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  • 101.
    Enander, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Dolphin, Gunnar
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Baltzer, Lars
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Designed, functionalized helix-loop-helix motifs that bind human carbonic anhydrase II: a new class of synthetic receptor molecules2004In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 126, no 14, p. 4464-4465Article in journal (Refereed)
    Abstract [en]

    Polypeptides designed to fold into helix−loop−helix motifs and to dimerize to form four-helix bundles were functionalized by the introduction of a sulfonamide derivative known to bind human carbonic anhydrase II (HCAII) and one or both of the dansyl- and methoxycoumarin fluorescent probes. The 42-residue sequence DC that carries all three substituents in solvent-exposed positions was found to bind HCAII with a dissociation constant of 5 nM in aqueous solution at pH 7. At 2 μM concentration, DC was mainly dimeric in aqueous solution but bound HCAII as a monomer. Upon addition of a large excess of a helix−loop−helix motif without a high-affinity ligand, KE2-Q, a ternary complex was formed between HCAII, DC, and KE2-Q. Hydrophobic interactions between DC and HCAII and coordination of the sulfonamide group to the zinc ion of HCAII contributed cooperatively to binding in a demonstration of the usefulness of folded polypeptide−small organic molecule chimera as novel protein receptors. The DC homodimer was found to be a very sensitive biosensor component due to intermolecular quenching of its fluorescence that was inhibited upon binding to HCAII.

  • 102.
    Enander, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Dolphin, Gunnar
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    Baltzer, Lars
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    A versatile polypeptide platform for integrated recognition and reporting: affinity arrays for protein-ligand interaction analysis2004In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 10, no 10, p. 2375-2385Article in journal (Refereed)
    Abstract [en]

    A molecular platform for protein detection and quantification is reported in which recognition has been integrated with direct monitoring of target-protein binding. The platform is based on a versatile 42-residue helix–loop–helix polypeptide that dimerizes to form four-helix bundles and allows site-selective modification with recognition and reporter elements on the side chains of individually addressable lysine residues. The well-characterized interaction between the model target-protein carbonic anhydrase and its inhibitor benzenesulfonamide was used for a proof-of-concept demonstration. An affinity array was designed where benzenesulfonamide derivatives with aliphatic or oligoglycine spacers and a fluorescent dansyl reporter group were introduced into the scaffold. The affinities of the array members for human carbonic anhydrase II (HCAII) were determined by titration with the target protein and were found to be highly affected by the properties of the spacers (dissociation constant Kd=0.02–3 μM). The affinity of HCAII for acetazolamide (Kd=4 nM) was determined in a competition experiment with one of the benzenesulfonamide array members to address the possibility of screening substance libraries for new target-protein binders. Also, successful affinity discrimination between different carbonic anhydrase isozymes highlighted the possibility of performing future isoform-expression profiling. Our platform is predicted to become a flexible tool for a variety of biosensor and protein-microarray applications within biochemistry, diagnostics and pharmaceutical chemistry.

  • 103.
    Enstedt, Henric
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Using a biotrickling filter for degradation of cypermethrin, an insecticide frequently used in Tahuapalca, Bolivia2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The feasibility of using bench-scale biotrickling filter reactors inoculated with the fungus UBAF004, isolated from soil in Tahuapalca, for treatment of water contaminated with cypermethrin was investigated. Wood chips, gravel and ceramics were tested as packing materials for the reactors in batch experiments in small glass flasks. Wood proved to be the material on which the fungus grew best and was thus chosen as the packing material for the reactors. It was determined that UBAF004 had quite low competitive strength compared to other microorganisms when growing on wood and gravel but not necessarily on ceramics. UBAF004 grew slowly in the reactors leading to poor degradation performance. The results obtained indicate that it will be challenging to use UBAF004 for treatment of water contaminated with cypermethrin in Tahuapalca. The single largest issue is to find a way to establish a stable population of the fungus in the reactor and to protect it from being out competed by other microorganisms.

  • 104.
    Erdtman, Edvin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Andersson, Mike
    Linköping University, Department of Physics, Chemistry and Biology, Applied Sensor Science. Linköping University, Faculty of Science & Engineering.
    Lloyd Spetz, Anita
    Linköping University, Department of Physics, Chemistry and Biology, Applied Sensor Science. Linköping University, Faculty of Science & Engineering.
    Ojamäe, Lars
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Simulations of the thermodynamics and kinetics of NH3 at the RuO2 (110) surface2017In: Surface Science, ISSN 0039-6028, E-ISSN 1879-2758, Vol. 656, p. 9p. 77-85Article in journal (Refereed)
    Abstract [en]

    Ruthenium(IV)oxide (RuO2) is a material used for various purposes. It acts as a catalytic agent in several reactions, for example oxidation of carbon monoxide. Furthermore, it is used as gate material in gas sensors. In this work theoretical and computational studies were made on adsorbed molecules on RuO2 (110) surface, in order to follow the chemistry on the molecular level. Density functional theory calculations of the reactions on the surface have been performed. The calculated reaction and activation energies have been used as input for thermodynamic and kinetics calculations. A surface phase diagram was calculated, presenting the equilibrium composition of the surface at different temperature and gas compositions. The kinetics results are in line with the experimental studies of gas sensors, where water has been produced on the surface, and hydrogen is found at the surface which is responsible for the sensor response.

  • 105.
    Ericsson, Emma
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Bui, Lan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Site-Specific and Covalent Attachment of His-Tagged Proteins by Chelation Assisted Photoimmobilization: A Strategy for Microarraying of Protein Ligands2013In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 29, no 37, p. 11687-11694Article in journal (Refereed)
    Abstract [en]

    A novel strategy for site-specific and covalent attachment of proteins has been developed, intended for robust and controllable immobilization of histidine (His)-tagged ligands in protein microarrays. The method is termed chelation assisted photoimmobilization (CAP) and was demonstrated using human IgG-Fc modified with C-terminal hexahistidines (His-IgGFc) as the ligand and protein A as the analyte. Alkanethiols terminated with either nitrilotriacetic acid (NTA), benzophenone (BP); or oligo(ethylene glycol) were synthesized and mixed self-assembled monolayers (SAMs) were prepared on gold and thoroughly characterized by infrared reflection absorption spectroscopy (IRAS), ellipsometry, and contact angle goniometry. In the process of CAP, NTA chelates Ni2+ and the complex coordinates the His-tagged ligand in an oriented assembly. The ligand is then photoimmobilized via BP, which forms covalent bonds upon UV light activation. In the development of affinity biosensors and protein microarrays, site-specific attachment of ligands in a fashion where analyte binding sites are available is often preferred to random coupling. Analyte binding performance of ligands immobilized either by CAP or by standard amine coupling was characterized by surface plasmon resonance in combination with IRAS. The relative analyte response with randomly coupled ligand was 2.5 times higher than when site-specific attachment was used. This is a reminder that also when immobilizing ligands via residues far from the binding site, there are many other factors influencing availability and activity. Still, CAP provides a valuable expansion of protein immobilization techniques since it offers attractive microarraying possibilities amenable to applications within proteomics.

  • 106.
    Ericsson, Emma M
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Bui, Lan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, The Institute of Technology.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, The Institute of Technology.
    Controlled orientation and covalent attachment of proteins on biosensor surfaces by Chelation Assisted Photoimmobilization2013Conference paper (Other academic)
    Abstract [en]

    In the context of surface chemistry for affinity biosensor chips, it is widely accepted that uniform orientation of the immobilized recognition element (ligand) is preferred over random orientation. However, this assumption has often been based on studies where differences in ligand immobilization level have not been taken into account. In this contribution, we present a novel two-step method for homogenous orientation and covalent attachment of proteins to sensing surfaces, called Chelation Assisted Photoimmobilization (CAP). Careful quantification of the effect of ligand orientation on analyte responses was performed by comparing this strategy to immobilization by conventional amine coupling.

     In CAP, the chelation agent is nitrilotriacetic acid (NTA) which chelates Ni2+. A His-tagged ligand forms an oriented assembly when binding Ni2+-NTA and is then covalently bound to the surface via photolabile benzophenone (BP), which attacks C-H bonds upon UV light activation. We relied on a surface chemistry based on self-assembled monolayers (SAMs) of oligo(ethylene glycol) (OEG)-containing alkanethiolates on gold. Alkanethiols terminated with either NTA, BP or OEG were synthesized and mixed SAMs were characterized by infrared reflection absorption spectroscopy (IRAS), ellipsometry and contact angle goniometry. IRAS was also used to quantify ligand immobilization levels obtained either by CAP or by amine coupling via the carboxyl groups of an NTA-presenting surface. The model ligand was human IgG-Fc modified with a C-terminal 6xHis-tag and the analyte was Protein A. The ligand-analyte interaction was quantified by a surface plasmon resonance biosensor.

     Analyte responses were normalized with respect to the ligand amounts obtained by the two immobilization strategies. Interestingly, the normalized analyte response with randomly oriented ligand was >2 times higher than that with ligand immobilized by CAP. This shows that oriented ligand immobilization is not necessarily a means of increasing the sensitivity of a biosensor. Factors that may influence performance include the valency of the ligand and constraints related to the surface chemistry used for orientation.

