uu.seUppsala universitets publikasjoner
1 - 26 of 26
rss atomLink til resultatlisten
Permanent link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
  • Disputas: 2019-04-23 09:15 B10:2, Uppsala
    Mahajan, Mayank
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    Evolution of cellular complexity and other remarkable features in Gemmataceae: Complex bacterial lineages defy prokaryotic trends2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Bacteria of the family Gemmataceae belong the phylum Planctomycetes and are remarkable because of their complex cellular architectures, previously considered to be traits exclusive to eukaryotes. This thesis provides clues to the atypical cell envelope, the enhanced radiotolerance and the amazing cellular complexity of these bacteria.

    A comparative genomics study of these bacteria revealed massive duplications and new combinations of structural domains that are highly abundant in eukaryotes but rare in bacteria. These domains are known to facilitate signalling and protein interactions. The proteins of these bacteria also contain long regions with no predicted domains. On average, eukaryotic proteins are longer and more disordered than prokaryotic proteins. Intriguingly, the length and fraction of disordered regions in proteins of some bacteria are higher than in many other prokaryotes, and these bacteria also have complex lifestyles. Many bacteria in the Planctomycetes, including the Gemmataceae, are among these few bacteria. This suggests that there is no sharp boundary between prokaryotes and eukaryotes with respect to protein length and domain composition patterns, as previously thought.

    A bioinformatics analysis revealed the loss of genes for the peptidoglycan cell wall in some lineages of the Planctomycetes. Loss of the gene for the FtsZ protein, the major cell division protein in bacteria, may have facilitated the evolution of budding in the Planctomycetales and led to the gradual loss of the cell wall and cell division gene cluster. These changes may have enabled the expansion of the inner membrane and triggered adaptive changes in conserved membrane proteins and transport systems. The loss of the peptidoglycan cell wall may also explain the altered cell morphology. A subcellular proteomics study showed that the DNA replication and repair proteins are associated with the cell envelope, which supports the cell factory model of DNA replication.

    T. immobilis, which has the simplest genome of all members of the Gemmataceae, was found to be naturally competent and most suitable for transformation experiments. T. immobilis was transformed to produce mutants in which the gene for DdrA, a double stranded break DNA repair protein, has been inactivated. The DdrA-null mutant showed a major loss in radiotolerance.

    Delarbeid
    1. Comparative genomics reveals massive paralogization and a role for protein interactions in the Gemmataceae, bacteria with complex cell structures
    Åpne denne publikasjonen i ny fane eller vindu >>Comparative genomics reveals massive paralogization and a role for protein interactions in the Gemmataceae, bacteria with complex cell structures
    Vise andre…
    2019 (engelsk)Manuskript (preprint) (Annet (populærvitenskap, debatt, mm))
    HSV kategori
    Forskningsprogram
    Biologi med inriktning mot molekylär evolution
    Identifikatorer
    urn:nbn:se:uu:diva-378565 (URN)
    Tilgjengelig fra: 2019-03-06 Laget: 2019-03-06 Sist oppdatert: 2019-03-22
    2. Independent losses of gene clusters for cell wall and cell division complexes in the Planctomycetes: clues to the evolution of cellular complexity
    Åpne denne publikasjonen i ny fane eller vindu >>Independent losses of gene clusters for cell wall and cell division complexes in the Planctomycetes: clues to the evolution of cellular complexity
    Vise andre…
    2019 (engelsk)Manuskript (preprint) (Annet (populærvitenskap, debatt, mm))
    HSV kategori
    Forskningsprogram
    Biologi med inriktning mot molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-378566 (URN)
    Tilgjengelig fra: 2019-03-06 Laget: 2019-03-06 Sist oppdatert: 2019-03-22
    3. Natural competence in the Planctomycetes and its use in transforming the Gemmata-related species Tuwongella immobilis
    Åpne denne publikasjonen i ny fane eller vindu >>Natural competence in the Planctomycetes and its use in transforming the Gemmata-related species Tuwongella immobilis
    Vise andre…
    2019 (engelsk)Manuskript (preprint) (Annet (populærvitenskap, debatt, mm))
    HSV kategori
    Forskningsprogram
    Biologi med inriktning mot molekylär evolution
    Identifikatorer
    urn:nbn:se:uu:diva-378567 (URN)
    Tilgjengelig fra: 2019-03-06 Laget: 2019-03-06 Sist oppdatert: 2019-03-22
    4. The subcellular proteome suggests that the replication machinery is located distinct from other information processing systems in the Gemmata-related bacterium Tuwongella immobilis.
    Åpne denne publikasjonen i ny fane eller vindu >>The subcellular proteome suggests that the replication machinery is located distinct from other information processing systems in the Gemmata-related bacterium Tuwongella immobilis.
    2019 (engelsk)Manuskript (preprint) (Annet (populærvitenskap, debatt, mm))
    HSV kategori
    Forskningsprogram
    Biologi med inriktning mot molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-378568 (URN)
    Tilgjengelig fra: 2019-03-06 Laget: 2019-03-06 Sist oppdatert: 2019-03-22
    5. Comparative proteomics identify the core proteome of growing bacterial cells of the family Gemmataceae
    Åpne denne publikasjonen i ny fane eller vindu >>Comparative proteomics identify the core proteome of growing bacterial cells of the family Gemmataceae
    2019 (engelsk)Manuskript (preprint) (Annet (populærvitenskap, debatt, mm))
    HSV kategori
    Forskningsprogram
    Biologi med inriktning mot molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-378569 (URN)
    Tilgjengelig fra: 2019-03-06 Laget: 2019-03-06 Sist oppdatert: 2019-03-22
  • Disputas: 2019-04-25 09:00 Hedstrandsalen, Uppsala
    Velickaite, Vilma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Analysis of regional atrophy on brain imaging compared with cognitive function in the elderly and in patients with dementia – cross-sectional and longitudinal evaluation2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    During aging, brain changes are not homogeneous throughout the entire brain, but are related to changes in the morphology of neurons, as well as to changes in the tissue density, and are specific to each region of the brain. Dementia is a broad category of brain disorders with a set of symptoms including memory, visual-spatial and language problems. Most types of dementia are slowly progressing, and by the time the person shows signs of the disorder, processes in the brain are already advanced. Dementia reduces not only the person’s ability to perform everyday activities, it also increases mortality rates significantly. Because of the increasing incidence of dementia, possible prevention and treatment of dementia as early as possible are essential.

    The aim of the PhD project is to compare a quantitative and qualitative image analysis of regional cerebral atrophy with cognitive function in the elderly persons.

    In paper I, 58 persons participated (84–88 years old) from the ULSAM (Uppsala Longitudinal Study of Adult Men) cohort. They underwent CT of the brain, cognitive testing and LP. This study showed that AD biomarkers seem to be less informative in subjects with an advanced age.

    In papers II–IV, the cohort included subjects from the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study.

    Paper II showed that at age 75, gender and education are confounders for MTA rating. Subjects with abnormal right MTA, but normal MMSE scores had developed worse MMSE scores 5 years later.

    Paper III showed that automated rating of MTA could be used in clinical practice to support the radiological evaluation. Automated rating of PA and F-GCA should be tested in future studies.

    In paper IV, we found a mild age-associated decrease in regional brain volumes in this healthy cohort with well-preserved cognitive and executive functions.

    In conclusion, the included studies in this thesis compare regional atrophy grades in the brain on CT and MRI and clinical data and provide knowledge that may be used in future investigations that aim to detect dementia in its early stages.

    Delarbeid
    1. Cognitive function in very old men does not correlate to biomarkers of Alzheimer's disease
    Åpne denne publikasjonen i ny fane eller vindu >>Cognitive function in very old men does not correlate to biomarkers of Alzheimer's disease
    Vise andre…
    2017 (engelsk)Inngår i: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 17, nr 1, artikkel-id 208Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: The Alzheimer's disease (AD) brain displays atrophy with amyloid-β (Aβ) and tau deposition, whereas decreased Aβ42 and increased tau are measured in cerebrospinal fluid (CSF). The aim of this study was to relate cognitive performance to the degree of brain atrophy, CSF biomarker levels and neuropathology in a cohort of aged men.

    METHODS: Fifty-eight 86-92-year-old men from the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort underwent cognitive testing, brain computed tomography and lumbar puncture. Atrophy was graded with established scales. Concentrations of CSF Aβ42, t-tau and p-tau were measured by ELISA. Thirteen brains were examined post mortem.

    RESULTS: Forty-six of the individuals were considered non-demented, whereas twelve were diagnosed with dementia, either at baseline (n = 4) or during follow-up (n = 8). When comparing subjects with and without dementia, there were no differences in the degree of atrophy, although the mini mental state examination (MMSE) scoring correlated weakly with the degree of medial temporal atrophy (MTA) (p = 0.04). Moreover, the CSF biomarker levels did not differ significantly between healthy (n = 27) and demented (n = 8) subjects (median values 715 vs 472 pg/ml for Aβ42, 414 vs 427 pg/ml for t-tau and 63 vs 60 pg/ml for p-tau). Similarly, there were no differences in the biomarker levels between individuals with mild (n = 24) and severe (n = 11) MTA (median values 643 vs 715 pg/ml for Aβ42, 441 vs 401 pg/ml for t-tau and 64 vs 53 pg/ml for p-tau). Finally, the neuropathological changes did not correlate with any of the other measures.

    CONCLUSION: In this cohort of aged men only a weak correlation could be seen between cognitive performance and MTA, whereas the various neuroradiological, biochemical and neuropathological measures did not correlate with each other. Thus, AD biomarkers seem to be less informative in subjects of an advanced age.

    Emneord
    AD biomarkers, Advanced age, Brain atrophy, CSF biomarkers, Cognitive performance, Neuropathology
    HSV kategori
    Forskningsprogram
    Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-329266 (URN)10.1186/s12877-017-0601-6 (DOI)000410449900002 ()28886705 (PubMedID)
    Merknad

    V. Velickaite and V. Giedraitis contributed equally.

    Tilgjengelig fra: 2017-09-11 Laget: 2017-09-11 Sist oppdatert: 2019-03-29bibliografisk kontrollert
    2. Medial temporal lobe atrophy ratings in a large 75-year-old population-based cohort: gender-corrected and education-corrected normative data
    Åpne denne publikasjonen i ny fane eller vindu >>Medial temporal lobe atrophy ratings in a large 75-year-old population-based cohort: gender-corrected and education-corrected normative data
    Vise andre…
    2018 (engelsk)Inngår i: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 28, nr 4, s. 1739-1747Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVES: To find cut-off values for different medial temporal lobe atrophy (MTA) measures (right, left, average, and highest), accounting for gender and education, investigate the association with cognitive performance, and to compare with decline of cognitive function over 5 years in a large population-based cohort.

    METHODS: Three hundred and ninety 75-year-old individuals were examined with magnetic resonance imaging of the brain and cognitive testing. The Scheltens's scale was used to assess visually MTA scores (0-4) in all subjects. Cognitive tests were repeated in 278 of them after 5 years. Normal MTA cut-off values were calculated based on the 10th percentile.

    RESULTS: Most 75-year-old individuals had MTA score ≤2. Men had significantly higher MTA scores than women. Scores for left and average MTA were significantly higher in highly educated individuals. Abnormal MTA was associated with worse results in cognitive test and individuals with abnormal right MTA had faster cognitive decline.

    CONCLUSION: At age 75, gender and education are confounders for MTA grading. A score of ≥2 is abnormal for low-educated women and a score of ≥2.5 is abnormal for men and high-educated women. Subjects with abnormal right MTA, but normal MMSE scores had developed worse MMSE scores 5 years later.

    KEY POINTS: • Gender and education are confounders for MTA grading. • We suggest cut-off values for 75-year-olds, taking gender and education into account. • Males have higher MTA scores than women. • Higher MTA scores are associated with worse cognitive performance.

    Emneord
    Cognitive test, Dementia, Longitudinal analysis, Medial temporal lobe atrophy (MTA), Population-based, Scheltens’s scale
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-333774 (URN)10.1007/s00330-017-5103-6 (DOI)000426645600044 ()29124383 (PubMedID)
    Forskningsfinansiär
    Stockholm County CouncilThe Karolinska Institutet's Research Foundation
    Tilgjengelig fra: 2017-11-16 Laget: 2017-11-16 Sist oppdatert: 2019-03-07bibliografisk kontrollert
    3. Automated ratings and volumetry versus visual ratings of regional brain atrophy in an elderly population
    Åpne denne publikasjonen i ny fane eller vindu >>Automated ratings and volumetry versus visual ratings of regional brain atrophy in an elderly population
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Medicinsk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-378288 (URN)
    Tilgjengelig fra: 2019-03-07 Laget: 2019-03-07 Sist oppdatert: 2019-03-07
    4. Visual rating versus volumetry of regional brain atrophy and longitudinal changes over a 5-year period in an elderly population
    Åpne denne publikasjonen i ny fane eller vindu >>Visual rating versus volumetry of regional brain atrophy and longitudinal changes over a 5-year period in an elderly population
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-378361 (URN)
    Tilgjengelig fra: 2019-03-07 Laget: 2019-03-07 Sist oppdatert: 2019-03-07
  • Disputas: 2019-04-25 09:00 Häggsalen, Ångströmlaboratoriet, Uppsala
    Song, Man
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Fasta tillståndets elektronik.
    Graphene Based Inks for Printed Electronics2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The outstanding properties of graphene make it attractive ink filler for conductive inks which plays an important role in printed electronics. This thesis focuses on the ink formulation based on graphene and graphene oxide (GO).

    Liquid phase exfoliation of graphite is employed to prepare graphene dispersions, i.e., shear- and electrochemical exfoliation. High concentration graphene dispersions with small size, few-layer graphene platelets are obtained by both methods. With the addition of ethyl cellulose stabilizer, shear-exfoliated graphene platelets in NMP were successfully inkjet printed on different substrates. The printed graphene film with electrical conductivity of ~3^104 S/m was obtained after annealing at 350 °C for one hour. Alternatively, the electrochemically exfoliated graphene nano-platelets were collected and redispersed in DMF to form inks. The printed film of conductivity ~2.5^103 S/m was obtained after annealing at 300 °C for one hour.

