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  • 1.
    Aagaard, Sunniva Margrethe Due
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Reticulate Evolution in Diphasiastrum (Lycopodiaceae)2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis relationships and the occurrence of reticulate evolutionary events in the club moss genus Diphasiastrum are investigated. Diphasiastrum is initially established as a monophyletic group within Lycopodiaceae using non recombinant chloroplast sequence data. Support is obtained for eight distinct parental lineages in Diphasiastrum, and relationships among the putative parent taxa in the hypothesized hybrid complexes; D. alpinum, D. complanatum, D. digitatum, D. multispicatum, D. sitchense, D. tristachyum and D. veitchii are presented.

    Feulgen DNA image densitometry data and sequence data obtained from three nuclear regions, RPB2, LEAFY and LAMB4, were used to infer the origins of three different taxa confirmed to be allopolyploid; D. zanclophyllum from South Africa, D. wightianum from Malaysia and an undescribed taxon from China. The two Asian polyploids have originated from two different hybrid combinations, D. multispicatum x D. veitchii and D. tristachyum x D. veitchii. Diphasiastrum zanclophyllum originates from a cross between D. digitatum and an unidentified diploid taxon.

    The occurrence of three homoploid hybrid combinations commonly recognized in Europe, D. alpinum x D. complanatum, D. alpinum x D. tristachyum and D. complanatum x D. tristachyum, are verified using the same three nuclear regions. Two of the three hybrid combinations are also shown to have originated from reciprocal crosses. Admixture analyses performed on an extended, dataset similarly identified predominately F1 hybrids and backcrosses. The observations and common recognition of hybrid species in the included populations are hence most likely due to frequent observations of neohybrids in hybrid zones. Reticulate patterns are, however, prominent in the presented dataset. Hence future studies addressing evolutionary and ecological questions in Diphasiastrum should emphasize the impact of gene flow between parent lineages rather than speciation as the result of hybridization.

    List of papers
    1. Resolving maternal relationships in the clubmoss genus Diphasiastrum (Lycopodiaceae)
    Open this publication in new window or tab >>Resolving maternal relationships in the clubmoss genus Diphasiastrum (Lycopodiaceae)
    2009 (English)In: Taxon, ISSN 0040-0262, E-ISSN 1996-8175, Vol. 58, no 3, p. 835-848Article in journal (Refereed) Published
    Abstract [en]

    Diphasiastrum comprises 20-30 species. In addition to a number of species with a circumboreal distribution, several island endemics and putative diploid hybrid species contribute to the diversity of the group. To assess the integrity and relationships of the recognized species, a global phylogeny of Diphasiastrum is constructed using five chloroplast regions comprising ~9000 bp. Six monophyletic groups are identified. Accessions identified as hybrid species cluster in all but one case together with one of its putative parents. Two microsatellite loci are identified, and allelic information combined with sequence information is found diagnostic for the three putative parental taxa in the Central Europe hybrid complexes. Haplotype screening is performed on six Central European populations, from where one or more putative diploid hybrid species have been reported to grow in sympatry with their parent species. The most common parental haplotypes are identified in all populations. Additional intraspecific variation, restricted to single populations, is identified in all sympatric populations at very low frequencies. Taking the low degree of sequence and microsatellite variation into consideration, the acknowledged morphological diversity in Central Europe is probably best explained by phenotypic plasticity, ancestral polymorphisms or relatively recent events of reticulate evolution.

    Keywords
    Chloroplast microsatellites, Diphasiastrum, Diploid hybrid species, Lycopodium, Lycopodiaceae, Plastid phylogeny
    National Category
    Biological Sciences
    Research subject
    Systematic Botany
    Identifiers
    urn:nbn:se:uu:diva-99576 (URN)000269774900012 ()
    Available from: 2009-03-16 Created: 2009-03-16 Last updated: 2017-12-13Bibliographically approved
    2. Occurrence and evolutionary origins of polyploids in the club moss genus Diphasiastrum (Lycopodiaceae)
    Open this publication in new window or tab >>Occurrence and evolutionary origins of polyploids in the club moss genus Diphasiastrum (Lycopodiaceae)
    2009 (English)In: Molecular Phylogenetics and Evolution, ISSN 1055-7903, E-ISSN 1095-9513, Vol. 52, no 3, p. 746-754Article in journal (Refereed) Published
    Abstract [en]

