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  • 151.
    Hoxha, A.
    et al.
    University of Padua, Italy; Karolinska Institute, Sweden.
    Ruffatti, A.
    University of Padua, Italy.
    Ambrosi, A.
    Karolinska Institute, Sweden.
    Ottosson, V.
    Karolinska Institute, Sweden.
    Hedlund, M.
    Karolinska Institute, Sweden.
    Ottosson, L.
    Karolinska Institute, Sweden.
    Anandapadamanaban, Madhanagopal
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sonesson, S. -E.
    Karolinska Institute, Sweden.
    Wahren-Herlenius, M.
    Karolinska Institute, Sweden.
    Identification of discrete epitopes of Ro52p200 and association with fetal cardiac conduction system manifestations in a rodent model2016In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 186, no 3, p. 284-291Article in journal (Refereed)
    Abstract [en]

    Congenital heart block (CHB) is a potentially lethal condition characterized by a third-degree atrioventricular block (AVB). Despite anti-Ro52 antibodies being detected in nearly 90% of mothers of affected children, CHB occurs in only 1-2% of anti-Ro/Sjogrens-syndrome-related antigen A (SSA) autoantibody-positive pregnancies. Maternal antibodies have been suggested to bind molecules crucial to fetal cardiac function; however, it remains unknown whether a single antibody profile associates with CHB or whether several specificities and cross-reactive targets exist. Here, we aimed to define further the reactivity profile of CHB-associated antibodies towards Ro52p200 (amino acid 200-239). We first analysed reactivity of a monoclonal anti-Ro52 antibody shown to induce AVB in rats (7.8C7) and of sera from anti-Ro52p200 antibody-positive mothers of children with CHB towards a panel of modified Ro52p200 peptides, and subsequently evaluated their potential to induce AVB in rats upon transfer during gestation. We observed that CHB maternal sera displayed a homogeneous reactivity profile targeting preferentially the C-terminal part of Ro52p200, in contrast to 7.8C7 that specifically bound the p200 N-terminal end. In particular, amino acid D233 appeared crucial to maternal antibody reactivity towards p200. Despite low to absent reactivity towards rat p200 and different binding profiles towards mutated rat peptides indicating recognition of different epitopes within Ro52p200, immunoglobulin (Ig)G purified from two mothers of children with CHB could induce AVB in rats. Our findings support the hypothesis that several fine antibody specificities and cross-targets may exist and contribute to CHB development in anti-Ro52 antibody-positive pregnancies.

  • 152.
    Imam, Mewlude
    et al.
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. European Spallat Source ESS AB, Sweden.
    Gaul, Konstantin
    University of Marburg, Germany; University of Marburg, Germany.
    Stegmueller, Andreas
    University of Marburg, Germany; University of Marburg, Germany.
    Höglund, Carina
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering. European Spallat Source ESS AB, Sweden.
    Jensen, Jens
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Hultman, Lars
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Birch, Jens
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Tonner, Ralf
    University of Marburg, Germany; University of Marburg, Germany.
    Pedersen, Henrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Gas phase chemical vapor deposition chemistry of triethylboron probed by boron-carbon thin film deposition and quantum chemical calculations2015In: Journal of Materials Chemistry C, ISSN 2050-7526, E-ISSN 2050-7534, Vol. 3, no 41, p. 10898-10906Article in journal (Refereed)
    Abstract [en]

    We present triethylboron (TEB) as a single-source precursor for chemical vapor deposition (CVD) of BxC thin films and study its gas phase chemistry under CVD conditions by quantum chemical calculations. A comprehensive thermochemical catalogue for the species of the gas phase chemistry of TEB is examined and found to be dominated by beta-hydride eliminations of C2H4 to yield BH3. A complementary bimolecular reaction path based on H-2 assisted C2H6 elimination to BH3 is also significant at lower temperatures in the presence of hydrogen. Furthermore, we find a temperature window of 600-1000 degrees C for the deposition of X-ray amorphous BxC films with 2.5 less than= x less than= 4.5 from TEB. Films grown at temperatures below 600 degrees C contain high amounts of H, while temperatures above 1000 degrees C result in C-rich films. The film density and hardness are determined to be in the range of 2.40-2.65 g cm(-3) and 29-39 GPa, respectively, within the determined temperature window.

  • 153.
    Imam, Mewlude
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering. European Spallat Source ESS AB, Sweden.
    Höglund, Carina
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering. European Spallation Source ERIC, Lund, Sweden.
    Jensen, Jens
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Schmidt, Susann
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering. European Spallation Source ERIC, Lund, Sweden.
    Ivanov, Ivan Gueorguiev
    Linköping University, Department of Physics, Chemistry and Biology, Semiconductor Materials. Linköping University, Faculty of Science & Engineering.
    Hall-Wilton, Richard
    European Spallation Source ERIC, Lund, Sweden.
    Birch, Jens
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Pedersen, Henrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Trimethylboron as single-source precursor for boron-carbonthin film synthesis by plasma chemical vapor deposition2015Manuscript (preprint) (Other academic)
    Abstract [en]

    Boron-carbon (BxC) thin films are potential neutron converting layers for 10B-based neutron detectors. However, as common material choices for such detectors do not tolerate temperature above 500°C, a low temperature deposition route is required for this application. Here we study trimethylboron B(CH3)3 (TMB) as a single-source precursor for the deposition of BxC thin films by plasma CVD using Ar plasma. The effect of plasma power, TMB/Ar ratio and total pressure on the film composition, morphology and structure are investigated. The highest B/C ratio of 1.9 was achieved at high TMB flow in a low total pressure and high plasma power which rendered an approximate substrate temperature of ~ 300 °C. X-ray photoelectron spectroscopy shows that B-C bonds prevail in the films, although C-C and B-O bonds are also present. Raman spectroscopy confirms the presence of amorphous carbon phases in the films. The H content in the films is found to be 15±5 at. % by the time of flight elastic recoil detection analysis (Tof-ERDA). The film density as determined from X-ray reflectivity (XRR) measurements is 2. 16 ± 0.01  g/cm3 and the internal compressive stresses are measured to be less than 400 MPa.

  • 154.
    Imam, Mewlude
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering. European Spallat Source ERIC, Sweden.
    Höglund, Carina
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering. European Spallat Source ERIC, Sweden.
    Schmidt, Susann
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering. European Spallat Source ERIC, Sweden; IHI Ionbond AG, Switzerland.
    Hall-Wilton, Richard
    European Spallat Source ERIC, Sweden; Mid Sweden Univ, Sweden.
    Birch, Jens
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Pedersen, Henrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Plasma CVD of hydrogenated boron-carbon thin films from triethylboron2018In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 148, no 3, article id 034701Article in journal (Refereed)
    Abstract [en]

    Low-temperature chemical vapor deposition (CVD) of B-C thin films is of importance for neutron voltaics and semiconductor technology. The highly reactive trialkylboranes, with alkyl groups of 1-4 carbon atoms, are a class of precursors that have been less explored for low-temperature CVD of B-C films. Herein, we demonstrate plasma CVD of B-C thin films using triethylboron (TEB) as a single source precursor in an Ar plasma. We show that the film density and B/C ratio increases with increasing plasma power, reaching a density of 2.20 g/cm(3) and B/C = 1.7. This is attributed to a more intense energetic bombardment during deposition and more complete dissociation of the TEB molecule in the plasma at higher plasma power. The hydrogen content in the films ranges between 14 and 20 at. %. Optical emission spectroscopy of the plasma shows that BH, CH, C-2, and H are the optically active plasma species from TEB. We suggest a plasma chemical model based on beta-hydrogen elimination of C2H4 to form BH3, in which BH3 and C2H4 are then dehydrogenated to form BH and C2H2. Furthermore, C2H2 decomposes in the plasma to produce C-2 and CH, which together with BH and possibly BH3-x(C2H5)(x) are the film forming species. (c) 2018 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution ( CC BY) license (http://creativecommons.org/licenses/by/4.0/).

  • 155.
    Imam, Mewlude
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering. European Spallat Source ERIC, Sweden.
    Souqui, Laurent
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Herritsch, Jan
    Philipps University of Marburg, Germany.
    Stegmueller, Andreas
    Philipps University of Marburg, Germany.
    Höglund, Carina
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering. European Spallat Source ERIC, Sweden.
    Schmidt, Susann
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Hall-Wilton, Richard
    European Spallat Source ERIC, Sweden; Mid Sweden University, Sweden.
    Högberg, Hans
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Birch, Jens
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Tonner, Ralf
    Philipps University of Marburg, Germany.
    Pedersen, Henrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Gas Phase Chemistry of Trimethylboron in Thermal Chemical Vapor Deposition2017In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 121, no 47, p. 26465-26471Article in journal (Refereed)
    Abstract [en]

    Alkylboranes, such as trimethylboron (TMB) and triethylboron (TEB), are promising alternative precursors in low temperature chemical vapor deposition (CVD) of boron-containing thin films. In this study, CVD growth of B-C films using TMB and quantum-chemical calculations to elucidate a gas phase chemical mechanism were undertaken. Dense, amorphous, boron-rich (B/C 1.5-3) films were deposited at 1000 degrees C in both dihydrogen and argon ambients, while films with crystalline B4C and B25C inclusions were deposited at 1100 degrees C in dihydrogen. A script-based automatization scheme was implemented for the quantum-chemical computations to enable time efficient screening of thousands of possible gas phase CVD reactions. The quantum-chemical calculations suggest TMB is mainly decomposed by an unimolecular alpha-H elimination of methane, which is complemented by dihydrogen-assisted elimination of methane in dihydrogen.

  • 156.
    Jansson, Felisa
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    The Effect of Microcrystalline Cellulose as cushioning excipient during controlled release2017Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    In the pharmaceutical industry, it is always important to have reproducible processes and raw materials of high quality to ensure good quality products. AstraZeneca, that is a leading manufacturer of different pharmaceuticals, works according to GMP to make sure that their processes deliver products of the same quality every time. A problem that has occurred at AstraZeneca is when a raw material is not properly understood and variations in the raw material affects the final product. Variations in drug release in one of AstraZeneca´s products, Product X, has been linked to the cushioning excipient Microcrystalline cellulose (MCC). Variations in drug release has been noticed during change from one batch of MCC to another. The aim of this study was to investigate which material attributes of MCC that contributes to variations in the final product. Particle size and moisture content were identified as critical material attributes (CMA´s) and were therefore chosen to be investigated more thoroughly. By variating particle size and moisture content during manufacturing of Product X, the influence of these attributes could be investigated using Design of Experiment (DoE). An additional experiment that compared two MCC batches from different suppliers was also performed during this study. The results from these experiments showed that the particle size and moisture content of MCC does affect the drug release. Large particles and high moisture content gave rise to a faster drug release compared to small particles and low moisture content that gave rise to a slower drug release. It is however hard to draw conclusions regarding how small differences in particle size and moisture content could affect the drug release. 

