakage fields in synchronous generators and the eddy current power losses they cause. The leakage fields also increase the hysteresis losses in the end regions. Magnetic flux that takes paths such that eddy current power losses increase in end regions of synchronous generators is considered to be leakage flux. Although only a small fraction of the total magnetic flux is end region leakage flux, it can cause hot spots, discoloration and reduce the service life of the insulation on the core laminations. If unattended, damaged insulation could lead to electric contact and eddy currents induced by the main flux between the outermost laminations. That gives further heating and deterioration of the insulation of laminations deeper into the core. In a severe case, the core can melt locally, cause a cavity, buckling and a short circuit of the main conductors. The whole stator may have to be replaced. However, the end region leakage flux primarily causes heating close to the main stator conductors which makes the damage possible to discover by visual inspection before it has become irrepairable.

    List of papers
    1. Axial Magnetic Fields at the Ends of a Synchronous Generator at Different Points of Operation
    Open this publication in new window or tab >>Axial Magnetic Fields at the Ends of a Synchronous Generator at Different Points of Operation
    2015 (English)In: IEEE transactions on magnetics, ISSN 0018-9464, E-ISSN 1941-0069, Vol. 51, no 2, 8100208Article in journal (Refereed) Published
    Abstract [en]

    Axial magnetic fields leaking out at the ends of a conventional rotating synchronous machine cause losses. Therefore, it is important to be able to predict the axial magnetic fields. A linear steady-state model for the axial magnetic flux density phasor in the end regions of non-salient synchronous generators has previously been verified experimentally. This paper describes an extension of the model to salient pole synchronous generators and a method for calculating the coefficients. Experiments and 3-D finite element simulations justify a distinction between axial flux density contributions from the d and q components of the stator current. How the coefficients and the axial magnetic fields in the ends of a small synchronous generator change with steady-state operation conditions is here shown with measurements and to some extent with 3-D finite element simulations.

    Keyword
    Axial magnetic flux, hydropower generator, operation conditions
    National Category
    Physical Sciences Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:uu:diva-255312 (URN)10.1109/TMAG.2014.2347269 (DOI)000353595800015 ()
    Available from: 2015-06-16 Created: 2015-06-15 Last updated: 2017-10-11Bibliographically approved
    2. Axial Magnetic Fields, Axial Force, and Losses in the Stator Core and Clamping Structure of a Synchronous Generator with Axially Displaced Stator
    Open this publication in new window or tab >>Axial Magnetic Fields, Axial Force, and Losses in the Stator Core and Clamping Structure of a Synchronous Generator with Axially Displaced Stator
    2017 (English)In: Electric power components and systems, ISSN 1532-5008, E-ISSN 1532-5016, Vol. 45, no 4, 410-419 p.Article in journal (Refereed) Published
    Abstract [en]

    Axial displacement of the stator in a synchronous machine gives rise to axial magnetic field both at the ends and deep inside the stator. The axial magnetic field causes losses. This article contains results from two studies with an axially displaced stator. In the first study, axial magnetic leakage fields in the ends of a small synchronous generator at load and no load were measured and simulated. In the second study, axial force and iron losses at no load were calculated with non-linear materials and a three-dimensional, time-stepped finite element method. For some machines with vertical shafts, the sum of iron losses and thrust bearing losses can be reduced if the rotor is lowered or the stator raised, whichever is best.

    Place, publisher, year, edition, pages
    TAYLOR & FRANCIS INC, 2017
    Keyword
    axial magnetic field, axial force, losses, synchronous generator, finite element analysis
    National Category
    Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:uu:diva-319683 (URN)10.1080/15325008.2016.1266062 (DOI)000397048400005 ()
    Available from: 2017-04-07 Created: 2017-04-07 Last updated: 2017-10-11Bibliographically approved
    3. Harmonically Time Varying, Traveling Electromagnetic Fields along a Plate and a Laminate with a Rectangular Cross Section, Isotropic Materials and Infinite Length
    Open this publication in new window or tab >>Harmonically Time Varying, Traveling Electromagnetic Fields along a Plate and a Laminate with a Rectangular Cross Section, Isotropic Materials and Infinite Length
    2017 (English)In: Progress in Electromagnetics Research B, ISSN 1937-6472, E-ISSN 1937-6472, Vol. 77, 117-136 p.Article in journal (Refereed) Published
    Abstract [en]

    This article contains derivation of propagation factors and Fourier series for harmonically time varying, traveling electromagnetic fields in a plate and a laminate with rectangular cross sections, isotropic materials and infinite length. Different and quite general fields are taken into account on all boundaries. Choices of boundary conditions and continuity conditions are discussed. Certain combinations of types of boundary conditions make the derivation possible for a laminate. Comparisons are made between results of Fourier series and finite element calculations.