    Water based GO/Ag hybrid inks were developed for screen printing. When high concentration GO aqueous dispersion was mixed with reactive silver ink, the viscosity of the mixture increased instantly to above 1000 cP as a result of reactions between oxygen functional groups (OFGs) on GO sheets and ingredients in the reactive silver ink. When the screen printed lines with different GO:Ag ratios were annealed in air, the conductivity of the resultant reduced graphene oxide/silver nanoparticles (RGO/AgNPX) composites decreased as silver content increased. As oxygen enriched compounds in RGO/AgNPX composites were detected, we proposed that AgOx compounds were generated on the AgNPs surface, which raised the contact resistance between AgNPs and RGO flakes. To solve this problem, the printed patterns were instead annealed in reducing gas (Ar/H2 5%). The electrical conductivity ~2.0^104 S/m was then achieved.

    Furthermore, the reduction of GO using ammonium formate as reducing reagent was investigated. When applying a hydrothermal method, ammonium formate shows excellent reduction ability, surpassing the widely used reducing agent, L-ascorbic acid, under same condition. Elemental analysis shows the C/O ratio of RGO as high as ~11 and most OFGs were removed in the reduction process. Meanwhile, incorporated nitrogen atoms introduced active sites in resultant RGO, making it a promising electrocatalyst for oxygen reduction reaction.

    Delarbeid
    1. Scalable inkjet printing of shear-exfoliated graphene transparent conductive films
    Åpne denne publikasjonen i ny fane eller vindu >>Scalable inkjet printing of shear-exfoliated graphene transparent conductive films
    2016 (engelsk)Inngår i: Carbon, ISSN 0008-6223, E-ISSN 1873-3891, Vol. 102, s. 51-57Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In this study, we demonstrate scalable and efficient inkjet printing of graphene flexible transparent conducting films (TCFs). The highly concentrated and stable graphene ink (3.2 mg/mL) that is dominated by 4-layer graphene flakes is achieved by means of shear exfoliation process. The printed graphene TCFs with DC conductivity of ∼4 × 104 S/m (sheet resistance 260 Ω/□ coupled with optical transparency of 86%) without intentional doping are readily obtained. Excellent flexibility and air stability of the printed graphene TCFs allow their potential applications in different flexible opto-electronics devices. Systematic investigation of the inkjet printing of graphene and the annealing effect on the graphene TCFs is presented.

    Emneord
    Graphene, Inkjet printing, Transparent conductive films
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-276479 (URN)10.1016/j.carbon.2016.02.013 (DOI)000372808200006 ()
    Forskningsfinansiär
    Swedish Foundation for Strategic Research , Dnr SE13-0061Swedish Research Council, 621-2014-5596
    Tilgjengelig fra: 2016-02-14 Laget: 2016-02-14 Sist oppdatert: 2019-02-25bibliografisk kontrollert
    2. Inkjet printing of electrochemically-exfoliated graphene nano-platelets
    Åpne denne publikasjonen i ny fane eller vindu >>Inkjet printing of electrochemically-exfoliated graphene nano-platelets
    Vise andre…
    2016 (engelsk)Inngår i: Synthetic metals, ISSN 0379-6779, E-ISSN 1879-3290, Vol. 220, s. 318-322Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In this study, we report on a facile method of inkjet printing of graphene nano-platelets (GNPs). The GNPs are exfoliated from graphite by means of an electrochemical process in an inorganic salt based electrolyte. The electrochemically exfoliated GNPs with oxygen-bearing functional groups exhibit spectroscopic features similar to those of reduced graphene oxides. As a result, ink formulation with such GNPs for inkjet printing readily accomplishes without using stabilizer and various conductive objects are easily fabricated on different substrates by inkjet printing. The as-printed films of the electrochemically exfoliated GNPs deliver an electrical conductivity of 44 S/m, a typical value for as-printed pristine GNP films in the literature. A simple thermal treatment results in an improved DC conductivity by two orders of magnitude to ~2.5 × 103 S/m.

    sted, utgiver, år, opplag, sider
    Elsevier, 2016
    Emneord
    Graphene; Electrochemical process; Inkjet printing
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-298103 (URN)10.1016/j.synthmet.2016.06.029 (DOI)000383811300040 ()
    Forskningsfinansiär
    Swedish Foundation for Strategic Research , Dnr SE13-0061Swedish Research Council, 621-2014-5596
    Tilgjengelig fra: 2016-06-29 Laget: 2016-06-29 Sist oppdatert: 2019-02-25bibliografisk kontrollert
    3. Screen Printed Conductive Composites with Reduced Graphene Oxide and Silver
    Åpne denne publikasjonen i ny fane eller vindu >>Screen Printed Conductive Composites with Reduced Graphene Oxide and Silver
    2018 (engelsk)Inngår i: 2018 IMAPS Nordic Conference on Microelectronics Packaging (NordPac), 2018, s. 35-39Konferansepaper, Publicerat paper (Fagfellevurdert)
    Abstract [en]

    This work provides a method to fabricate conductive composites by screen printing of aqueous hybrid inks with graphene oxide (GO) and silver acetate as silver source. The formulation of the aqueous hybrid inks is realized by mixing highly concentrated GO solution and reactive silver solution, which readily results in a formation of viscous pastes. Composite films with four-probe structure were fabricated by means of blade coating, followed by annealing at 160 °C in air and subsequently at 600 °C in Ar/H 2 . While the reactive silver solution without GO can be completely reduced when annealed at 90 °C in air, resulting in elemental Ag films with resistivity close to the bulk value, no reduction occurs in the hybrid inks under the same annealing condition. Silver nanoparticles are formed from the hybrid inks at 160 °C and discretely distributed on the reduced GOs (rGOs), which shows a retardation effect of GO on the reduction of silver. Further annealing at 600 °C in Ar/H 2 leads to partial restoration of sp 2 lattice in the rGOs. The resistivity of the composite films increases as the silver content is increased, which is interpreted by using a percolation model with rGO networks.

    Emneord
    annealing, coatings, electrical conductivity, electrical resistivity, graphene compounds, mixing, nanocomposites, nanofabrication, nanoparticles, percolation, reduction (chemical), silver, thin films, aqueous hybrid inks, silver acetate, reactive silver solution, silver nanoparticles, reduced graphene oxide, screen printed conductive composites, viscous pastes, four-probe structure, blade coating, retardation effect, percolation model, temperature 160.0 degC, temperature 600.0 degC, temperature 90.0 degC, CO-Ag, Ink, Films, Conductivity, Printing, Graphene, graphene oxide, conductive composite, screen printing
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-363974 (URN)10.23919/NORDPAC.2018.8423856 (DOI)
    Konferanse
    2018 IMAPS Nordic Conference on Microelectronics Packaging (NordPac), 12th – 14th June 2018, Oulu, Finland
    Forskningsfinansiär
    Swedish Research Council, No. 621-2014-5596Swedish Foundation for Strategic Research , Dnr SE13-0061
    Tilgjengelig fra: 2018-10-22 Laget: 2018-10-22 Sist oppdatert: 2019-03-14bibliografisk kontrollert
    4. Efficient Gelation of Graphene Oxide Aqueous Dispersion Induced by Sonication-Promoted Leuckart Reaction
    Åpne denne publikasjonen i ny fane eller vindu >>Efficient Gelation of Graphene Oxide Aqueous Dispersion Induced by Sonication-Promoted Leuckart Reaction
    Vise andre…
    2018 (engelsk)Inngår i: ChemNanoMat, ISSN 2199-692X, Vol. 4, nr 11, s. 1145-1152Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Abstract Graphene oxide (GO) undergoes a rapid gelation process in the presence of ammonium hydroxide and formic acid at room temperature which is promoted by ultrasonication. Infrared and X-ray photoelectron spectroscopy proved partial reduction of GO and nitrogen incorporation, resulting from sonication-promoted Leuckart reactions at GO carbonyl groups. The amine groups produced via Leuckart reactions undergo further reactions that result in salt bridges with carboxylic groups and covalent cross-links, both of which contribute to the stabilization of the resulting hydrogel. The resultant GO hydrogel exhibits enhanced thermal stability.

    Emneord
    Gelation, graphene oxide, hydrogels, Leuckart reaction, ultrasonication
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-363972 (URN)10.1002/cnma.201800286 (DOI)000452398900006 ()
    Forskningsfinansiär
    Swedish Foundation for Strategic Research , SE13-0061Swedish Research Council, No. 621-2014-5596Knut and Alice Wallenberg Foundation
    Tilgjengelig fra: 2018-10-22 Laget: 2018-10-22 Sist oppdatert: 2019-02-25
    5. Nitrogen-doped Reduced Graphene Oxide Hydrogel Achieved via a One-Step Hydrothermal Process
    Åpne denne publikasjonen i ny fane eller vindu >>Nitrogen-doped Reduced Graphene Oxide Hydrogel Achieved via a One-Step Hydrothermal Process
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    We report an efficient one-step method to achieve highly reduced graphene oxide (rGO) hydrogel doped with nitrogen where the rGO sheets are interconnected forming a porous structure by means of hydrothermal process. During the synthesis, ammonium formate is used as reducing reagent and simultaneously as nitrogen supplier, which delivers nitrogen-doped rGO (NRGO) hydrogel that exhibits C/O atomic ratio as high as at ~11.1 and contains decent ~5.4 at.% nitrogen. As comparison, the reduction efficiency is only half of the value and no nitrogen doping can be obtained when L-ascorbic acid is used as reducing reagent. The resultant NRGO shows enhanced electrocatalytic ability for oxygen reduced reaction indicating its great potential of the one-step method for the catalyst and energy applications. 

    Emneord
    reduced graphene oxide, ammonium formate, hydrothermal, reduction, oxygen reduction reaction
    HSV kategori
    Forskningsprogram
    Teknisk fysik med inriktning mot elektronik
    Identifikatorer
    urn:nbn:se:uu:diva-377624 (URN)
    Forskningsfinansiär
    Swedish Foundation for Strategic Research , Dnr SE13-0061Swedish Research Council, 621-2014-5596
    Tilgjengelig fra: 2019-02-22 Laget: 2019-02-22 Sist oppdatert: 2019-02-25
  • Disputas: 2019-04-25 13:15 Room 2005, Uppsala
    Han, Yuanyuan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Biosensing platforms using graphene based bioreactive nanostructures with various dimensions2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Nanomaterials have brought new aspects and improvements to the biosensing field due to their unique physical and chemical properties that are not shown in the bulk state. This thesis focuses on concepting, developing and testing of biosensors where nanomaterials including graphene gold nanoparticles (AuNPs) and magnetic nanoparticles (MNPs) constitute the biosensors. The motivation is to improve the properties of biosensors for protein and nucleic acids by using the nanomaterials’ high surface volume ratio, their unique electrical properties, their good stability and biocompatibility.

    The synthesis of well controlled hybrid materials was essential to obtain well performing nucleic acids sensors, whereas a protein sensor contained mainly graphene and organic molecules. The nanomechanical measurements were applied on pyrene-maltose functionalized graphene surfaces after incubating them with the protein. When the Concanavalin A was captured by the pyrene-maltose, the adhesion force of biosensor surface increased significantly. This detection principle was employed to quantify the Concanavalin A attachment to the surface sensitively.

    In the development of the eletrocatalytic microRNA sensor, AuNPs were packaged into graphene oxide (GO) sheets to form three-dimensional network structures that both guide the electrical current and increase the surface area of the electrodes. Prior to the assembly of these GO-AuNPs hybrid materials, a duplex-specific nuclease-assisted target recycling reaction was employed for opening the surface of the DNA functionalized AuNPs. The electrocatalytical water splitting activity increased with the fraction of the AuNP surface and thus with the activity of the nuclease-assisted target recycling reaction.

    Owing to the high shape anisotropy of graphene, a two-dimensional optomagnetic label GO-MNP nanohybrid was investigated for DNA detection. The DNA coils that were generated through rolling circle amplification absorbed on GO-MNP nanohybrid, leading to a hydrodynamic size increase or aggregation of the proposed nanolabels that can be detected by an optomagnetic sensor. An MNP assembly-based microRNA biosensing strategy is also included in the thesis. DNA scaffolds of the MNP assemblies contain DNAzyme substrate and thus can form cleavage catalytic structures in the presence of microRNA, leading to the disintegration of assemblies. The proposed nanomaterials based biosensing platforms show great potential in the clinical and biomedical applications.

    Delarbeid
    1. Graphene Based Mechanical Biosensor by Employing Non-covalent Stacking Functionalization
    Åpne denne publikasjonen i ny fane eller vindu >>Graphene Based Mechanical Biosensor by Employing Non-covalent Stacking Functionalization
    Vise andre…
    2019 (engelsk)Inngår i: Artikkel i tidsskrift, News item (Annet vitenskapelig) Submitted
    Abstract [en]

    Herein we demonstrate a novel methodology to achieve mechanical biosensor by employing the distinguished interaction forces between the atomic force microscope (AFM) probe and sensor surfaces as the response signal. This mechanical biosensor is fabricated by utilizing the non-covalent π-π stacking of pyrene-maltose onto graphene surfaces with Concanavalin A (Con A) as a target protein. The atomic resolution scanning tunneling microscopy (STM) images indicate the successful formation of the self-assembled and densely packed pyrene-maltose layer on the sensor surface, which gives distinct atomic lattice structure as compared to pristine graphene. This mechanical biosensor exhibits detection of Con A with the sensitivity down to nanomolar level. Therefore, this proposed mechanical biosensor has the potential to be employed in a variety of bio-sensing applications.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-378559 (URN)
    Tilgjengelig fra: 2019-03-06 Laget: 2019-03-06 Sist oppdatert: 2019-03-06
    2. MicroRNA detection based on duplex-specific nuclease-assisted target recycling and gold nanoparticle/graphene oxide nanocomposite-mediated electrocatalytic amplification
    Åpne denne publikasjonen i ny fane eller vindu >>MicroRNA detection based on duplex-specific nuclease-assisted target recycling and gold nanoparticle/graphene oxide nanocomposite-mediated electrocatalytic amplification
    Vise andre…
    2019 (engelsk)Inngår i: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 127, s. 188-193Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    DNA technology based bio-responsive nanomaterials have been widely studied as promising tools for biomedical applications. Gold nanoparticles (AuNPs) and graphene oxide (GO) sheets are representative zero- and two-dimensional nanomaterials that have long been combined with DNA technology for point-of-care diagnostics. Herein, a cascade amplification system based on duplex-specific nuclease (DSN)-assisted target recycling and electrocatalytic water-splitting is demonstrated for the detection of microRNA. Target microRNAs can form DNA: RNA heteroduplexes with DNA probes on the surface of AuNPs, which can be hydrolyzed by DSN. MicroRNAs are preserved during the reaction and released into the suspension for the digestion of multiple DNA probes. After the DSN-based reaction, AuNPs are collected and mixed with GO to form AuNP/GO nanocomposite on an electrode for the following electrocatalytic amplification. The utilization of AuNP/GO nanocomposite offers large surface area, exceptional affinity to water molecules, and facilitated mass diffusion for the water-splitting reaction. For let-7b detection, the proposed biosensor achieved a limit detection of 1.5 fM in 80 min with a linear detection range of approximately four orders of magnitude. Moreover, it has the capability of discriminating non-target microRNAs containing even single-nucleotide mismatches, thus holding considerable potential for clinical diagnostics.