    Two polyploid taxa are commonly recognized in the genus Diphasiastrum, D. wightianum from Asia and D. zanclophyllum from South Africa and Madagascar. Here we present results from Feulgen DNA image densitometry analyses providing the first evidence for the polyploid origin of D. zanclophyllum. Reported for the first time is also data confirming that D. multispicatum and D. veitchii, representing putative parent lineages for D. wightianum, are diploids. Phylogenetic analyses of nuclear regions RPB2, LEAFY and LAMB4 reveal that putative tetraploid accessions are of allopolyploid origin. Diphasiastrum zanclophyllum shows close relationships to the North American taxon D. digitatum on the maternal side, but the paternal relationship is less clear. Two accessions from Asia, both found to be polyploid, have D. veitchii as maternal parent, whereas the paternal paralogs show relationships to D. multispicatum and D. tristachyum, respectively. None of these parental combinations have previously been hypothesized.

    Keywords
    Diphasiastrum, Feulgen DNA image densitometry, Lycopodium, Lycopodiaceae, low-copy nuclear genes, phylogenies, polyploidy
    National Category
    Biological Sciences
    Research subject
    Systematic Botany
    Identifiers
    urn:nbn:se:uu:diva-99577 (URN)10.1016/j.ympev.2009.05.004 (DOI)000268265800016 ()
    Available from: 2009-03-16 Created: 2009-03-16 Last updated: 2017-12-13Bibliographically approved
    3. Reticulate phylogenetic patterns in diploid European Diphasiastrum (Lycopodiaceae).
    Open this publication in new window or tab >>Reticulate phylogenetic patterns in diploid European Diphasiastrum (Lycopodiaceae).
    (English)Manuscript (Other academic)
    Abstract [en]

    In Central Europe, three species belonging to Diphasiastrum are considered to be of homoploid hybrid origin. Diphasiastrum issleri is suggested to have originated from a cross between D. alpinum and D. complanatum, D. oellgaardii from D. alpinum and D. tristachyum, and D. zeilleri from D. complanatum and D. tristachyum. Variation at three nuclear regions and two chloroplast microsatellites verify the presence of all three putative parental combinations in Europe. Data obtained with Feulgen DNA image densitometry confirms that all specimens displaying such pattern are diploid. Also, two of three parental combinations have probably arisen repeatedly, implied by the occurrence of chloroplast haplotypes associated with different parents. The presented dataset cannot be used as argument for the existence of independent evolutionary entities hybrid origin. This is nonetheless an important first step in order to address the influence of reticulate evolutionary events in European Diphasiastrum

    Keywords
    Keywords – Diphasiastrum, homoploid hybridization, Lycopodiaceae, Lycopodium, low copy nuclear genes, phylogenies, Feulgen DNA image densitometry
    Identifiers
    urn:nbn:se:uu:diva-99578 (URN)
    Available from: 2009-03-16 Created: 2009-03-16 Last updated: 2010-01-14
    4. Homoploid hybridization in Central European Diphasiastrum (Lycopodiaceae).
    Open this publication in new window or tab >>Homoploid hybridization in Central European Diphasiastrum (Lycopodiaceae).
    (English)Manuscript (Other academic)
    Abstract [en]

    Three species of homoploid hybrid origin are commonly recognized among Central European Diphasiastrum, and reticulate evolutionary events have for a long time been acknowledged as an important factor contributing to the species count in the genus. Presented evidence obtained from molecular data has until recently been scarce and inconclusive. Recent studies have, however, documented reticulate phylogenetic patterns involving all putative parental combinations reported from Central Europe. Reciprocal crosses involving the same parental combinations have also been confirmed. In order to further explore these putative reticulate events, admixture analyses using a Bayesian approach as implemented in the program NewHybrids are conducted on an expanded dataset obtained from six Central European populations from where putative hybrid taxa are reported. A majority of the accessions included in the analyses were inferred to represent pure bred D. alpinum, D. complanatum, D. tristachyum, F1 hybrids, F2 hybrids or backcrosses with one of the parent species. Accessions displaying ambiguous classification were found in both allopatric parent populations as well as in Central European hybrid populations. Presented results indicate the presence of frequently occurring hybrid zones with first and second generation hybrids as well as backcrosses.