    National Category
    Mathematics Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-331171 (URN)10.2528/PIERB17061909 (DOI)
    Available from: 2017-10-11 Created: 2017-10-11 Last updated: 2017-10-18Bibliographically approved
    4. Harmonically Time Varying, Traveling Electromagnetic Fields along a Laminate Approximated by a Homogeneous, Anisotropic Block with Infinite Length
    Open this publication in new window or tab >>Harmonically Time Varying, Traveling Electromagnetic Fields along a Laminate Approximated by a Homogeneous, Anisotropic Block with Infinite Length
    2017 (English)In: Progress in Electromagnetics Research B, ISSN 1937-6472, E-ISSN 1937-6472Article in journal (Refereed) Submitted
    Abstract [en]

    Analytical expressions that include arbitrarily directed fields on all laminate boundaries can be used for calculation of the fields inside the laminate when the boundary fields are known from, e.g., measurements. A linear laminate block could be used in non-destructive testing for comparisons between different laminates. This article contains derivation of Fourier series of harmonically time varying, traveling electromagnetic fields in homogeneous, anisotropic approximations of laminates. The component of the magnetic field strength in the stacking direction is used as a source term in two-dimensional Poisson equations for the magnetic field strength in other directions. This approximation is here used in three dimensions under the precondition that the conductivity is much smaller in the laminate stacking direction than in the other directions. Sine interpolation and different choices of types of boundary conditions are discussed. Different alternative subdivisions of the Poisson boundary value problems are treated. Shorted derivations of simple analytical expressions are given for both traveling and standing waves in two dimensions. Results from Fourier series in the three-dimensional case are compared with results from finite element calculations.

    National Category
    Mathematical Analysis Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-331175 (URN)
    Available from: 2017-10-11 Created: 2017-10-11 Last updated: 2017-10-17
    5. A Loss Model and Finite Element Analyses of the Influence of Load Angle Oscillation on Stator Eddy Current Losses in a Synchronous Generator
    Open this publication in new window or tab >>A Loss Model and Finite Element Analyses of the Influence of Load Angle Oscillation on Stator Eddy Current Losses in a Synchronous Generator
    2017 (English)In: IEEE transactions on magnetics, ISSN 0018-9464, E-ISSN 1941-0069Article in journal (Refereed) Submitted
    Abstract [en]

    The load angle of a synchronous generator connected to a power grid has an eigenfrequency that depends on the operating conditions. The existence of an eigenfrequency can make the generator sensitive to electrical and mechanical disturbances and motivates the use of damper windings and power stabilizing systems. The eddy current losses in the stator core and clamping structure increase as a consequence of the load angle oscillations. This is shown both with transient finite element analyses and analytically via a loss model derived from a steady state phasor model of the eddy current loss density. The model is also applicable to the quasi-steady states occurring during load angle oscillations.