  • 157.
    Jansson, Lennie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    Purification and refolding of a novel dipeptidyl peptidase III2019Independent thesis Basic level (degree of Bachelor), 10,5 credits / 16 HE creditsStudent thesis
    Abstract [en]

    There is a continuous search for novel enzymes to complement the abilities of today’s commercially available enzyme and find tailor-fit alternatives to suit the diverse array of bio-based industries. One application could be to increase biogas yield by finding substrate degrading proteases that can be added to the anaerobic digestion process and survive degradation themselves. A novel enzyme identified as a hypothetical dipeptidyl peptidase III, a zinc dependent metallo-protease, was found by a metaproteogenomics approach to be produced by the microorganisms of a thermophilic biogas process. The aim of this study was to express and refold a recombinant variant of the novel DPP III to its active form after production in inclusion bodies in Escherichia Coli. Assaying of refolding conditions was performed by stepwise dialysis and drip dilution. Nine attempts were performed based on findings in literature, although no other variant of DPP III has earlier been successfully refolded from inclusion bodies. The study resulted in a limited set of conditions of temperature, volumes, metal ions, salts and other additives being tested in the refolding buffers. Enzyme refolding and activation was monitored by the hydrolysis of the DPP III fluorescent substrate Arg-Arg β-naphthylamide trihydrochloride, alongside with measurements of protein concentration and SDS-PAGE. The novel DPP III was successfully purified but no definite strategy of producing correctly folded protein was found.

  • 158.
    Jarl, Anngelica
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Andrésen, Cecilia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Eriksson, Laila
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Svensson, Magdalena
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    AEDANS labeled MexR variants and their DNA interactionManuscript (preprint) (Other academic)
    Abstract [en]

    MexR is a transcriptional repressor of the multidrug efflux-pump operon in the bacterial pathogen Pseudomonas aeruginosa, and thus, malfunction in the DNA-binding of the MexR protein leads to multidrug resistance (Poole et al., 1996). lt has been shown that mutations in the MexR protein lead to lost DNA binding ability (Saito et al., 2003). X-ray studies of the MexR protein (Lim et al., 2002) show that the protein contains a winged helix-turn-helix motif and this type of motif is known to be involved in DNA-binding (Gajiwala & Burley, 2000), but no exact DNA-binding sequence in MexR has yet been determined.

    This study attempts to identify regions in the MexR protein involved in DNA-binding using a molecular probe as mapping tool. Three cysteines naturally occur in the MexR protein, located in positions 30, 62 and 138, respectively, and we have used two of them to map the DNA-binding site. Preliminary results show that the fluorescence of an TAEDANS probe attached to cys 62 is affected by DNA-binding, while a probe at cys 30 is not affected. Further studies are required to analyse the implications of these results.

  • 159.
    Johansson, Leif B. G.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lantz, Linda
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Eriksson, Mikaela
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nygren, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    A variety of thiophene based ligands for detection of protein aggregates by surface plasmon resonanceManuscript (preprint) (Other academic)
    Abstract [en]

    By attaching an azide functional group via a tetraethylene glycol linker to the α-terminal position of a variety of oligothiophenes, thiophene-based ligands that can be utilized for detection of protein aggregates with surface plasmon resonance have been developed. All ligands displayed selectivity towards recombinant amyloid fibrils and the LCO/protein aggregate interaction could be detected by fluorescence as well as by surface plasmon resonance.

  • 160.
    Johansson, Leif B. G.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Simon, Rozalyn
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bergström, Gunnar
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Eriksson, Mikaela
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Prokop, Stefan
    Charite, Germany.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Heppner, Frank L.
    Charite, Germany.
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    An azide functionalized oligothiophene ligand - A versatile tool for multimodal detection of disease associated protein aggregates2015In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 63, p. 204-211Article in journal (Refereed)
    Abstract [en]

    Ligands for identifying protein aggregates are of great interest as such deposits are the pathological hallmark of a wide range of severe diseases including Alzheimers and Parkinsons disease. Here we report the synthesis of an azide functionalized fluorescent pentameric oligothiophene that can be utilized as a ligand for multimodal detection of disease-associated protein aggregates. The azide functionalization allows for attachment of the ligand to a surface by conventional click chemistry without disturbing selective interaction with protein aggregates and the oligothiophene-aggregate interaction can be detected by fluorescence or surface plasmon resonance. In addition, a methodology where the oligothiophene ligand is employed as a capturing molecule selective for aggregated proteins in combination with an antibody detecting a distinct peptide/protein is also presented. We foresee that this methodology will offer the possibility to create a variety of multiplex sensing systems for sensitive and selective detection of protein aggregates, the pathological hallmarks of several neurodegenerative diseases.

  • 161.
    Johansson, Leif B.G.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Asymmetric Oligothiophenes: Chemical Evolution of Multimodal Amyloid Ligands2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Luminescent conjugated polymers (LCPs) and luminescent conjugated oligothiophenes (LCOs) can be used as molecular probes to study diseases associated with protein aggregation. The conventionally used dyes to study and detect protein aggregates, denoted amyloid, have been Congo red (CR) and Thioflavin T (ThT). In contrast to these amyloid ligands, LCOs offer the possibility to detect aggregated proteinaceous species occurring at earlier stages of amyloid formation as well as to distinguish different morphotypes of protein aggregates. The interaction between the LCOs and the protein deposits can be studied by fluorescence spectroscopy and microscopy both in vitro and ex vivo. In this thesis we report the development of multimodal asymmetric LCOs that can be utilized with two novel techniques, Surface Plasmon Resonance (SPR) and Positron Emission Tomography (PET), to study the interaction between LCO and amyloid fibrils in real time. With SPR, we have been able to determine binding affinities between LCO and amyloid, and with PET we have shown that radiolabelled LCOs can be used as a non-invasive method to study amyloid deposits in vivo. In addition, by alteration of the backbone (change of thiophene units), and of adding different side chains functionalities, we have shown that the properties of the amyloid ligands have a huge impact of the binding to different stages or forms of protein aggregates. By making asymmetrical LCOs, which can be attached to a surface, we also foresee a methodology that will offer the possibility to create a sensitive and selective detection method, and maybe lead to a lab-on-a-chip-application.

    List of papers
    1. Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates
    Open this publication in new window or tab >>Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates
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    2011 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, no 24, p. 8356-8370Article in journal (Refereed) Published
    Abstract [en]

    Molecular probes for selective identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying protein aggregation diseases. Here we report the chemical design of a library of anionic luminescent conjugated oligothiophenes (LCOs), which can be utilized as ligands for detection of protein aggregates. Certain molecular requirements were shown to be necessary for detecting (i) early non-thioflavinophilic protein assemblies of A beta 1-42 and insulin preceding the formation of amyloid fibrils and (ii) for obtaining distinct spectral signatures of the two main pathological hallmarks observed in human Alzheimers diease brain tissue (A beta plaques and neurofibrillary tangles). Our findings suggest that a superior anionic LCO-based ligand should have a backbone consisting of five to seven thiophene units and carboxyl groups extending the conjugated thiophene backbone. Such LCOs will be highly useful for studying the underlying molecular events of protein aggregation diseases and could also be utilized for the development of novel diagnostic tools for these diseases.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2011
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:liu:diva-73487 (URN)10.1039/c1ob05637a (DOI)000297354100019 ()
    Available from: 2012-01-04 Created: 2012-01-04 Last updated: 2019-11-08
    2. An azide functionalized oligothiophene ligand - A versatile tool for multimodal detection of disease associated protein aggregates
    Open this publication in new window or tab >>An azide functionalized oligothiophene ligand - A versatile tool for multimodal detection of disease associated protein aggregates
    Show others...
    2015 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 63, p. 204-211Article in journal (Refereed) Published
    Abstract [en]

    Ligands for identifying protein aggregates are of great interest as such deposits are the pathological hallmark of a wide range of severe diseases including Alzheimers and Parkinsons disease. Here we report the synthesis of an azide functionalized fluorescent pentameric oligothiophene that can be utilized as a ligand for multimodal detection of disease-associated protein aggregates. The azide functionalization allows for attachment of the ligand to a surface by conventional click chemistry without disturbing selective interaction with protein aggregates and the oligothiophene-aggregate interaction can be detected by fluorescence or surface plasmon resonance. In addition, a methodology where the oligothiophene ligand is employed as a capturing molecule selective for aggregated proteins in combination with an antibody detecting a distinct peptide/protein is also presented. We foresee that this methodology will offer the possibility to create a variety of multiplex sensing systems for sensitive and selective detection of protein aggregates, the pathological hallmarks of several neurodegenerative diseases.

    Place, publisher, year, edition, pages
    Elsevier, 2015
    Keywords
    Protein aggregates; Oligothiophene; Fluorescence; Surface plasmon resonance; Click chemistry
    National Category
    Chemical Sciences Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-112169 (URN)10.1016/j.bios.2014.07.042 (DOI)000343337000030 ()25089818 (PubMedID)
    Note

    Funding Agencies|Swedish Foundation for Strategic Research; Ehrling Persson Foundation; ERC Starting Independent Researcher grant (Project: MUMID)

    Available from: 2014-11-18 Created: 2014-11-18 Last updated: 2019-01-22
    3. 11C and 18FRadiolabeling of Tetra- and Pentathiophenes as PET-ligands for Amyloid Protein Aggregates
    Open this publication in new window or tab >>11C and 18FRadiolabeling of Tetra- and Pentathiophenes as PET-ligands for Amyloid Protein Aggregates
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    2016 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 7, no 4, p. 368-373Article in journal (Refereed) Published
    Abstract [en]

    Three oligothiophenes were evaluated as PET tracers for the study of local and systemic amyloidosis ex vivo using tissue from patients with amyloid deposits and in vivo using healthy animals and PET-CT. The ex vivo binding studies revealed that all three labeled compounds bound specifically to human amyloid deposits. Specific binding was found in the heart, kidney, liver and spleen. To verify the specificity of the oligothiophenes towards amyloid deposits, tissue sections with amyloid pathology were stained using the fluorescence exhibited by the compounds and evaluated with multiphoton microscopy. Furthermore, in vivo rat and monkey PET-CT studies showed very low uptake in the brain, pancreas and heart of the healthy animals indicating low non-specific binding to healthy tissue. The biological evaluations indicated that this is a promising group of compounds for the visualization of systemic and localized amyloidosis.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2016
    National Category
    Chemical Sciences Cell Biology
    Identifiers
    urn:nbn:se:liu:diva-122273 (URN)10.1021/acsmedchemlett.5b00309 (DOI)000374436700007 ()
    Note

    Funding agencies:  Swedish Research Council; Swedish Foundation for Strategic Research; LiU-Neuro; Ehrling-Persson Foundation; Goran-Gustafsson Foundation; ERC Starting Independent Researcher grant (Project: MUMID)

    Vid tiden för disputation förelåg publikationen som manuskript

    Available from: 2015-10-27 Created: 2015-10-27 Last updated: 2018-04-25Bibliographically approved
    4. A variety of thiophene based ligands for detection of protein aggregates by surface plasmon resonance
    Open this publication in new window or tab >>A variety of thiophene based ligands for detection of protein aggregates by surface plasmon resonance
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    By attaching an azide functional group via a tetraethylene glycol linker to the α-terminal position of a variety of oligothiophenes, thiophene-based ligands that can be utilized for detection of protein aggregates with surface plasmon resonance have been developed. All ligands displayed selectivity towards recombinant amyloid fibrils and the LCO/protein aggregate interaction could be detected by fluorescence as well as by surface plasmon resonance.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:liu:diva-122274 (URN)
    Available from: 2015-10-27 Created: 2015-10-27 Last updated: 2015-10-27Bibliographically approved
  • 162.
    Johansson, Mikaela
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Metaproteogenomics-guided enzyme discovery: Targeted identification of novel proteases in microbial communities2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Industrial biotechnology is a large and growing industry as it is part of establishing a “greener” and more sustainable bioeconomy-based society. Using enzymes as biocatalysts is a viable alternative to chemicals and energy intense industrial processes and is en route to a more sustainable industry. Enzymes have been used in different areas for ages and are today used in many industrial processes such as biofuels production, food industry, tanning, chemical synthesis, pharmaceuticals etc. Enzymes are today a billion-dollar industry in itself and the demand for novel catalysts for various present and future processes of renewable resources are high and perfectly in line with converting to a more sustainable society.