    Keywords
    admixture analysis, Bayesian clustering, Diphasiastrum, homoploid hybridization, Lycopodiaceae, Lycopodium, NewHybrids.
    National Category
    Biological Systematics
    Research subject
    Systematic Botany; Population Biology
    Identifiers
    urn:nbn:se:uu:diva-99579 (URN)
    Available from: 2009-03-16 Created: 2009-03-16 Last updated: 2010-01-14
    5. Revised lectotypification of Lycopodium complanatum L. (Lycopodiaceae)
    Open this publication in new window or tab >>Revised lectotypification of Lycopodium complanatum L. (Lycopodiaceae)
    2009 (English)In: Taxon, ISSN 0040-0262, E-ISSN 1996-8175, Vol. 58, no 3, p. 974-976Article in journal (Refereed) Published
    Abstract [en]

    The currently accepted lectotype of the circumboreal species Lycopodium complanatum L., or Diphasiastrum complanatum (L.) Holub, is a specimen of the related species L. tristachyum Pursh, or D. tristachyum (Pursh) Holub, mainly distributed in eastern North America and Europe. This lectotype, in LINN, is here superseded in favour of an alternative original element in the Celsius herbarium in Uppsala, supported by an epitype, on the grounds of conflict with the protologue. Thereby the traditional usage of the well-known name L. complanatum can be maintained.

    Keywords
    Diphasiastrum, nomenclature, Lycopodium, Lycopodiaceae, typification.
    National Category
    Biological Systematics
    Research subject
    Systematic Botany; Biology with specialization in Systematics
    Identifiers
    urn:nbn:se:uu:diva-99572 (URN)000269774900026 ()
    Available from: 2009-03-16 Created: 2009-03-16 Last updated: 2017-12-13Bibliographically approved
  • 2.
    Abbas, Qaisar
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Numerical Analysis.
    Weak Boundary and Interface Procedures for Wave and Flow Problems2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, we have analyzed the accuracy and stability aspects of weak boundary and interface conditions (WBCs) for high order finite difference methods on Summations-By-Parts (SBP) form. The numerical technique has been applied to wave propagation and flow problems.

    The advantage of WBCs over strong boundary conditions is that stability of the numerical scheme can be proven. The boundary procedures in the advection-diffusion equation for a boundary layer problem is analyzed. By performing Navier-Stokes calculations, it is shown that most of the conclusions from the model problem carries over to the fully nonlinear case.

    The work was complemented to include the new idea of using WBCs on multiple grid points in a region, where the data is known, instead of at a single point. It was shown that we can achieve high accuracy, an increased rate of convergence to steady-state and non-reflecting boundary conditions by using this approach.

    Using the SBP technique and WBCs, we have worked out how to construct conservative and energy stable hybrid schemes for shocks using two different approaches. In the first method, we combine a high order finite difference scheme with a second order MUSCL scheme. In the second method, a procedure to locally change the order of accuracy of the finite difference schemes is developed. The main purpose is to obtain a higher order accurate scheme in smooth regions and a low order non-oscillatory scheme in the vicinity of shocks.

    Furthermore, we have analyzed the energy stability of the MUSCL scheme, by reformulating the scheme in the framework of SBP and artificial dissipation operators. It was found that many of the standard slope limiters in the MUSCL scheme do not lead to a negative semi-definite dissipation matrix, as required to get pointwise stability.

    Finally, high order simulations of shock diffracting over a convex wall with two facets were performed. The numerical study is done for a range of Reynolds numbers. By monitoring the velocities at the solid wall, it was shown that the computations were resolved in the boundary layer. Schlieren images from the computational results were obtained which displayed new interesting flow features.