    National Category
    Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:uu:diva-331176 (URN)
    Available from: 2017-10-11 Created: 2017-10-11 Last updated: 2017-10-17
  • Public defence: 2017-11-30 09:30 B21, Uppsala
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Solute Carriers in Metabolism: Regulation of known and putative solute carriers in the central nervous system2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Solute carriers (SLCs) are membrane-bound transporter proteins, important for nutrient, ion, drug and metabolite transport across membranes. A quarter of the human genome codes for membrane-bound proteins, and SLCs make up the largest group of transporter proteins. Due to their ability to transport a large repertoire of substances across, not just the plasma membrane, but also the membrane of internal organelles, they hold a key position in maintaining homeostasis affecting metabolic pathways. Unfortunately, some of the more than 400 identified SLCs are still not fully characterized, even though a quarter of these are associated with human disease. In addition, there are about 30 membrane-bound proteins with strong resemblance to SLCs, of which very little is known. The aim of this thesis is to characterize some of these putative SLCs, focusing on their localization and function in the central nervous system. Since many of the known SLCs play a vital part in metabolism and related pathways, the response to different nutritional conditions has been used as a key method. MFSD14A and MFSD14B, characterized in Paper I, are putative SLCs belonging to the Major Facilitator Superfamily (MFS) and found to be neuronal, differentially expressed in the mouse central nervous system and transiently upregulated in mouse embryonic cortex cultures due to amino acid deprivation. They were also altered in areas of the mouse brain after starvation as well as after high fat diet. In Paper II, the effect on gene regulation due to complete amino acid starvation was monitored in a mouse hypothalamic cell line and 47 different genes belonging to SLCs, or putative SLCs, were found to be affected. Of these, 15 genes belonged to already known amino acid transporters, whereas 32 were putative SLCs with no known function or SLCs not known to react to amino acids. The three SV2 proteins, SV2A, SV2B and SV2C, were studied in Paper III using human neuroblastoma cell lines. The high metabolic state of cancers often result in an upregulation and alteration of transporter proteins, and alterations of the SV2 proteins were found following different treatments performed in this study. Paper IV focused on putative SLCs of MFS type and their role in glucose metabolism. Mouse embryonic cortex cultures were subjected to glucose starvation and the gene expression of 19 putative transporters were analyzed. All but four of the putative transporters were affected either at 3h or 12h of glucose deprivation. In conclusion, several SLCs and putative SLCs studied in this thesis are strongly affected by alteration in metabolism, either due to amino acids or glucose or both. This makes the putative SLCs dynamic membrane-bound proteins, possibly transporters, highly affected by nutritional status and most likely regulated to maintain homeostasis.

    List of papers
    1. Putative Membrane-Bound Transporters MFSD14A and MFSD14B Are Neuronal and Affected by Nutrient Availability
    Open this publication in new window or tab >>Putative Membrane-Bound Transporters MFSD14A and MFSD14B Are Neuronal and Affected by Nutrient Availability
    Show others...
    2017 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, 11Article in journal (Refereed) Published
    Abstract [en]

    Characterization of orphan transporters is of importance due to their involvement in cellular homeostasis but also in pharmacokinetics and pharmacodynamics. The tissue and cellular localization, as well as function, is still unknown for many of the solute carriers belonging to the major facilitator superfamily (MFS) Pfam clan. Here, we have characterized two putative novel transporters MFSD14A (HIAT1) and MFSD14B (HIATL1) in the mouse central nervous system and found protein staining throughout the adult mouse brain. Both transporters localized to neurons and MFSD14A co-localized with the Golgi marker Giantin in primary embryonic cortex cultures, while MFSD14B staining co-localized with an endoplasmic retention marker, KDEL. Based on phylogenetic clustering analyses, we predict both to have organic substrate profiles, and possible involvement in energy homeostasis. Therefore, we monitored gene regulation changes in mouse embryonic primary cultures after amino acid starvations and found both transporters to be upregulated after 3 h of starvation. Interestingly, in mice subjected to 24 h of food starvation, both transporters were downregulated in the hypothalamus, while Mfsdl4a was also downregulated in the brainstem. In addition, in mice fed a high fat diet (HFD), upregulation of both transporters was seen in the striatum. Both MFSD14A and MFSD14B were intracellular neuronal membrane bound proteins, expressed in the Golgi and Endoplasmic reticulum, affected by both starvation and HFD to varying degree in the mouse brain.

    Keyword
    MFSD14A, HIAT1, MFSD14B, HIATL1, SLC, MFSD, transporter protein
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-316413 (URN)10.3389/fnmol.2017.00011 (DOI)000392751300001 ()28179877 (PubMedID)
    Funder
    Swedish Research CouncilThe Swedish Brain FoundationSwedish Society for Medical Research (SSMF)Novo NordiskMagnus Bergvall Foundation
    Available from: 2017-03-02 Created: 2017-03-02 Last updated: 2017-10-12Bibliographically approved
    2. The gene expression of numerous SLC transporters isaltered in the immortalized hypothalamic cell line N25/2following amino acid starvation
    Open this publication in new window or tab >>The gene expression of numerous SLC transporters isaltered in the immortalized hypothalamic cell line N25/2following amino acid starvation
    2017 (English)In: FEBS Open Bio, E-ISSN 2211-5463, Vol. 7, no 2, 249-264 p.Article in journal (Refereed) Published
    Abstract [en]