    Most enzymes used in industry today have been identified from isolated and pure cultured microorganisms with identified desirable traits and enzymatic capacities. However, it is known that less than 1% of all microorganisms can be can be obtained in pure cultures. Thus, if we were to rely solely on pure culturing, this would leave the 99% of the microorganisms that constitutes the “microbial dark matter” uninvestigated for their potential in coding for and producing valuable novel enzymes. Therefore, to investigate these “unculturable” microorganisms for novel and valuable enzymes, pure-culture independent methods are needed.

    During the last two decades there has been a fast and extensive development in techniques and methods applicable for this purpose. Especially important has been the advancements made in mass spectrometry for protein identification and next generation sequencing of DNA. With these technical developments new research fields of proteomics and genomics have been developed, by which the complete protein complement of cells (the proteome) and all genes (the genome) of organisms can be investigated. When these techniques are applied to microbial communities these fields of research are known as meta-proteomics and meta-genomics.

    However, when applied to complex microbial communities, difficulties different from those encountered in their original usage for analysis of single multicellular organisms or cell linages arises, and when used independently both methods have their own limitations and bottlenecks. In addition, both metaproteomics and metagenomics are largely non-targeting techniques. Thus, if the purpose is still to - somewhat contradictory – use these non-targeting methods for targeted identification of novel enzymes with certain desired activities and properties from within microbial communities, special measures need to be taken.

    The work presented in this thesis describes the development of a method that combines

    metaproteomics and metagenomics (i.e. metaproteogenomics) for the targeted discovery of novel enzymes with desired activities, and their correct coding genes, from within microbial communities. Thus, what is described is a method that can be used to circumvent the pure-culturing problem so that a much larger fraction of the microbial dark matter can be specifically investigated for the identification of novel valuable enzymes.

    List of papers
    1. Applying theories of microbial metabolism for induction of targeted enzyme activity in a methanogenic microbial community at a metabolic steady state
    Open this publication in new window or tab >>Applying theories of microbial metabolism for induction of targeted enzyme activity in a methanogenic microbial community at a metabolic steady state
    2016 (English)In: Applied Microbiology and Biotechnology, ISSN 0175-7598, E-ISSN 1432-0614, Vol. 100, no 18, p. 7989-8002Article in journal (Refereed) Published
    Abstract [en]

    Novel enzymes that are stable in diverse conditions are intensively sought because they offer major potential advantages in industrial biotechnology, and microorganisms in extreme environments are key sources of such enzymes. However, most potentially valuable enzymes are currently inaccessible due to the pure culturing problem of microorganisms. Novel metagenomic and metaproteomic techniques that circumvent the need for pure cultures have theoretically provided possibilities to identify all genes and all proteins in microbial communities, but these techniques have not been widely used to directly identify specific enzymes because they generate vast amounts of extraneous data. In a first step towards developing a metaproteomic approach to pinpoint targeted extracellular hydrolytic enzymes of choice in microbial communities, we have generated and analyzed the necessary conditions for such an approach by the use of a methanogenic microbial community maintained on a chemically defined medium. The results show that a metabolic steady state of the microbial community could be reached, at which the expression of the targeted hydrolytic enzymes were suppressed, and that upon enzyme induction a distinct increase in the targeted enzyme expression was obtained. Furthermore, no cross talk in expression was detected between the two focal types of enzyme activities under their respective inductive conditions. Thus, the described approach should be useful to generate ideal samples, collected before and after selective induction, in controlled microbial communities to clearly discriminate between constituently expressed proteins and extracellular hydrolytic enzymes that are specifically induced, thereby reducing the analysis to only those proteins that are distinctively up-regulated.

    Place, publisher, year, edition, pages
    Springer, 2016
    Keywords
    Microbial community; Enzyme discovery; Metaproteomics; Biogas; Cellulase; Protease
    National Category
    Microbiology
    Identifiers
    urn:nbn:se:liu:diva-131888 (URN)10.1007/s00253-016-7547-z (DOI)000382008000017 ()27115757 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [621-2009-4150]; InZymes Biotech AB

    Available from: 2016-10-13 Created: 2016-10-11 Last updated: 2018-05-15
    2. Assessment of sample preparation methods for metaproteomics of extracellular proteins
    Open this publication in new window or tab >>Assessment of sample preparation methods for metaproteomics of extracellular proteins
    2017 (English)In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 516, p. 23-36Article in journal (Refereed) Published
    Abstract [en]

    Enzyme discovery in individual strains of microorganisms is compromised by the limitations of pure culturing. In principle, metaproteomics allows for fractionation and study of different parts of the protein complement but has hitherto mainly been used to identify intracellular proteins. However, the extracellular environment is also expected to comprise a wealth of information regarding important proteins. An absolute requirement for metaproteomic studies of protein expression, and irrespective of downstream methods for analysis, is that sample preparation methods provide clean, concentrated and representative samples of the protein complement. A battery of methods for concentration, extraction, precipitation and resolubilization of proteins in the extracellular environment of a constructed microbial community was assessed by means of 2D gel electrophoresis and image analysis to elucidate whether it is possible to make the extracellular protein complement available for metaproteomic analysis. Most methods failed to provide pure samples and therefore negatively influenced protein gel migration and gel background clarity. However, one direct precipitation method (TCA-DOC/acetone) and one extraction/precipitation method (phenol/methanol) provided complementary high quality 2D gels that allowed for high spot detection ability and thereby also spot detection of less abundant extracellular proteins.

    Place, publisher, year, edition, pages
    Elsevier, 2017
    Keywords
    Enzyme discovery, Microbial community, Metaproteome, Extracellular, Sample preparation, 2D gel electrophoresis
    National Category
    Analytical Chemistry Biocatalysis and Enzyme Technology
    Identifiers
    urn:nbn:se:liu:diva-132902 (URN)10.1016/j.ab.2016.10.008 (DOI)000388056800005 ()27742212 (PubMedID)
    Funder
    Swedish Research Council, 621-2009-4150
    Note

    Funding agencies: Swedish Research Council [621-2009-4150]; Tekniska Verken i Linkoping AB; InZymes Biotech AB

    Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2018-05-15Bibliographically approved
  • 163.
    Johansson, Per-Ola
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Jansson, Katarina
    Medivir AB, Huddinge, Sweden.
    Vrang, Lotta
    Medivir AB, Huddinge, Sweden.
    Hamelink, Elizabeth
    Medivir AB, Huddinge, Sweden.
    Hallberg, Anders
    Department of Medicinal Chemistry, Uppsala University, BMC, Uppsala, Sweden.
    Rosenqvist, Åsa
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
    Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template2006In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 15, p. 5136-5151Article in journal (Refereed)
    Abstract [en]

    The HCV NS3 protease is essential for replication of the hepatitis C virus (HCV) and therefore constitutes a promising new drug target for anti-HCV therapy. Several potent and promising HCV NS3 protease inhibitors, some of which display low nanomolar activities, were identified from a series of novel inhibitors incorporating a trisubstituted cyclopentane dicarboxylic acid moiety as a surrogate for the widely used N-acyl-(4R)-hydroxyproline in the P2 position.

  • 164.
    Johansson, Per-Ola
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Chen, Yantao
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Belfrage, Anna Karin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Blackman, Michael J.
    Division of Parasitology, National Institute for Medical Research, London, United Kingdom.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Jansson, Katarina
    Medivir AB, Huddinge, Sweden.
    Vrang, Lotta
    Medivir AB, Huddinge, Sweden.
    Hamelink, Elizabeth
    Medivir AB, Huddinge, Sweden.
    Hallberg, Anders
    Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
    Rosenquist, Åsa
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Medivir AB, Huddinge, Sweden and Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
    Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II: use of solid-phase synthesis to explore novel statine motifs2004In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, no 13, p. 3353-3366Article in journal (Refereed)
    Abstract [en]

    Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 μM. Several inhibitors have been identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.

  • 165.
    Johansson, Per-Ola
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Lindberg, Jimmy
    Department of Cell and Molecular Biology, BMC, Uppsala University, Uppsala, Sweden.
    Blackman, Michael J.
    Division of Parasitology, National Institute for Medical Research, United Kingdom.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Vrang, Lotta
    Medivir AB, Huddinge, Sweden.
    Hamelink, Elizabeth
    Medivir AB, Huddinge, Sweden.
    Hallberg, Anders
    Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
    Rosenquist, Åsa
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Medivir AB, Huddinge, Sweden and Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
    Design and synthesis of potent inhibitors of plasmepsin I and II: x-ray crystal structure of inhibitor in complex with plasmepsin II2005In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, no 13, p. 4400-4409Article in journal (Refereed)
    Abstract [en]

    New and potent inhibitors of the malarial aspartic proteases plasmepsin (Plm) I and II, from the deadliest malaria parasite Plasmodium falciparum, have been synthesized utilizing Suzuki coupling reactions on previously synthesized bromobenzyloxy-substituted statine-like inhibitors. The enzyme inhibition activity has been improved up to eight times by identifying P1 substituents that effectively bind to the continuous S1-S3 crevice of Plasmepsin I and II. By replacement of the bromo atom in the P1 p-bromobenzyloxy-substituted inhibitors with different aryl substituents, several inhibitors exhibiting Ki values in the low nanomolar range for both Plm I and II have been identified. Some of these inhibitors are also effective in attenuating parasite growth in red blood cells, with the best inhibitors, compounds 2 and 4, displaying 70% and 83% inhibition, respectively, at a concentration of 5 μM. The design was partially guided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitor 1 in complex with plasmepsin II. © 2005 American Chemical Society.

  • 166.
    Jonson, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Investigating Amyloid β toxicity in Drosophila melanogaster2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis Drosophila melanogaster (the fruit fly) has been used as a model organism to study the aggregation and toxic properties of the human amyloid β (Aβ) peptide involved in the onset of Alzheimer's disease (AD). AD is one of many misfolding diseases where the important event of a protein to adopt its’ specific three-dimensional structure has failed, leading to aggregation and formation of characteristic amyloid fibrils. AD has a complex pathology and probably reflects a variety of related molecular and cellular abnormalities, however, the most apparent common denominator so far is abnormal Amyloid-β precursor protein (APP) processing, resulting in a pool of various Aβ-peptides. In AD, the Aβ peptide misfolds, aggregates and forms amyloid plaques in the brain of patients, resulting in progressive neurodegeneration that eventually leads to death.