  • 107.
    Eriksson, Emma S. E.
    et al.
    Department of Chemistry and Molecular Biology, University of Gothenburg.
    Erdtman, Edvin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Eriksson, Leif A.
    Department of Chemistry and Molecular Biology, University of Gothenburg.
    Permeability of 5-aminolevulinic acid oxime derivatives in lipid membranes2016In: Theoretical Chemistry accounts, ISSN 1432-881X, E-ISSN 1432-2234, Vol. 135, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    The endogenous molecule 5-aminolevulinic acid (5ALA) and its methyl ester (Me-5ALA) have been used as prodrugs in photodynamic treatment of actinic keratosis and superficial non-melanoma skin cancers for over a decade. Recently, a novel set of 5ALA derivatives based on introducing a hydrolyzable oxime functionality was proposed and shown to generate considerably stronger onset of the photoactive molecule protoporphyrin IX (PpIX) in the cells. In the current work, we employ molecular dynamics simulation techniques to explore whether the higher intercellular concentration of PpIX caused by the oxime derivatives is related to enhanced membrane permeability, or whether other factors contribute to this. It is concluded that the oximes show overall similar accumulation at the membrane headgroup regions as the conventional derivatives and that the transmembrane permeabilities are in general close to that of 5ALA. The highest permeability of all compounds explored is found for Me-5ALA, which correlates with a considerably lower fee energy barrier at the hydrophobic bilayer center. The high PpIX concentration must hence be sought in other factors, where slow hydrolysis of the oxime functionality is a plausible reason, enabling stronger buildup of PpIX over time.

  • 108.
    Eriksson, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Appelqvist, Hanna
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Analysis of Lysosomal pH by Flow Cytometry Using FITC-Dextran Loaded Cells2017In: Lysosomes: Methods and Protocols / [ed] Karin Öllinger;Hanna Appelqvist, Humana Press, 2017, Vol. 1594, p. 179-189Chapter in book (Refereed)
    Abstract [en]

    The acidic environment of the lysosomal lumen provides an optimal milieu for the acid hydrolases and is also essential for fusion/fission of endo-lysosomal compartments and sorting of cargo. Evidence suggests that maintaining lysosomal acidity is essential to avoid disease. In this chapter, we describe a protocol for analyzing the lysosomal pH in cultured cells using the fluorescent probe fluorescein isothiocyanate (FITC)-dextran together with a dual-emission ratiometric technique suitable for flow cytometry. Fluorescence-labeled dextran is endocytosed and accumulated in the lysosomal compartment. FITC shows a pH-dependent variation in fluorescence when analyzed at maximum emission wavelength and no variation when analyzing at the isosbestic point, thereby the ratio can be used to determine the lysosomal pH. A standard curve is obtained by equilibrating intralysosomal pH with extracellular pH using the ionophore nigericin. The protocol also includes information regarding procedures to induce lysosomal alkalinization and lysosomal membrane permeabilization.

  • 109.
    Eriksson, Jens
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    Khranovskyy, Volodymyr
    Linköping University, Department of Physics, Chemistry and Biology, Semiconductor Materials. Linköping University, The Institute of Technology.
    Söderlind, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Käll, Per-Olov
    Linköping University, Department of Physics, Chemistry and Biology, Physical Chemistry. Linköping University, The Institute of Technology.
    Yakimova, Rositsa
    Linköping University, Department of Physics, Chemistry and Biology, Semiconductor Materials. Linköping University, The Institute of Technology.
    Lloyd-Spets, Anita
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    ZnO nanoparticles or ZnO films: A comparison of the gas sensing capabilities2009In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 137, no 1, p. 94-102Article in journal (Refereed)
    Abstract [en]

    Zinc oxide is an interesting material for bio and chemical sensors. it is a semiconducting metal oxide with potential as an integrated multisensing sensor platform, which simultaneously detects Parameters like change in field effect, mass and Surface resistivity. in this investigation we have used resistive sensor measurements regarding the oxygen gas sensitivity in order to characterize sensing layers based on electrochemically produced ZnO nanoparticles and PE-MOCVD grown ZnO films. Proper annealing procedures were developed in order to get stable sensing properties and the oxygen sensitivity towards operation temperature was investigated. The ZnO nanoparticles showed a considerably increased response to oxygen as compared to the films. Preliminary investigations were also performed regarding the selectivity to other gases present in car exhausts or flue gases.

  • 110.
    Espinosa, Alexander
    et al.
    Rheumatology Unit, Department of Medicine, CMM L8:04, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
    Hennig, Janosch
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Ambrosi, Aurélie
    Rheumatology Unit, Department of Medicine, CMM L8:04, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
    Anandapadamanaban, Madhanagopal
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sandberg Abelius, Martina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sheng, Yi
    Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Canada.
    Nyberg, Filippa
    Department of Clinical Sciences at Danderyd Hospital, Karolinska Institute, Stockholm, Sweden.
    Arrowsmith, Cheryl H.
    Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Canada.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Wahren-Herlenius, Marie
    Rheumatology Unit, Department of Medicine, CMM L8:04, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
    Anti-Ro52 Autoantibodies from Patients with Sjögren's Syndrome Inhibit the Ro52 E3 Ligase Activity by Blocking the E3/E2 Interface2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 42, p. 36478-36491Article in journal (Refereed)
    Abstract [en]

    Ro52 (TRIM21) is an E3 ligase of the tripartite motif family that negatively regulates proinflammatory cytokine production by ubiquitinating transcription factors of the interferon regulatory factor family. Autoantibodies to Ro52 are present in patients with lupus and Sjögren's syndrome, but it is not known if these autoantibodies affect the function of Ro52. To address this question, the requirements for Ro52 E3 ligase activity were first analyzed in detail. Scanning a panel of E2 ubiquitin-conjugating enzymes, we found that UBE2D1–4 and UBE2E1–2 supported the E3 ligase activity of Ro52 and that the E3 ligase activity of Ro52 was dependent on its RING domain. We also found that the N-terminal extensions in the class III E2 enzymes affected their interaction with Ro52. Although the N-terminal extension in UBE2E3 made this E2 enzyme unable to function together with Ro52, the N-terminal extensions in UBE2E1 and UBE2E2 allowed for a functional interaction with Ro52. Anti-Ro52-positive patient sera and affinity-purified anti-RING domain autoantibodies inhibited the E3 activity of Ro52 in ubiquitination assays. Using NMR, limited proteolysis, ELISA, and Ro52 mutants, we mapped the interactions between Ro52, UBE2E1, and anti-Ro52 autoantibodies. We found that anti-Ro52 autoantibodies inhibited the E3 ligase activity of Ro52 by sterically blocking the E2/E3 interaction between Ro52 and UBE2E1. Our data suggest that anti-Ro52 autoantibodies binding the RING domain of Ro52 may be actively involved in the pathogenesis of rheumatic autoimmune disease by inhibiting Ro52-mediated ubiquitination.

  • 111.
    Fritschi, Sarah K.
    et al.
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany; University of Tubingen, Germany.
    Cintron, Amarallys
    Emory University, GA 30329 USA.
    Ye, Lan
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany; University of Tubingen, Germany.
    Mahler, Jasmin
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany; University of Tubingen, Germany.
    Buehler, Anika
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany.
    Baumann, Frank
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany.
    Neumann, Manuela
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Walker, Lary C.
    Emory University, GA 30329 USA; Emory University, GA 30322 USA.
    Jucker, Mathias
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany .
    A beta seeds resist inactivation by formaldehyde2014In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 128, no 4, p. 477-484Article in journal (Refereed)
    Abstract [en]

    Cerebral beta-amyloidosis can be exogenously induced by the intracerebral injection of brain extracts containing aggregated beta-amyloid (A beta) into young, pre-depositing A beta precursor protein- (APP) transgenic mice. Previous work has shown that the induction involves a prion-like seeding mechanism in which the seeding agent is aggregated A beta itself. Here we report that the beta-amyloid-inducing activity of Alzheimers disease (AD) brain tissue or aged APP-transgenic mouse brain tissue is preserved, albeit with reduced efficacy, after formaldehyde fixation. Moreover, spectral analysis with amyloid conformation-sensitive luminescent conjugated oligothiophene dyes reveals that the strain-like properties of aggregated A beta are maintained in fixed tissues. The resistance of A beta seeds to inactivation and structural modification by formaldehyde underscores their remarkable durability, which in turn may contribute to their persistence and spread within the body. The present findings can be exploited to establish the relationship between the molecular structure of A beta aggregates and the variable clinical features and disease progression of AD even in archived, formalin-fixed autopsy material.

  • 112.
    Fröberg, Henric
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    A metaproteomics-based method for environmental assessment: A pilot study2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Metaproteomics, as a proteomic approach to analyse environmental samples, is a new and expanding field of research. The field promises new ways of determining the status of the organisms present in a sample, and could provide additional information compared to metagenomics. Being a novel field of research, robust methods and protocols have not yet been established. In this thesis, we examine several methods for a reliable extraction of protein from soil and periphyton samples. The extraction should preferably be fast, compatible with downstream analysis by mass spectrometry and extract proteins in proportion to their presence in the original sample. A variety of methods and buffers were used to extract proteins from soil and periphyton samples. Concentration determinations showed that all of these methods extracted enough protein for further analysis. For purification and digestion of the samples, several methods were used. The purified samples were analysed on three different mass spectrometers, with the Orbitrap Velos Pro delivering the best results. The results were matched against four genomic and metagenomic databases for identification of proteins, of which the UniProt/SwissProt database gave the best result. A maximum of 52 proteins were identified from periphyton samples when searching against UniProt/SwissProt with strict settings, of which the majority were highly conserved proteins. The main limitation for this type of work is currently the lack of proper metagenomic databases.