    Emneord
    Gold nanoparticles, Graphene oxide, MicroRNA detection, Electrocatalytic amplification, Duplex-specific nuclease
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-377203 (URN)10.1016/j.bios.2018.12.027 (DOI)000457508800026 ()30611105 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 2016-05259Knut and Alice Wallenberg FoundationEU, Horizon 2020, 713683
    Tilgjengelig fra: 2019-02-25 Laget: 2019-02-25 Sist oppdatert: 2019-03-07bibliografisk kontrollert
    3. MicroRNA Detection through DNAzyme-Mediated Disintegration of Magnetic Nanoparticle Assemblies
    Åpne denne publikasjonen i ny fane eller vindu >>MicroRNA Detection through DNAzyme-Mediated Disintegration of Magnetic Nanoparticle Assemblies
    Vise andre…
    2018 (engelsk)Inngår i: ACS Sensors, ISSN 2379-3694, Vol. 3, s. 1884-1891Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    DNA-assembled nanoparticle superstructures offer numerous bioresponsive properties that can be utilized for point-of-care diagnostics. Functional DNA sequences such as deoxyribozymes (DNAzymes) provide novel bioresponsive strategies and further extend the application of DNA-assembled nanoparticle superstructures. In this work, we describe a microRNA detection biosensor that combines magnetic nanoparticle (MNP) assemblies with DNAzyme-assisted target recycling. The DNA scaffolds of the MNP assemblies contain substrate sequences for DNAzyme and can form cleavage catalytic structures in the presence of target DNA or RNA sequences, leading to rupture of the scaffolds and disintegration of the MNP assemblies. The target sequences are preserved during the cleavage reaction and release into the suspension to trigger the digestion of multiple DNA scaffolds. The high local concentration of substrate sequences in the MNP assemblies reduces the diffusion time for target recycling. The concentration of released MNPs, which is proportional to the concentration of the target, can be quantified by a 405 nm laser-based optomagnetic sensor. For the detection of let-7b in 10% serum, after 1 h of isothermal reaction at 50 degrees C, we found a linear detection range between 10 pM and 100 nM with a limit of detection of 6 pM. For the quantification of DNA target in buffer solution, a limit of detection of 1.5 pM was achieved. Compared to protein enzyme-based microRNA detection methods, the proposed DNAzyme-based biosensor has an increased stability, a reduced cost and a possibility to be used in living cells, all of which are valuable features for biosensing applications.

    HSV kategori
    Forskningsprogram
    Teknisk fysik med inriktning mot fasta tillståndets fysik
    Identifikatorer
    urn:nbn:se:uu:diva-363317 (URN)10.1021/acssensors.8b00850 (DOI)000446276300038 ()30188122 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council Formas, 221-2012-444Swedish Research Council Formas, 2011-1692EU, FP7, Seventh Framework Programme, 604448-NanoMag
    Tilgjengelig fra: 2018-10-16 Laget: 2018-10-16 Sist oppdatert: 2019-03-06bibliografisk kontrollert
    4. Self-Assembled Magnetic Nanoparticle−Graphene Oxide Nanotag for Optomagnetic Detection of DNA
    Åpne denne publikasjonen i ny fane eller vindu >>Self-Assembled Magnetic Nanoparticle−Graphene Oxide Nanotag for Optomagnetic Detection of DNA
    Vise andre…
    (engelsk)Inngår i: Artikkel i tidsskrift, News item (Fagfellevurdert) Accepted
    Abstract [en]

    In this work, a two-dimensional self-assembled magnetic nanoparticle-graphene oxide (MNP-GO) nanocomposite is reported for the detection of DNA. Single-stranded DNA (ssDNA) coils, generated through a rolling circle amplification (RCA) reaction triggered by the hybridization of target oligos and padlock probes, have a strong interaction with MNP-GO nanotags through several mechanisms including π−π stacking, hydrogen bonding, van der Waals, electrostatic, and hydrophobic interactions. This interaction leads to a hydrodynamic size increase or aggregation of MNP-GO nanotags, which can be detected by a simple optomagnetic setup. Due to the high shape anisotropy, MNP-GO nanotags provide stronger optomagnetic signal than individual MNPs. Moreover, the avoidance of DNA probes (i.e., short ssDNA sequences as the biosensing receptor) provides easier material preparation and lower measurement cost. From real-time measurements of interactions between MNP-GO and RCA products amplified from a highly conserved E. coli 16S rDNA sequence, a limit of detection of 2 pM was achieved with a total assay time of 90 min. Although the nonspecific binding force between GO and ssDNA is much weaker than the specific base-pairing force in a DNA duplex, the proposed method provides a detection limit similar to DNA probe-based magnetic biosensors, which can be ascribed to the abundant binding sites between GO and ssDNA. In addition, for target concentrations higher than 100 pM, the MNP-GO nanotags can be applied for a qualitative naked eye detection strategy based on nanotag-ssDNA flocculation.

    sted, utgiver, år, opplag, sider
    USA: American Chemical Society (ACS)
    Emneord
    Magnetic nanoparticles; graphene oxide; rolling circle amplification; single stranded DNA detection; optomagnetic sensing
    HSV kategori
    Forskningsprogram
    Analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-378551 (URN)10.1021/acsanm.9b00127 (DOI)
    Tilgjengelig fra: 2019-03-06 Laget: 2019-03-06 Sist oppdatert: 2019-03-13
    5. Size-dependent elasticity of gold nanoparticle measured by atomic force microscope based nanoindentation
    Åpne denne publikasjonen i ny fane eller vindu >>Size-dependent elasticity of gold nanoparticle measured by atomic force microscope based nanoindentation
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The elasticity is one of the key properties in gold nanoparticles (AuNPs) and plays an essential role in the process design and applications. In this work, we have proposed an Argon plasma based technique to obtain well dispersed and neat AuNPs without surface functional groups. Our investigation on the size-dependent elasticity focused on the AuNPs with the size ranging from 2 nm to 12 nm by using atomic force microscope based nanoindentation technique under the peakforce quantitative nanomechanical mapping mode. The results show clearly that when the AuNPs are smaller than 6 nm, there is a significant increase in the elasticity as the smallest nanoparticles displacing an elastic modulus of ~140 GPa.  Our result provides important experimental evidence that contributes to a better understanding of the size-property relations as well as process design in AuNPs, and it also can be applied to measure the mechanical properties in a wide range of nano-objects.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-378556 (URN)
    Tilgjengelig fra: 2019-03-06 Laget: 2019-03-06 Sist oppdatert: 2019-03-06
  • Disputas: 2019-04-26 09:00 Ång 4101, Uppsala
    Ryeznik, Yevgen
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Matematiska institutionen.
    Optimal adaptive designs and adaptive randomization techniques for clinical trials2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In this Ph.D. thesis, we investigate how to optimize the design of clinical trials by constructing optimal adaptive designs, and how to implement the design by adaptive randomization. The results of the thesis are summarized by four research papers preceded by three chapters: an introduction, a short summary of the results obtained, and possible topics for future work.

    In Paper I, we investigate the structure of a D-optimal design for dose-finding studies with censored time-to-event outcomes. We show that the D-optimal design can be much more efficient than uniform allocation design for the parameter estimation. The D-optimal design obtained depends on true parameters of the dose-response model, so it is a locally D-optimal design. We construct two-stage and multi-stage adaptive designs as approximations of  the D-optimal design when prior information about model parameters is not available. Adaptive designs provide very good approximations to the locally D-optimal design, and can potentially reduce total sample size in a study with a pre-specified stopping criterion.

    In Paper II, we investigate statistical properties of several restricted randomization procedures which target unequal allocation proportions in a multi-arm trial. We compare procedures in terms of their operational characteristics such as balance, randomness, type I error/power, and allocation ratio preserving (ARP) property. We conclude that there is no single “best” randomization procedure for all the target allocation proportions, but the choice of randomization can be done through computer-intensive simulations for a particular target allocation.

    In Paper III, we combine the results from the papers I and II to implement optimal designs in practice when the sample size is small. The simulation study done in the paper shows that the choice of randomization procedure has an impact on the quality of dose-response estimation. An adaptive design with a small cohort size should be implemented with a procedure that ensures a “well-balanced” allocation according to the D-optimal design at each stage.

    In Paper IV, we obtain an optimal design for a comparative study with unequal treatment costs and investigate its properties. We demonstrate that unequal allocation may decrease the total study cost while having the same power as traditional equal allocation. However, a larger sample size may be required. We suggest a strategy on how to choose a suitable randomization procedure which provides a good trade-off between balance and randomness to implement optimal allocation. If there is a strong linear trend in observations, then the ARP property is important to maintain the type I error and power at a certain level. Otherwise, a randomization-based inference can be a good alternative for non-ARP procedures.

    Delarbeid
    1. Adaptive Optimal Designs for Dose-Finding Studies with Time-to-Event Outcomes
    Åpne denne publikasjonen i ny fane eller vindu >>Adaptive Optimal Designs for Dose-Finding Studies with Time-to-Event Outcomes
    2018 (engelsk)Inngår i: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, nr 1, artikkel-id 24Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We consider optimal design problems for dose-finding studies with censored Weibull time-to-event outcomes. Locally D-optimal designs are investigated for a quadratic dose-response model for log-transformed data subject to right censoring. Two-stage adaptive D-optimal designs using maximum likelihood estimation (MLE) model updating are explored through simulation for a range of different dose-response scenarios and different amounts of censoring in the model. The adaptive optimal designs are found to be nearly as efficient as the locally D-optimal designs. A popular equal allocation design can be highly inefficient when the amount of censored data is high and when the Weibull model hazard is increasing. The issues of sample size planning/early stopping for an adaptive trial are investigated as well. The adaptive D-optimal design with early stopping can potentially reduce study size while achieving similar estimation precision as the fixed allocation design.

    sted, utgiver, år, opplag, sider
    Springer, 2018
    Emneord
    adaptive design, censoring, D-optimal design, dose finding, Weibull distribution
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-347660 (URN)10.1208/s12248-017-0166-5 (DOI)000424638500012 ()
    Forskningsfinansiär
    EU, FP7, Seventh Framework Programme
    Tilgjengelig fra: 2018-04-06 Laget: 2018-04-06 Sist oppdatert: 2019-02-22bibliografisk kontrollert
    2. A comparative study of restricted randomization procedures for multiarm trials with equal or unequal treatment allocation ratios
    Åpne denne publikasjonen i ny fane eller vindu >>A comparative study of restricted randomization procedures for multiarm trials with equal or unequal treatment allocation ratios
    2018 (engelsk)Inngår i: Statistics in Medicine, ISSN 0277-6715, E-ISSN 1097-0258, Vol. 37, nr 21, s. 3056-3077Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Randomization designs for multiarm clinical trials are increasingly used in practice, especially in phase II dose-ranging studies. Many new methods have been proposed in the literature; however, there is lack of systematic, head-to-head comparison of the competing designs. In this paper, we systematically investigate statistical properties of various restricted randomization procedures for multiarm trials with fixed and possibly unequal allocation ratios. The design operating characteristics include measures of allocation balance, randomness of treatment assignments, variations in the allocation ratio, and statistical characteristics such as type I error rate and power. The results from the current paper should help clinical investigators select an appropriate randomization procedure for their clinical trial. We also provide a web-based R shiny application that can be used to reproduce all results in this paper and run simulations under additional user-defined experimental scenarios.