    By expressing the human Aβ protein in the fly, we have studied the mechanisms and toxicity of the aggregation in detail and how different cell types in the fly are affected. We have also used this model to investigate the effect of potential drugs that can have a positive impact on disease progression. In the first and second work in this thesis, we have, in a systematic way, proved that the length of the Aβ-peptide is essential for its toxicity and propensity to aggregate. If the peptide expressed ends at amino acid 42 it is extremely toxic to the fly nervous system. However, this toxicity can be completely abolished by expressing a variant that is shorter than 42 amino acids (1-37 to 1-41 aa), or be significantly reduced by expressing a longer variant (1-43 aa). Toxicity can be partly mitigated in trans by co-expressing the 1-42 variant with a 1-38 variant. This supports the theory that the disease progression could be inhibited if the formation of Aβ 1-42 is decreased. In the third work we demonstrate that amyloid aggregates can be found in various cell types of Drosophila, however, the toxicity seem to be selective to neurons. Our results indicate that the aggregates of glial expressing flies have a more mature structure, which appear to be less toxic. This also suggests that glial cells might spread Aβ aggregates without being harmed. The last work in this thesis investigates how curcumin (turmeric) can affect Aβ aggregation and toxicity. Curcumin appears to shift the equilibrium between the less stable

    aggregates and mature fibers toward the final stage resulting in an improved lifespan for treated flies.

    In summary, this thesis demonstrates that the toxicity of Aβ in Drosophila is highly dependent on the Aβ variant expressed, the structure of the protein aggregates and which cell type that expresses the protein. We have also shed light on the potential of using Drosophila when it comes to examining possible therapeutic substances as a tool for drug discovery.

    List of papers
    1. Systematic A beta Analysis in Drosophila Reveals High Toxicity for the 1-42, 3-42 and 11-42 Peptides, and Emphasizes N- and C-Terminal Residues
    Open this publication in new window or tab >>Systematic A beta Analysis in Drosophila Reveals High Toxicity for the 1-42, 3-42 and 11-42 Peptides, and Emphasizes N- and C-Terminal Residues
    Show others...
    2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133272Article in journal (Refereed) Published
    Abstract [en]

    Brain amyloid plaques are a hallmark of Alzheimers disease (AD), and primarily consist of aggregated A beta peptides. While A beta 1-40 and A beta 1-42 are the most abundant, a number of other A beta peptides have also been identified. Studies have indicated differential toxicity for these various A beta peptides, but in vivo toxicity has not been systematically tested. To address this issue, we generated improved transgenic Drosophila UAS strains expressing 11 pertinent A beta peptides. UAS transgenic flies were generated by identical chromosomal insertion, hence removing any transgenic position effects, and crossed to a novel and robust Gal4 driver line. Using this improved Gal4/UAS set-up, survival and activity assays revealed that A beta 1-42 severely shortens lifespan and reduces activity. N-terminal truncated peptides were quite toxic, with 3-42 similar to 1-42, while 11-42 showed a pronounced but less severe phenotype. N-terminal mutations in 3-42 (E3A) or 11-42 (E11A) resulted in reduced toxicity for 11-42, and reduced aggregation for both variants. Strikingly, C-terminal truncation of A beta (1-41, -40, -39, -38, -37) were non-toxic. In contrast, C-terminal extension to 1-43 resulted in reduced lifespan and activity, but not to the same extent as 1-42. Mutating residue 42 in 1-42 (A42D, A42R and A42W) greatly reduced A beta accumulation and toxicity. Histological and biochemical analysis revealed strong correlation between in vivo toxicity and brain A beta aggregate load, as well as amount of insoluble A beta. This systematic Drosophila in vivo and in vitro analysis reveals crucial N- and C-terminal specificity for A beta neurotoxicity and aggregation, and underscores the importance of residues 1-10 and E11, as well as a pivotal role of A42.

    Place, publisher, year, edition, pages
    Public Library of Science, 2015
    National Category
    Chemical Sciences Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-120740 (URN)10.1371/journal.pone.0133272 (DOI)000358622000074 ()26208119 (PubMedID)
    Note

    Funding Agencies|Swedish VINNOVA; King Gustaf Vs and Queen Victorias Freemasons Foundation; AstraZeneca, Sodertalje; Swedish Research Council; VINNOVA grant, "Innovations for future health"

    Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2018-04-25
    2. Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila
    Open this publication in new window or tab >>Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila
    Show others...
    2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2Article in journal (Refereed) Published
    Abstract [en]

    The pathology of Alzheimers disease (AD) is characterized by the presence of extracellular deposits of misfolded and aggregated amyloid-beta (A beta) peptide and intraneuronal accumulation of tangles comprised of hyperphosphorylated Tau protein. For several years, the natural compound curcumin has been proposed to be a candidate for enhanced clearance of toxic A beta amyloid. In this study we have studied the potency of feeding curcumin as a drug candidate to alleviate A beta toxicity in transgenic Drosophila. The longevity as well as the locomotor activity of five different AD model genotypes, measured relative to a control line, showed up to 75% improved lifespan and activity for curcumin fed flies. In contrast to the majority of studies of curcumin effects on amyloid we did not observe any decrease in the amount of A beta deposition following curcumin treatment. Conformation-dependent spectra from p-FTAA, a luminescent conjugated oligothiophene bound to A beta deposits in different Drosophila genotypes over time, indicated accelerated pre-fibrillar to fibril conversion of A beta(1-42) in curcumin treated flies. This finding was supported by in vitro fibrillation assays of recombinant A beta(1-42). Our study shows that curcumin promotes amyloid fibril conversion by reducing the pre-fibrillar/oligomeric species of A beta, resulting in a reduced neurotoxicity in Drosophila.

    Place, publisher, year, edition, pages
    Public Library of Science, 2012
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-73502 (URN)10.1371/journal.pone.0031424 (DOI)000302733900047 ()
    Note
    funding agencies|Knut and Alice Wallenberg foundation||Swedish Foundation for Strategic Research||Hjarnfonden||Swedish Research Council||Gustaf V. foundation||European Union||Available from: 2012-01-05 Created: 2012-01-05 Last updated: 2018-04-25
  • 167.
    Jonson, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sandberg, Alexander
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Carlback, Marcus
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Michno, Wojciech
    Univ Gothenburg, Sweden.
    Hanrieder, Jorg
    Univ Gothenburg, Sweden; UCL, England.
    Starkenberg, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Peter, K.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Amyloid fibril polymorphism and cell-specific toxicity in vivo2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, no sup1, p. 136-137Article in journal (Refereed)
    Abstract [en]

    n/a

  • 168.
    Jonsson, Maria
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sandberg, Alexander
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Carlback, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Michno, Wojciech
    Univ Gothenburg, Sweden.
    Hanrieder, Jorg
    Univ Gothenburg, Sweden; UCL, England.
    Starkenberg, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Aggregated A beta 1-42 Is Selectively Toxic for Neurons, Whereas Glial Cells Produce Mature Fibrils with Low Toxicity in Drosophila2018In: Cell Chemical Biology, ISSN 2451-9456, E-ISSN 2451-9448, Vol. 25, no 5, p. 595-610Article in journal (Refereed)
    Abstract [en]

    The basis for selective vulnerability of certain cell types for misfolded proteins (MPs) in neurodegenerative diseases is largely unknown. This knowledge is crucial for understanding disease progression in relation to MPs spreading in the CNS. We assessed this issue in Drosophila by cell-specific expression of human A beta 1-42 associated with Alzheimers disease. Expression of A beta 1-42 in various neurons resulted in concentration-dependent severe neurodegenerative phenotypes, and intraneuronal ringtangle-like aggregates with immature fibril properties when analyzed by aggregate-specific ligands. Unexpectedly, expression of A beta 1-42 from a pan-glial driver produced a mild phenotype despite massive brain load of A beta 1-42 aggregates, even higher than in the strongest neuronal driver. Glial cells formed more mature fibrous aggregates, morphologically distinct from aggregates found in neurons, and was mainly extracellular. Our findings implicate that A beta 1-42 cytotoxicity is both cell and aggregate morphotype dependent.

  • 169.
    Jonsson, Maria
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Pokrzywa, Malgorzata
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Starkenberg, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Systematic A beta Analysis in Drosophila Reveals High Toxicity for the 1-42, 3-42 and 11-42 Peptides, and Emphasizes N- and C-Terminal Residues2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133272Article in journal (Refereed)
    Abstract [en]

    Brain amyloid plaques are a hallmark of Alzheimers disease (AD), and primarily consist of aggregated A beta peptides. While A beta 1-40 and A beta 1-42 are the most abundant, a number of other A beta peptides have also been identified. Studies have indicated differential toxicity for these various A beta peptides, but in vivo toxicity has not been systematically tested. To address this issue, we generated improved transgenic Drosophila UAS strains expressing 11 pertinent A beta peptides. UAS transgenic flies were generated by identical chromosomal insertion, hence removing any transgenic position effects, and crossed to a novel and robust Gal4 driver line. Using this improved Gal4/UAS set-up, survival and activity assays revealed that A beta 1-42 severely shortens lifespan and reduces activity. N-terminal truncated peptides were quite toxic, with 3-42 similar to 1-42, while 11-42 showed a pronounced but less severe phenotype. N-terminal mutations in 3-42 (E3A) or 11-42 (E11A) resulted in reduced toxicity for 11-42, and reduced aggregation for both variants. Strikingly, C-terminal truncation of A beta (1-41, -40, -39, -38, -37) were non-toxic. In contrast, C-terminal extension to 1-43 resulted in reduced lifespan and activity, but not to the same extent as 1-42. Mutating residue 42 in 1-42 (A42D, A42R and A42W) greatly reduced A beta accumulation and toxicity. Histological and biochemical analysis revealed strong correlation between in vivo toxicity and brain A beta aggregate load, as well as amount of insoluble A beta. This systematic Drosophila in vivo and in vitro analysis reveals crucial N- and C-terminal specificity for A beta neurotoxicity and aggregation, and underscores the importance of residues 1-10 and E11, as well as a pivotal role of A42.

  • 170.
    Kalered, Emil
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Quantum chemical studies of deposition and catalytic surface reactions2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Quantum chemical calculations have been used to model chemical reactions in epitaxial growth of silicon carbide by chemical vapor deposition (CVD) processes and to study heterogeneous catalytic reactions for methanol synthesis. CVD is a common method to produce high-quality materials and e.g. thin films in the semiconductor industry, and one of the many usages of methanol is as a promising future renewable and sustainable energy carrier. To optimize the chemical processes it is essential to understand the reaction mechanisms. A comprehensive theoretical model for the process is therefore desired in order to be able to explore various variables that are difficult to investigate in situ. In this thesis reaction paths and reaction energies are computed using quantum chemical calculations. The quantum-chemical results can subsequently be used as input for thermodynamic, kinetic and computational fluid dynamics modelling in order to obtain data directly comparable with the experimental observations.