  • 113.
    Fyrner, Timmy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Ederth, Thomas
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Liedberg, Bo
    Nanyang Technology University, Singapore .
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Linköping, .
    Synthesis of oligo(lactose)-based thiols and their self-assembly onto gold surfaces2013In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 105, p. 187-193Article in journal (Refereed)
    Abstract [en]

    The ability to produce monomolecular coatings with well-defined structural and functional properties is of key importance in biosensing, drug delivery, and many recently developed applications of nanotechnology. Organic chemistry has proven to be a powerful tool to achieve this in many research areas. Herein, we present the synthesis of three oligo(lactosides) glycosylated in a (1 → 3) manner, and which are further functionalized with amide-linked short alkanethiol spacers. The oligosaccharides (di-, tetra-, and hexasaccharide) originate from the inexpensive and readily available lactose disaccharide. These thiolated derivatives were immobilized onto gold surfaces, and the thus formed self-assembled monolayers (SAMs) on planar gold were characterized by wettability, ellipsometry and infrared reflection–absorption spectroscopy. Further, the ability of these SAMs to stabilize gold nanoparticles in saline solutions was also demonstrated, indicating that the oligosaccharides may be used as stabilizing agents in gold nanoparticle-based assays.

  • 114.
    Fyrner, Timmy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lee, Hung-Hsun
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Mangone, Alberto
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Ekblad, Tobias
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Pettitt, Michala E
    University of Birmingham, UK.
    Callow, Maureen E
    University of Birmingham, UK.
    Callow, James A
    University of Birmingham, UK.
    Conlan, Sheelagh L
    Newcastle University, UK.
    Mutton, Robert
    Newcastle University, UK.
    Clare, Anthony S
    Newcastle Universitym, UK.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Ederth, Thomas
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Saccharide-Functionalized Alkanethiols for Fouling-Resistant Self-Assembled Monolayers: Synthesis, Monolayer Properties, and Antifouling Behavior2011In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, no 24, p. 15034-15047Article in journal (Refereed)
    Abstract [en]

    We describe the synthesis of a series of mono-, di-, and trisaccharide-functionalized alkanethiols as well as the formation of fouling-resistant self-assembled monolayers (SAMs) from these. The SAls,,Is were characterized using ellipsometry, wetting measurements, and infrared reflection absorption spectroscopy (WAS). We show that the structure of the carbohydrate moiety affects the packing density and that this also alters the alkane chain organization. Upon increasing the size of the sugar moieties (from mono- to di- and trisaccharides), the structural qualities of the monolayers deteriorated with increasing disorder, and for the trisaccharide, slow reorganization dynamics in response to changes in the environmental polarity were observed. The antifouling properties of these SAMs were investigated through protein adsorption experiments from buffer solutions as well as settlement (attachment) tests using two common marine fouling species, zoospores of the green macroalga Ulva linza and cypris larvae of the barnacle Balanus amphitrite. The SAMs showed overall good resistance to fouling by both the proteins and the tested marine organisms. To improve the packing density of the SAMs with bulky headgroups, we employed mixed SAMs where the saccharide-thiols are diluted with a filler molecule having a small 2-hydroxyethyl headgroup. This method also provides a means by which the steric availability of sugar moieties can be varied, which is of interest for specific interaction studies with surface-bound sugars. The results of the surface dilution study and the low nonspecific adsorption onto the SAMs both indicate the feasibility of this approach.

  • 115.
    Fändrich, M.
    et al.
    Ulm Univ, Germany.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Bockmann, A.
    Univ Lyon, France.
    LeVine, H. III
    Univ Kentucky, KY 40536 USA; Univ Kentucky, KY USA.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Amyloid fibril polymorphism: a challenge for molecular imaging and therapy2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 3, p. 218-237Article in journal (Refereed)
    Abstract [en]

    The accumulation of misfolded proteins (MPs), both unique and common, for different diseases is central for many chronic degenerative diseases. In certain patients, MP accumulation is systemic (e.g. TTR amyloid), and in others, this is localized to a specific cell type (e.g. Alzheimers disease). In neurodegenerative diseases, NDs, it is noticeable that the accumulation of MP progressively spreads throughout the nervous system. Our main hypothesis of this article is that MPs are not only markers but also active carriers of pathogenicity. Here, we discuss studies from comprehensive molecular approaches aimed at understanding MP conformational variations (polymorphism) and their bearing on spreading of MPs, MP toxicity, as well as MP targeting in imaging and therapy. Neurodegenerative disease (ND) represents a major and growing societal challenge, with millions of people worldwide suffering from Alzheimers or Parkinsons diseases alone. For all NDs, current treatment is palliative without addressing the primary cause and is not curative. Over recent years, particularly the shape-shifting properties of misfolded proteins and their spreading pathways have been intensively researched. The difficulty in addressing ND has prompted most major pharma companies to severely downsize their nervous system disorder research. Increased academic research is pivotal for filling this void and to translate basic research into tools for medical professionals. Recent discoveries of targeting drug design against MPs and improved model systems to study structure, pathology spreading and toxicity strongly encourage future studies along these lines to provide an opportunity for selective imaging, prognostic diagnosis and therapy.

  • 116.
    Gabrielsson, Erik
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Armgarth, Astrid
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Spatiotemporal Control of Amyloid-Like A Plaque Formation Using a Multichannel Organic Electronic Device2016In: Macromolecular materials and engineering (Print), ISSN 1438-7492, E-ISSN 1439-2054, Vol. 301, no 4, p. 359-363Article in journal (Refereed)
    Abstract [en]

    We herein report on an iontronic device to drive and control A1-40 and A1-42 fibril formation. This system allows kinetic control of A aggregation by regulation of H+ flows. The formed aggregates show both nanometer-sized fibril structure and microscopic growth, thus mimicking senile plaques, at the H+-outlet. Mechanistically we observed initial accumulation of A1-40 likely driven by electrophoretic migration which preceded nucleation of amyloid structures in the accumulated peptide cluster.

  • 117.
    Gabrielsson, Erik O.
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Armgarth, Astrid
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Nilsson, K. Peter N.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Controlled Microscopic Formation of Amyloid-Like Aβ Aggregates Using an Organic Electronic DeviceManuscript (preprint) (Other academic)
    Abstract [en]

    Alzheimer’s disease (AD), primarily associated with formation of fibrillar amyloid-beta peptide (Aβ) aggregates in the brain, is one of the most common old-age diseases. It is therefore crucial with an elevated scientific interest in Aβ, and its fundamental properties in a wide sense, to develop efficient methods for early detection and to combat AD. For the development of new techniques, both for AD detection and prevention, researchers are dependent on either tissue samples from deceased patients, animal models or in vitro systems. In vitro systems, such as producing protein aggregates of the Aβ-peptide in a test tube by incubation under denaturing conditions, offers us a simple but rather blunt tool for evaluating aggregation inhibition caused by compounds or to investigate new detection methods. We recently introduced the organic electronic ion pump (OEIP) as a method for creating amyloid-like aggregates at high spatiotemporal control as compared to the resulting aggregates manufactured using regular test tube-conditions. Combined with a fluorescent probe that is specific for the fibrillar aggregated form of misfolded peptides commonly seen in AD, this allowed us to control and to monitor the aggregation of a model peptide system in a highly confined space.

    To further elaborate the functionality of the OEIP together with amyloid-specific probes, we here present experiments demonstrating electronically controlled micron sized formation of Aβ-aggregates with morphologies ranging from fine fibers, to bundles of fibers, and thick mesh-like fiber structures. We foresee that the methodology can be implemented in multi array systems that can be utilized for studies of protein aggregation in confined spaces or together with cultured cells, as well as for the development of screening platforms for assessment of molecules influencing the Aβ-aggregation process.

  • 118.
    Gallardo, Rodrigo
    et al.
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Ramakers, Meine
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    De Smet, Frederik
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Claes, Filip
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Khodaparast, Ladan
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Khodaparast, Laleh
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Couceiro, Jose R.
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Langenberg, Tobias
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Siemons, Maxime
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Young, Laurence J.
    University of Cambridge, England; University of Leeds, England; University of Leeds, England.
    Laine, Romain F.
    University of Cambridge, England.
    Young, Lydia
    University of Cambridge, England; University of Leeds, England; University of Leeds, England.
    Radaelli, Enrico
    VIB Centre Biol Disease, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Benilova, Iryna
    VIB Centre Biol Disease, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Kumar, Manoj
    Katholieke University of Leuven, Belgium.
    Staes, An
    VIB, Belgium; University of Ghent, Belgium.
    Desager, Matyas
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Beerens, Manu
    Katholieke University of Leuven, Belgium.
    Vandervoort, Petra
    Katholieke University of Leuven, Belgium.
    Luttun, Aernout
    Katholieke University of Leuven, Belgium.
    Gevaert, Kris
    VIB, Belgium; University of Ghent, Belgium.
    Bormans, Guy
    Katholieke University of Leuven, Belgium.
    Dewerchin, Mieke
    Katholieke University of Leuven, Belgium; VIB, Belgium.
    Van Eldere, Johan
    Katholieke University of Leuven, Belgium.
    Carmeliet, Peter
    Katholieke University of Leuven, Belgium; VIB, Belgium.
    Vande Velde, Greetje
    Katholieke University of Leuven, Belgium.
    Verfaillie, Catherine
    Katholieke University of Leuven, Belgium.
    Kaminski, Clemens F.
    University of Cambridge, England.
    De Strooper, Bart
    VIB Centre Biol Disease, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Serpell, Louise
    University of Sussex, England.
    Schymkowitz, Joost
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Rousseau, Frederic
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    De novo design of a biologically active amyloid2016In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 354, no 6313, p. 720-+Article in journal (Refereed)
    Abstract [en]

    Most human proteins possess amyloidogenic segments, but only about 30 are associated with amyloid-associated pathologies, and it remains unclear what determines amyloid toxicity. We designed vascin, a synthetic amyloid peptide, based on an amyloidogenic fragment of vascular endothelial growth factor receptor 2 (VEGFR2), a protein that is not associated to amyloidosis. Vascin recapitulates key biophysical and biochemical characteristics of natural amyloids, penetrates cells, and seeds the aggregation of VEGFR2 through direct interaction. We found that amyloid toxicity is observed only in cells that both express VEGFR2 and are dependent on VEGFR2 activity for survival. Thus, amyloid toxicity here appears to be both protein-specific and conditional-determined by VEGFR2 loss of function in a biological context in which target protein function is essential.