    Amino acids are known to play a key role in gene expression regulation,and in mammalian cells, amino acid signaling is mainly mediated via twopathways, the mammalian target of rapamycin complex 1 (mTORC1) pathwayand the amino acid responsive (AAR) pathway. It is vital for cells tohave a system to sense amino acid levels, in order to control protein andamino acid synthesis and catabolism. Amino acid transporters are crucialin these pathways, due to both their sensing and transport functions. Inthis large-scale study, an immortalized mouse hypothalamic cell line (N25/2)was used to study the gene expression changes following 1, 2, 3, 5 or 16 hof amino acid starvation. We focused on genes encoding solute carriers(SLCs) and putative SLCs, more specifically on amino acid transporters.The microarray contained 28 270 genes and 86.2% of the genes wereexpressed in the cell line. At 5 h of starvation, 1001 genes were upregulatedand 848 genes were downregulated, and among these, 47 genes from theSLC superfamily or atypical SLCs were found. Of these, 15 were genesencoding amino acid transporters and 32 were genes encoding other SLCsor atypical SLCs. Increased expression was detected for genes encodingamino acid transporters from system A, ASC, L, N, T, xc-, and y+. UsingGO annotations, genes involved in amino acid transport and amino acidtransmembrane transporter activity were found to be most upregulated at3 h and 5 h of starvation.

    National Category
    Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-331260 (URN)10.1002/2211-5463.12181 (DOI)
    Funder
    Swedish Research Council
    Available from: 2017-10-12 Created: 2017-10-12 Last updated: 2017-10-18Bibliographically approved
    3. Treatment of two human neuroblastoma cell lines with growth factors, ATRA or VIP alters synaptic vesicle glycoprotein 2 (SV2) expression.
    Open this publication in new window or tab >>Treatment of two human neuroblastoma cell lines with growth factors, ATRA or VIP alters synaptic vesicle glycoprotein 2 (SV2) expression.
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-331276 (URN)
    Available from: 2017-10-12 Created: 2017-10-12 Last updated: 2017-10-12
    4. Glucose deprived mouse embryonal cortex cultures respond by altering MFS transporter expression and localization
    Open this publication in new window or tab >>Glucose deprived mouse embryonal cortex cultures respond by altering MFS transporter expression and localization
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-331327 (URN)
    Available from: 2017-10-12 Created: 2017-10-12 Last updated: 2017-10-12
  • Public defence: 2017-12-01 09:00 Friessalen, Uppsala
    Andersson, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Extent and limitations of functional redundancy among bacterial communities towards dissolved organic matter2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    One of the key processes in the carbon cycle on our planet is the degradation of dissolved organic matter (DOM) in aquatic environments. The use of organic matter by bacteria links energy from DOM to higher trophic levels of the ecosystem when bacteria are consumed by other organisms. This is referred to as the microbial loop. In this thesis I examined if the communities were functionally redundant in their ability to utilize organic matter, or if variation in bacterial composition and richness is of importance. To test this overarching question several experiments were conducted that include methods such as illumina sequencing of the 16S rRNA gene for taxonomic identification of bacterial communities, flow cytometry to follow the growth of communities and spectroscopic measurement to describe the composition of the organic matter pool. Initially we demonstrated how to optimally sterilize organic matter for experimental studies in order to preserve its natural complexity. In further experiments we found that bacterial communities are redundant in their utilization of organic matter and can maintain optimal performance towards a range of organic matter pools. Related to this we found that pre-adaptation to organic matter played a small role as communities performed equally well regardless of their environmental history. We saw a small effect of richness and composition of bacterial communities on the efficiency of organic matter use, but conclude that this is of minor importance relative to abiotic factors. Still, we also show that organic matter can put strong selection pressure on bacterial communities with regards to richness and composition. Additionally we found that the supply rate of a carbon compound greatly influenced the energy utilization of the compound, i.e. a higher growth rate can be maintained if substrate is delivered in pulses relative to a continuous flow. Finally we conclude that the variation in bacterial communities is unlikely to have a major influence on carbon cycling in boreal lakes, but to enable a finer understanding, the genetics underlying the carbon utilization needs to be further explored. 