    Emneord
    allocation ratio preserving, dose ranging, multiarm trial, randomization design, unequal allocation
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-362628 (URN)10.1002/sim.7817 (DOI)000441861400003 ()29869347 (PubMedID)
    Tilgjengelig fra: 2018-10-10 Laget: 2018-10-10 Sist oppdatert: 2019-02-22bibliografisk kontrollert
    3. Implementing Optimal Designs for Dose-Response Studies Through Adaptive Randomization for a Small Population Group
    Åpne denne publikasjonen i ny fane eller vindu >>Implementing Optimal Designs for Dose-Response Studies Through Adaptive Randomization for a Small Population Group
    2018 (engelsk)Inngår i: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, nr 5, artikkel-id 85Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In dose-response studies with censored time-to-event outcomes, D-optimal designs depend on the true model and the amount of censored data. In practice, such designs can be implemented adaptively, by performing dose assignments according to updated knowledge of the dose-response curve at interim analysis. It is also essential that treatment allocation involves randomization-to mitigate various experimental biases and enable valid statistical inference at the end of the trial. In this work, we perform a comparison of several adaptive randomization procedures that can be used for implementing D-optimal designs for dose-response studies with time-to-event outcomes with small to moderate sample sizes. We consider single-stage, two-stage, and multi-stage adaptive designs. We also explore robustness of the designs to experimental (chronological and selection) biases. Simulation studies provide evidence that both the choice of an allocation design and a randomization procedure to implement the target allocation impact the quality of dose-response estimation, especially for small samples. For best performance, a multi-stage adaptive design with small cohort sizes should be implemented using a randomization procedure that closely attains the targeted D-optimal design at each stage. The results of the current work should help clinical investigators select an appropriate randomization procedure for their dose-response study.

    sted, utgiver, år, opplag, sider
    SPRINGER, 2018
    Emneord
    D-optimal, randomization design, small population group, time-to-event outcome, unequal allocation
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-361482 (URN)10.1208/s12248-018-0242-5 (DOI)000439535200001 ()30027336 (PubMedID)
    Tilgjengelig fra: 2018-09-26 Laget: 2018-09-26 Sist oppdatert: 2019-02-22bibliografisk kontrollert
    4. Implementing Unequal Randomization in Clinical Trials with Heterogeneous Treatment Costs
    Åpne denne publikasjonen i ny fane eller vindu >>Implementing Unequal Randomization in Clinical Trials with Heterogeneous Treatment Costs
    2019 (engelsk)Inngår i: Statistics in MedicineArtikkel i tidsskrift (Fagfellevurdert) Submitted
    Abstract [en]

    Equal randomization has been a popular choice in clinical trial practice. However, in trials with heterogeneous variances and/or variable treatment costs, as well as in the settings where maximization of every trial participant’s benefit is an important design consideration, optimal allocation proportions may be unequal across study treatment arms. In this paper, we investigate optimal allocation designs minimizing study cost under statistical efficiency constraints for parallel group clinical trials comparing several investigational treatments against the control. We show theoretically that equal allocation designs may be suboptimal, and unequal allocation designs can provide higher statistical power for the same budget, or result in a smaller cost for the same level of power. We also show how the optimal allocation can be implemented in practice by means of restricted randomization procedures, and how to perform statistical inference following these procedures, using invoked population-based or randomization-based approaches. Our results provide further support to some previous findings in the literature that unequal randomization designs can be cost-efficient and can be successfully implemented in practice. We conclude that the choice of the target allocation, the randomization procedure and the statistical methodology for data analysis are essential components to ensure valid, powerful, and robust clinical trial results.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-377608 (URN)
    Tilgjengelig fra: 2019-02-22 Laget: 2019-02-22 Sist oppdatert: 2019-02-22
  • Disputas: 2019-04-26 09:00 Humanistiska Teatern, Uppsala
    von der Heyde, Benedikt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Translating Cardiac and Cardiometabolic GWAS Using Zebrafish2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified thousands of loci associated with cardiac and cardiometabolic traits. However, the trait-associated variants usually do not clearly point to causal gene(s), mechanism(s) or tissue(s). Model systems that allow for a comprehensive and quick candidate gene screening are necessary, ideally in vivo. The overall objective of my thesis is to establish large-scale, imaged-based screens in zebrafish embryos and larvae to examine candidate genes for their effects on heart rate and rhythm, as well as on early-onset atherosclerosis and dyslipidemia.

    In Study 1, I prioritized 18 candidate genes in eight loci identified in a meta-analysis of GWAS for heart rate variability. Some of these genes were already known to be involved in cardiac pacemaking, whereas others require functional characterization.

    In Study 2, I established an experimental pipeline to examine genetic effects on cardiac rate and rhythm and used it to characterize orthologues of six human candidate genes for heart rate and rhythm. I confirmed known effects of rgs6 and hcn4, and established a role for KIAA1755 in HRV.

    In Study 3, I contributed to large-scale experiments to establish the zebrafish as a model system for early-onset atherosclerosis and dyslipidemia. Overfeeding and cholesterol-supplementation of the diet were shown to propel independent pro-atherogenic effects. Atherosclerotic burden was alleviated using commonly prescribed drugs in humans. Lastly, the effects of proof-of-concept genes known to be involved in lipid metabolism were examined and showed higher LDLc (apoea) and early-onset atherosclerosis (apobb1).

    In Study 4, I characterized genes in GWAS-identified loci for triglyceride levels for a role in lipid metabolism and early-stage atherosclerosis. I identified three previously unanticipated genes that influence triglyceride levels in zebrafish larvae. Several additional genes influence other cardiometabolic risk factors. Interestingly, two genes showed trends towards lower triglycerides levels (dock7 and lpar2a), with directionally opposite effects on vascular inflammation. This emphasizes that candidate genes need to be examined comprehensively to guide further mechanistic studies.

    Delarbeid
    1. Genetic loci associated with heart rate variability and their effects on cardiac disease risk
    Åpne denne publikasjonen i ny fane eller vindu >>Genetic loci associated with heart rate variability and their effects on cardiac disease risk
    Vise andre…
    2017 (engelsk)Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikkel-id 15805Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

    sted, utgiver, år, opplag, sider
    NATURE PUBLISHING GROUP, 2017
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-329672 (URN)10.1038/ncomms15805 (DOI)000403216600001 ()28613276 (PubMedID)
    Tilgjengelig fra: 2017-09-19 Laget: 2017-09-19 Sist oppdatert: 2019-03-11bibliografisk kontrollert
    2. Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo, image-based, large-scale genetic screen in zebrafish
    Åpne denne publikasjonen i ny fane eller vindu >>Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo, image-based, large-scale genetic screen in zebrafish
    Vise andre…
    (engelsk)Inngår i: Artikkel i tidsskrift (Fagfellevurdert) Submitted
    Abstract [en]

    A meta-analysis of genome-wide association studies (GWAS) identified eight loci that are associated with heart rate variability (HRV) in data from 53,174 individuals. However, functional follow-up experiments - aiming to identify and characterize causal genes in these loci - have not yet been performed. We developed an image- and CRISPR-Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos and larvae. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in fertilized eggs from fish that transgenically express GFP on smooth muscle cells (Tg(acta2:GFP)), to visualize the beating heart using a fluorescence microscope. An automated analysis of repeated 30s recordings of 381 live zebrafish atria at 2 and 5 days post-fertilization highlighted genes that influence HRV (hcn4 and kiaa1755); heart rate (rgs6 and hcn4) and the risk of sinoatrial pauses and arrests (hcn4). Hence, our screen confirmed the role of established genes for heart rate (rgs6 and hcn4), and highlighted a novel gene implicated in HRV (kiaa1755).

    Emneord
    GWAS, Zebrafish
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-378938 (URN)
    Tilgjengelig fra: 2019-03-11 Laget: 2019-03-11 Sist oppdatert: 2019-03-11
    3. Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
    Åpne denne publikasjonen i ny fane eller vindu >>Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
    Vise andre…
    (engelsk)Inngår i: Artikkel i tidsskrift (Fagfellevurdert) Submitted
    Abstract [en]

    Background: Hundreds of loci have been robustly associated with circulating lipids, atherosclerosis and coronary artery disease; but for most loci the causal genes and mechanisms remain uncharacterized.

    Methods: We developed a semi-automated experimental pipeline for systematic, quantitative, large-scale characterization of mechanisms, drugs and genes associated with dyslipidemia and atherosclerosis in a zebrafish model system. We validated our pipeline using a dietary (n>2000), drug treatment (n>1000), and genetic intervention (n=384).

    Results: Our results show that five days of overfeeding and cholesterol supplementation had independent pro-atherogenic effects, which could be diminished by concomitant treatment with atorvastatin and ezetimibe. CRISPR-Cas9-induced mutations in orthologues of proof-of-concept genes resulted in higher LDL cholesterol levels (apoea), and more early stage atherosclerosis (apobb.1).

    Conclusions: In summary, our pipeline facilitates systematic, in vivo characterization of drugs and candidate genes to increase our understanding of disease etiology, and can likely help identify novel targets for therapeutic intervention.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-378939 (URN)
    Tilgjengelig fra: 2019-03-11 Laget: 2019-03-11 Sist oppdatert: 2019-03-11
    4. Characterising candidate genes for cardiometabolic risk factors in GWAS-identified loci for triglyceride levels using a high-throughput zebrafish screen
    Åpne denne publikasjonen i ny fane eller vindu >>Characterising candidate genes for cardiometabolic risk factors in GWAS-identified loci for triglyceride levels using a high-throughput zebrafish screen
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-378940 (URN)
    Tilgjengelig fra: 2019-03-11 Laget: 2019-03-11 Sist oppdatert: 2019-03-11
  • Disputas: 2019-04-26 09:15 Sal X, Uppsala
    Berglund, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Socialmedicinsk epidemiologi.
    Adherence to drug treatment and interpretation of treatment effects2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Suboptimal adherence to medical treatments is prevalent across several clinical conditions and can lead to treatment failure. Adherence is a far from fully explored phenomenon and there is little knowledge about how patients interpret treatment effects. Commonly used treatment evaluation measures are often relative measures, which may be difficult for lay people and patients to understand.

    The overall aim of this thesis was to investigate factors with relevance to adherence, to estimate treatment effects with the time-based Delay of Event (DoE) measure in anticoagulant preventive treatments, and to explore how lay people responded to the DoE measure, as compared with established measures, regarding treatment decisions and effect interpretation.

    A quantitative population-based cross-sectional design was used for Study I. Study II used data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) clinical trial and estimated effects as DoEs. Studies III and IV were carried out as randomised survey experiments.

    The results showed that general adherence behaviour was associated with both environmental and social factors. Estimations of DoE showed that stroke or systemic embolism was delayed 181 (95% CI 76 to 287) days through twenty-two months of apixaban use, as compared with  warfarin use. The delay of major and intracranial bleeding was 206 (95% CI 130 to 281) and 392 (95% CI 249 to 535) days, respectively, due to apixaban use for twenty-two months, as compared with  warfarin use. Presenting preventive treatment effects as DoEs to lay people was associated with high willingness to initiate treatment and positive views on treatment benefits and willingness to pay for treatment.

    Non-optimal adherence was partly associated with modifiable factors and it might be possible to increase adherence by managing these factors. Estimations of DoEs in preventive treatments gave information on effects regarding delay of different outcomes; the estimation also provides tools that might be useful for interpreting and communicating treatment effects in clinical decision-making. Lay people seemed to react rationally to variations in DoE magnitude; a higher proportion accepted treatment when the magnitude was greater.

    Delarbeid
    1. Living environment, social support and informal caregiving are associated with health care seeking behaviour and adherence to medication treatment: a cross-sectional population study
    Åpne denne publikasjonen i ny fane eller vindu >>Living environment, social support and informal caregiving are associated with health care seeking behaviour and adherence to medication treatment: a cross-sectional population study
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Despite the well-known associations between local environment and health, few studies have focused on environment and health care utiliza-tion, for instance health care seeking behaviour or adherence. This study was aimed at analysing housing type, behaviour based on perceived local outdoor safety, social support, informal caregiving, demographics, socioeconomics, and long-term illness, and associations with health-seeking and adherence behaviours at a population level. This study used data from the Swedish National Public Health Survey 2004–2014, an annually repeated, large sample, cross-sectional, population-based sur-vey study. In all, questionnaires from 100,433 individuals were returned by post, making the response rate 52.9% (100,433/190,000). Descrip-tive statistics and multiple logistic regressions were used to investigate associations between explanatory variables and the outcomes of refrain-ing from seeking care and non-adherence behaviour. Living in rented apartment, lodger, a dorm or other was associated with reporting refrain-ing from seeking care (adjusted OR 1.16, 95% CI 1.00–1.22), and non-adherence (adjusted OR 1.22; 95% CI 1.13–1.31). Refraining from go-ing out due to a perceived unsafe neighbourhood was associated with refraining from seeking care (adjusted OR 1.59, 95% CI 1.51–1.67) and non-adherence (adjusted OR 1.26, 95% CI 1.17–1.36). Social support and status as an informal caregiver was associated with higher odds of refraining from seeking medical care and non-adherence. This study suggests that living in rental housing, refraining from going out due to neighbourhood safety concerns, lack of social support or informal care-giver status are associated with lower health-seeking behaviour and non-adherence to prescribed medication.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-379066 (URN)
    Tilgjengelig fra: 2019-03-11 Laget: 2019-03-11 Sist oppdatert: 2019-03-11
    2. Effects of apixaban compared with warfarin as gain in event-free time – a novel assessment of the results of the ARISTOTLE trial
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of apixaban compared with warfarin as gain in event-free time – a novel assessment of the results of the ARISTOTLE trial
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-379073 (URN)
    Tilgjengelig fra: 2019-03-11 Laget: 2019-03-11 Sist oppdatert: 2019-03-11
    3. Treatment effect expressed as the novel Delay of Event measure is associated with high willingness to initiate preventive treatment - A randomized survey experiment comparing effect measures
    Åpne denne publikasjonen i ny fane eller vindu >>Treatment effect expressed as the novel Delay of Event measure is associated with high willingness to initiate preventive treatment - A randomized survey experiment comparing effect measures
    2016 (engelsk)Inngår i: Patient Education and Counseling, ISSN 0738-3991, E-ISSN 1873-5134, Vol. 99, nr 12, s. 2005-2011Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objectives: This study aimed to investigate patients' willingness to initiate a preventive treatment and compared two established effect measures to the newly developed Delay of Events (DoE) measure that expresses treatment effect as a gain in event-free time. Methods: In this cross-sectional, randomized survey experiment in the general Swedish population, 1079 respondents (response rate 60.9%) were asked to consider a preventive cardiovascular treatment. Respondents were randomly allocated to one of three effect descriptions: DoE, relative risk reduction (RRR), or absolute risk reduction (ARR). Univariate and multivariate analyses were performed investigating willingness to initiate treatment, views on treatment benefit, motivation and importance to adhere and willingness to pay for treatment. Results: Eighty-one percent were willing to take the medication when the effect was described as DoE, 83.0% when it was described as RRR and 62.8% when it was described as ARR. DoE and RRR was further associated with positive views on treatment benefit, motivation, importance to adhere and WTP. Conclusions: Presenting treatment effect as DoE or RRR was associated with a high willingness to initiate treatment. Practice implications: An approach based on the novel time-based measure DoE may be of value in clinical communication and shared decision making.