  • 119.
    Golob-Schwarzi, Nicole
    et al.
    Med Univ Graz, Austria; Ctr Biomaker Res Med, Austria.
    Bettermann, Kira
    Med Univ Graz, Austria.
    Mehta, Anita Kuldeep
    Med Univ Graz, Austria; Dana Farber Canc Inst, MA 02215 USA.
    Kessler, Sonja M.
    Med Univ Graz, Austria; Saarland Univ, Germany.
    Unterluggauer, Julia
    Med Univ Graz, Austria.
    Krassnig, Stefanie
    Med Univ Graz, Austria.
    Kojima, Kensuke
    Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Chen, Xintong
    Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Hoshida, Yujin
    Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Bardeesy, Nabeel M.
    Harvard Med Sch, MA USA.
    Mueller, Heimo
    Med Univ Graz, Austria.
    Svendova, Vendula
    Med Univ Graz, Austria.
    Schimek, Michael G.
    Med Univ Graz, Austria.
    Diwoky, Clemens
    Graz Univ Technol, Austria; Karl Franzens Univ Graz, Austria.
    Lipfert, Alexandra
    Graz Univ Technol, Austria.
    Mahajan, Vineet
    Med Univ Graz, Austria.
    Stumptner, Cornelia
    Med Univ Graz, Austria.
    Thueringer, Andrea
    Med Univ Graz, Austria.
    Froehlich, Leopold F.
    Med Univ Graz, Austria; Univ Munster, Germany.
    Stojakovic, Tatjana
    Med Univ Graz, Austria.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kolbe, Thomas
    Univ Vet Med Vienna, Austria; Univ Bodenkultur Wien, Austria.
    Ruelicke, Thomas
    Univ Vet Med Vienna, Austria.
    Magin, Thomas M.
    Univ Leipzig, Germany.
    Strnad, Pavel
    Univ Hosp RWTH Aachen, Germany.
    Kiemer, Alexandra K.
    Ctr Biomaker Res Med, Austria.
    Moriggl, Richard
    Univ Vet Med Vienna, Austria; Ludwig Bolzmann Inst Canc Res, Austria; Med Univ Vienna, Austria.
    Haybaeck, Johannes
    Med Univ Graz, Austria; Otto von Guericke Univ, Germany.
    High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype2019In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 12, no 2, p. 256-268Article in journal (Refereed)
    Abstract [en]

    BACKGROUND amp; AIMS: Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, liver cell ballooning, cytoplasmic aggregates termedMallory-Denk bodies (MDBs), inflammation, and fibrosis at late stage. Disturbance of the keratin cytoskeleton and aggregation of keratins (KRTs) are essential for MDB formation. METHODS: Weanalyzed livers of aged Krt18(-/-) mice that spontaneously developed in the majority of cases SH-associated HCC independent of sex. Interestingly, the hepatic lipid profile in Krt18(-/-) mice, which accumulate KRT8, closely resembles human SH lipid profiles and shows that the excess of KRT8 over KRT18 determines the likelihood to develop SH-associated HCC linked with enhanced lipogenesis. RESULTS: Our analysis of the genetic profile of Krt18(-/-) mice with 26 human hepatoma cell lines and with data sets of amp;gt;300 patients with HCC, where Krt18(-/-) gene signatures matched human HCC. Interestingly, a high KRT8/18 ratio is associated with an aggressive HCC phenotype. CONCLUSIONS: We can prove that intermediate filaments and their binding partners are tightly linked to hepatic lipid metabolism and to hepatocarcinogenesis. We suggest KRT8/18 ratio as a novel HCC biomarker for HCC.

  • 120.
    Granquist, Linda
    et al.
    Swedish Natl Forens Ctr NFC, S-58194 Linkoping, Sweden.
    Carlsson, Andreas
    Swedish Natl Forens Ctr NFC, S-58194 Linkoping, Sweden.
    Jonson, Sten
    Swedish Natl Forens Ctr NFC, S-58194 Linkoping, Sweden.
    Andersson, Kjell
    Swedish Natl Forens Ctr NFC, S-58194 Linkoping, Sweden.
    Karlsson, Per
    Swedish Natl Forens Ctr NFC, S-58194 Linkoping, Sweden.
    Dahlén, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Swedish Natl Forens Ctr NFC, S-58194 Linkoping, Sweden.
    Dunne, Simon
    Swedish Natl Forens Ctr NFC, S-58194 Linkoping, Sweden.
    Optimization of peak area precision of a GC-MS drug screening method using a nonparametric sign test2019In: Accreditation and Quality Assurance, ISSN 0949-1775, E-ISSN 1432-0517, Vol. 24, no 3, p. 215-226Article in journal (Refereed)
    Abstract [en]

    The optimization of a number ofgas chromatography-mass spectrometry (GC-MS) parameters in order to improve peak area precision through the application of a nonparametric statistical test (the sign test) is demonstrated. As an example, the drug screening method used at the Swedish National Forensic Centre (NFC) is optimized, but in principle, any GC-MS method could be optimized using this approach. The GC-MS parameters investigated were those often overlooked in the optimization process, namely injection volume, liner type, oven temperature program, final oven temperature, MS scan range and MS scan rate. The influence of these parameters on the precision of the peak area responses of 11 different compounds in a test mixture was evaluated using the sign test for pairwise comparison. This nonparametric test provides probability values which facilitate the ranking of parameters according to their influence on peak area variation as well as providing a measure of their statistical significance. This study presents the resulting optimized method and shows that the decreased total variation depended predominantly on liner type and MS scan rate settings. This work also shows that optimization of analytical methods can be achieved using simple and easily accessible statistical tools.

  • 121.
    Groenning, Minna
    et al.
    University of Copenhagen, Denmark.
    Campos Melo, Raul Ivan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hirschberg, Daniel
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Vestergaard, Bente
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Considerably Unfolded Transthyretin Monomers Preceed and Exchange with Dynamically Structured Amyloid Protofibrils2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 11443Article in journal (Refereed)
    Abstract [en]

    Despite numerous studies, a detailed description of the transthyretin (TTR) self-assembly mechanism and fibril structure in TTR amyloidoses remains unresolved. Here, using a combination of primarily small -angle X-ray scattering (SAXS) and hydrogen exchange mass spectrometry (HXMS) analysis, we describe an unexpectedly dynamic TTR protofibril structure which exchanges protomers with highly unfolded monomers in solution. The protofibrils only grow to an approximate final size of 2,900 kDa and a length of 70 nm and a comparative HXMS analysis of native and aggregated samples revealed a much higher average solvent exposure of TTR upon fibrillation. With SAXS, we reveal the continuous presence of a considerably unfolded TTR monomer throughout the fibrillation process, and show that a considerable fraction of the fibrillating protein remains in solution even at a late maturation state. Together, these data reveal that the fibrillar state interchanges with the solution state. Accordingly, we suggest that TTR fibrillation proceeds via addition of considerably unfolded monomers, and the continuous presence of amyloidogenic structures near the protofibril surface offers a plausible explanation for secondary nucleation. We argue that the presence of such dynamic structural equilibria must impact future therapeutic development strategies.

  • 122.
    Gundersen, Per Ole M.
    et al.
    St Olavs Univ Hosp, Norway; Norwegian Univ Sci and Technol, Norway.
    Spigset, Olav
    St Olavs Univ Hosp, Norway; Norwegian Univ Sci and Technol, Norway.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Natl Forens Ctr, Drug Unit, Linkoping, Sweden.
    Screening, quantification, and confirmation of synthetic cannabinoid metabolites in urine by UHPLC-QTOF-MS2019In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 11, no 1, p. 51-67Article in journal (Refereed)
    Abstract [en]

    Synthetic cannabinoids are one of the most significant groups within the category new psychoactive substances (NPS) and in recent years new compounds have continuously been introduced to the market of recreational drugs. A sensitive and quantitative screening method in urine with metabolites of frequently seized compounds in Norway (AB-FUBINACA, AB-PINACA, AB-CHMINACA, AM-2201, AKB48, 5F-AKB48, BB-22, JWH-018, JWH-073, JWH-081, JWH-122, JWH-203, JWH-250, PB-22, 5F-PB-22, RCS-4, THJ-2201, and UR-144) using ultra-high pressure liquid chromatography-quadrupole time of flight-mass spectrometry (UHPLC-QTOF-MS) has been developed. The samples were treated with ss-glucuronidase prior to extraction and solid-phase extraction was used. Liquid handling was automated using a robot. Chromatographic separation was achieved using a C18-column and a gradient of water and acetonitrile, both with 0.1% formic acid. Each sample was initially screened for identification and quantification followed by a second injection for confirmation. The concentrations by which the compounds could be confirmed varied between 0.1 and 12 ng/mL. Overall the validation showed that the method fulfilled the set criteria and requirements for matrix effect, extraction recovery, linearity, precision, accuracy, specificity, and stability. One thousand urine samples from subjects in drug withdrawal programs were analyzed using the presented method. The metabolite AB-FUBINACA M3, hydroxylated metabolite of 5F-AKB48, hydroxylated metabolite of AKB48, AKB48 N-pentanoic acid, 5F-PB-22 3-carboxyindole, BB-22 3-carboxyindole, JWH-018 N-(5-hydroxypentyl), JWH-018 N-pentanoic acid, and JWH-073 N-butanoic acid were quantified and confirmed in 2.3% of the samples. The method was proven to be sensitive, selective and robust for routine use for the investigated metabolites.