    List of papers
    1. Effects of sterilization on composition and bacterial utilization of dissolved organic carbon
    Open this publication in new window or tab >>Effects of sterilization on composition and bacterial utilization of dissolved organic carbon
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Sterilization of dissolved organic carbon (DOC) is an essential step in research on interactions between DOC and organisms, for example where the effect of different microbial communities on DOC is studied or vice versa. Few studies have, however, gone beyond acknowledging that sterilization of DOC influences its characteristics. Here we aimed to provide further knowledge that enables scientists to better tailor their sterilization methods to their research question. To meet this aim, we conducted a sterilization experiment with DOC from 4 boreal lakes treated with 4 sterilization methods, 2 filtrations (0.2 µm, 0.1 µm) and 2 autoclaving approaches (single autoclaving and double with intermediate pH adjustment). Quantity and spectroscopic properties of DOC were compared before and after sterilization and DOC was further tested as a substrate for bacterial growth. We found that the filtration methods better preserved the qualities of DOC, particularly the 0.2 µm filtration. On the contrary, autoclaving caused major inconsistent shifts in both qualitative and quantitative measurements of DOC as well as an increase of the maximum abundance of bacteria in growth experiments. Nonetheless, there remains a trade-off between retaining the quality of DOC and achieving sterile conditions. Therefore, the sterilization method of choice should be guided by the scientific question at hand.    

    Keyword
    sterilization, autoclave, filtration, dissolved organic carbon, excitation emission matrices, parallel factor analysis
    National Category
    Biological Sciences
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:uu:diva-331676 (URN)
    Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-10-23
    2. Influence of pulsed and continuous substrate inputs on freshwater bacterial community composition and functioning in bioreactors
    Open this publication in new window or tab >>Influence of pulsed and continuous substrate inputs on freshwater bacterial community composition and functioning in bioreactors
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Aquatic environments are typically not homogenous, but characterized by changing substrate concentration gradients and nutrient patches. This heterogeneity in substrate availability creates a multitude of niches allowing bacteria with different substrate utilization strategies to hypothetically coexist even when competing for the same substrate. To study the impact of heterogeneous distribution of organic substrates on bacterioplankton, bioreactors with freshwater bacterial communities were fed artificial freshwater medium with acetate supplied either continuously or in pulses. After a month-long incubation, bacterial biomass and community-level substrate uptake rates were twice as high in the pulsed treatment compared to the continuously fed reactors even if the same total amount of acetate was supplied to both treatments. The composition of the bacterial communities emerging in the two treatments differed significantly with specific taxa overrepresented in the respective treatments. The higher estimated growth yield in cultures that received pulsed substrate inputs, imply that such conditions enable bacteria to use resources more efficiently for biomass production. This finding agrees with established concepts of basal maintenance energy requirements and high energetic costs to assimilate substrates at low concentration. Our results further imply that degradation of organic matter is influenced by temporal and spatial heterogeneity in substrate availability. 

    National Category
    Biological Sciences
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:uu:diva-331692 (URN)
    Available from: 2017-10-17 Created: 2017-10-17 Last updated: 2017-10-23
    3. Response and effect interactions between bacterial communities and organic matter
    Open this publication in new window or tab >>Response and effect interactions between bacterial communities and organic matter
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The interaction between bacteria and dissolved organic matter (DOM) is crucial for the global carbon cycling. Despite decades of research there are, however, few consistent patterns regarding the relationship between bacterial diversity and community composition and DOM. Here we hypothesized that one reason for such inconsistences among studies is that bacterial communities can adapt to a DOM source over time, whereby a change in the functioning of a community can be, at least partly, decoupled from its composition and diversity. To test this idea we performed a reciprocal transplant experiment with medium (i.e. DOM source) and bacterial communities from two boreal lakes. In this experiment the two communities were allowed to adapt to their indigenous and their foreign source of DOM over 42 days. Bacterial community composition (BCC) was measured throughout the experiment. In addition we measured the capacity of the communities to use DOM, in repeated short (5 days) separated bioassays. The results show a response of bacterial community composition to the DOM sources which was influenced by the origin of the community. In contrast, we could not show an effect of BCC on DOM-processing and functional performance. Indeed, communities of different origin processed the two DOM sources equally well even at the beginning of the experiment. This work demonstrates that the DOM pool can be a strong selective force for BCC but not vice versa. 