    Emneord
    Preventive measures, Adherence, Decision-making, Treatment outcome, Randomized, Survey experiment
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-315088 (URN)10.1016/j.pec.2016.07.028 (DOI)000391223200012 ()27499030 (PubMedID)
    Forskningsfinansiär
    Swedish Society of Medicine
    Tilgjengelig fra: 2017-02-08 Laget: 2017-02-08 Sist oppdatert: 2019-03-11bibliografisk kontrollert
    4. Length of time periods in treatment effect descriptions and willingness to initiate preventive therapy: a randomised survey experiment
    Åpne denne publikasjonen i ny fane eller vindu >>Length of time periods in treatment effect descriptions and willingness to initiate preventive therapy: a randomised survey experiment
    2018 (engelsk)Inngår i: BMC Medical Informatics and Decision Making, ISSN 1472-6947, E-ISSN 1472-6947, Vol. 18, artikkel-id 106Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background Common measures used to describe preventive treatment effects today are proportional, i.e. they compare the proportions of events in relative or absolute terms, however they are not easily interpreted from the patient's perspective and different magnitudes do not seem to clearly discriminate between levels of effect presented to people. Methods In this randomised cross-sectional survey experiment, performed in a Swedish population-based sample (n=1041, response rate 58.6%), the respondents, aged between 40 and 75years were given information on a hypothetical preventive cardiovascular treatment. Respondents were randomised into groups in which the treatment was described as having the effect of delaying a heart attack for different periods of time (Delay of Event,DoE): 1month, 6months or 18months. Respondents were thereafter asked about their willingness to initiate such therapy, as well as questions about how they valued the proposed therapy. ResultsLonger DoE:s were associated with comparatively greater willingness to initiate treatment. The proportions accepting treatment were 81, 71 and 46% when postponement was 18months, 6months and 1month respectively. In adjusted binary logistic regression models the odds ratio for being willing to take therapy was 4.45 (95% CI 2.72-7.30) for a DoE of 6months, and 6.08 (95% CI 3.61-10.23) for a DoE of 18months compared with a DoE of 1month. Greater belief in the necessity of medical treatment increased the odds of being willing to initiate therapy. ConclusionsLay people's willingness to initiate preventive therapy was sensitive to the magnitude of the effect presented as DoE. The results indicate that DoE is a comprehensible effect measure, of potential value in shared clinical decision-making.

    sted, utgiver, år, opplag, sider
    BMC, 2018
    Emneord
    Medical decision-making, Risk communication, Risk perception, Necessity-concern framework
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-371868 (URN)10.1186/s12911-018-0662-2 (DOI)000450786000002 ()30458757 (PubMedID)
    Tilgjengelig fra: 2019-01-07 Laget: 2019-01-07 Sist oppdatert: 2019-03-11bibliografisk kontrollert
  • Disputas: 2019-04-26 10:00 Zootissalen, Uppsala
    Jones, William
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Zooekologi.
    Avian Malaria and Interspecific Interactions in Ficedula Flycatchers2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Parasitism is a core theme in ecological and evolutionary studies. Despite this, there are still gaps in our knowledge regarding host-parasite interactions in nature. Furthermore, in an era of human-induced, global climatic and environmental change revealing the roles that parasites play in host life-histories, interspecific interactions and host distributions is of the utmost importance. In this thesis, I explore avian malaria parasites (haemosporidians) in two species of passerine birds: the collared flycatcher Ficedula albicollis and the pied flycatcher F. hypoleuca. In Paper I, I show that an increase in spring temperature has led to rapid divergence in breeding times for the two flycatcher species, with collared flycatchers breeding significantly earlier than pied flycatchers. This has facilitated regional coexistence through the build up of temporal isolation. In Paper II, I explore how malaria assemblages across the breeding ranges of collared and pied flycatchers vary. I find that pied flycatcher populations have significantly higher infection prevalence than collared flycatchers, but collared flycatchers have a higher diversity of parasites. Additionally, I find that recently colonised flycatchers have kept their original parasite assemblages while gaining further parasites from native pied flycatchers. In Paper III, I explore age-related patterns of malaria infections in collared flycatchers. I find that female collared flycatchers have higher overall infection rates than males and that infected female collared flycatchers have significantly higher mortality rates than uninfected females while males pay no survival cost. Despite this, female collared flycatchers do not pay a fitness cost, despite their shorter lifespans. In Paper IV, I explore nest defence behaviours of infected and uninfected collared flycatchers. I find that malaria infection significantly interacts with age and that young, infected collared flycatchers have a lower intensity of defence behaviours than uninfected individuals, while the opposite pattern is present in older collared flycatchers, with infected birds having higher defence behaviours. Therefore, I argue that Papers III and VI suggest patterns of terminal investment are present in collared flycatchers. Finally, in Paper V, I investigate parasite transmission in pied and collared flycatchers. I find that infected individuals of both species produce higher quantities of volatile organic compounds (VOCs) than uninfected individuals. Additionally, there is a significant increase in VOCs produced when the number of malaria gametocytes is higher. This suggests that malaria parasites are able to manipulate their hosts into producing insect-vector attracting compounds and that this is further increased at peak infectivity. These findings help to fill in some of the gaps in the literature regarding host-parasite relationships and the role of environmental change on hosts.

    Delarbeid
    1. Climate-driven build-up of temporal isolation within a recently formed avian hybrid zone.
    Åpne denne publikasjonen i ny fane eller vindu >>Climate-driven build-up of temporal isolation within a recently formed avian hybrid zone.
    Vise andre…
    2018 (engelsk)Inngår i: Evolution, ISSN 0014-3820, E-ISSN 1558-5646, Vol. 72, nr 2, s. 363-374Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Divergence in the onset of reproduction can act as an important source of reproductive isolation (i.e., allochronic isolation) between co-occurring young species, but evidence for the evolutionary processes leading to such divergence is often indirect. While advancing spring seasons strongly affect the onset of reproduction in many taxa, it remains largely unexplored whether contemporary spring advancement directly affects allochronic isolation between young species. We examined how increasing spring temperatures affected onset of reproduction and thereby hybridization between pied and collared flycatchers (Ficedula spp.) across habitat types in a young secondary contact zone. We found that both species have advanced their timing of breeding in 14 years. However, selection on pied flycatchers to breed earlier was weaker, resulting in a slower response to advancing springs compared to collared flycatchers and thereby build-up of allochronic isolation between the species. We argue that a preadaptation to a broader niche use (diet) of pied flycatchers explains the slower response to raising spring temperature, but that reduced risk to hybridize may contribute to further divergence in the onset of breeding in the future. Our results show that minor differences in the response to environmental change of co-occurring closely related species can quickly cause allochronic isolation.

    Emneord
    Competitive exclusion, ecological speciation, prezygotic isolation, reinforcement, speciation, temporal segregation
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-341102 (URN)10.1111/evo.13404 (DOI)000424131100011 ()29214649 (PubMedID)
    Forskningsfinansiär
    Swedish Research CouncilAcademy of Finland
    Tilgjengelig fra: 2018-02-06 Laget: 2018-02-06 Sist oppdatert: 2019-03-10bibliografisk kontrollert
    2. Interspecific transfer of parasites following a range‐shift in Ficedula flycatcher
    Åpne denne publikasjonen i ny fane eller vindu >>Interspecific transfer of parasites following a range‐shift in Ficedula flycatcher
    Vise andre…
    2018 (engelsk)Inngår i: Ecology and Evolution, ISSN 2045-7758, E-ISSN 2045-7758, Vol. 8, nr 23, s. 12183-12192Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Human‐induced climate change is expected to cause major biotic changes in species distributions and thereby including escalation of novel host‐parasite associations. Closely related host species that come into secondary contact are especially likely to exchange parasites and pathogens. Both the Enemy Release Hypothesis (where invading hosts escape their original parasites) and the Novel Weapon Hypothesis (where invading hosts bring new parasites that have detrimental effects on native hosts) predict that the local host will be most likely to experience a disadvantage. However, few studies evaluate the occurrence of interspecific parasite transfer by performing wide‐scale geographic sampling of pathogen lineages, both within and far from host contact zones. In this study, we investigate how haemosporidian (avian malaria) prevalence and lineage diversity vary in two, closely related species of passerine birds; the pied flycatcher Ficedula hypoleuca and the collared flycatcher F. albicollis in both allopatry and sympatry. We find that host species is generally a better predictor of parasite diversity than location, but both prevalence and diversity of parasites vary widely among populations of the same bird species. We also find a limited and unidirectional transfer of parasites from pied flycatchers to collared flycatchers in a recent contact zone. This study therefore rejects both the Enemy Release Hypothesis and the Novel Weapon Hypothesis and highlights the complexity and importance of studying host‐parasite relationships in an era of global climate change and species range shifts.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-366254 (URN)10.1002/ece3.4677 (DOI)000454107200069 ()30598810 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council
    Tilgjengelig fra: 2018-11-19 Laget: 2018-11-19 Sist oppdatert: 2019-03-10bibliografisk kontrollert
    3. Sex-specific decrease in longevity following malaria infection in a natural bird population
    Åpne denne publikasjonen i ny fane eller vindu >>Sex-specific decrease in longevity following malaria infection in a natural bird population
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    Avian malaria, BaSTA, collared flycatcher, sex bias, survival, terminal investment
    HSV kategori
    Forskningsprogram
    Biologi med inriktning mot zooekologi
    Identifikatorer
    urn:nbn:se:uu:diva-378637 (URN)
    Tilgjengelig fra: 2019-03-07 Laget: 2019-03-07 Sist oppdatert: 2019-03-10
    4. Age and malaria infection affect nest defence behaviours in collared flycatchers
    Åpne denne publikasjonen i ny fane eller vindu >>Age and malaria infection affect nest defence behaviours in collared flycatchers
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    Avian malaria, Collared flycatcher, Ficedula albicollis, nest-defence, terminal investment
    HSV kategori
    Forskningsprogram
    Biologi med inriktning mot zooekologi
    Identifikatorer
    urn:nbn:se:uu:diva-378638 (URN)
    Tilgjengelig fra: 2019-03-07 Laget: 2019-03-07 Sist oppdatert: 2019-03-10
    5. Malaria infected birds produce higher levels of vector-attracting compounds
    Åpne denne publikasjonen i ny fane eller vindu >>Malaria infected birds produce higher levels of vector-attracting compounds
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    Avian malaria, Ficedula, gametocytaemia, host manipulation, malaria vector, volatile organic compounds
    HSV kategori
    Forskningsprogram
    Biologi med inriktning mot zooekologi
    Identifikatorer
    urn:nbn:se:uu:diva-378936 (URN)
    Tilgjengelig fra: 2019-03-10 Laget: 2019-03-10 Sist oppdatert: 2019-03-10
  • Disputas: 2019-04-26 10:15 Sal IV, Uppsala
    Kadarik, Kati
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Kulturgeografiska institutionen. Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutet för bostads- och urbanforskning (IBF).
    Moving out, moving up, becoming employed: Studies in the residential segregation and social integration of immigrants in Sweden2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis investigates the complex relationship between residential segregation and social integration. The dominant discourse in Sweden and Europe sees residential segregation as hindering socioeconomic and cultural integration, creating parallel societies and even threatening the social cohesion of European societies. Residential segregation might be a sign of social exclusion and discrimination, but it might also result from informed choices to self-segregate into particular neighbourhoods. Minority ethnic clustering, some argue, might have positive attributes, such as providing access to social capital embedded in ethnic communities. This thesis analyses the relationship between segregation and integration from the perspectives of two research traditions: drivers of segregation and neighbourhood effects. The thesis employs individual annual Swedish registry data and a k-nearest neighbour approach to identify residential neighbourhood contexts.

    Paper I studies the out-mobility of three cohorts of young adults from large housing estates (LHEs) in Stockholm County against the backdrop of increasing inequality, stigmatization, and deteriorating conditions in these areas. From 1990 to 2014, income became more and ethnicity less important in explaining mobility. However, it is the combination of the two that determined sorting for all cohorts. The study also clarifies how different neighbourhood conditions within LHEs affect sorting patterns.

    Paper II analyses the residential mobility of immigrants towards native-dominated neighbourhoods. The study concludes that ethnic hierarchies strongly shape residential outcomes and increased income alone does not necessarily translate into residential mobility. However, spatial integration can be facilitated by a better housing market position at the start of the housing career in Sweden, improved socioeconomic outcomes, and residing outside metropolitan areas.

    Paper III examines the potential of ethnic economic capital in the neighbourhood (measured as share of employed co-ethnics) to bolster employment prospects. The results of the multi-scalar analysis of four immigrant groups show that an increase in ethnic economic capital can have a positive effect on immigrant males’ employment prospects, but the effect size varies between groups and neighbourhood scales.

    The main conclusion of this thesis is that the relationship between residential segregation and social integration is not straightforward, but rather is complex and nuanced. It varies between groups with different backgrounds, but also between settlement contexts within Sweden and between neighbourhood contexts within cities. It changes over time and is influenced by the spatial scale of neighbourhood context measurements. This thesis demonstrates the usefulness of employing flexible scalable individual neighbourhoods in conceptualising space when studying social processes.

    Delarbeid
    1. Out-mobility from Stockholm’s large housing estates: local neighbourhood context and the changing importance of income over ethnicity
    Åpne denne publikasjonen i ny fane eller vindu >>Out-mobility from Stockholm’s large housing estates: local neighbourhood context and the changing importance of income over ethnicity
    (engelsk)Inngår i: Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    Abstract [en]

    In political discussions, large housing estates (LHEs) in Stockholm, like in many other European cities, have become shorthand for a range of housing and socioeconomic problems. In recent decades, many such estates have displayed increasing signs of stigmatization, social exclusion, and outflow of relatively affluent people. This selective character of residential mobility from LHEs is considered problematic because it leads to neighbourhood decline. This paper improves our knowledge of how these changes in residential composition have affected out-mobility from these areas over time and how different neighbourhood conditions within LHEs affect sorting patterns. Individual annual Swedish registry data (1990–2014) are employed to longitudinally study the out-mobility patterns of three cohorts that grew up in the estates against the backdrop of growing inequality and deteriorating conditions. This study supplements the existing literature on housing estates by clarifying how income has become more and ethnicity less important over time in explaining sorting patterns from these estates. However, despite substantial changes in the importance of income and ethnic background, it is the combination of the two that has determined sorting throughout the study period. The role of neighbourhood context is, however, less clear: neighbourhoods with the lowest socioeconomic status in the estates display greater sorting based on income, but an opposite pattern is evident for ethnic background.