    List of papers
    1. Weak versus strong no-slip boundary conditions for the Navier-Stokes equations
    Open this publication in new window or tab >>Weak versus strong no-slip boundary conditions for the Navier-Stokes equations
    2010 (English)In: Engineering Applications of Computational Fluid Mechanics, ISSN 1994-2060, Vol. 4, p. 29-38Article in journal (Refereed) Published
    National Category
    Computational Mathematics Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-112977 (URN)000276898600003 ()
    Available from: 2010-01-24 Created: 2010-01-24 Last updated: 2018-01-12Bibliographically approved
    2. A weak boundary procedure for high order finite difference approximations of hyperbolic problems
    Open this publication in new window or tab >>A weak boundary procedure for high order finite difference approximations of hyperbolic problems
    2011 (English)Report (Other academic)
    Series
    Technical report / Department of Information Technology, Uppsala University, ISSN 1404-3203 ; 2011-019
    National Category
    Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-159353 (URN)
    Available from: 2011-09-23 Created: 2011-09-28 Last updated: 2011-11-04Bibliographically approved
    3. Accurate and stable calculations involving shocks using a new hybrid scheme
    Open this publication in new window or tab >>Accurate and stable calculations involving shocks using a new hybrid scheme
    2009 (English)In: Proc. 19th AIAA CFD Conference, AIAA , 2009Conference paper, Published paper (Refereed)
    Place, publisher, year, edition, pages
    AIAA, 2009
    Series
    Conference Proceeding Series ; 2009-3985
    National Category
    Computational Mathematics Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-110133 (URN)
    Available from: 2009-11-04 Created: 2009-11-04 Last updated: 2018-01-12Bibliographically approved
    4. A stable and conservative method for locally adapting the design order of finite difference schemes
    Open this publication in new window or tab >>A stable and conservative method for locally adapting the design order of finite difference schemes
    2011 (English)In: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 230, p. 4216-4231Article in journal (Refereed) Published
    National Category
    Computational Mathematics Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-134055 (URN)10.1016/j.jcp.2010.11.020 (DOI)000290185000007 ()
    Available from: 2010-11-20 Created: 2010-11-21 Last updated: 2018-01-12Bibliographically approved
    5. Energy stability of the MUSCL scheme
    Open this publication in new window or tab >>Energy stability of the MUSCL scheme
    2010 (English)In: Numerical Mathematics and Advanced Applications: 2009, Berlin: Springer-Verlag , 2010, p. 61-68Conference paper, Published paper (Refereed)
    Place, publisher, year, edition, pages
    Berlin: Springer-Verlag, 2010
    National Category
    Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-132925 (URN)10.1007/978-3-642-11795-4_5 (DOI)000395207900005 ()978-3-642-11794-7 (ISBN)
    Available from: 2010-10-29 Created: 2010-10-29 Last updated: 2018-06-16Bibliographically approved
    6. The Effect of Reynolds Number in High Order Accurate Calculations with Shock Diffraction
    Open this publication in new window or tab >>The Effect of Reynolds Number in High Order Accurate Calculations with Shock Diffraction
    2010 (English)In: Proc. 7th South African Conference on Computational and Applied Mechanics, South African Association for Theoretical and Applied Mechanics , 2010, p. 416-423Conference paper, Published paper (Refereed)
    Place, publisher, year, edition, pages
    South African Association for Theoretical and Applied Mechanics, 2010
    National Category
    Computational Mathematics Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-113571 (URN)978-0-620-49192-1 (ISBN)
    Available from: 2010-01-29 Created: 2010-01-29 Last updated: 2018-01-12Bibliographically approved
  • 3.
    Abdurakhmanov, Eldar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Discovery and evaluation of direct acting antivirals against hepatitis C virus2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Until recently, the standard therapy for hepatitis C treatment has been interferon and ribavirin. Such treatment has only 50% efficacy and is not well tolerated. The emergence of new drugs has increased the treatment efficacy to 90%. Despite such an achievement, the success is limited since the virus mutates rapidly, causing the emergence of drug resistant forms. In addition, most new drugs were developed to treat genotype 1 infections. Thus, development of new potent antivirals is needed and drug discovery against hepatitis C is continued.

    In this thesis, a FRET-based protease assay was used to evaluate new pyrazinone based NS3 protease inhibitors that are structurally different to the newly approved and currently developing drugs. Several compounds in this series showed good potencies in the nanomolar range against NS3 proteases from genotype 1, 3, and the drug resistance variant R155K. We assume that these compounds can be further developed into drug candidates that possess activity against above mentioned enzyme variants.

    By using SPR technology, we analyzed interaction mechanisms and characteristics of allosteric inhibitors targeting NS5B polymerases from genotypes 1 and 3. The compounds exhibited different binding mechanisms and displayed a low affinity against NS5B from genotype 3.

    In order to evaluate the activity and inhibitors of the NS5B polymerase, we established an SPR based assay, which enables the monitoring of polymerization and its inhibition in real time. This assay can readily be implemented for the discovery of inhibitors targeting HCV.

    An SPR based fragment screening approach has also been established. A screen of a fragment library has been performed in order to identify novel scaffolds that can be used as a starting point for development of new allosteric inhibitors against NS5B polymerase. Selected fragments will be further elaborated to generate a new potent allosteric drug candidate.

    Alternative approaches have successfully been developed and implemented to the discovery of potential lead compounds targeting two important HCV drug targets.