    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-331696 (URN)
    Available from: 2017-10-17 Created: 2017-10-17 Last updated: 2017-10-23
    4. The relative importance of richness and BCC for DOC degradation
    Open this publication in new window or tab >>The relative importance of richness and BCC for DOC degradation
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The importance of biodiversity has been of primary interest for ecologist the last 20 years, giving rise to biodiversity ecosystem function (BEF) studies. Within the traditional field of ecology reoccurring patterns have emerged but within microbial ecology the importance of species richness for functioning is still poorly understood with few consistent patterns. In this study we examined the effect of species richness for dissolved organic matter degradation in lakes. This was examined within a smaller span of species richness compared to what is typically in microbial BEF experiments. Bacterial communities of reduced species richness were exposed to a range of DOC environments to test if reduced richness changed the functioning of communities and if the effect was similar among DOC environments. This was conducted in a full factorial design of 3 levels, with 6 dilutions, 5 media and 3 inocula resulting in 90 treatments. Overall, richness and community composition appeared to have effects on DOC degradation, but these effects were minor compared to the variation caused by the different DOC sources. Further, the importance of species richness varied among media and, thus, the chemical complexity of the environment influenced the biodiversity-ecosystem functioning relationship. 

    National Category
    Biological Sciences
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:uu:diva-331693 (URN)
    Available from: 2017-10-17 Created: 2017-10-17 Last updated: 2017-10-23
  • Public defence: 2017-12-01 09:15 Sal IX, Uppsala
    Fängström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    ‘I don’t even remember anything’: Optimising the choice of method when interviewing preschoolers2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    There is increasing need and demand in various contexts to take children’s perspectives into account, including the views and opinions of the youngest children. However, listening to the voices of children is a challenging and complex task, and the field is normatively loaded. There is thus a growing need for valid and reliable methods and techniques that aid children to verbalise their experiences. The overall aim of this thesis was to examine the ability of the In My Shoes computer assisted interview and a Standard verbal interview to elicit accurate information and evaluative content, when used with preschool-aged children and determine their suitability in relation to situationally shy children.

    Our studies show that the two interview methods, in general, provided equally accurate and complete statements. In addition, the IMS interview can be a more useful and suitable tool during the rapport phase with situationally shy children compared to the Standard verbal method. For non-shy children, the interview methods were equally adequate. In relation to evaluative information, the recommended open-ended questions in the Standard verbal interview were insufficient. Children appeared to need evaluative questions in order to provide evaluative content. Examining the ability of IMS to elicit subjective experiences showed that using IMS aided children to provide detailed and varied descriptions of emotions, somatic experiences, and objects such as toys.  

    Thus, when choosing the optimal child interview method, there are several aspects that need to be considered, including the degree to which children’s statements need to be accurate and complete and/or contain evaluative information and the child’s level of shyness. These studies have increased the number of evaluated methods for interviewing children and contributed to new knowledge about the challenging task of optimising the choice of method for interviewing preschoolers.

    List of papers
    1. In My Shoes - Validation of a computer assisted approach for interviewing children
    Open this publication in new window or tab >>In My Shoes - Validation of a computer assisted approach for interviewing children
    Show others...
    2016 (English)In: Child Abuse & Neglect: The International Journal, ISSN 0145-2134, Vol. 58, 160-172 p.Article in journal (Refereed) Published
    Abstract [en]

    Interviewing young children presents a challenge because they tend to provide incomplete accounts and are easily misled. Therefore there is a need for techniques to improve young children's recall, while maintaining accuracy and increasing completeness. The computer-assisted interview In My Shoes (IMS) is an aid that potentially offers a way for young children to provide accounts of their experiences. This study examined the validity of IMS, by comparing it with a forensic best practice interview approach using a real life clinical situation to ensure high ecological validity. Children were randomly assigned to either method and both accuracy and completeness of statements made by 4- and 5-year-olds (N = 54) regarding a video-documented health check-up were assessed. The In My Shoes interviews were as good as best practice interviews on all accuracy measures for both age groups, except for object accuracy that was better in the forensic interview condition. Events description completeness was similar in both interview conditions; however, IMS interviews generated more complete statements about people present at the visit. The findings suggest that the IMS approach yields comparable results to a best practice interview, and it can be used as an alternative aid in child interviews.