    Emneord
    residential mobility, neighbourhood change, large housing estates, Stockholm
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-378588 (URN)
    Tilgjengelig fra: 2019-03-10 Laget: 2019-03-10 Sist oppdatert: 2019-03-10
    2. What affects immigrants’ mobility towards native-dominated neighbourhoods? The role of individual resources, ethnicity, and settlement context
    Åpne denne publikasjonen i ny fane eller vindu >>What affects immigrants’ mobility towards native-dominated neighbourhoods? The role of individual resources, ethnicity, and settlement context
    (engelsk)Inngår i: Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    Abstract [en]

    In Sweden, immigrants’ integration and residential patterns are much disputed. Segregation is seen as a threat to social cohesion and policies at least rhetorically aim to create mixed neighbourhoods. Spatial assimilation theory argues that immigrants’ socioeconomic success translates into less segregation in housing for that group. In contrast, place stratification theory emphasizes the importance of ethnicity and structural mechanisms in residential mobility. This study investigates immigrants’ mobility towards native-dominated neighbourhoods by clarifying the role of ethnic hierarchies in association with immigrants’ social and work backgrounds, emphasizing the importance of settlement context. The paper presents a survival analysis based on everyone who migrated to Sweden from 1990 to 2010. The conclusion is that ethnic hierarchies strongly shape residential outcomes, and that spatial integration can be facilitated by a better housing market position at the start of the housing career in Sweden and by outcomes in other life domains, such as labour market participation and good educational attainment. Importantly, increased income alone does not necessarily translate into neighbourhood mobility and spatial integration. There are better prospects of ending up in native Swedish neighbourhoods outside metropolitan areas, whereas in metropolitan areas, the opportunity structures for spatial integration are much more constrained, especially for refugees.

    Emneord
    segregation, spatial assimilation, place stratification, residential mobility, k-nearest neighbour, survival analysis, Sweden
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-378788 (URN)
    Tilgjengelig fra: 2019-03-10 Laget: 2019-03-10 Sist oppdatert: 2019-03-10
    3. Ethnic economic capital in neighbourhoods: impact on immigrants’ employment opportunities
    Åpne denne publikasjonen i ny fane eller vindu >>Ethnic economic capital in neighbourhoods: impact on immigrants’ employment opportunities
    (engelsk)Inngår i: Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    Abstract [en]

    Does living in areas characterized by high co-ethnic concentrations deprive ethnic minority groups, or does potential access to an extended ethnic network with valuable resources further their integration? This paper takes a new approach to analysing the potential of ethnic economic capital in neighbourhoods to increase employment opportunities. While many studies employ aggregated administrative neighbourhood data, an important methodological advance here is that we use individualized, scalable neighbourhoods. This enables us to apply a flexible approach in studying the existence and impact of ethnic economic capital in neighbourhoods. In addition, we not only focus on the concentration of co-ethnics, or on local economic factors, but also measure ethnic economic capital in neighbourhoods as the rate of employed co-ethnics. We employ individual longitudinal Swedish registry data for 2000–2010 on working-age males of Iraqi, Iranian, Turkish, and Somalian backgrounds in Stockholm, Göteborg, and Malmö. We find that an increased share of employed co-ethnics positively affects males’ employment prospects. We add to existing knowledge by showing that the effect of ethnic clustering on employment outcomes is conditional on the quality of ethnic networks – i.e., ethnic economic capital – and on the scale of measurement.

    Emneord
    neighbourhood effects, ethnic economic capital, employment, scale, Sweden
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-378789 (URN)
    Tilgjengelig fra: 2019-03-10 Laget: 2019-03-10 Sist oppdatert: 2019-03-10
  • Disputas: 2019-04-29 13:00 Rudbecksalen, Uppsala
    Abramenkovs, Andris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Induction and repair of clustered DNA damage sites after exposure to ionizing radiation2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The mechanisms that maintain genomic stability safeguard cells from constant DNA damage produced by endogenous and external stressors. Therefore, this thesis aimed to specifically address questions regarding the requirement and involvement of DNA repair proteins in the repair of various types of radiation-induced DNA damage.

    The first aim was to determine whether the phosphorylation of DNA-PKcs, a major kinase involved in non-homologous end joining pathway, can be utilized to score the DNA double-strand break (DSB) content in cells. DNA-PKcs phosphorylated (pDNA-PKcs) at T2609 was more sensitive to the cellular DSB content than ɣH2AX, as analyzed by flow cytometry. Further, pDNA-PKcs at T2609 could discriminate between DSB repair-compromised and normal cells, confirming that the pDNA-PKcs can be used as a DSB repair marker. In paper II, the DSB repair was assessed in cells with reduced levels of DNA-PKcs. The reduction in DNA-PKcs resulted in decreased cell survival and unaffected DSB repair. These results clearly indicate that DNA-PKcs plays an additional role in promoting cell survival in addition to its function in DSB repair.

    The second part of the thesis focused on the characterization of complex DNA damage. DNA damage was investigated after exposure to α-particles originating from Ra-223. The Ra-223 treatment induced a nonrandom DSB distribution consistent with damage induced by high-linear energy transfer radiation. The exposure to Ra-223 significantly reduced cell survival in monolayers and 3D cell structures. The last paper unraveled the fate of heat-sensitive clustered DNA damage site (HSCS) repair in cells. HSCS repair was independent of DSB repair, and these lesions did not contribute to the generation of additional DSBs during repair. Prolonged heating of DNA at relatively low temperatures induced structural changes in the DNA that contributed to the production of DNA artifacts.

    In conclusion, these results demonstrate that DNA-PKcs can be used to monitor DSB repair in cells after exposure to ionizing radiation. However, the functions of DNA-PKcs are not limited to DSB repair, as it can promote cell survival through other mechanisms. The complexity of the DNA damage produced by high-LET radiation is a major contributor to cell death. However, not all clusters produced in irradiated cells are converted into DSBs during repair.

    Delarbeid
    1. Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity
    Åpne denne publikasjonen i ny fane eller vindu >>Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity
    2017 (engelsk)Inngår i: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 188, nr 6, s. 597-604Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Uncontrolled generation of DNA double-strand breaks (DSBs) in cells is regarded as a highly toxic event that threatens cell survival. Radiation-induced DNA DSBs are commonly measured by pulsed-field gel electrophoresis, microscopic evaluation of accumulating DNA damage response proteins (e.g., 53BP1 or gamma-H2AX) or flow cytometric analysis of gamma-H2AX. The advantage of flow cytometric analysis is that DSB formation and repair can be studied in relationship to cell cycle phase or expression of other proteins. However, gamma-H2AX is not able to monitor repair kinetics within the first 60 min postirradiation, a period when most DSBs undergo repair. A key protein in non-homologous end joining repair is the catalytic subunit of DNA-dependent protein kinase. Among several phosphorylation sites of DNA-dependent protein kinase, the threonine at position 2609 (T2609), which is phosphorylated by ataxia telangiectasia mutated (ATM) or DNA-dependent protein kinase catalytic subunit itself, activates the end processing of DSB. Using flow cytometry, we show here that phosphorylation at T2609 is faster in response to DSBs than gamma-H2AX. Furthermore, flow cytometric analysis of T2609 resulted in a better representation of fast repair kinetics than analysis of gamma-H2AX. In cells with reduced ligase IV activity, and wild-type cells where DNA-dependent protein kinase activity was inhibited, the reduced DSB repair capacity was observed by T2609 evaluation using flow cytometry. In conclusion, flow cytometric evaluation of DNA-dependent protein kinase T2609 can be used as a marker for early DSB repair and gives a better representation of early repair events than analysis of gamma-H2AX.

    sted, utgiver, år, opplag, sider
    RADIATION RESEARCH SOC, 2017
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-343567 (URN)10.1667/RR14693.1 (DOI)000416744600001 ()
    Forskningsfinansiär
    Swedish Cancer SocietySwedish Radiation Safety Authority
    Tilgjengelig fra: 2018-03-02 Laget: 2018-03-02 Sist oppdatert: 2019-03-08bibliografisk kontrollert
    2. Suppression of DNA-dependent protein kinase sensitize cells to radiation without affecting DSB repair
    Åpne denne publikasjonen i ny fane eller vindu >>Suppression of DNA-dependent protein kinase sensitize cells to radiation without affecting DSB repair
    2014 (engelsk)Inngår i: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 769, s. 1-10Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Efficient and correct repair of DNA double-strand break (DSB) is critical for cell survival. Defects in the DNA repair may lead to cell death, genomic instability and development of cancer. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is an essential component of the non-homologous end joining (NHEJ) which is the major DSB repair pathway in mammalian cells. In the present study, by using siRNA against DNA-PKcs in four human cell lines, we examined how low levels of DNA-PKcs affected cellular response to ionizing radiation. Decrease of DNA-PKcs levels by 80-95%, induced by siRNA treatment, lead to extreme radiosensitivity, similar to that seen in cells completely lacking DNA-PKcs and low levels of DNA-PKcs promoted cell accumulation in G2/M phase after irradiation and blocked progression of mitosis. Surprisingly, low levels of DNA-PKcs did not affect the repair capacity and the removal of 53BP1 or gamma-H2AX foci and rejoining of DSB appeared normal. This was in strong contrast to cells completely lacking DNA-PKcs and cells treated with the DNA-PKcs inhibitor NU7441, in which DSB repair were severely compromised. This suggests that there are different mechanisms by which loss of DNA-PKcs functions can sensitize cells to ionizing radiation. Further, foci of phosphorylated DNA-PKcs (T2609 and S2056) co-localized with DSB and this was independent of the amount of DNA-PKcs but foci of DNA-PKcs was only seen in siRNA-treated cells. Our study emphasizes on the critical role of DNA-PKcs for maintaining survival after radiation exposure which is uncoupled from its essential function in DSB repair. This could have implications for the development of therapeutic strategies aiming to radiosensitize tumors by affecting the DNA-PKcs function.

    Emneord
    DNA repair, DNA-PKcs, Ionizing radiation, DNA-PK deficiency, NU7441
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-237292 (URN)10.1016/j.mrfmmm.2014.06.004 (DOI)000343625700001 ()
    Tilgjengelig fra: 2014-12-03 Laget: 2014-12-01 Sist oppdatert: 2019-03-08bibliografisk kontrollert
    3. The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survival
    Åpne denne publikasjonen i ny fane eller vindu >>The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survival
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended survival and palliative effects in treatment of bone metastases in patients with prostate cancer. The alpha-particle emitter Ra-223, administered as Ra-223 dichloride, targets regions undergoing active bone remodeling and strongly binds hydroxyapatite found in bone. However, the mechanisms mediating toxicity and properties of Ra-223 binding to hydroxyapatite are not fully understood. In the current study, we show that the alpha-particles originating from the Ra-223 decay chain produce a track-like distribution of the DNA damage response proteins 53BP1 and ɣH2AX and induce high amounts of clustered DNA double-strand breaks in prostate cancer cell nuclei. The Ra-223 treatment inhibited growth of prostate cancer cells, grown in 2D- and 3D- models in vitro, independent of prostate cancer cell type and androgen receptor variant 7 (ARv7) expression. The rapid binding with a high affinity of Ra-223 to bone structures was verified in an in silico assay (KD= 19.2 ± 6.5 e-18) and almost no dissociation was detected within 24 hours. Importantly, there was no significant uptake of Ra-223 in cells. Further, we demonstrate the importance of the local dose-distribution of this treatment; there was more than 100-fold increase in cell killing when Ra-223 was attached to the bone-like hydroxyapatite structure, compared to when the radioactivity was distributed in the cell growth media. However, independent of the exposure condition, the high cell killing efficacy of the Ra-223 was attributed to the clustered DNA damaged sites induced by the released α-particles.

    Emneord
    Prostate cancer, ARv7, DNA damage, Ra-223, high-LET
    HSV kategori
    Forskningsprogram
    Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-378720 (URN)
    Tilgjengelig fra: 2019-03-08 Laget: 2019-03-08 Sist oppdatert: 2019-03-08
    4. Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair
    Åpne denne publikasjonen i ny fane eller vindu >>Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair
    2018 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 12, artikkel-id e0209594Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    DNA double-strand breaks (DSBs) are the most deleterious lesions that can arise in cells after ionizing radiation or radiometric drug treatment. In addition to prompt DSBs, DSBs may also be produced during repair, evolving from a clustered DNA damaged site, which is composed of two or more distinct lesions that are located within two helical turns. A specific type of cluster damage is the heat-sensitive clustered site (HSCS), which transforms into DSBs upon treatment at elevated temperatures. The actual lesions or mechanisms that mediate the HSCS transformation into DSBs are unknown. However, there are two possibilities; either these lesions are transformed into DSBs due to DNA lesion instability, e.g., transfer of HSCS into single-strand breaks (SSBs), or they are formed due to local DNA structure instability, e.g., DNA melting, where two SSBs on opposite strands meet and transform into a DSB. The importance of these processes in living cells is not understood, but they significantly affect estimates of DSB repair capacity. In this study, we show that HSCS removal in human cells is not affected by defects in DSB repair or inhibition of DSB repair. Under conditions where rejoining of prompt DSBs was almost completely inhibited, heat-sensitive DSBs were successfully rejoined, without resulting in increased DSB levels, indicating that HSCS do not transfer into DSB in cells under physiological conditions. Furthermore, analysis by atomic force microscopy suggests that prolonged heating of chromosomal DNA can induce structural changes that facilitate transformation of HSCS into DSB. In conclusion, the HSCS do not generate additional DSBs at physiological temperatures in human cells, and the repair of HSCS is independent of DSB repair.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-374120 (URN)10.1371/journal.pone.0209594 (DOI)000454621900032 ()30592737 (PubMedID)
    Forskningsfinansiär
    Swedish Cancer Society, CAN2014/661Swedish Cancer Society, CAN2016/649Swedish Radiation Safety Authority, SSM2017-2374Swedish Radiation Safety Authority, SSM2018-2181
    Tilgjengelig fra: 2019-01-23 Laget: 2019-01-23 Sist oppdatert: 2019-03-08bibliografisk kontrollert
  • Disputas: 2019-05-03 09:00 Enghoffsalen, Uppsala
    Sundbom, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Asthma and Sleep Disturbances: Associations to Comorbidities and Asthma Control2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis aimed to investigate the associations between asthma control, asthma-related comorbidity, and sleep. Insomnia symptoms with asthma are common, and have commonly been explained by poor asthma control and asthma symptoms during the night, which affect most asthmatics to some degree. The impact of asthma-related comorbidity, however, is not fully known. Further aims were to analyze the effects of asthma control and comorbidities on asthma-related quality of life, and to analyze the effects of co-existing asthma and obstructive sleep apnea on objective sleep quality. 