    List of papers
    1. Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
    Open this publication in new window or tab >>Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
    Show others...
    2016 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, no 12, p. 2603-2620Article in journal (Refereed) Published
    Abstract [en]

    Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

    Keywords
    Hepatitis C virus; Drug resistance; Pyrazinone; NS3 protease inhibitors; R155K
    National Category
    Organic Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-243315 (URN)10.1016/j.bmc.2016.03.066 (DOI)000376727800002 ()27160057 (PubMedID)
    Funder
    Swedish Research Council, D0571301
    Available from: 2015-02-08 Created: 2015-02-08 Last updated: 2017-12-04Bibliographically approved
    2. Pyrazinone based hepatitis C virus NS3 protease inhibitors targeting genotype 1a, 3a and the drug-resistant enzyme variant R155K
    Open this publication in new window or tab >>Pyrazinone based hepatitis C virus NS3 protease inhibitors targeting genotype 1a, 3a and the drug-resistant enzyme variant R155K
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265295 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
    3. Resolution of the Interaction Mechanisms and Characteristics of Non-nucleoside Inhibitors of Hepatitis C Virus Polymerase - Laying the Foundation for Discovery of Allosteric HCV Drugs
    Open this publication in new window or tab >>Resolution of the Interaction Mechanisms and Characteristics of Non-nucleoside Inhibitors of Hepatitis C Virus Polymerase - Laying the Foundation for Discovery of Allosteric HCV Drugs
    Show others...
    2013 (English)In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 97, no 3, p. 356-368Article in journal (Other academic) Published
    Abstract [en]

    Development of allosteric inhibitors into efficient drugs is hampered by their indirect mode-of-action and complex structure-kinetic relationships. To enablethe design of efficient allosteric drugs targeting the polymerase of hepatitis C virus(NS5B), the interaction characteristics of three non-nucleoside compounds (filibuvir, VX-222, and tegobuvir) inhibiting HCV replication via NS5B have been analyzed. Since there was no logical correlation between the anti-HCV replicative and enzyme inhibitory effects of the compounds, surface plasmon resonance biosensor technology was used to resolve the mechanistic, kinetic, thermodynamic and chemodynamic features of their interactions with their target and their effect on itsinteraction with RNA. Tegobuvir could not be seen to interact with NS5B at all while filibuvir interacted in a single reversible step (except at low temperatures) and VX-222 in two serial steps, interpreted as an induced fit mechanism. Both filibuvir and VX-222 interfered with the interaction between NS5B and RNA. They competed for binding to the enzyme, suggesting that they had a common inhibition mechanism and identical or overlapping binding sites. The greater anti-HCV replicative activityof VX-222 over filibuvir is hypothesized to be due to a greater allosteric conformational effect, resulting in the formation of a less catalytically competent complex. In addition, the induced fit mechanism of VX-222 gives it a kinetic advantage over filibuvir, exhibited as a longer residence time. These insights have important consequences for the selection and optimization of new allosteric NS5Binhibitors.

    Keywords
    HCV, NS5B, filibuvir, VX-222, tegobuvir, allosteric inhibitor, induced fit, kinetics, chemodynamics, thermodynamics
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biochemistry; Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-171996 (URN)10.1016/j.antiviral.2012.12.027 (DOI)000317709400018 ()
    Available from: 2012-04-03 Created: 2012-03-31 Last updated: 2017-12-07Bibliographically approved
    4. Characterization of allosteric inhibitors of hepatitis C virus polymerase – a genotype comparative study
    Open this publication in new window or tab >>Characterization of allosteric inhibitors of hepatitis C virus polymerase – a genotype comparative study
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265287 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
    5. A time-resolved surface plasmon resonance based hepatitis C virus NS5B polymerase assay and its application for drug discovery
    Open this publication in new window or tab >>A time-resolved surface plasmon resonance based hepatitis C virus NS5B polymerase assay and its application for drug discovery
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265290 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
    6. Fragment library screening addressing Hepatitis C protein NS5B from genotypes 1 and 3 using an SPR-based approach
    Open this publication in new window or tab >>Fragment library screening addressing Hepatitis C protein NS5B from genotypes 1 and 3 using an SPR-based approach
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265292 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
  • 4.
    Abenius, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Numerical Analysis.
    Direct and Inverse Methods for Waveguides and Scattering Problems in the Time Domain2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Numerical simulation is an important tool in understanding the electromagnetic field and how it interacts with the environment. Different topics for time-domain finite-difference (FDTD) and finite-element (FETD) methods for Maxwell's equations are treated in this thesis.

    Subcell models are of vital importance for the efficient modeling of small objects that are not resolved by the grid. A novel model for thin sheets using shell elements is proposed. This approach has the advantage of taking into account discontinuities in the normal component of the electric field, unlike previous models based on impedance boundary conditions (IBCs). Several results are presented to illustrate the capabilities of the shell element approach.