    Keyword
    Interviewing aid, Child, Computer-assisted interview, Validity, In My Shoes
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Research subject
    Social Medicine; Psychology
    Identifiers
    urn:nbn:se:uu:diva-303099 (URN)10.1016/j.chiabu.2016.06.022 (DOI)000381241400016 ()27394051 (PubMedID)
    Funder
    VINNOVA, 259-2012-68Forte, Swedish Research Council for Health, Working Life and Welfare, 259-2012-68
    Note

    Forskningsfinansiär: Allmänna Barnhuset, FB13-0014

    Available from: 2016-09-28 Created: 2016-09-15 Last updated: 2017-10-13
    2. The computer-assisted interview In My Shoes can benefit shy preschool children's communication
    Open this publication in new window or tab >>The computer-assisted interview In My Shoes can benefit shy preschool children's communication
    2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, e0182978Article in journal (Refereed) Published
    Abstract [en]

    Interviewing children is a cognitively, socially, and emotionally challenging situation, especially for young and shy children. Thus, finding methods that aid rapport and increase these children's communication is important. The present study investigated whether children's verbal and non-verbal communicative behavior developed differently during the rapport phase, depending on whether children were situationally shy or not, and whether the interview was conducted using the computer-assisted interview In My Shoes (IMS) or a Standard verbal interview. The sample consisted of 60 children aged 4 to 5-years-old. The results showed that for the shy children in the IMS group their talkativeness increased and their answer latency decreased including the amount of encouragement the child needed to talk, while no changes were observed for the shy children in the Standard verbal interview group. There were no significant differences in the non-verbal behavior for the shy children regardless of the interview method used. For the non-shy children, overall, the interview method did not affect either the verbal or the non-verbal outcomes. Our findings indicate that IMS can be a useful tool during the rapport-building phase with shy children as it helps these children to improve their verbal communication.

    Keyword
    child, interview, communication, In My Shoes
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Research subject
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-328584 (URN)10.1371/journal.pone.0182978 (DOI)000407550500034 ()28813534 (PubMedID)
    Funder
    Swedish Research Council, 259-2012-68Swedish Research Council FormasVINNOVA
    Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2017-11-14Bibliographically approved
    3. “And they gave me a shot, it really hurt” – Evaluative content in investigative interviews with young children
    Open this publication in new window or tab >>“And they gave me a shot, it really hurt” – Evaluative content in investigative interviews with young children
    Show others...
    2017 (English)In: Children and youth services review, ISSN 0190-7409, E-ISSN 1873-7765, Vol. 82, 434-443 p.Article in journal (Refereed) Published
    Abstract [en]

    Research is scarce on the suitability of the evidence-based components of child investigative interviews when used in non-forensic contexts such as social work or school, particularly in relation to children’s reports on emotional content.

    This explorative study investigated to what extent a structured forensic interview protocol aids children in verbalizing negative emotional experiences of distress or discomfort. To do this we assessed and compared children’s displayed distress or discomfort during a video-recorded health visit with the verbalized distress or discomfort in interviews 2-4 weeks later about this visit. The children, aged 4 and 5 years (N = 26), were interviewed with a forensic interview protocol. Children’s statements regarding distress and discomfort and the interviewer questions preceding these statements were analyzed qualitatively.

    The results showed that 46% of the 4-year-olds and 39 % of the 5-year-olds displayed discomfort or distress during their health visit. In the interviews, open-ended questions were posed to all children, however, these questions were sufficient to aid only some children (n = 6) to share evaluative content. None of the children who displayed distress or discomfort during the visit verbalized such experiences after an invitation only. Most children who described experiences of distress or discomfort did so in relation to evaluative questions.

    The results suggest that more research is warranted to investigate exactly how and when evaluative questions should be posed and whether this differs depending on severity of experience or the child’s age. The need for protocol development and its suitability when used in other fields of practice is discussed.

    Keyword
    investigative interviews, evaluative, emotion, question, distress
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Research subject
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-328585 (URN)10.1016/j.childyouth.2017.10.017 (DOI)
    Funder
    Swedish Research Council, 259-2012-68
    Note

    Forskningsfinansiär: Allmänna Barnhuset, FB13-0014

    Available from: 2017-10-11 Created: 2017-10-11 Last updated: 2017-10-19
    4. 'I felt a little bubbly in my tummy': Eliciting pre-schoolers' accounts of their health visit using a computer-assisted interview method.
    Open this publication in new window or tab >>'I felt a little bubbly in my tummy': Eliciting pre-schoolers' accounts of their health visit using a computer-assisted interview method.