  • 123.
    Gunnarsson, Rickard
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Plasma and Coating Physics. Linköping University, Faculty of Science & Engineering.
    Brenning, Nils
    Linköping University, Department of Physics, Chemistry and Biology, Plasma and Coating Physics. Linköping University, Faculty of Science & Engineering. KTH Royal Inst Technol, Sweden.
    Ojamäe, Lars
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kalered, Emil
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Raadu, Michael Allan
    KTH Royal Inst Technol, Sweden.
    Helmersson, Ulf
    Linköping University, Department of Physics, Chemistry and Biology, Plasma and Coating Physics. Linköping University, Faculty of Science & Engineering.
    Nucleation of titanium nanoparticles in an oxygen-starved environment. II: theory2018In: Journal of Physics D: Applied Physics, ISSN 0022-3727, E-ISSN 1361-6463, Vol. 51, no 45, article id 455202Article in journal (Refereed)
    Abstract [en]

    The nucleation and growth of pure titanium nanoparticles in a low-pressure sputter plasma has been believed to be essentially impossible. The addition of impurities, such as oxygen or water, facilitates this and allows the growth of nanoparticles. However, it seems that this route requires such high oxygen densities that metallic nanoparticles in the hexagonal alpha Ti-phase cannot be synthesized. Here we present a model which explains results for the nucleation and growth of titanium nanoparticles in the absent of reactive impurities. In these experiments, a high partial pressure of helium gas was added which increased the cooling rate of the process gas in the region where nucleation occurred. This is important for two reasons. First, a reduced gas temperature enhances Ti-2 dimer formation mainly because a lower gas temperature gives a higher gas density, which reduces the dilution of the Ti vapor through diffusion. The same effect can be achieved by increasing the gas pressure. Second, a reduced gas temperature has a more than exponential effect in lowering the rate of atom evaporation from the nanoparticles during their growth from a dimer to size where they are thermodynamically stable, r*. We show that this early stage evaporation is not possible to model as a thermodynamical equilibrium. Instead, the single-event nature of the evaporation process has to be considered. This leads, counter intuitively, to an evaporation probability from nanoparticles that is exactly zero below a critical nanoparticle temperature that is size-dependent. Together, the mechanisms described above explain two experimentally found limits for nucleation in an oxygen-free environment. First, there is a lower limit to the pressure for dimer formation. Second, there is an upper limit to the gas temperature above which evaporation makes the further growth to stable nuclei impossible.

  • 124.
    Gunnarsson, Svante
    et al.
    Linköping University, Department of Electrical Engineering, Automatic Control. Linköping University, The Institute of Technology.
    Herbertsson, Helena
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Kindgren, Annalena
    Linköping University, The Institute of Technology.
    Wiklund, Ingela
    Linköping University, The Institute of Technology.
    Willumsen, Louise
    Technical University of Denmark, Denmark.
    Vigild, Martin E.
    Technical University of Denmark, Denmark.
    Using the CDIO Syllabus in Formulation of Program Goals - Experiences and Comparisons2009In: Proceedings of the 5th International CDIO Conference, 2009Conference paper (Refereed)
    Abstract [en]

    This paper presents experiences and results from large scale and systematic use of the CDIO Syllabus for developing program goals and formulating learning outcomes at Linköping University (LiU), Sweden, and Technical University of Denmark (DTU). The approaches are based on the use of tools for program design such as ITU-matrices and skill progression matrices. During the process local adaptations of the Syllabus have been made in order to meet regulations by authorities in higher education as well as to cover programs in related areas as natural sciences. The experiences are that the CDIO Syllabus is a very useful tool in this process and that the way of organizing the management of the education programs is important for success as well as support from students, faculty members and stakeholders.

  • 125.
    Gunnarsson, Svante
    et al.
    Linköping University, Department of Electrical Engineering, Automatic Control. Linköping University, Faculty of Science & Engineering.
    Herbertsson, Helena
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Petersson, Håkan
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Using Course and Program Matrices as Components in a Quality Assurance System2019In: The 15th International CDIO Conference: Proceedings – Full Papers / [ed] Jens Bennedsen, Aage Birkkjær Lauritsen, Kristina Edström, Natha Kuptasthien, Janne Roslöf & Robert Songer, Aarhus: Aarhus University , 2019, p. 110-119Conference paper (Refereed)
    Abstract [en]

    The CDIO framework is an integrated and important part of the new quality assurance system within the Faculty of Science and Engineering at Linköping University. Both the CDIO Syllabus and the CDIO Standards are used extensively in the system. First, the paper presents the development and use of the second generation of course matrices (previously denoted ITU-matrices) and program matrices, which build upon an adapted and extended version of the CDIO Syllabus. The extension is made to also include bachelor’s and master’s program in subjects outside the engineering field. Second, the paper presents how the CDIO Standards are used in the quality reports, which are vital parts of the quality assurance systems. As a result, the CDIO framework is used for the design, management, and quality assurance of all education programs ( approximately 60 programs) within the Faculty of Science and Engineering at Linköping University.

  • 126.
    Gustafsson, Håkan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ahrén, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Söderlind, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Córdoba Gallego, José M.
    Linköping University, Department of Physics, Chemistry and Biology, Nanostructured Materials. Linköping University, The Institute of Technology.
    Käll, Per-Olov
    Linköping University, Department of Physics, Chemistry and Biology, Physical Chemistry. Linköping University, Faculty of Science & Engineering.
    Nordblad, Per
    Uppsala Universitet.
    Westlund, Per-Olof
    Umeå Universitet.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences.
    Magnetic and Electron Spin Relaxation Properties of (GdxY1-x)2O3 (0 ≤ x ≤ 1) Nanoparticles Synthesized by the Combustion Method. Increased Electron Spin Relaxation Times with Increasing Yttrium Content2011In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 115, no 13, p. 5469-5477Article in journal (Refereed)
    Abstract [en]

    The performance of a magnetic resonance imaging contrast agent (CA) depends on several factors, including the relaxation times of the unpaired electrons in the CA. The electron spin relaxation time may be a key factor for the performance of new CAs, such as nanosized Gd2O3 particles. The aim of this work is, therefore, to study changes in the magnetic susceptibility and the electron spin relaxation time of paramagnetic Gd2O3 nanoparticles diluted with increasing amounts of diamagnetic Y2O3. Nanoparticles of (GdxY1-x)2O3 (0 e x e 1) were prepared by the combustion method and thoroughly characterized (by X-ray di.raction, transmission electron microscopy, thermogravimetry coupled with mass spectroscopy, photoelectron spectroscopy, Fourier transform infrared spectroscopy, and magnetic susceptibility measurements). Changes in the electron spin relaxation time were estimated by observations of the signal line width in electron paramagnetic resonance spectroscopy, and it was found that the line width was dependent on the concentration of yttrium, indicating that diamagnetic Y2O3 may increase the electron spin relaxation time of Gd2O3 nanoparticles.

  • 127.
    Gustafsson, Håkan
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Biomedical Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology. Norwegian University of Science and Technology, Norway.
    Kolbun, Natallia
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Jonson, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    de Muinck, Ebo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Zachrisson, Helene
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Visualization of oxidative stress in ex vivo biopsies using electron paramagnetic resonance imaging2015In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 73, no 4, p. 1682-1691Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The purpose of this study was to develop an X-Band electron paramagnetic resonance imaging protocol for visualization of oxidative stress in biopsies.

    METHODS: The developed electron paramagnetic resonance imaging protocol was based on spin trapping with the cyclic hydroxylamine spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine and X-Band EPR imaging. Computer software was developed for deconvolution and back-projection of the EPR image. A phantom containing radicals of known spatial characteristic was used for evaluation of the developed protocol. As a demonstration of the technique electron paramagnetic resonance imaging of oxidative stress was performed in six sections of atherosclerotic plaques. Histopathological analyses were performed on adjoining sections.

    RESULTS: The developed computer software for deconvolution and back-projection of the EPR images could accurately reproduce the shape of a phantom of known spatial distribution of radicals. The developed protocol could successfully be used to image oxidative stress in six sections of the three ex vivo atherosclerotic plaques.

    CONCLUSIONS: We have shown that oxidative stress can be imaged using a combination of spin trapping with the cyclic hydroxylamine spin probe cyclic hydroxylamine spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine and X-Band EPR imaging. A thorough and systematic evaluation on different types of biopsies must be performed in the future to validate the proposed technique. Magn Reson Med, 2014.

  • 128.
    Göransson, Anna-Lena
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Kanmert, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kågedal, Katarina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Identification of distinct physiochemical properties of the toxic prefibrillar species formed by Aβ peptide variants2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 420, no 4, p. 895-900Article in journal (Refereed)
    Abstract [en]

    The formation of amyloid-β peptide (Aβ) aggregates at an early stage during the self-assembly process is an important factor in the development of Alzheimer’s disease. The toxic effect is believed to be exerted by prefibrillar species of Aβ. It is therefore important to identify which prefibrillar species are toxic and characterize their distinct properties. In the present study, we investigated the in vitro aggregation behavior of Aβ-derived peptides possessing different levels of neurotoxic activity, using fluorescence spectroscopy in combination with transmission electron microscopy. The toxicity of various Aβ aggregates was assessed by using cultures of human neuroblastoma cells. Through combined use of the fluorescence probe 8-anilino-1-napthalenesulfonate (ANS) and the novel luminescent probe pentamer formyl thiophene acetic acid (p-FTAA), we were able to identify those Aβ peptide-derived prefibrillar species which exhibited cellular toxicity. In particular, species, which formed early during the aggregation process and showed strong p-FTAA and ANS fluorescence, were the species that possessed toxic activities. Moreover, by manipulating the aggregation conditions, it was possible to change the capacity of the Aβ peptide to form nontoxic versus toxic species.