    Waveguides are of fundamental importance in many microwave applications, for example in antenna feeds. The key issues of excitation and truncation of waveguides are addressed. A complex frequency shifted form of the uniaxial perfectly matched layer (UPML) absorbing boundary condition (ABC) in FETD is developed. Prism elements are used to promote automatic grid generation and enhance the performance. Results are presented where reflection errors below -70dB are obtained for different types of waveguides, including inhomogeneous cases. Excitation and analysis via the scattering parameters are achieved using waveguide modes computed by a general frequency-domain mode solver for the vector Helmholtz equation. Huygens surfaces are used in both FDTD and FETD for excitation in waveguide ports.

    Inverse problems have received an increased interest due to the availability of powerful computers. An important application is non-destructive evaluation of material. A time-domain, minimization approach is presented where exact gradients are computed using the adjoint problem. The approach is applied to a general form of Maxwell's equations including dispersive media and UPML. Successful reconstruction examples are presented both using synthetic and experimental measurement data. Parameter reduction of complex geometries using simplified models is an interesting topic that leads to an inverse problem. Gradients for subcell parameters are derived and a successful reconstruction example is presented for a combined dielectric sheet and slot geometry.

    List of papers
    1. Hybrid time domain solvers for the Maxwell equations in 2D
    Open this publication in new window or tab >>Hybrid time domain solvers for the Maxwell equations in 2D
    Show others...
    2002 (English)In: International Journal for Numerical Methods in Engineering, ISSN 0029-5981, E-ISSN 1097-0207, Vol. 53, p. 2185-2199Article in journal (Refereed) Published
    National Category
    Computational Mathematics Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-44333 (URN)10.1002/nme.380 (DOI)
    Projects
    GEMS
    Available from: 2007-01-26 Created: 2007-01-26 Last updated: 2018-01-11Bibliographically approved
    2. Waveguide Truncation Using UPML in the Finite-Element Time-Domain Method
    Open this publication in new window or tab >>Waveguide Truncation Using UPML in the Finite-Element Time-Domain Method
    2005 (English)Report (Other academic)
    Series
    Technical report / Department of Information Technology, Uppsala University, ISSN 1404-3203 ; 2005-026
    National Category
    Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-80256 (URN)
    Projects
    GEMS
    Available from: 2007-02-03 Created: 2007-02-03 Last updated: 2014-09-03Bibliographically approved
    3. Solving inverse electromagnetic problems using FDTD and gradient-based minimization
    Open this publication in new window or tab >>Solving inverse electromagnetic problems using FDTD and gradient-based minimization
    2006 (English)In: International Journal for Numerical Methods in Engineering, ISSN 0029-5981, E-ISSN 1097-0207, Vol. 68, p. 650-673Article in journal (Refereed) Published
    National Category
    Computational Mathematics Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-80802 (URN)10.1002/nme.1731 (DOI)000241713800003 ()
    Projects
    GEMS
    Available from: 2007-01-26 Created: 2007-01-26 Last updated: 2018-01-13Bibliographically approved
    4. Thin Sheet Modeling Using Shell Elements in the Finite-Element Time-Domain Method
    Open this publication in new window or tab >>Thin Sheet Modeling Using Shell Elements in the Finite-Element Time-Domain Method
    2006 (English)In: IEEE Transactions on Antennas and Propagation, ISSN 0018-926X, E-ISSN 1558-2221, Vol. 54, p. 28-34Article in journal (Refereed) Published
    National Category
    Computational Mathematics Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-80325 (URN)10.1109/TAP.2005.861554 (DOI)000235016700004 ()
    Projects
    GEMS
    Available from: 2007-01-26 Created: 2007-01-26 Last updated: 2018-01-13Bibliographically approved
    5. Modeling of inhomogeneous waveguides using hybrid methods
    Open this publication in new window or tab >>Modeling of inhomogeneous waveguides using hybrid methods
    2005 (English)Manuscript (preprint) (Other academic)
    National Category
    Computational Mathematics Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-93590 (URN)
    Projects
    GEMS
    Available from: 2005-10-11 Created: 2005-10-11 Last updated: 2018-01-13Bibliographically approved
  • 5.
    Abrahamson, Alexandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Gill EROD Activity in Fish: A Biomarker for Waterborne Ah-receptor Agonists2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Induction of the cytochrome P450(CYP)1A protein and the connected increase in 7-ethoxyresorufin O-deethylase (EROD) activity are common biomarkers in fish. Enhanced activity of this protein signals exposure to Ah-receptor agonists such as chlorinated dioxins, co-planar polychlorinated biphenyls (PCBs) and certain polycyclic aromatic hydrocarbons (PAHs). The EROD biomarker is commonly analyzed in liver microsomes. However, the gill is directly exposed to waterborne pollutants, and in this thesis the gill filament EROD assay was therefore evaluated as a monitoring tool for waterborne CYP1A inducers in fish. Originally developed in rainbow trout (Oncorhynchus mykiss), the assay was here applied in various limnic and marine species. Following exposure to low waterborne concentrations of the readily metabolized CYP1A inducers benzo(a)pyrene (BaP) and indigo, a strong EROD induction was observed in the gill but not in the liver. This likely reflected metabolic clearance of the inducers in gill and other extrahepatic tissues. The high sensitivity of the gill was confirmed in studies of fish caged in waters in urban and rural areas in Sweden where the gill consistently showed a more pronounced EROD induction compared with the liver and the kidney. Fish caged in the reference waters showed surprisingly strong gill EROD induction and CYP1A immunostaining. Consequently, there may be CYP1A inducers present in the aquatic environment that are not yet identified. The assay was further applied in Atlantic cod (Gadus morhua) as a biomarker of exposure to crude oil and produced water (PW) from oil fields in the North Sea. The assay was finally adapted to detect inhibiting compounds, and an imidazole, a triazole and a plant flavonoid turned out to be potent gill EROD inhibitors. The overall conclusion from the studies of this thesis is that the gill filament EROD assay is a practical and sensitive biomarker of exposure to waterborne CYP1A inducers in various fish species. The induction of gill EROD activity in fish also at the reference sites in the field studies calls for further studies on background contamination in Swedish waters.