    Four different populations were investigated: the two large community-based cohorts GA2LEN (n=25,610) and LifeGene (n=23,875), a cohort of 369 young asthma patients (MIDAS), and a polysomnography study of 384 women (SHE).

    The GA2LEN study confirmed that insomnia symptoms remain a common problem among asthmatics. Poor asthma control and nasal congestion were important risk factors for insomnia symptoms. Smoking and obesity were other risk factors for insomnia symptoms among asthmatics.

    Asthma control, as assessed using the Asthma Control Test (ACT), was identified as the most important predictor of asthma-related quality of life in the MIDAS study. Combining the ACT score with data on insomnia, anxiety, and depression showed considerable additive effects of the conditions. 

    In the SHE study, co-existing asthma and OSA were associated with worse objective sleep quality and more profound nocturnal hypoxemia than either of the conditions alone. The group with both asthma and OSA had the highest levels of the markers of systemic inflammation CRP and IL-6.  

    Uncontrolled asthma was a risk factor for all insomnia symptoms in the LifeGene study. Asthma-related comorbidity had a great impact on sleep quality; in particular, the combination of uncontrolled asthma and any comorbidity was unfavorable. Chronic rhinosinusitis was a risk factor for both insomnia symptoms and uncontrolled asthma. 

    These findings have a high clinical relevance and underline the importance of structured evaluation of asthma control and attention to comorbidity in asthma care, as insomnia symptoms are common and affect quality of life. Optimizing asthma control is crucial for sleep quality, but treating asthma-related comorbidity must not be overlooked.

    Delarbeid
    1. Asthma symptoms and nasal congestion as independent risk factors for insomnia in a general population: Results from the GA 2 LEN survey
    Åpne denne publikasjonen i ny fane eller vindu >>Asthma symptoms and nasal congestion as independent risk factors for insomnia in a general population: Results from the GA 2 LEN survey
    Vise andre…
    2013 (engelsk)Inngår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 68, nr 2, s. 213-219Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background Asthma and rhinitis have been related to insomnia. The aim of this study was to further analyse the association between asthma, nasal symptoms and insomnia and to identify risk factors for sleep disturbance among patients with asthma, in a large population-based set of material. Method In 2008, a postal questionnaire was sent to a random sample of 45 000 adults in four Swedish cities. The questionnaire included questions on insomnia, asthma, rhinitis, weight, height, tobacco use and physical activity. Results Twenty-five thousand six hundred and ten subjects participated. Asthma was defined as either current medication for asthma or at least one attack of asthma during the last 12 months, and 1830 subjects (7.15%) were defined as asthmatics. The prevalence of insomnia symptoms was significantly higher among asthmatics than non-asthmatics (47.3% vs 37.2%, <0.0001). In the subgroup reporting both asthma and nasal congestion, 55.8% had insomnia symptoms compared with 35.3% in subjects without both asthma and nasal congestion. The risk of insomnia increased with the severity of asthma, and the adjusted OR for insomnia was 2.65 in asthmatics with three symptoms compared with asthmatics without symptoms. Nasal congestion (OR 1.50), obesity (OR 1.54) and smoking (OR 1.71) also increased the risk of insomnia. Conclusion Insomnia remains a common problem among asthmatics. Uncontrolled asthma and nasal congestion are important, treatable risk factors for insomnia. Lifestyle factors, such as smoking and obesity, are also risk factors for insomnia among asthmatics.

    Emneord
    asthma, epidemiology, rhinitis, sleep
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-194860 (URN)10.1111/all.12079 (DOI)000313727300010 ()
    Tilgjengelig fra: 2013-02-20 Laget: 2013-02-19 Sist oppdatert: 2019-03-13bibliografisk kontrollert
    2. Effects of poor asthma control, insomnia, anxiety and depression on quality of life in young asthmatics
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of poor asthma control, insomnia, anxiety and depression on quality of life in young asthmatics
    Vise andre…
    2016 (engelsk)Inngår i: Journal of Asthma, ISSN 0277-0903, E-ISSN 1532-4303, Vol. 53, nr 4, s. 398-403Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVE: Asthma-related quality of life has previously been shown to be associated with asthma control. The aims of the present study were to further analyze this correlation, identify other variables with impact on asthma-related quality of life, and investigate the covariance among these variables.

    METHODS: Information was retrieved from a cohort of 369 patients, aged 12-35, with physician-diagnosed asthma requiring anti-inflammatory treatment for at least 3 months per year. Questionnaire data [including the mini Asthma Quality of Life Questionnaire (mAQLQ), Asthma Control Test (ACT), and Hospital Anxiety and Depression Scale (HADS)], quality of sleep, lung function data and blood samples were analyzed. Linear regression models with the mAQLQ score as the dependent scalar variable were calculated.

    RESULTS: ACT was the single variable that had the highest explanatory value for the mAQLQ score (51.5%). High explanatory power was also observed for anxiety and depression (17.0%) and insomnia (14.1%). The population was divided into groups depending on presence of anxiety and depression, uncontrolled asthma, and insomnia. The group that reported none of these conditions had the highest mean mAQLQ score (6.3 units), whereas the group reporting all of these conditions had the lowest mAQLQ score (3.8 units).

    CONCLUSIONS: The ACT score was the single most important variable in predicting asthma-related quality of life. Combining the ACT score with the data on insomnia, anxiety and depression showed considerable additive effects of the conditions. Hence, we recommend the routine use of the ACT and careful attention to symptoms of insomnia, anxiety or depression in the clinical evaluation of asthma-related quality of life.

    Emneord
    Asthma; epidemiology; asthma control; ACT; mAQLQ; quality of life; sleep; HADS; anxiety; depression
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-270378 (URN)10.3109/02770903.2015.1126846 (DOI)000374991200009 ()26666333 (PubMedID)
    Forskningsfinansiär
    VINNOVA
    Tilgjengelig fra: 2015-12-27 Laget: 2015-12-27 Sist oppdatert: 2019-03-13bibliografisk kontrollert
    3. Effects of Coexisting Asthma and Obstructive Sleep Apnea on Sleep Architecture, Oxygen Saturation, and Systemic Inflammation in Women
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of Coexisting Asthma and Obstructive Sleep Apnea on Sleep Architecture, Oxygen Saturation, and Systemic Inflammation in Women
    2018 (engelsk)Inngår i: Journal of Clinical Sleep Medicine (JCSM), ISSN 1550-9389, E-ISSN 1550-9397, Vol. 14, nr 2, s. 253-259Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    STUDY OBJECTIVES: Both asthma and obstructive sleep apnea (OSA) are strongly associated with poor sleep. Asthma and OSA also have several features in common, including airway obstruction, systemic inflammation, and an association with obesity. The aim was to analyze the effect of asthma, OSA, and the combination of asthma and OSA on objectively measured sleep quality and systemic inflammation.

    METHODS: Sleep and health in women is an ongoing community-based study in Uppsala, Sweden. Three hundred eighty-four women ages 20 to 70 years underwent overnight polysomnography and completed questionnaires on airway diseases and sleep complaints. C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor α were analyzed.

    RESULTS: = .04) than the group with OSA alone. The results were consistent after adjusting for age, body mass index, and smoking status. Asthma was independently associated with lower oxygen saturation, whereas OSA was not.

    CONCLUSIONS: Our data indicate that coexisting asthma and OSA are associated with poorer sleep quality and more profound nocturnal hypoxemia than either of the conditions alone. The results are similar to earlier findings related to OSA and chronic obstructive pulmonary disease, but they have not previously been described for asthma.

    sted, utgiver, år, opplag, sider
    American Academy of Sleep Medicine, 2018
    Emneord
    OSA, asthma, inflammation, polysomnography
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-343517 (URN)10.5664/jcsm.6946 (DOI)000425136900013 ()29394961 (PubMedID)
    Tilgjengelig fra: 2018-02-27 Laget: 2018-02-27 Sist oppdatert: 2019-03-13bibliografisk kontrollert
    4. Insomnia symptoms and asthma control – interrelations and importance of comorbidities
    Åpne denne publikasjonen i ny fane eller vindu >>Insomnia symptoms and asthma control – interrelations and importance of comorbidities
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background

     

    Insomnia symptoms are common with asthma. The aim of the study was to analyze the associations between insomnia symptoms and asthma control, asthma severity, and asthma-related comorbidity in a community-based population.

     

    Methods

    Adults (n=23,875, ages 18-45) from the community-based LifeGene study answered a questionnaire on insomnia symptoms, airway symptoms, asthma diagnosis, asthma medication, and asthma-related comorbidities (chronic rhinosinusitis, gastro-esophageal reflux, anxiety, depression, or obesity).

     

    Results

    Of the participants, 1,272 (5.3%) had asthma. The prevalence of any insomnia symptom was higher in participants with uncontrolled asthma (n=201) than with controlled or partially controlled asthma (32.2% vs. 19.9% and 20.1%, respectively, p<0.01). There was no significant difference in the prevalence of insomnia symptoms between subjects with controlled asthma and subjects without asthma. 

     

    Subjects with asthma and any asthma-related comorbidity reported more insomnia symptoms (29.0% vs. 22.4%, p<0.01) compared to asthmatics without comorbidity. Moreover, the prevalence was highest among subjects reporting both uncontrolled asthma and any asthma-related comorbidity (45.1%, p<0.01).

     

    Uncontrolled asthma remained significantly associated with insomnia symptoms (OR 1.72 (1.15-2.56)) after adjusting for age, sex, BMI, smoking history, comorbidities, physical activity, and educational level, while medication level was not. Among asthma-related comorbidities, chronic rhinosinusitis (OR 1.62 (1.20-2.19)), obesity (1.87 (1.07-3.25)), and depression (OR 1.85 (1.34-2.55)) were independently associated with insomnia symptoms. 

     

    Conclusion

     

    Uncontrolled asthma was significantly associated with insomnia symptoms, while controlled or partially controlled asthma was not. Asthma-related comorbidity is of great importance, and asthma control seems to be more important than asthma severity for sleep quality.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-379139 (URN)
    Tilgjengelig fra: 2019-03-12 Laget: 2019-03-12 Sist oppdatert: 2019-03-13
  • Disputas: 2019-05-03 09:15 Rudbecksalen, Uppsala
    Gudmundsson, Sanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Translational Research of Mendelian Disorders: Applications of Cutting-Edge Sequencing Techniques and Molecular Tools2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Up to 8% of all live-born children are affected with a congenital disorder. Some are Mendelian disorders of known etiology, but many are of undetermined genetic cause and mechanism, limiting diagnosis and treatment. This project aims to investigate the underlying causes of unresolved Mendelian disorders, and especially syndromes associated with intellectual disability, by using cutting-edge sequencing techniques and molecular tools in a translational setting that intends to directly benefit affected families.

    In Paper I, we report the first keratitis-ichthyosis-deafness syndrome patient presenting with reversion of disease phenotype, a phenomenon known as revertant mosaicism. Third-generation sequencing and a cell assay were used to pin-point the mechanism of the somatic variants giving rise to healthy looking skin in the patient. In Paper II, we describe a novel approach to investigate parental origin, gonadal mosaicism, and estimate recurrence risk of disease in two families. Third-generation sequencing was used for haplotype phasing and detection of low-frequency variants in paternal sperm. The recurrence risk in future offspring in the families affected with Noonan syndrome and Treacher Collins syndrome was determined to be 40% and <0.1% respectively. In Paper III, we describe a novel variant in a patient affected with Cornelia de Lange Syndrome, primarily associated with intellectual disability. The affected gene is linked to an extremely rare form of the syndrome, with limited cases described in the literature, usually associated with mild symptoms. Investigation of rare intellectual disability syndromes was continued in Paper IV, by clinical and genetic characterization of six affected males with a likely pathogenic variant in the TAF1 gene. By creating the first TAF1 orthologue knockout we revealed that taf1 is essential for life and that lack of functional taf1 during embryonic development in zebrafish primarily impacts expression of genes in pathways associated with neurodevelopment. 

    By progressive translational research, using state-of-the-art methodology, this project has illuminated the implication of revertant and gonadal mosaicism in disease (Papers I-II), as well as two extremely rare intellectual disability syndromes (Papers III-IV). In total, five families affected with five different disorders have gained clinical and genetic diagnosis and/or further understanding of prognosis and recurrence risk. The study has led to improved understanding of disease etiology and basic developmental processes, enabling development of new therapies and improved care of future patients.

    Delarbeid
    1. Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26
    Åpne denne publikasjonen i ny fane eller vindu >>Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26
    Vise andre…
    2017 (engelsk)Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, nr 6, s. 1070-1077Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Revertant mosaicism(RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c. 148G>A, p. Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultradeep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p. Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p. Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.

    sted, utgiver, år, opplag, sider
    OXFORD UNIV PRESS, 2017
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-324349 (URN)10.1093/hmg/ddx017 (DOI)000400911000004 ()28158657 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, K2013-57X-22309-3
    Tilgjengelig fra: 2017-06-15 Laget: 2017-06-15 Sist oppdatert: 2019-03-17bibliografisk kontrollert
    2. A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders
    Åpne denne publikasjonen i ny fane eller vindu >>A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders
    Vise andre…
    2017 (engelsk)Inngår i: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 37, nr 11, s. 1146-1154Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objective

    De novo mutations contribute significantly to severe early-onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred.

    Methods

    We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction.

    Results

    In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk.