  • 129.
    Haage, Pernilla
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Calistri, Simona
    Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands / Scuola di Scienze della Salute Umana, Università degli studi di Firenze, Florence, Italy.
    van Schaik, Ron H N
    Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype2018In: Pharmacology Research & Perspectives, ISSN 2052-1707, Vol. 6, no 4, article id e00419Article in journal (Refereed)
    Abstract [en]

    Tramadol is a complex drug, being metabolized by polymorphic enzymes and administered as a racemate with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. The study aimed to simultaneously determine the enantiomer concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol following a single dose, and elucidate if enantioselective pharmacokinetics is associated with the time following drug intake and if interindividual differences may be genetically explained. Nineteen healthy volunteers were orally administered either 50 or 100 mg tramadol, whereupon blood samples were drawn at 17 occasions. Enantiomer concentrations in whole blood were measured by LC-MS/MS and the CYP2D6,CYP2B6 and CYP3A4 genotype were determined, using the xTAG CYP2D6 Kit, pyrosequencing and real-time PCR, respectively. A positive correlation between the (+)/(-)-enantiomer ratio and time following drug administration was shown for all four enantiomer pairs. The largest increase in enantiomer ratio was observed for N-desmethyltramadol in CYP2D6 extensive and intermediate metabolizers, rising from about two to almost seven during 24 hours following drug intake. CYP2D6 poor metabolizers showed metabolic profiles markedly different from the ones of intermediate and extensive metabolizers, with large area under the concentration curves (AUCs) of the N-desmethyltramadol enantiomers and low corresponding values of the O-desmethyltramadol and N,O-didesmethyltramadol enantiomers, especially of the (+)-enantiomers. Homozygosity of CYP2B6 *5 and *6 indicated a reduced enzyme function, although further studies are required to confirm it. In conclusion, the increase in enantiomer ratios over time might possibly be used to distinguish a recent tramadol intake from a past one. It also implies that, even though (+)-O-desmethyltramadol is regarded the enantiomer most potent in causing adverse effects, one should not investigate the (+)/(-)-enantiomer ratio of O-desmethyltramadol in relation to side effects without consideration for the time that has passed since drug intake.

  • 130.
    Hahn, Katharina
    et al.
    Christian Albrechts University of Kiel, Germany.
    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.
    Urban, Peter
    Institute Pathol and Dermatopathol, Germany.
    Ruediger Meliss, Rolf
    Institute Dermatopathol, Germany.
    Behrens, Hans-Michael
    Christian Albrechts University of Kiel, Germany.
    Krueger, Sandra
    Christian Albrechts University of Kiel, Germany.
    Roecken, Christoph
    Christian Albrechts University of Kiel, Germany.
    Establishing and validating the fluorescent amyloid ligand h-FTAA (heptamer formyl thiophene acetic acid) to identify transthyretin amyloid deposits in carpal tunnel syndrome2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no 2, p. 78-86Article in journal (Refereed)
    Abstract [en]

    Transthyretin-derived (ATTR) amyloidosis is a frequent finding in carpal tunnel syndrome. We tested the following hypotheses: the novel fluorescent amyloid ligand heptameric formic thiophene acetic acid (h-FTAA) has a superior sensitivity for the detection of amyloid compared with Congo red-staining; Amyloid load correlates with patient gender and/or patient age. We retrieved 208 resection specimens obtained from 184 patients with ATTR amyloid in the carpal tunnel. Serial sections were stained with Congo red, h-FTAA and an antibody directed against transthyretin (TTR). Stained sections were digitalized and forwarded to computational analyses. The amount of amyloid was correlated with patient demographics. Amyloid stained intensely with h-FTAA and an anti-TTR-antibody. Congo red-staining combined with fluorescence microscopy was significantly less sensitive than h-FTAA-fluorescence and TTR-immunostaining: the highest percentage area was found in TTR-immunostained sections, followed by h-FTAA and Congo red. The Pearson correlation coefficient was .8 (Congo red vs. h-FTAA) and .9 (TTR vs. h-FTAA). Amyloid load correlated with patient gender, anatomical site and patient age. h-FTAA is a highly sensitive method to detect even small amounts of ATTR amyloid in the carpal tunnel. The staining protocol is easy and h-FTAA may be a much more sensitive procedure to detect amyloid at an earlier stage.

  • 131.
    Hamedi, Mahiar
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Tvinstedt, Kristofer
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Karlsson, Roger H
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Asberg, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Bridging Dimensions in Organic Electronics: Assembly of Electroactive Polymer Nanodevices from Fluids2009In: Nano letters (Print), ISSN 1530-6984, E-ISSN 1530-6992, Vol. 9, no 2, p. 631-635Article in journal (Refereed)
    Abstract [en]

    Processing and patterning of electroactive materials from solvents is a hallmark of flexible organic electronics,(1) and commercial applications based on these properties are now emerging. Printing and ink-jetting are today preferred technologies for patterning, but these limit the formation of nanodevices, as they give structures way above the micrometer lateral dimension. There is therefore a great need for cheap, large area patterning of nanodevices and methods for top-down registration of these. Here we demonstrate large area patterning of connected micro/nanolines and nanotransistors from the conducting polymer PEDOT, assembled from fluids. We thereby simultaneously solve problems of large area nanopatterning, and nanoregistration.

  • 132.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    BIOLUMINESCENCE IMAGING Photonic amyloids2019In: Nature Photonics, ISSN 1749-4885, Vol. 13, no 7, p. 442-444Article in journal (Refereed)
    Abstract [en]

    Emerging data reveal that amyloid fibrils possess intrinsic photonic activity, showing luminescence over a wide range of the electromagnetic spectrum from the ultraviolet to the near-infrared.

  • 133.
    Hammarström, Per
    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.
    Porcine prion protein amyloid2015In: Prion, ISSN 1933-6896, E-ISSN 1933-690X, Vol. 9, no 4, p. 266-277Article in journal (Refereed)
    Abstract [en]

    Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions.

  • 134.
    Hecker, Andreas
    et al.
    University of Giessen, Germany.
    Kuellmar, Mira
    University of Giessen, Germany.
    Wilker, Sigrid
    University of Giessen, Germany.
    Richter, Katrin
    University of Giessen, Germany; University of Giessen, Germany.
    Zakrzewicz, Anna
    University of Giessen, Germany.
    Atanasova, Srebrena
    University of Giessen, Germany.
    Mathes, Verena
    University of Giessen, Germany.
    Timm, Thomas
    University of Giessen, Germany.
    Lerner, Sabrina
    University of Giessen, Germany.
    Klein, Jochen
    Goethe University of Frankfurt, Germany.
    Kaufmann, Andreas
    University of Marburg, Germany.
    Bauer, Stefan
    University of Marburg, Germany.
    Padberg, Winfried
    University of Giessen, Germany.
    Kummer, Wolfgang
    University of Giessen, Germany.
    Janciauskiene, Sabina
    Hannover Medical Sch, Germany.
    Fronius, Martin
    University of Giessen, Germany; University of Otago, New Zealand.
    Schweda, Elke
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lochnit, Guenter
    University of Giessen, Germany.
    Grau, Veronika
    University of Giessen, Germany.
    Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1 beta Release2015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 5, p. 2325-2334Article in journal (Refereed)
    Abstract [en]

    IL-1 beta is a potent proinflammatory cytokine of the innate immune system that is involved in host defense against infection. However, increased production of IL-1 beta plays a pathogenic role in various inflammatory diseases, such as rheumatoid arthritis, gout, sepsis, stroke, and transplant rejection. To prevent detrimental collateral damage, IL-1 beta release is tightly controlled and typically requires two consecutive danger signals. LPS from Gram-negative bacteria is a prototypical first signal inducing pro-IL-1 beta synthesis, whereas extracellular ATP is a typical second signal sensed by the ATP receptor P2X7 that triggers activation of the NLRP3-containing inflammasome, proteolytic cleavage of pro-IL-1 beta by caspase-1, and release of mature IL-1 beta. Mechanisms controlling IL-1 beta release, even in the presence of both danger signals, are needed to protect from collateral damage and are of therapeutic interest. In this article, we show that acetylcholine, choline, phosphocholine, phosphocholine-modified LPS from Haemophilus influenzae, and phosphocholine-modified protein efficiently inhibit ATP-mediated IL-1 beta release in human and rat monocytes via nicotinic acetylcholine receptors containing subunits alpha 7, alpha 9, and/or alpha 10. Of note, we identify receptors for phosphocholine-modified macromolecules that are synthesized by microbes and eukaryotic parasites and are well-known modulators of the immune system. Our data suggest that an endogenous anti-inflammatory cholinergic control mechanism effectively controls ATP-mediated release of IL-1 beta and that the same mechanism is used by symbionts and misused by parasites to evade innate immune responses of the host.

  • 135.
    Hederos, Markus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Efficient routes to ethyl-2-deoxy-2-phthalimido-1-β-D-thio-galactosamine derivatives via epimerization of the corresponding glucosamine compounds2005In: Journal of carbohydrate chemistry, ISSN 0732-8303, E-ISSN 1532-2327, Vol. 24, no 3, p. 297-320Article in journal (Refereed)
    Abstract [en]

    Short synthetic routes to protected ethyl 2-deoxy-2-phthalimido-1-β-D- thio-galactosamine derivatives via epimerization of the corresponding glucosamine compounds are described. Starting from D-glucosamine hydrochloride, the epimerizations were performed by displacement of presynthesized triflates with nitrite anions and by an oxidation/reduction route. The latter method involved Moffatt oxidation to the corresponding 4-ketohexoses and subsequent reduction using sodium borohydride/ tetrabutylammonium borohydride, zinc borohydride, or lithium tri-sec-butyl borohydride in THF. The displacement route was found to be the preferred method for epimerization of 3-O-acyl (benzoyl) derivatives. For glucosamine compounds with 3-O-etheral- (allyl or benzyl) and 6-O-benzyl protecting groups, the oxidation/reduction route was the most convenient procedure to achieve corresponding galactosamine compounds. The produced galactosamine derivatives will be useful building blocks in the synthesis of antifreeze glycoproteins substances and analogues thereof.