    List of papers
    1. EROD activity in gill filaments from anadromous and marine fish as a biomarker of dioxin-like pollutants
    Open this publication in new window or tab >>EROD activity in gill filaments from anadromous and marine fish as a biomarker of dioxin-like pollutants
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    2003 (English)In: Comparative Biochemistry and Physiology Part C, Vol. 136, p. 235-243Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95920 (URN)
    Available from: 2007-05-09 Created: 2007-05-09 Last updated: 2009-04-02Bibliographically approved
    2. Cytochrome P4501A induction in rainbow trout gills and liver following exposure to waterborne indigo, benzo(a)pyrene and 3,3',4,4',5-pentachlorobiphenyl
    Open this publication in new window or tab >>Cytochrome P4501A induction in rainbow trout gills and liver following exposure to waterborne indigo, benzo(a)pyrene and 3,3',4,4',5-pentachlorobiphenyl
    2006 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 79, no 3, p. 226-232Article in journal (Refereed) Published
    Abstract [en]

    We have developed a gill-filament based ethoxyresorufin O-deethylase (EROD) assay to be used as a tool to monitor cytochrome P4501A (CYP1A) induction in caged fish. The present study aimed to compare temporal patterns of EROD induction in gills and liver of rainbow trout (Oncorhynchus mykiss) exposed in the laboratory to readily metabolized and persistent CYP1A inducers, i.e. indigo, benzo[a]pyrene (BaP), and 3,3',4,4',5-pentachlorobiphenyl (PCB#126). Branchial and hepatic EROD activities were examined in fish exposed for 6, 12, or 24h and in fish exposed for 24h and then held in clean water for 2 or 14 days. Furthermore, branchial CYP1A protein expression was localized by immunohistochemistry. All compounds strongly induced branchial EROD activity within 6 h. The highest EROD inductions observed for indigo, BaP, and PCB#126 were roughly similar in gills (52-, 76-, and 74-fold), but differed considerably in liver (11-, 78-, and 200-fold). In indigo- and BaP-exposed fish, both hepatic and branchial EROD activities decreased rapidly in clean water. In PCB#126-exposed fish, decreased branchial and increased hepatic EROD activities were observed following transfer to clean water. The substances gave rise to immunostaining for CYP1A at different cellular sites. All inducers increased the CYP1A-immunostaining in the gill filament secondary lamellae, but PCB#126 also induced a pronounced CYP1A immunoreactivity in cells near the basal membrane of the epithelium of the primary lamellae. The observation that the low BaP and indigo concentrations induced EROD activity markedly in the gills but only slightly or not at all in the liver, supports the contention that readily metabolized AhR agonists may escape detection when hepatic EROD activity is used for environmental monitoring. The results show that gill filament EROD activity is a sensitive biomarker both for persistent and readily metabolized AhR agonists in polluted water.