    For the CVD process, the effect of halogen addition to the gas mixture is studied by modelling the adsorption and diffusion of SiH2, SiCl2 and SiBr2 on the (0001̅) 4H-SiC surface. SiH2 was found to bind strongest to the surface and SiBr2 binds slightly stronger than the SiCl2 molecule. The diffusion barrier is shown to be lower for SiH2 than for SiBr2 and SiCl2 which have similar barriers. SiBr2 and SiCl2 are found to have similar physisorption energies and bind stronger than the SiH2 molecule. Gibbs free-energy calculations also indicate that the SiC surface is not fully hydrogen terminated at CVD conditions since missing-neighboring pair of surface hydrogens is found to be common. Calculations for the (0001) surface show that SiCl, SiCl2, SiHCl, SiH, and SiH2 likely adsorb on a methylene site, but the processes are thermodynamically less favorable than their reverse reactions. However, the adsorbed products may be stabilized by subsequent surface reactions to form a larger structure. The formation of these larger structures is found to be fast enough to compete with the desorption processes. Also the Gibbs free energies for adsorption of Si atoms, SiX, SiX2, and SiHX where X is F or Br are presented. Adsorption of Si atoms is shown to be the most thermodynamically favorable reaction followed by SiX, SiHX, and SiX2, X being a halide. The results in this study suggest that the major Si contributors in the SiC–CVD process are Si atoms, SiX and SiH.

    Methanol can be synthesized from gaseous carbon dioxide and hydrogen using solid metal-metal oxide mixtures acting as heterogeneous catalysts. Since a large surface area of the catalyst enhances the speed of the heterogeneous reaction, the use of nanoparticles (NP) is expected to be advantageous due to the NPs’ large area to surface ratio. The plasma-induced creation of copper NPs is investigated. One important element during particle growth is the charging process where the variation of the work function (W) with particle size is a key quantity, and the variation becomes increasingly pronounced at smaller NP sizes. The work functions are computed for a set of NP charge numbers, sizes and shapes, using copper as a case study. A derived analytical expression for W is shown to give quite accurate estimates provided that the diameter of the NP is larger than about a nanometer and that the NP has relaxed to close to a spherical shape. For smaller sizes W deviates from the approximative expression, and also depends on the charge number. Some consequences of these results for NP charging process are outlined.

    Key reaction steps in the methanol synthesis reaction mechanism using a Cu/ZrO2 nanoparticle catalyst is investigated. Two different reaction paths for conversion of CO2 to CO is studied. The two paths result in the same complete reaction 2 CO2 → 2 CO + O2 where ZrO2 (s) acts as a catalyst. The highest activation energies are significantly lower compared to that of the gas phase reaction. The presence of oxygen vacancies at the surface appear to be decisive for the catalytic process to be effective. Studies of the reaction kinetics show that when oxygen vacancies are present on the ZrO2 surface, carbon monoxide is produced within a microsecond. The IR spectra of CO2 and H2 interacting with ZrO2 and Cu under conditions that correspond to the catalyzed CH3OH production process is also studied experimentally and compared to results from the theoretical computations. Surface structures and gas-phase molecules are identified through the spectral lines by matching them to specific vibrational modes from the literature and from the new computational results. Several surface structures are verified and can be used to pin point surface structures in the reaction path. This gives important information that help decipher how the reaction mechanism of the CO2 conversion and ultimately may aid to improve the methanol synthesis process.

    List of papers
    1. Adsorption and surface diffusion of silicon growth species in silicon carbide chemical vapour deposition processes studied by quantum-chemical computations
    Open this publication in new window or tab >>Adsorption and surface diffusion of silicon growth species in silicon carbide chemical vapour deposition processes studied by quantum-chemical computations
    2013 (English)In: Theoretical Chemistry accounts, ISSN 1432-881X, E-ISSN 1432-2234, Vol. 132, no 12Article in journal (Refereed) Published
    Abstract [en]

    The effect chlorine addition to the gas mixture has on the surface chemistry in the chemical vapour deposition (CVD) process for silicon carbide (SiC) epitaxial layers is studied by quantum-chemical calculations of the adsorption and diffusion of SiH2 and SiCl2 on the (000-1) 4H–SiC surface. SiH2 was found to bind more strongly to the surface than SiCl2 by approximately 100 kJ mol−1 and to have a 50 kJ mol−1 lower energy barrier for diffusion on the fully hydrogen-terminated surface. On a bare SiC surface, without hydrogen termination, the SiCl2 molecule has a somewhat lower energy barrier for diffusion. SiCl2 is found to require a higher activation energy for desorption once chemisorbed, compared to the SiH2 molecule. Gibbs free energy calculations also indicate that the SiC surface may not be fully hydrogen terminated at CVD conditions since missing neighbouring pair of surface hydrogens is found to be a likely type of defect on a hydrogen-terminated SiC surface.

    Place, publisher, year, edition, pages
    Springer Verlag (Germany), 2013
    Keywords
    Quantum-chemical calculations, Density functional theory (DFT), B3LYP, Chemical vapour deposition (CVD), Silicon carbide (SiC), SiCl2, SiH2, Surface reactions, Adsorption, Reaction path, Activation energy, Diffusion, Hydrogen termination
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-100478 (URN)10.1007/s00214-013-1403-3 (DOI)000325724400001 ()
    Available from: 2013-11-08 Created: 2013-11-08 Last updated: 2018-06-19Bibliographically approved
    2. Brominated chemistry for chemical vapor deposition of electronic grade SiC
    Open this publication in new window or tab >>Brominated chemistry for chemical vapor deposition of electronic grade SiC
    Show others...
    2015 (English)In: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 27, no 3, p. 793-801Article in journal (Refereed) Published
    Abstract [en]

    Chlorinated chemical vapor deposition (CVD) chemistry for growth of homoepitaxial layers of silicon carbide (SiC) has paved the way for very thick epitaxial layers in short deposition time as well as novel crystal growth processes for SiC. Here, we explore the possibility to also use a brominated chemistry for SiC CVD by using HBr as additive to the standard SiC CVD precursors. We find that brominated chemistry leads to the same high material quality and control of material properties during deposition as chlorinated chemistry and that the growth rate is on average 10 % higher for a brominated chemistry compared to chlorinated chemistry. Brominated and chlorinated SiC CVD also show very similar gas phase chemistries in thermochemical modelling. This study thus argues that brominated chemistry is a strong alternative for SiC CVD since the deposition rate can be increased with preserved material quality. The thermochemical modelling also suggest that the currently used chemical mechanism for halogenated SiC CVD might need to be revised.

    National Category
    Chemical Sciences Physical Sciences
    Identifiers
    urn:nbn:se:liu:diva-111075 (URN)10.1021/acs.chemmater.5b00074 (DOI)000349934500016 ()
    Available from: 2014-10-07 Created: 2014-10-07 Last updated: 2018-06-19Bibliographically approved
    3. Growth Mechanism of SiC Chemical Vapor Deposition: Adsorption and Surface Reactions of Active Si Species
    Open this publication in new window or tab >>Growth Mechanism of SiC Chemical Vapor Deposition: Adsorption and Surface Reactions of Active Si Species
    Show others...
    2018 (English)In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 122, no 1, p. 648-661Article in journal (Refereed) Published
    Abstract [en]

    Silicon carbide is a wide bandgap semiconductor ideally suitable for high temperature and high power applications. An active SiC layer is usually fabricated using halide-assisted chemical vapor deposition (CVD). In this work, we use quantum chemical density functional theory (B3LYP and M06-2X) and transition state theory to study adsorptions of active Si species in the CVD process on both the Si face and the C face of 4H-SiC. We show that adsorptions of SiCl, SiCl2, SiHCl, SiH, and SiH2 on the Si face likely occur on a methylene site, CH2(ads), but the processes are thermodynamically less favorable than their reverse or desorptions. Nevertheless, the adsorbed products become stabilized with the help of subsequent surface reactions to form a larger cluster. These cluster formation reactions happen with rates that are fast enough to compete with the desorption processes. On the C face, the adsorptions likely occur on a surface site terminated by a dangling bond, *(ads), and produce the products which are thermodynamically stable. Lastly, we present the Gibbs free energies of adsorptions of Si atoms, SiX, SiX2, and SiHX, for X being F and Br. Adsorptions of Si atoms are shown to be the most thermodynamically favorable among all the species in the study. Among the halide-containing species, the Gibbs free energies (ARG) from smallest to largest are observed in the adsorptions of SiX, SiHX, and SiX2, for X being the halides. The results in this study suggest that the major Si contributors in the SiC CVD process are Si atoms, SiX (for X being the halide) and SiH.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2018
    National Category
    Inorganic Chemistry
    Identifiers
    urn:nbn:se:liu:diva-144885 (URN)10.1021/acs.jpcc.7b10751 (DOI)000422814200069 ()
    Note

    Funding Agencies|Swedish Foundation for Strategic Research from Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University [2009 00971]; Swedish Research Council (VR) [2016-05137_4]

    Available from: 2018-02-09 Created: 2018-02-09 Last updated: 2018-06-19
    4. On the work function and the charging of small (r <= 5 nm) nanoparticles in plasmas
    Open this publication in new window or tab >>On the work function and the charging of small (r <= 5 nm) nanoparticles in plasmas
    Show others...
    2017 (English)In: Physics of Plasmas, ISSN 1070-664X, E-ISSN 1089-7674, Vol. 24, no 1, article id 013702Article in journal (Refereed) Published
    Abstract [en]

    The growth of nanoparticles (NPs) in plasmas is an attractive technique where improved theoretical understanding is needed for quantitative modeling. The variation of the work function W with size for small NPs, r(NP) amp;lt;= 5 nm, is a key quantity for modeling of three NP charging processes that become increasingly important at a smaller size: electron field emission, thermionic electron emission, and electron impact detachment. Here we report the theoretical values of the work function in this size range. Density functional theory is used to calculate the work functions for a set of NP charge numbers, sizes, and shapes, using copper for a case study. An analytical approximation is shown to give quite accurate work functions provided that r(NP) amp;gt; 0.4 nm, i.e., consisting of about amp;gt; 20 atoms, and provided also that the NPs have relaxed close to spherical shape. For smaller sizes, W deviates from the approximation, and also depends on the charge number. Some consequences of these results for nanoparticle charging are outlined. In particular, a decrease in W for NP radius below about 1 nm has fundamental consequences for their charge in a plasma environment, and thereby on the important processes of NP nucleation, early growth, and agglomeration. Published by AIP Publishing.

    Place, publisher, year, edition, pages
    AMER INST PHYSICS, 2017
    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:liu:diva-136218 (URN)10.1063/1.4973443 (DOI)000395395100092 ()
    Note

    Funding Agencies|Knut and Alice Wallenberg foundation (KAW) [2014.0276]; Swedish Research Council via the Linkoping Linneaus Environment LiLi-NFM [2008-6572]

    Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2018-06-19
  • 171.
    Kalered, Emil
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Brenning, N.
    KTH Royal Institute Technology, Sweden.
    Pilch, Iris
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Caillault, L.
    University of Paris 11, France.
    Minea, T.
    University of Paris 11, France.
    Ojamäe, Lars
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    On the work function and the charging of small (r <= 5 nm) nanoparticles in plasmas2017In: Physics of Plasmas, ISSN 1070-664X, E-ISSN 1089-7674, Vol. 24, no 1, article id 013702Article in journal (Refereed)
    Abstract [en]

    The growth of nanoparticles (NPs) in plasmas is an attractive technique where improved theoretical understanding is needed for quantitative modeling. The variation of the work function W with size for small NPs, r(NP) amp;lt;= 5 nm, is a key quantity for modeling of three NP charging processes that become increasingly important at a smaller size: electron field emission, thermionic electron emission, and electron impact detachment. Here we report the theoretical values of the work function in this size range. Density functional theory is used to calculate the work functions for a set of NP charge numbers, sizes, and shapes, using copper for a case study. An analytical approximation is shown to give quite accurate work functions provided that r(NP) amp;gt; 0.4 nm, i.e., consisting of about amp;gt; 20 atoms, and provided also that the NPs have relaxed close to spherical shape. For smaller sizes, W deviates from the approximation, and also depends on the charge number. Some consequences of these results for nanoparticle charging are outlined. In particular, a decrease in W for NP radius below about 1 nm has fundamental consequences for their charge in a plasma environment, and thereby on the important processes of NP nucleation, early growth, and agglomeration. Published by AIP Publishing.