  • 136.
    Hederos, Markus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Synthesis of the core tetrasaccharide of Trypanosoma cruzi glycoinositolphospholipids: manp(α1→6)-Manp(α1→4)-6-(2-aminoethylphosphonic acid)-GlcNp(α1→6)-myo-Ins-1-PO42005In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 70, no 18, p. 7196-7207Article in journal (Refereed)
    Abstract [en]

    Synthesis of the core tetrasaccharide Manp(α1→6)-Manp(α1→4)-6-(2-aminoethylphosphonic acid)-GlcNp(α1→6)-myo-Ins-1-PO4, found in glycoinositolphospholipids of Trypanosoma cruzi parasites, is described. The key building block, 6-O-(2-azido-3-O-benzyl-6-O-((2-benzyloxycarbonylaminoethyl)phosphonic acid benzyl ester)-2-deoxy-α-d-glucopyranosyl)-1-di-O-benzylphosphoryl-4,5-O-isopropylidene-2,3-O-(d-1,7,7-trimethyl[2,2,1]bicyclohept-6-ylidene)-d-myo-inositol, was synthesized using a partially protected glucosyl d-camphorinositolphosphate and a (2-benzyloxycarbonylaminoethyl)phosphonic acid derivative in a regioselective phosphonate esterfication. Elongation with ethyl 2-O-benzoyl-3,4,6-tri-O-benzyl-α-d-mannopyranosyl-(1→6)-2,3,4-tri-O-benzyl-1-α-d-thiomannopyranoside using dimethyl(methylthio)sulfonium trifluoromethanesulfonate gave a fully protected tetrasaccharide which was successfully deprotected subsequently with sodium methoxide, sodium in liquid ammonia, and aq hydrochloric acid to give title compound.

  • 137.
    Hederos, Markus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Synthesis of the Trypanosoma cruzi LPPG heptasaccharyl myo-inositol2006In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 128, no 10, p. 3414-3419Article in journal (Refereed)
    Abstract [en]

    Synthesis of the heptasaccharyl myo-inositol found in Trypanosoma cruzi lipopeptidophosphoglycan was accomplished using a convergent assembly of three building blocks. The target compound is the first complete 2-aminoethyl phosphonic acid substituted glycan related to the glycosylphosphatidylinositol anchor family to be synthesized. The order of assembly enables synthesis of phosphoinositol oligosaccharides related to other glycosylinositolphospholipids in Tr. cruzi, the protozoan parasite causing Chagas' disease, which is endemic in South America.

  • 138.
    Hederos, Markus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Borgh, Annika
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Mimicking the properties of antifreeze glycoproteins: synthesis and characterization of a model system for ice nucleation and antifreeze studies2005In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 109, no 33, p. 15849-15859Article in journal (Refereed)
    Abstract [en]

    Synthesis of β-D-Gal-(1 → 3)-β-D-GalNAc coupled to HOC2H4NHCOC15H30SH is described. This compound was coadsorbed at various proportions with C2H5OC2H4NHCOC15H30SH to form statistically mixed self-assembled monolayers (SAMs) on gold in an attempt to mimic the properties of the active domain in antifreeze glycoproteins (AFGPs). The monolayers were characterized by null ellipsometry, contact angle goniometry, X-ray photoelectron spectroscopy, and infrared reflection−absorption spectroscopy. The disaccharide compound adsorbed preferentially, and SAMs prepared at a solution molar ratio >0.3 displayed total wetting. The mixed SAMs showed well-organized alkyl chains up to a disaccharide surface fraction of 0.8. The amount of gauche conformers in the alkyls increased rapidly above this point, and the monolayers became disordered and less densely packed. Furthermore, the generated mixed SAMs were subjected to water vapor at constant relative humidity and the subsequent ice crystallization on a cooled substrate was monitored via an optical microscope. Interestingly, rapid crystallization occurred within a narrow range of temperatures on mixed SAMs with a high disaccharide content, surface fraction >0.3. The reported crystallization temperatures and the ice layer topography were compared with results obtained for a much simpler reference system composed of −OH/−CH3 terminated n-alkanethiols in order to account for changes in topography of the water/ice layer with surface energy. Although preliminary, the obtained results can be useful in the search for the molecular mechanism behind the antifreeze activity of AFGPs.

  • 139.
    Hederos, Markus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Synthesis and self-assembly of galactose-terminated alkanethiols and their ability to resist proteins2005In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 21, no 7, p. 2971-2980Article in journal (Refereed)
    Abstract [en]

    The synthesis of two galactose-terminated alkanethiols with the structural formula X−OC2H5NHCO(CH2)15SH (X = 2,3,4,6-tetra-O-methyl-β-d-Gal or β-d-Gal) is described. Single-component and mixed self-assembled monolayers (SAMs) of the methylated and nonmethylated compounds were prepared on gold and subsequently characterized with ellipsometry, contact angle goniometry, and infraredreflection−absorption spectroscopy. Studies of the irreversible protein adsorption onto the SAMs using ex-situ ellipsometry revealed very low levels of fibrinogen and lysozyme adsorption onto mixed SAMs displaying advancing water contact angles between 24° and 45° and below 45°, respectively. A monomethylated compound (X = 6-O-methyl-β-d-Gal) was also synthesized and assembled on gold. This particular compound was found to possess wettability properties corresponding to the low adsorption regime of the mixed SAMs, and the results from the same set of fibrinogen and lysozyme adsorption experiments showed very low levels of protein adsorption. Our findings suggest that the protein rejecting properties rely on a fine balance between the surface energy and/or hydrogen bond donating/accepting properties of the SAM surface.

  • 140.
    Heilbronner, Goetz
    et al.
    University of Tubingen, Germany .
    Eisele, Yvonne S.
    University of Tubingen, Germany .
    Langer, Franziska
    University of Tubingen, Germany .
    Kaeser, Stephan A.
    University of Tubingen, Germany .
    Novotny, Renata
    University of Tubingen, Germany .
    Nagarathinam, Amudha
    University of Tubingen, Germany .
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    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.
    Jucker, Mathias
    University of Tubingen, Germany .
    Seeded strain-like transmission of beta-amyloid morphotypes in APP transgenic mice2013In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 14, no 11, p. 1017-1022Article in journal (Refereed)
    Abstract [en]

    The polymorphic beta-amyloid lesions present in individuals with Alzheimers disease are collectively known as cerebral beta-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop beta-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and A beta 40/A beta 42 peptide ratio. To determine the nature of such beta-amyloid morphotypes, beta-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally injected into the hippocampus of young APP23 or APPPS1 transgenic mice. APPPS1 brain extract injected into young APP23 mice induced beta-amyloid deposition with the morphological, conformational, and A beta 40/A beta 42 ratio characteristics of beta-amyloid deposits in aged APPPS1 mice, whereas APP23 brain extract injected into young APP23 mice induced b-amyloid deposits with the characteristics of beta-amyloid deposits in aged APP23 mice. Injecting the two extracts into the APPPS1 host revealed a similar difference between the induced beta-amyloid deposits, although less prominent, and the induced deposits were similar to the beta-amyloid deposits found in aged APPPS1 hosts. These results indicate that the molecular composition and conformation of aggregated A beta in APP transgenic mice can be maintained by seeded conversion.

  • 141.
    Helander, Sara
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Structural biology of transcriptional regulation in the c-Myc network2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The oncogene c-­‐Myc is overexpressed in many types of human cancers and regulation of c-­‐Myc expression is crucial in a normal cell. The intrinsically disordered N-­‐terminal transactivation domain interacts with a wide range of proteins regulating c-­‐Myc activity. The highly conserved Myc box I region includes residues Thr58 and Ser62, which are involved in the phosphorylation events that control c-­‐Myc degradation by ubiquitination. Aggressive cell growth, leading to tumor formation, occurs if activated c-­‐ Myc is not degraded by ubiquitination. Such events may be triggered by defects in the regulated network of interactions involving Pin1 and phospho-­‐dependent kinases.

    In this thesis, the properties of the intrinsically disordered unphosphorylated c-­‐Myc1-­‐88 and its interaction with Bin1 are studied by nuclear magnetic resonance (NMR) spectroscopy and surface plasmon resonance (SPR). Furthermore, the interaction of Myc1-­‐88 with Pin1 is analyzed in molecular detail, both for unphosphorylated and Ser62 phosphorylated c-­‐Myc1-­‐88, providing a first molecular description of a disordered but specific c-­‐Myc complex. A detailed analysis of the dynamics and structural properties of the transcriptional activator TAF in complex with TBP, both by NMR spectroscopy and crystallography, provides insight into transcriptional regulation and how c-­‐Myc could interact with TBP. Finally, the structure of a novel N-­‐terminal domain motif in FKBP25, which we name the Basic Tilted Helix Bundle (BTHB) domain, and its binding to YY1, which also binds c-­‐Myc, is described. By investigating the structural and dynamic properties of c-­‐Myc and c-­‐Myc-­‐interacting proteins, this thesis thus provides further insight to the molecular basis for c-­‐Myc functionality in transcriptional regulation.