    Keywords
    benzo[a]pyrene, CYP1A, gill, indigo, liver, 3, 3 ', 4, 4 ', 5-pentachlorobiphenyl (PCB#126)
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-95921 (URN)10.1016/j.aquatox.2006.06.006 (DOI)000240567200003 ()16872689 (PubMedID)
    Available from: 2007-05-09 Created: 2007-05-09 Last updated: 2017-12-14Bibliographically approved
    3. Monitoring contaminants from oil production at sea by measuring gill EROD activity in Atlantic cod (Gadus morhua)
    Open this publication in new window or tab >>Monitoring contaminants from oil production at sea by measuring gill EROD activity in Atlantic cod (Gadus morhua)
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    2008 (English)In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 153, no 1, p. 169-175Article in journal (Refereed) Published
    Abstract [en]

    An ex vivo gill EROD assay was applied in Atlantic cod (Gadus morhua) as a biomarker for waterborne CYP1A-inducing compounds derived from oil production at sea. Exposure to nominal concentrations of 1 ppm or 10 ppm North Sea crude oil in a static water system for 24 h caused a concentration-dependent gill EROD induction. Further, exposure of cod for 14 days to environmentally relevant concentrations of produced water (PW, diluted 1:200 or 1:1000) from a platform in the North Sea using a flow-through system resulted in a concentration-dependent induction of gill EROD. Crude oil (0.2 ppm) from the same oil field also proved to induce EROD. Finally, gill EROD activity in cod caged for 6 weeks at 500-10 000 m from two platforms outside Norway was measured. The activities in these fish were very low and did not differ from those in fish caged at reference sites.

    Keywords
    Atlantic cod, Biomarker, CYP1A, Crude oil, EROD, Gill, Produced water
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-95922 (URN)10.1016/j.envpol.2007.07.025 (DOI)000255819300020 ()17854961 (PubMedID)
    Available from: 2007-05-09 Created: 2007-05-09 Last updated: 2017-12-14Bibliographically approved
    4. Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters
    Open this publication in new window or tab >>Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters
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    2007 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 85, no 1, p. 1-8Article in journal (Refereed) Published
    Abstract [en]

    The gill filament 7-ethoxyresorufin O-deethylase (EROD) assay was evaluated as a monitoring tool for waterborne cytochrome P4501 A (CYP1A) inducers using rainbow trout (Oncorhynchus mykiss) caged in urban area waters in Sweden. To compare the CYP1A induction response in different tissues, EROD activity was also analyzed in liver and kidney microsomes. Immunohistochemistry was used to localize CYP1A protein in gill and kidney. In two separate experiments fish were caged at sites with fairly high expected polyaromatic hydrocarbon (PAH) contamination. In the first experiment, gill EROD activities were analyzed in fish exposed for 1-21 days in a river running through Uppsala. The reference site was upstream of Uppsala. In the second, gill, liver and kidney EROD activities were analyzed in fish exposed for 1-5 days in fresh or brackish waters of Stockholm and in a reference lake 60 km north of Stockholm. Fish exposed for 5 days followed by 2 days of recovery in tap water in the laboratory were also examined. The gill consistently showed a higher EROD induction compared with the liver and the kidney. After I day of caging, gill EROD activity was markedly induced (6-17-fold) at all sites examined. Induction in gill was pronounced (5-7-fold) also in fish caged at the reference sites. In the 21-day exposure study gill EROD activity remained highly induced throughout the experiment (26-fold at most) and the induced CYP1A protein was exclusively confined to the gill secondary lamellae. In the 5-day exposure experiment, EROD activity peaked after I day and then declined in both gill and liver, while CYP1A immunostaining in the gill remained intense over the 5-day period. In the kidney, CYP1A staining was weak or absent. We conclude that gill EROD activity is a more sensitive biomarker of exposure to waterborne CYP1A inducers than EROD activity in liver and kidney.

    Keywords
    fish; gill; CYP1A; EROD; monitoring
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-95923 (URN)10.1016/j.aquatox.2007.07.013 (DOI)000250181300001 ()
    Available from: 2007-05-09 Created: 2007-05-09 Last updated: 2017-12-14Bibliographically approved
    5. Inhibition of CYP1A activity in fish detected by the gill filament EROD assay - studies on ketoconazole, bitertanol, acacetin and omeprazole
    Open this publication in new window or tab >>Inhibition of CYP1A activity in fish detected by the gill filament EROD assay - studies on ketoconazole, bitertanol, acacetin and omeprazole
    (English)Manuscript (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-95924 (URN)