  • 172.
    Kalered, Emil
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Pedersen, Henrik
    Linköping University, Department of Physics, Chemistry and Biology, Semiconductor Materials. Linköping University, The Institute of Technology.
    Janzén, Erik
    Linköping University, Department of Physics, Chemistry and Biology, Semiconductor Materials. Linköping University, The Institute of Technology.
    Ojamäe, Lars
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Adsorption and surface diffusion of silicon growth species in silicon carbide chemical vapour deposition processes studied by quantum-chemical computations2013In: Theoretical Chemistry accounts, ISSN 1432-881X, E-ISSN 1432-2234, Vol. 132, no 12Article in journal (Refereed)
    Abstract [en]

    The effect chlorine addition to the gas mixture has on the surface chemistry in the chemical vapour deposition (CVD) process for silicon carbide (SiC) epitaxial layers is studied by quantum-chemical calculations of the adsorption and diffusion of SiH2 and SiCl2 on the (000-1) 4H–SiC surface. SiH2 was found to bind more strongly to the surface than SiCl2 by approximately 100 kJ mol−1 and to have a 50 kJ mol−1 lower energy barrier for diffusion on the fully hydrogen-terminated surface. On a bare SiC surface, without hydrogen termination, the SiCl2 molecule has a somewhat lower energy barrier for diffusion. SiCl2 is found to require a higher activation energy for desorption once chemisorbed, compared to the SiH2 molecule. Gibbs free energy calculations also indicate that the SiC surface may not be fully hydrogen terminated at CVD conditions since missing neighbouring pair of surface hydrogens is found to be a likely type of defect on a hydrogen-terminated SiC surface.

  • 173.
    Kalkat, Manpreet
    et al.
    Univ Toronto, Canada; Univ Hlth Network, Canada.
    Resetca, Diana
    Univ Toronto, Canada; Univ Hlth Network, Canada.
    Lourenco, Corey
    Univ Toronto, Canada; Univ Hlth Network, Canada.
    Chan, Pak-Kei
    Univ Hlth Network, Canada.
    Wei, Yong
    Univ Hlth Network, Canada; Struct Genom Consortium, Canada.
    Shiah, Yu-Jia
    Ontario Inst Canc Res, Canada.
    Vitkin, Natasha
    Univ Hlth Network, Canada.
    Tong, Yufeng
    Struct Genom Consortium, Canada; Univ Toronto, Canada.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Done, Susan J.
    Univ Toronto, Canada; Univ Hlth Network, Canada.
    Boutros, Paul C.
    Univ Toronto, Canada; Ontario Inst Canc Res, Canada.
    Raught, Brian
    Univ Toronto, Canada; Univ Hlth Network, Canada.
    Penn, Linda Z.
    Univ Toronto, Canada; Univ Hlth Network, Canada.
    MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis2018In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 72, no 5, p. 836-+Article in journal (Refereed)
    Abstract [en]

    Transforming members of the MYC family (MYC, MYCL1, and MYCN) encode transcription factors containing six highly conserved regions, termed MYC homology boxes (MBs). By conducting proteomic profiling of the MB interactomes, we demonstrate that half of the MYC interactors require one or more MBs for binding. Comprehensive phenotypic analyses reveal that two MBs, MBO and MBII, are universally required for transformation. MBII mediates interactions with acetyltransferase-containing complexes, enabling histone acetylation, and is essential for MYC-dependent tumor initiation. By contrast, MBO mediates interactions with transcription elongation factors via direct binding to the general transcription factor TFIIF. MBO is dispensable for tumor initiation but is a major accelerator of tumor growth. Notably, the full transforming activity of MYC can be restored by co-expression of the non-transforming MBO and MBII deletion proteins, indicating that these two regions confer separate molecular functions, both of which are required for oncogenic MYC activity.

  • 174.
    Karlsson, Anna-Carin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Elgland, Mathias
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Laur, Katriann
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Fyrner, Timmy
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Laska, Matthias
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Red junglefowl have individual body odors2010In: JOURNAL OF EXPERIMENTAL BIOLOGY, ISSN 0022-0949, Vol. 213, no 10, p. 1619-1624Article in journal (Refereed)
    Abstract [en]

    Olfaction may play an important role in regulating bird behavior, and has been suggested to be involved in feather-pecking. We investigated possible differences in the body odors of red junglefowl females by using an automated olfactometer which assessed the ability of trained mice to discriminate between the odors of uropygial gland secretions (the main carrier of potential individual odors in chickens) of six feather-pecked and six non-pecked birds. All mice were clearly able to discriminate between all individual red junglefowl odors, showing that each bird has an individual body odor. We analyzed whether it was more difficult to discriminate between the odors of two feather-pecked, or two non-pecked birds, than it was to discriminate between the odors of two randomly selected birds. This was not the case, suggesting that feather-pecked birds did not share a common odor signature. Analyses using gas chromatography and mass spectrometry showed that the composition of aliphatic carboxylic acids in uropygial gland secretions differed consistently between individuals. However, chemical composition did not vary according to feather-pecking status. We conclude that red junglefowl have individual body odors which appear to be largely based on differences in the relative abundance of aliphatic carboxylic acids, but there is no evidence of systematic differences between the body odors of pecked and non-pecked birds.

  • 175.
    Karlsson, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Magic, Ivana
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Bostner, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dyrager, Christine
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lysholm, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Lundström, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, p. e0145013-Article in journal (Refereed)
    Abstract [en]

    Background

    The AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer.

    Materials and methods

    Whole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1.

    Results

    Genome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies.

  • 176.
    Karlsson, Martin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Carlsson, Uno
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Protein adsorption orientation in the light of fluorescent probes: mapping of the interaction between site-directly labeled human carbonic anhydrase II and silica nanoparticles2005In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 88, no 5, p. 3536-3544Article in journal (Refereed)
    Abstract [en]

    Little is known about the direction and specificity of protein adsorption to solid surfaces, a knowledge that is of great importance in many biotechnological applications. To resolve the direction in which a protein with known structure and surface potentials binds to negatively charged silica nanoparticles, fluorescent probes were attached to different areas on the surface of the protein human carbonic anhydrase II. By this approach it was clearly demonstrated that the adsorption of the native protein is specific to limited regions at the surface of the N-terminal domain of the protein. Furthermore, the adsorption direction is strongly pH-dependent. At pH 6.3, a histidine-rich area around position 10 is the dominating adsorption region. At higher pH values, when the histidines in this area are deprotonated, the protein is also adsorbed by a region close to position 37, which contains several lysines and arginines. Clearly the adsorption is directed by positively charged areas on the protein surface toward the negatively charged silica surface at conditions when specific binding occurs.

  • 177.
    Karlsson, Martin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Ekeroth, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Elwing, Hans
    Department of Cell and Molecular Biology, Göteborg University, Sweden.
    Carlsson, Uno
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Reduction of irreversible protein adsorption on solid surfaces by protein engineering for increased stability2005In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 280, no 27, p. 25558-25564Article in journal (Refereed)
    Abstract [en]

    The influence of protein stability on the adsorption and desorption behavior to surfaces with fundamentally different properties (negatively charged, positively charged, hydrophilic, and hydrophobic) was examined by surface plasmon resonance measurements. Three engineered variants of human carbonic anhydrase II were used that have unchanged surface properties but large differences in stability. The orientation and conformational state of the adsorbed protein could be elucidated by taking all of the following properties of the protein variants into account: stability, unfolding, adsorption, and desorption behavior. Regardless of the nature of the surface, there were correlation between (i) the protein stability and kinetics of adsorption, with an increased amplitude of the first kinetic phase of adsorption with increasing stability; (ii) the protein stability and the extent of maximally adsorbed protein to the actual surface, with an increased amount of adsorbed protein with increasing stability; (iii) the protein stability and the amount of protein desorbed upon washing with buffer, with an increased elutability of the adsorbed protein with increased stability. All of the above correlations could be explained by the rate of denaturation and the conformational state of the adsorbed protein. In conclusion, protein engineering for increased stability can be used as a strategy to decrease irreversible adsorption on surfaces at a liquid-solid interface.

  • 178.
    Karlsson, Martin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Mårtensson, Lars-Göran
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Carlsson, Uno
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Adsorption of human carbonic anhydrase II variants to silica nanoparticles occur stepwise: binding is followed by successive conformational changes to a molten-globule-like state2000In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 16, no 22, p. 8470-8479Article in journal (Refereed)
    Abstract [en]

    The surface adsorption behavior of protein variants of the enzyme human carbonic anhydrase II (HCA II) to silica nanoparticles has been investigated. Various destabilized mutants were produced by site-directed mutagenesis of amino acids located in the interior of the protein. The silica particles induced a molten-globule-like state in all of the variants. All protein variants initially adsorbed to the particles, and then underwent conformational rearrangements in a stepwise manner, as indicated by the loss of activity and the subsequent loss of tertiary structure. Activity, CD, and ANS fluorescence measurements showed that a decrease in the global stability of the protein is strongly correlated to increased rates of conformational change following particle adsorption. In contrast to unfolding processes induced by chemical denaturants or heat, in the transition to the molten-globule-like state induced by the silica particles, the active site region unfolds before the majority of the tertiary interactions are broken.

  • 179.
    Karlsson, Martin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Mårtensson, Lars-Göran
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Karlsson, Carin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Carlsson, Uno
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Denaturant-assisted formation of a stabilizing disulfide bridge from engineered cysteines in nonideal conformations2005In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 44, no 9, p. 3487-3493Article in journal (Refereed)
    Abstract [en]

    The engineered disulfide bridge A23C/L203C in human carbonic anhydrase II, inserted from homology modeling of Neisseria gonorrhoeae carbonic anhydrase, significantly stabilizes the native state of the protein. The inserted cysteine residues are placed in the interior of the structure, and because of the conformationally restrained localization, the protein is expressed in the reduced state and the cysteines are not readily oxidized. However, upon exposure to low concentrations of denaturant (0.6 M guanidine hydrochloride), corresponding to the lower part of the denaturation curve for the first unfolding transition, the oxidation rate of correctly formed disulfide bridges was markedly increased. By entropy estimations it appears that the increased flexibility, induced by the denaturant, enables the cysteines to find each other and hence to form the disulfide bridge. The outlined strategy of facilitating formation of disulfide bonds by addition of adjusted concentrations of a denaturant should be applicable to other proteins in which engineered cysteine residues are located in nonideal conformations. Moreover, a S99C/V242C variant was constructed, in which the cysteine residues are located on the surface. In this mutant the disulfide bridge was spontaneously formed and the native state was considerably stabilized (midpoint concentration of unfolding was increased from 1.0 to 1.4 M guanidine hydrochloride).