    Conclusions

    Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-342916 (URN)10.1002/pd.5156 (DOI)000415897200012 ()28921562 (PubMedID)
    Forskningsfinansiär
    Swedish Society for Medical Research (SSMF)
    Tilgjengelig fra: 2018-02-26 Laget: 2018-02-26 Sist oppdatert: 2019-03-17bibliografisk kontrollert
    3. A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 - Review of the literature.
    Åpne denne publikasjonen i ny fane eller vindu >>A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 - Review of the literature.
    Vise andre…
    2018 (engelsk)Inngår i: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, artikkel-id S1769-7212(18)30189-7Artikkel i tidsskrift (Fagfellevurdert) Epub ahead of print
    Abstract [en]

    Cornelia de Lange syndrome (CdLS) is a heterogeneous developmental disorder where 70% of clinically diagnosed patients harbor a variant in one of five CdLS associated cohesin proteins. Around 500 variants have been identified to cause CdLS, however only eight different alterations have been identified in the RAD21 gene, encoding the RAD21 cohesin complex component protein that constitute the link between SMC1A and SMC3 within the cohesin ring. We report a 15-month-old boy presenting with developmental delay, distinct CdLS-like facial features, gastrointestinal reflux in early infancy, testis retention, prominent digit pads and diaphragmatic hernia. Exome sequencing revealed a novel RAD21 variant, c.1774_1776del, p.(Gln592del), suggestive of CdLS type 4. Segregation analysis of the two healthy parents confirmed the variant as de novo and bioinformatic analysis predicted the variant as disease-causing. Assessment by in silico structural model predicted that the p.Gln592del variant results in a discontinued contact between RAD21-Lys591 and the SMC1A residues Glu1191 and Glu1192, causing changes in the RAD21-SMC1A interface. In conclusion, we report a patient that expands the clinical description of CdLS type 4 and presents with a novel RAD21 p.(Glu592del) variant that causes a disturbed RAD21-SMC1A interface according to in silco structural modeling.

    Emneord
    Cohesin complex, Cohesin protein, Cohesinopathy, Cornelia de Lange syndrome type 4, RAD21 cohesin complex component
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-379362 (URN)10.1016/j.ejmg.2018.08.007 (DOI)30125677 (PubMedID)
    Tilgjengelig fra: 2019-03-15 Laget: 2019-03-15 Sist oppdatert: 2019-03-17
    4. TAF1, associated with intellectual disability in humans, is essential for life and regulates neurodevelopmental processes in zebrafish
    Åpne denne publikasjonen i ny fane eller vindu >>TAF1, associated with intellectual disability in humans, is essential for life and regulates neurodevelopmental processes in zebrafish
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1’s molecular function remains elusive. In this study, we present a five-generation family affected with X-linked intellectual disability, co-segregating with a TAF1 c.3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while carrier females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment during early embryogenesis by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial role of human TAF1 during early embryogenesis can be inferred from the model, demonstrating that an intact taf1 is essential for life from early embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment of genes in pathways associated with neurodevelopmental processes. In conclusion, we suggest that TAF1 is essential for life and that functional TAF1 is vital for early neurogenesis.

    Emneord
    taf1, intellectual disability, zebrafish
    HSV kategori
    Forskningsprogram
    Medicinsk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-379358 (URN)
    Tilgjengelig fra: 2019-03-15 Laget: 2019-03-15 Sist oppdatert: 2019-03-17
  • Disputas: 2019-05-03 09:15 B21, Uppsala
    Svensson, Robin J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Pharmacometric Models to Improve the Treatment and Development of Drugs against Tuberculosis2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    With 10 million new infections yearly, tuberculosis has a major impact on the human well-being of the world. Most patients have infections susceptible to a first-line treatment with a treatment success rate of 80%, a number that can potentially be improved by optimising the first-line treatment. Besides susceptible disease, each year half a million patients are infected by tuberculosis with resistance to first-line treatment where only 50% of patients get cured. Thus, new drugs against resistant tuberculosis are desperately needed but given the inefficiency of developing new anti-tuberculosis drugs, enough new drugs will not reach patients in time. The aim of this thesis was to develop pharmacometric models to optimise the development and use of current and future drugs for treating tuberculosis.

    A population pharmacokinetic model for rifampicin, the most prominent first-line drug, was developed and later used for developing exposure-response models followed by clinical trial simulations. The developed exposure-response models were based on liquid culture data and were expanded to describe the relationship between liquid culture results and a new biomarker, the molecular bacterial load assay which is a quicker alternative to liquid culture and is also contamination-free.

    The in vitro-derived semi-mechanistic Multistate Tuberculosis Pharmacometric (MTP) model was applied to clinical rifampicin and clofazimine colony forming unit datasets. This novel application of the MTP model allowed detection of statistically significant exposure-response relationships between rifampicin and clofazimine for the specific killing of non-multiplying, persister bacteria. Furthermore, the MTP model was compared to conventional statistical analyses for detecting drug effects in Phase IIa. If designing and analysing Phase IIa using the MTP model, the required sample size for detecting drug effects can be lowered. An improved design and analysis of pre-clinical treatment outcome assessments was developed which increased the information gain compared to a conventional design yet kept the animal use at a minimum. Lastly, a therapeutic drug monitoring approach was suggested based on updated targets for rifampicin, a framework easily expandable to second-line drugs.

    In conclusion this thesis presents the development of pharmacometric models which will streamline both the development and use of drugs against tuberculosis.

    Delarbeid
    1. A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses
    Åpne denne publikasjonen i ny fane eller vindu >>A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses
    Vise andre…
    2018 (engelsk)Inngår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 103, nr 4, s. 674-683Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Accumulating evidence suggests that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics, and antimycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty-three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week. This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using nonlinear mixed effects modeling. The final population pharmacokinetic model included an enzyme turnover model accounting for time-dependent elimination due to autoinduction, concentration-dependent clearance, and dose-dependent bioavailability. The relationship between clearance and concentration was characterized by a Michaelis–Menten relationship. The relationship between bioavailability and dose was described using an Emax relationship. The model will be key in determining exposure–response relationships for rifampicin and should be considered when designing future trials and when treating future patients with high-dose rifampicin.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-342737 (URN)10.1002/cpt.778 (DOI)000427114900030 ()28653479 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 115337EU, FP7, Seventh Framework Programme
    Tilgjengelig fra: 2018-02-23 Laget: 2018-02-23 Sist oppdatert: 2019-03-15bibliografisk kontrollert
    2. Greater Early Bactericidal Activity at Higher Rifampicin Doses Revealed by Modeling and Clinical Trial Simulations
    Åpne denne publikasjonen i ny fane eller vindu >>Greater Early Bactericidal Activity at Higher Rifampicin Doses Revealed by Modeling and Clinical Trial Simulations
    Vise andre…
    2018 (engelsk)Inngår i: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 218, nr 6, s. 991-999Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background. The currently recommended rifampicin dose (10 mg/kg) for treating tuberculosis is suboptimal. The PanACEA HIGHRIF1 trial evaluated the pharmacokinetics and early bactericidal activity of rifampicin doses of up to 40 mg/kg. Conventional statistical analyses revealed no significant exposure-response relationship. Our objectives were to explore the exposure-response relationship for high-dose rifampicin by using pharmacokinetic-pharmacodynamic modeling and to predict the early bactericidal activity of 50 mg/kg rifampicin.

    Methods. Data included time to Mycobacterium tuberculosis positivity of liquid cultures of sputum specimens from 83 patients with tuberculosis who were treated with 10 mg/kg rifampicin (n = 8; reference arm) or 20, 25, 30, 35, or 40 mg/kg rifampicin (n = 15/arm) for 7 days. We used a semimechanistic time-to-event approach to model the time-to-positivity data. Rifampicin exposure and baseline time to culture positivity were explored as covariates.

    Results. The baseline time to culture positivity was a significant covariate on the predicted initial bacterial load, and rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity. The 90% prediction interval for the predicted median day 7 increase in time to positivity for 50 mg/kg rifampicin was 7.25-10.3 days.

    Conclusions. A significant exposure-response relationship was found between rifampicin exposure and early bactericidal activity. Clinical trial simulations showed greater early bactericidal activity for 50 mg/kg rifampicin.

    Emneord
    Pharmacodynamics, tuberculosis, pharmacokinetics, patients, time to positivity, early bactericidal activity, models, bactericidal effect, Mycobacterium tuberculosis
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-362631 (URN)10.1093/infdis/jiy242 (DOI)000441792600017 ()29718390 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 521-2011-3442EU, FP7, Seventh Framework Programme
    Tilgjengelig fra: 2018-10-10 Laget: 2018-10-10 Sist oppdatert: 2019-03-15bibliografisk kontrollert
    3. Model-based relationship between the molecular bacterial load assay and time-to-positivity in liquid culture
    Åpne denne publikasjonen i ny fane eller vindu >>Model-based relationship between the molecular bacterial load assay and time-to-positivity in liquid culture
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The molecular bacterial load (MBL) assay is a new tuberculosis biomarker, a substantially faster, contamination-free alternative to the current standard assay of time-to-positivity (TTP) in liquid culture. The MBL-TTP relationship has not been thoroughly studied. We aimed to develop a semi-mechanistic model for MBL and identify the MBL-TTP relationship in patients. The model was developed on data from 105 tuberculosis patients with joint MBL and TTP observations collected for 12 weeks. Treatment consisted of isoniazid, pyrazinamide and ethambutol in standard doses together with rifampicin 10 or 35 mg/kg. The developed MBL-TTP model was semi-mechanistic, including several linked sub-models; a sputum sub-model describing decline of bacterial load in sputum,  a mycobacterial growth model describing growth in liquid culture and a hazard model translating bacterial growth in liquid culture to the probability of a positive TTP signal. Additional components for contaminated and negative TTP samples were included in the final model. The model gave good fit to the observed data. The model predicted greater total sample loss for TTP than MBL due to contamination and negative samples. The model detected an increase in bacterial killing for 35 versus 10 mg/kg rifampicin (p=0.002). In conclusion, a semi-mechanistic combined model for MBL and TTP was developed that described the MBL-TTP relationship. The MBL-TTP model can distinguish regimen efficacy in clinical trials, as a full MBL-TTP model or each sub-model used separately. Secondly, the model can be used to predict biomarker response for MBL given TTP data or vice versa in historical or future trials.

    Emneord
    Pharmacometrics, Pharmacodynamics, Modelling, Biomarker, Tuberculosis
    HSV kategori
    Forskningsprogram
    Farmaceutisk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-379314 (URN)
    Tilgjengelig fra: 2019-03-15 Laget: 2019-03-15 Sist oppdatert: 2019-03-15
    4. The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis
    Åpne denne publikasjonen i ny fane eller vindu >>The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis
    Vise andre…
    2018 (engelsk)Inngår i: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 67, nr 1, s. 34-41Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background. Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin. Methods. Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg. The response measure was time to stable sputum culture conversion (TSCC). We derived individual exposure metrics with a previously developed population pharmacokinetic model of rifampicin. TSCC was modeled using a parametric time-to-event approach, and a sequential exposure-response analysis was performed. Results. Higher rifampicin exposures increased the probability of early culture conversion. No maximal limit of the effect was detected within the observed range. The expected proportion of patients with stable culture conversion on liquid medium at week 8 was predicted to increase from 39% (95% confidence interval, 37%-41%) to 55% (49%-61%), with the rifampicin area under the curve increasing from 20 to 175 mg/L.h (representative for 10 and 35 mg/kg, respectively). Other predictors of TSCC were baseline bacterial load, proportion of culture results unavailable, and substitution of ethambutol for either moxifloxacin or SQ109. Conclusions. Increasing rifampicin exposure shortened TSCC, and the effect did not plateau, indicating that doses >35 mg/kg could be yet more effective. Optimizing rifampicin dosage while preventing toxicity is a clinical priority.

    sted, utgiver, år, opplag, sider
    OXFORD UNIV PRESS INC, 2018
    Emneord
    high-dose rifampicin, pharmacometrics, PK-PD, exposure-response, sputum culture conversion
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-361283 (URN)10.1093/cid/ciy026 (DOI)000438446600010 ()29917079 (PubMedID)
    Tilgjengelig fra: 2018-09-27 Laget: 2018-09-27 Sist oppdatert: 2019-03-15bibliografisk kontrollert
    5. Application of the Multistate Tuberculosis Pharmacometric Model in Patients With Rifampicin-Treated Pulmonary Tuberculosis
    Åpne denne publikasjonen i ny fane eller vindu >>Application of the Multistate Tuberculosis Pharmacometric Model in Patients With Rifampicin-Treated Pulmonary Tuberculosis
    2016 (engelsk)Inngår i: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 5, nr 5, s. 264-273Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    This is the first clinical implementation of the Multistate Tuberculosis Pharmacometric (MTP) model describing fast-, slow-, and nonmultiplying bacterial states of Mycobacterium tuberculosis. Colony forming unit data from 19 patients treated with rifampicin were analyzed. A previously developed rifampicin population pharmacokinetic (PK) model was linked to the MTP model previously developed using in vitro data. Drug effect was implemented as exposure-response relationships tested at several effect sites, both alone and in combination. All MTP model parameters were fixed to in vitro estimates except B-max. Drug effect was described by an on/off effect inhibiting growth of fast-multiplying bacteria in addition to linear increase of the stimulation of the death rate of slow-and nonmultiplying bacteria with increasing drug exposure. Clinical trial simulations predicted well three retrospective clinical trials using the final model that confirmed the potential utility of the MTP model in antitubercular drug development.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-303399 (URN)10.1002/psp4.12079 (DOI)000381566700004 ()27299939 (PubMedID)
    Tilgjengelig fra: 2016-09-19 Laget: 2016-09-19 Sist oppdatert: 2019-03-15bibliografisk kontrollert
    6. Drug effect of clofazimine on persisters explain an unexpected increase in bacterial load from patients
    Åpne denne publikasjonen i ny fane eller vindu >>Drug effect of clofazimine on persisters explain an unexpected increase in bacterial load from patients
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Tuberculosis (TB) drug development is dependent on informative trials to secure development of new antibiotics and combination regimens. Clofazimine (CFZ) and pyrazinamid (PZA) are important components of recommended standard multi-drug treatments of TB. Paradoxically, in a Phase IIa trial aiming to define the early bactericidal activity (EBA) of CFZ and PZA monotherapy over the first 14 days of treatment, no significant drug effect was demonstrated for the two drugs using traditional statistical analysis. Using a model-based analysis we characterized statistically significant exposure-response relationships for both drugs that could explain the original findings of increase in colony forming units (CFU) with CFZ treatment and no effect with PZA. Sensitive analyses are crucial for exploring drug effects in early clinical trials to make right decisions for advancement to further development. We propose that this quantitative semi-mechanistic approach provides a rational framework for analysing Phase IIa EBA studies, and can accelerate anti-TB drug development.

    Emneord
    Pharmacometrics, Pharmacodynamics, Pharmacokinetics, Biomarker, Tuberculosis
    HSV kategori
    Forskningsprogram
    Farmaceutisk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-379356 (URN)
    Tilgjengelig fra: 2019-03-15 Laget: 2019-03-15 Sist oppdatert: 2019-03-15