  • 180.
    Karlsson, Martin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Mårtensson, Lars-Göran
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Olofsson, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Carlsson, Uno
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Circumnavigating misfolding traps in the energy landscape through protein engineering: suppression of molten globule and aggregation in carbonic anhydrase2004In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 43, no 21, p. 6803-6807Article in journal (Refereed)
    Abstract [en]

    The native state of the enzyme human carbonic anhydrase (HCA II) has been stabilized by the introduction of a disulfide bond, the oxidized A23C/L203C mutant. This stabilized protein variant undergoes an apparent two-state unfolding process with suppression of the otherwise stable equilibrium, molten-globule intermediate, which is normally very prone to aggregation. Stopped-flow measurements also showed that lower amounts of the transiently occurring molten globule were formed during refolding. This led to a markedly lowered tendency for aggregation during equilibrium denaturing conditions and, more importantly, to significantly higher reactivation yields upon refolding of the fully denatured protein. Thus, a general strategy to circumvent aggregation during the refolding of proteins could be to stabilize the native state of a protein at the expense of partially folded intermediates, thereby shifting the unfolding behavior from a three-state process to a two-state one.

  • 181.
    Khan, Yagoob
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Tajammul Hussain, Syed
    National Centre for Physics, Quaid-e-Azam University Campus, Islamabad, Pakistan.
    Abbasi, Mazhar Ali
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Käll, Per-Olov
    Linköping University, Department of Physics, Chemistry and Biology, Physical Chemistry. Linköping University, The Institute of Technology.
    Söderlind, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Nanostructured Materials. Linköping University, The Institute of Technology.
    On the decoration of 3D nickel foam with single crystal ZnO nanorod arrays and their cathodoluminescence study2013In: Materials letters (General ed.), ISSN 0167-577X, E-ISSN 1873-4979, Vol. 90, p. 126-130Article in journal (Refereed)
    Abstract [en]

    Starting with an ammonical solution of zinc acetate, dense single crystal ZnO nanorod arrays were grown directly on high surface area porous 3D nickel foam substrates using a low temperature hydrothermal route. Heterogeneous nucleation of the nanorods with diameters around 100 nm can be conveniently and reproducibly Controlled by adjusting the amount of ammonia added to the growth solution. X-ray diffraction and HRTEM analysis confirmed the single phase wurtzite structure and c-axis orientation of the as grown ZnO nanorod arrays. Cathodoluminescence measurements indicate that the as-grown nanorod arrays were rich in atomic defects and gave strong orange emissions in the visible region. The nanorod arrays on unique 3D substrate are expected to improve the sensitivity and efficiency of ZnO based electrochemical sensors and heterogeneous catalysts.

  • 182.
    Khodaparast, Ladan
    et al.
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Khodaparast, Laleh
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Gallardo, Rodrigo
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Louros, Nikolaos N.
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Michiels, Emiel
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Ramakrishnan, Reshmi
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Ramakers, Meine
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Claes, Filip
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Young, Lydia
    Univ Leeds, England; Univ Leeds, England.
    Shahrooei, Mohammad
    KULeuven, Belgium.
    Wilkinson, Hannah
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Desager, Matyas
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Tadesse, Wubishet Mengistu
    KULeuven, Belgium.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Aertsen, Abram
    KULeuven, Belgium.
    Carpentier, Sebastien
    KULeuven, Belgium.
    Van Eldere, Johan
    KULeuven, Belgium.
    Rousseau, Frederic
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Schymkowitz, Joost
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 866Article in journal (Refereed)
    Abstract [en]

    Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichia coli and Acinetobacter baumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy.

  • 183.
    Kingbäck, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Karlsson, Louise
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna-Lena
    National Board of Forensic Medicine, Linköping, Sweden.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Linköping, Sweden.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Kugelberg, Fredrik C
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood2012In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 214, no 1-3, p. 124-134Article in journal (Refereed)
    Abstract [en]

    Venlafaxine (VEN) is an antidepressant drug mainly metabolized by the cytochrome P450 (CYP) enzyme CYP2D6 to the active metabolite O-desmethylvenlafaxine (ODV). VEN is also metabolized to N-desmetylvenlafaxine (NDV) via CYP3A4. ODV and NDV are further metabolized to N,O-didesmethylvenlafaxine (DDV). VEN is a racemic mixture of the S- and R-enantiomers and these have in vitro displayed different degrees of serotonin and noradrenaline reuptake inhibition. The aim of the study was to investigate if an enantioselective analysis of VEN and its metabolites, in combination with genotyping for CYP2D6, could assist in the interpretation of forensic toxicological results in cases with different causes of deaths. Concentrations of the enantiomers of VEN and metabolites were determined in femoral blood obtained from 56 autopsy cases with different causes of death. The drug analysis was done by liquid chromatography tandem mass spectrometry (LC/MS/MS) and the CYP2D6 genotyping by PCR and pyrosequencing. The mean (median) enantiomeric S/R ratios of VEN, ODV, NDV and DDV were 0.99 (0.91), 2.17 (0.93), 0.92 (0.86) and 1.08 (1.03), respectively. However, a substantial variation in the relationship between the S- and R-enantiomers of VEN and metabolites was evident (S/R ratios ranging from 0.23 to 17.6). In six cases, a low S/R VEN ratio (mean 0.5) was associated with a high S/R ODV ratio (mean 11.9). Genotyping showed that these individuals carried two inactive CYP2D6 genes indicating a poor metabolizer phenotype. From these data we conclude that enantioselective analysis of VEN and ODV can predict if a person is a poor metabolizer genotype/phenotype for CYP2D6. Knowledge of the relationship between the S- and R-enantiomers of this antidepressant drug and its active metabolite is also important since the enantiomers display different pharmacodynamic profiles.

  • 184.
    Kleinhans, Henrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Evaluation of the Carbonization of Thermo-Stabilized Lignin Fibers into Carbon Fibers2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Thermo-stabilized lignin fibers from pH-fractionated softwood kraft lignin were carbonized to various temperatures during thermomechanical analysis (TMA) under static and increasing load and different rates of heating. The aim was to optimize the carbonization process to obtain suitable carbon fiber material with good mechanical strength potential (high tensile strength and high E-modulus). The carbon fibers were therefore mainly evaluated of mechanical strength in Dia-Stron uniaxial tensile testing.

    In addition, chemical composition, in terms of functional groups, and elemental (atomic) composition was studied in Fourier transform infrared spectroscopy (FTIR) and in energy-dispersive X-ray spectroscopy (EDS), respectively. The structure of carbon fibers was imaged in scanning electron microscope (SEM) and light microscopy. Thermogravimetrical analysis was performed on thermo-stabilized lignin fibers to evaluate the loss of mass and to calculate the stress-changes and diameter-changes that occur during carbonization.

    The TMA-analysis of the deformation showed, for thermo-stabilized lignin fibers, a characteristic behavior of contraction during carbonization. Carbonization temperatures above 1000°C seemed most efficient in terms of E-modulus and tensile strength whereas rate of heating did not matter considerably. The E-modulus for the fibers was improved significantly by slowly increasing the load during the carbonization. The tensile strength remained however unchanged.

    The FTIR-analysis indicated that many functional groups, mainly oxygen containing, dissociate from the lignin polymers during carbonization. The EDS supported this by showing that the oxygen content decreased. Accordingly, the relative carbon content increased passively to around 90% at 1000°C. Aromatic structures in the carbon fibers are thought to contribute to the mechanical strength and are likely formed during the carbonization. However, the FTIR result showed no evident signs that aromatic structures had been formed, possible due to some difficulties with the KBr-method.

    In the SEM and light microscopy imaging one could observe that porous formations on the surface of the fibers increased as the temperature increased in the carbonization. These formations may have affected the mechanical strength of the carbon fibers, mainly tensile strength.

    The carbonization process was optimized in the sense that any heating rate can be used. No restriction in production speed exists. The carbonization should be run to at least 1000°C to achieve maximum mechanical strength, both in E-modulus and tensile strength. To improve the E-modulus further, a slowly increasing load can be applied to the lignin fibers during carbonization. The earlier the force is applied, to counteract the lignin fiber contraction that occurs (namely around 300°C), the better. However, in terms of mechanical performance, the lignin carbon fibers are still far from practical use in the industry.

  • 185.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Fluorescent thiophene-based ligands for detection and characterization of disease-associated protein aggregates2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis the unique optical properties of fluorescent ligands termed luminescent conjugated oligothiophenes (LCOs) have been used to study a variety of protein aggregates associated with human protein misfolding disease. This heterogeneous group of diseases contains well known and fatal members such as Alzheimer´s and Huntington´s disease and the development of sensitive tools for the detection and characterization of protein aggregates is crucial for unravelling the complexity of these pathologies. Conventionally, the molecular dyes Congo red and thioflavin T (ThT) have been the primary choices for detecting and monitoring protein misfolding events. However, the rigid scaffold of both Congo red and ThT only offers an on or off mode and limits their ability to make fine distinctions at the molecular level. In contrast, LCOs have a flexible conjugated backbone and in addition to detect a broader subset of misfolded proteins, LCO can be used to visualize the heterogeneity of protein aggregates.

    The work presented in this thesis has given novel insights regarding the close connection between LCO design and optical performance. By altering the backbone length and the arrangement of substituents as well as replacing thiophene units with moieties affecting conjugation length and conformational freedom, the structural requirements of an optimal LCO for a certain application have been revealed. LCOs having a pentameric thiophene backbone with carboxyl end-groups were able to i) cross the blood-brain barrier and selectively stain cerebral amyloid β (Aβ) plaques, ii) detect non-thioflavinophilic Aβ aggregates and non-congophilic prion aggregates, iii) spectrally discriminate Aβ from tau aggregates and iiii) strongly label protein inclusion bodies. However, in some applications this design was outdone by others and in general, the conjugation length and the level of conformational freedom of the backbone were important determinants of the performance of the LCO.

    Overall, the findings in this thesis illustrate how small alterations in the LCO molecular scaffold may have large impact on the ligand properties. The results highlight the importance of having a toolbox of diverse ligands in order to increase our knowledge regarding the complex nature of protein aggregates.

    List of papers
    1. Novel Pentameric Thiophene Derivatives for in Vitro and in Vivo Optical Imaging of a Plethora of Protein Aggregates in Cerebral Amyloidoses
    Open this publication in new window or tab >>Novel Pentameric Thiophene Derivatives for in Vitro and in Vivo Optical Imaging of a Plethora of Protein Aggregates in Cerebral Amyloidoses
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    2009 (English)In: ACS CHEMICAL BIOLOGY, ISSN 1554-8929, Vol. 4, no 8, p. 673-684Article in journal (Refereed) Published
    Abstract [en]

    Molecular probes for selective Identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying cerebral amyloidoses. Here we report the chemical design of pentameric thiophene derivatives, denoted luminescent conjugated oligothiophenes (LCOs), which could be used for real-time visualization of cerebral protein aggregates in transgenic mouse models of neurodegenerative diseases by multiphoton microscopy. One of the LCOs, p-FTAA, could be utilized for ex vivo spectral assignment of distinct prion deposits from two, mouse-adapted prion strains. p-FTAA also revealed a transient soluble pre-fibrillar non-thioflavinophilic A beta-assemblies during in vitro fibrillation of A beta peptides. In brain tissue samples, A beta deposits and neurofibrillary tangles (NFTs) were readily identified by a strong fluorescence from p-FTAA and the LCO staining showed complete co-localliation with conventional antibodies (6E10 and AT8). In addition, a patchy islet-like staining of individual A beta plaque was unveiled by the anti-oligomer A11 antibody during co-staining with p-FTAA. The major hallmarks of Alzheimers disease, namely, A beta aggregates versus NFTs, could also be distinguished because of distinct emission spectra from p-FTAA. Overall, we demonstrate that LCOs can be utilized as powerful practical research tools for studying protein aggregation diseases and facilitate the study of amyloid origin, evolution and maturation, A beta-tau interactions, and pathogenesis both ex vivo and in vivo.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-20420 (URN)10.1021/cb900112v (DOI)
    Available from: 2009-09-08 Created: 2009-09-07 Last updated: 2018-04-25
    2. Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates
    Open this publication in new window or tab >>Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates
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    2011 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, no 24, p. 8356-8370Article in journal (Refereed) Published
    Abstract [en]

    Molecular probes for selective identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying protein aggregation diseases. Here we report the chemical design of a library of anionic luminescent conjugated oligothiophenes (LCOs), which can be utilized as ligands for detection of protein aggregates. Certain molecular requirements were shown to be necessary for detecting (i) early non-thioflavinophilic protein assemblies of A beta 1-42 and insulin preceding the formation of amyloid fibrils and (ii) for obtaining distinct spectral signatures of the two main pathological hallmarks observed in human Alzheimers diease brain tissue (A beta plaques and neurofibrillary tangles). Our findings suggest that a superior anionic LCO-based ligand should have a backbone consisting of five to seven thiophene units and carboxyl groups extending the conjugated thiophene backbone. Such LCOs will be highly useful for studying the underlying molecular events of protein aggregation diseases and could also be utilized for the development of novel diagnostic tools for these diseases.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2011
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:liu:diva-73487 (URN)10.1039/c1ob05637a (DOI)000297354100019 ()
    Available from: 2012-01-04 Created: 2012-01-04 Last updated: 2019-11-08
    3. The structural basis for optimal performance of oligothiophene based fluorescent amyloid ligands: Conformational flexibility is essential for spectral assignment of a diversity of protein aggregates
    Open this publication in new window or tab >>The structural basis for optimal performance of oligothiophene based fluorescent amyloid ligands: Conformational flexibility is essential for spectral assignment of a diversity of protein aggregates
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Protein misfolding diseases are characterized by deposition of protein aggregates and optical ligands for molecular characterization of these disease-associated structures are important for understanding their potential role in the pathogenesis of the disease. Luminescent conjugated oligothiophenes (LCOs) have proven useful for optical identification of a broader subset of disease-associated protein aggregates than conventional ligands, such as Thioflavin T (ThT) and Congo red. Herein, the molecular requirements for achieving LCOs able to detect non-thioflavinophilic Aβ aggregates or non-congophilic prion aggregates, as well as spectrally discriminate Aβ and tau aggregates, were investigated. An anionic pentameric LCO was subjected to chemical engineering by i) replacing thiophene units with selenophene or phenylene moieties or ii) alternating the anionic substituents along the  thiophene backbone. In addition, two asymmetric tetrameric ligands were  generated. Overall, the results from this study identified conformational  freedom and extended conjugation of the conjugated backbone as crucial  determinants for obtaining superior thiophene-based optical ligands for  sensitive detection and spectral assignment of diseaseassociated protein aggregates.

    Keywords
    Luminescent conjugated oligothiophenes, protein aggregates, fluorescence, Alzheimer´s disease, prion
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-92771 (URN)
    Available from: 2013-05-21 Created: 2013-05-21 Last updated: 2014-04-08
    4. Cross beta-Sheet Conformation of Keratin 8 Is a Specific Feature of Mallory-Denk Bodies Compared With Other Hepatocyte Inclusions
    Open this publication in new window or tab >>Cross beta-Sheet Conformation of Keratin 8 Is a Specific Feature of Mallory-Denk Bodies Compared With Other Hepatocyte Inclusions
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    2011 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 141, no 3, p. 1080-U428Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND andamp; AIMS: Mallory-Denk bodies (MDBs) are cytoplasmic protein aggregates in hepatocytes in steato-hepatitis and other liver diseases. We investigated the molecular structure of keratin 8 (K8) and 18 (K18), sequestosome 1/p62, and ubiquitin, which are the major constituents of MDBs, to investigate their formation and role in disease pathogenesis. METHODS: Luminescent conjugated oligothiophenes (LCOs), h-HTAA, and p-FTAA are fluorescent amyloid ligands that specifically bind proteins with cross beta-sheet conformation. We used LCOs to investigate conformational changes in MDBs in situ in human and murine livers as well as in transfection studies. RESULTS: LCO analysis showed cross beta-sheet conformation in human MDBs from patients with alcoholic and nonalcoholic steatohepatitis or hepatocellular carcinoma, but not in intracellular hyaline bodies, alpha(1)-antitrypsin deficiency, or ground-glass inclusions. LCOs bound to MDBs induced by 3,5diethoxycarbonyl-1,4-dihydrocollidine feeding of mice at all developmental stages. CHO-K1 cells transfected with various combinations of SQSTM1/p62, ubi, and Krt8/Krt18 showed that K8 was more likely to have cross beta-sheet conformation than K18, whereas p62 never had cross beta-sheet conformation. The different conformational properties of K8 and K18 were also shown by circular dichroism analysis. CONCLUSIONS: K8 can undergo conformational changes from predominantly alpha-helical to cross beta-sheet, which would allow it to form MDBs. These findings might account for the observation that krt8(-/-) mice do not form MDBs, whereas its excess facilitates MDB formation. LCOs might be used in diagnosis of liver disorders; they can be applied to formalin-fixed, paraffin-embedded tissues to characterize protein aggregates in liver cells.

    Place, publisher, year, edition, pages
    WB Saunders, 2011
    Keywords
    Liver Disease, Protein Aggregation, Keratin, p62, NASH
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-70739 (URN)10.1053/j.gastro.2011.05.039 (DOI)000294281200047 ()
    Note

    Funding Agencies|Austrian Genome Program (GEN-AU)||Medical University of Graz||Swedish Foundation for Strategic Research||Knut and Alice Wallenberg Foundation||

    Available from: 2011-09-16 Created: 2011-09-16 Last updated: 2017-12-08
    5. Luminescent Conjugated Oligothiophenes for Sensitive Fluorescent Assignment of Protein Inclusion Bodies
    Open this publication in new window or tab >>Luminescent Conjugated Oligothiophenes for Sensitive Fluorescent Assignment of Protein Inclusion Bodies
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    2013 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 14, no 5, p. 607-616Article in journal (Refereed) Published
    Abstract [en]

    Small hydrophobic ligands identifying intracellular protein deposits are of great interest, as protein inclusion bodies are the pathological hallmark of several degenerative diseases. Here we report that fluorescent amyloid ligands, termed luminescent conjugated oligothiophenes (LCOs), rapidly and with high sensitivity detect protein inclusion bodies in skeletal muscle tissue from patients with sporadic inclusion body myositis (s-IBM). LCOs having a conjugated backbone of at least five thiophene units emitted strong fluorescence upon binding, and showed co-localization with proteins reported to accumulate in s-IBM protein inclusion bodies. Compared with conventional amyloid ligands, LCOs identified a larger fraction of immunopositive inclusion bodies. When the conjugated thiophene backbone was extended with terminal carboxyl groups, the LCO revealed striking spectral differences between distinct protein inclusion bodies. We conclude that 1) LCOs are sensitive, rapid and powerful tools for identifying protein inclusion bodies and 2) LCOs identify a wider range of protein inclusion bodies than conventional amyloid ligands.

    Place, publisher, year, edition, pages
    Wiley-VCH Verlag Berlin, 2013
    Keywords
    amyloid beta-peptides, biosensors, fluorescent probes, luminescent conjugated oligothiophene, protein inclusion body
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-91341 (URN)10.1002/cbic.201200731 (DOI)000316285600010 ()
    Note

    Funding Agencies|Swedish Foundation for Strategic Research||European Research Council (ERC)||EU||

    Available from: 2013-04-23 Created: 2013-04-22 Last updated: 2017-12-06Bibliographically approved
  • 186.
    Klingstedt, Therése
    et al.
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Mahler, Jasmin
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Wegenast-Braun, Bettina M.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Goedert, Michel
    MRC, England.
    Jucker, Mathias
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Distinct Spacing Between Anionic Groups: An Essential Chemical Determinant for Achieving Thiophene-Based Ligands to Distinguish Beta-Amyloid or Tau Polymorphic Aggregates2015In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 25, p. 9072-9082Article in journal (Refereed)
    Abstract [en]

    The accumulation of protein aggregates is associated with many devastating neurodegenerative diseases and the existence of distinct aggregated morphotypes has been suggested to explain the heterogeneous phenotype reported for these diseases. Thus, the development of molecular probes able to distinguish such morphotypes is essential. We report an anionic tetrameric oligothiophene compound that can be utilized for spectral assignment of different morphotypes of -amyloid or tau aggregates present in transgenic mice at distinct ages. The ability of the ligand to spectrally distinguish between the aggregated morphotypes was reduced when the spacing between the anionic substituents along the conjugated thiophene backbone was altered, which verified that specific molecular interactions between the ligand and the protein aggregate are necessary to detect aggregate polymorphism. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between different morphotypes of protein aggregates.

  • 187.
    Klingstedt, Therése
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Cairns, Nigel J.
    Washington University, MO USA .
    Sigurdson, Christina J.
    University of Calif San Diego, CA USA .
    Goedert, Michel
    MRC, England .
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    The Structural Basis for Optimal Performance of Oligothiophene-Based Fluorescent Amyloid Ligands: Conformational Flexibility is Essential for Spectral Assignment of a Diversity of Protein Aggregates2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 31, p. 10179-10192Article in journal (Refereed)
    Abstract [en]

    Protein misfolding diseases are characterized by deposition of protein aggregates, and optical ligands for molecular characterization of these disease-associated structures are important for understanding their potential role in the pathogenesis of the disease. Luminescent conjugated oligothiophenes (LCOs) have proven useful for optical identification of a broader subset of disease-associated protein aggregates than conventional ligands, such as thioflavin T and Congo red. Herein, the molecular requirements for achieving LCOs able to detect nonthioflavinophilic Aβ aggregates or non-congophilic prion aggregates, as well as spectrally discriminate Aβ and tau aggregates, were investigated. An anionic pentameric LCO was subjected to chemical engineering by: 1) replacing thiophene units with selenophene or phenylene moieties, or 2) alternating the anionic substituents along the thiophene backbone. In