    List of papers
    1. Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding
    Open this publication in new window or tab >>Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding
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    2012 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, no 13, p. 6353-6366Article in journal (Refereed) Published
    Abstract [en]

    The crucial role of Myc as an oncoprotein and as a key regulator of cell growth makes it essential to understand the molecular basis of Myc function. The N-terminal region of c-Myc coordinates a wealth of protein interactions involved in transformation, differentiation and apoptosis. We have characterized in detail the intrinsically disordered properties of Myc-1-88, where hierarchical phosphorylation of S62 and T58 regulates activation and destruction of the Myc protein. By nuclear magnetic resonance (NMR) chemical shift analysis, relaxation measurements and NOE analysis, we show that although Myc occupies a very heterogeneous conformational space, we find transiently structured regions in residues 22-33 and in the Myc homology box I (MBI; residues 45-65); both these regions are conserved in other members of the Myc family. Binding of Bin1 to Myc-1-88 as assayed by NMR and surface plasmon resonance (SPR) revealed primary binding to the S62 region in a dynamically disordered and multivalent complex, accompanied by population shifts leading to altered intramolecular conformational dynamics. These findings expand the increasingly recognized concept of intrinsically disordered regions mediating transient interactions to Myc, a key transcriptional regulator of major medical importance, and have important implications for further understanding its multifaceted role in gene regulation.

    Place, publisher, year, edition, pages
    Oxford University Press (OUP): Policy C / Oxford University Press, 2012
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-82076 (URN)10.1093/nar/gks263 (DOI)000306970700051 ()
    Note

    Funding Agencies|VINNOVA||CIHR||Swedish Research Council||Swedish Cancer Foundation||Swedish Child Cancer Foundation||Canadian Cancer Society||Ontario Research Fund|GL2-01-030|NIH Protein Structure Initiative grant|U54 GM094597|Canada Research Chairs Program||Swedish NMR Centre||Knut and Alice Wallenberg Foundation||Linkoping University||

    Available from: 2012-09-28 Created: 2012-09-28 Last updated: 2017-12-07
    2. High-resolution structure of TBP with TAF1 reveals anchoring patterns in transcriptional regulation
    Open this publication in new window or tab >>High-resolution structure of TBP with TAF1 reveals anchoring patterns in transcriptional regulation
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    2013 (English)In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 20, no 8, p. 1008-+Article in journal (Refereed) Published
    Abstract [en]

    The general transcription factor TFIID provides a regulatory platform for transcription initiation. Here we present the crystal structure (1.97 angstrom) and NMR analysis of yeast TAF1 N-terminal domains TAND1 and TAND2 bound to yeast TBP, together with mutational data. We find that yeast TAF1-TAND1, which in itself acts as a transcriptional activator, binds TBPs concave DNA-binding surface by presenting similar anchor residues to TBP as does Mot1 but from a distinct structural scaffold. Furthermore, we show how TAF1-TAND2 uses an aromatic and acidic anchoring pattern to bind a conserved TBP surface groove traversing the basic helix region, and we find highly similar TBP-binding motifs also presented by the structurally distinct TFIIA, Mot1 and Brf1 proteins. Our identification of these anchoring patterns, which can be easily disrupted or enhanced, provides insight into the competitive multiprotein TBP interplay critical to transcriptional regulation.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA, 2013
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-96977 (URN)10.1038/nsmb.2611 (DOI)000322715300016 ()
    Note

    Funding Agencies|Swedish Research Council|621-2011-6028621-2012-5250621-2012-5136|VINNOVA|P32045-1|Swedish Cancer Foundation|11 0681|Swedish Child Cancer Foundation|PROJ09/092|Forum Scientium Award||Canadian Institutes for Health Research|MT-13611|Japan Society for the Promotion of Science|23370077|Knut and Alice Wallenberg foundation||Canada Research Chair||

    Available from: 2013-09-05 Created: 2013-09-02 Last updated: 2017-12-06
    3. Basic Tilted Helix Bundle - A new protein fold in human FKBP25/FKBP3 and HectD1
    Open this publication in new window or tab >>Basic Tilted Helix Bundle - A new protein fold in human FKBP25/FKBP3 and HectD1
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    2014 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 447, no 1, p. 26-31Article in journal (Refereed) Published
    Abstract [en]

    In this paper, we describe the structure of a N-terminal domain motif in nuclear-localized FKBP251-73, a member of the FKBP family, together with the structure of a sequence-related subdomain of the E3 ubiquitin ligase HectD1 that we show belongs to the same fold. This motif adopts a compact 5-helix bundle which we name the Basic Tilted Helix Bundle (BTHB) domain. A positively charged surface patch, structurally centered around the tilted helix H4, is present in both FKBP25 and HectD1 and is conserved in both proteins, suggesting a conserved functional role. We provide detailed comparative analysis of the structures of the two proteins and their sequence similarities, and analysis of the interaction of the proposed FKBP25 binding protein YY1. We suggest that the basic motif in BTHB is involved in the observed DNA binding of FKBP25, and that the function of this domain can be affected by regulatory YY1 binding and/or interactions with adjacent domains.

    Place, publisher, year, edition, pages
    Elsevier, 2014
    National Category
    Chemical Sciences Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-106183 (URN)10.1016/j.bbrc.2014.03.068 (DOI)000335806700005 ()24667607 (PubMedID)
    Available from: 2014-04-28 Created: 2014-04-28 Last updated: 2017-12-05Bibliographically approved
    4. Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity
    Open this publication in new window or tab >>Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity
    Show others...
    2015 (English)In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 23, no 12, p. 2267-2279Article in journal (Refereed) Published
    Abstract [en]

    Hierarchic phosphorylation and concomitant Pin1-mediated proline isomerization of the oncoprotein c-Myc controls its cellular stability and activity. However, the molecular basis for Pin1 recognition and catalysis of c-Myc and other multisite, disordered substrates in cell regulation and disease is unclear. By nuclear magnetic resonance, surface plasmon resonance, and molecular modeling, we show that Pin1 subdomains jointly pre-anchor unphosphorylated c-Myc1–88 in the Pin1 interdomain cleft in a disordered, or “fuzzy”, complex at the herein named Myc Box 0 (MB0) conserved region N-terminal to the highly conserved Myc Box I (MBI). Ser62 phosphorylation in MBI intensifies previously transient MBI-Pin1 interactions in c-Myc1–88 binding, and increasingly engages Pin1PPIase and its catalytic region with maintained MB0 interactions. In cellular assays, MB0 mutated c-Myc shows decreased Pin1 interaction, increased protein half-life, but lowered rates of Myc-driven transcription and cell proliferation. We propose that dynamic Pin1 recognition of MB0 contributes to the regulation of c-Myc activity in cells

    Place, publisher, year, edition, pages
    Cell Press, 2015
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-106184 (URN)10.1016/j.str.2015.10.010 (DOI)
    Note

    The previous status of this article was Manuscript and the original title was Pre-anchoring of Pin1 to unphosphorylated c-Myc in a dynamic complex affects c-Myc stability andactivity.

    Funding Agencies|Knut and Alice Wallenberg Foundation; Swedish Cancer Foundation; Swedish Child Cancer Foundation; Carl Trygger foundation; LiU Cancer Research Network; Swedish Research Council; NCI [R01s CA129040, CA100855]

    Available from: 2014-04-28 Created: 2014-04-28 Last updated: 2018-05-06Bibliographically approved
  • 142.
    Helander, Sara
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Montecchio, Meri
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Lemak, Alexander
    Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Canada.
    Farès, Christophe
    Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Canada.
    Almlöf, Jonas
    Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Sweden.
    Li, Yanjun
    Structural Genomics Consortium, University of Toronto, Canada.
    Yee, Adelinda
    Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Canada.
    Arrowsmith, Cheryl H
    Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Canada.
    Dhe-Paganon, Sirano
    Structural Genomics Consortium, University of Toronto, Canada.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Basic Tilted Helix Bundle - A new protein fold in human FKBP25/FKBP3 and HectD12014In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 447, no 1, p. 26-31Article in journal (Refereed)
    Abstract [en]

    In this paper, we describe the structure of a N-terminal domain motif in nuclear-localized FKBP251-73, a member of the FKBP family, together with the structure of a sequence-related subdomain of the E3 ubiquitin ligase HectD1 that we show belongs to the same fold. This motif adopts a compact 5-helix bundle which we name the Basic Tilted Helix Bundle (BTHB) domain. A positively charged surface patch, structurally centered around the tilted helix H4, is present in both FKBP25 and HectD1 and is conserved in both proteins, suggesting a conserved functional role. We provide detailed comparative analysis of the structures of the two proteins and their sequence similarities, and analysis of the interaction of the proposed FKBP25 binding protein YY1. We suggest that the basic motif in BTHB is involved in the observed DNA binding of FKBP25, and that the function of this domain can be affected by regulatory YY1 binding and/or interactions with adjacent domains.

  • 143.
    Helander, Sara
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Montecchio, Meri
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Pilstål, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Su, Yulong
    Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
    Kuruvilla, Jacob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Sweden.
    Johansson, Malin
    Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Sweden.
    Mohammed, Javed
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Lundström, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Sears, Rosalie
    Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
    Wallner, Björn
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Department of Social and Welfare Studies, Learning, Aesthetics, Natural science. Linköping University, Faculty of Educational Sciences. Linköping University, Faculty of Science & Engineering.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity2015In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 23, no 12, p. 2267-2279Article in journal (Refereed)
    Abstract [en]

    Hierarchic phosphorylation and concomitant Pin1-mediated proline isomerization of the oncoprotein c-Myc controls its cellular stability and activity. However, the molecular basis for Pin1 recognition and catalysis of c-Myc and other multisite, disordered substrates in cell regulation and disease is unclear. By nuclear magnetic resonance, surface plasmon resonance, and molecular modeling, we show that Pin1 subdomains jointly pre-anchor unphosphorylated c-Myc1–88 in the Pin1 interdomain cleft in a disordered, or “fuzzy”, complex at the herein named Myc Box 0 (MB0) conserved region N-terminal to the highly conserved Myc Box I (MBI). Ser62 phosphorylation in MBI intensifies previously transient MBI-Pin1 interactions in c-Myc1–88 binding, and increasingly engages Pin1PPIase and its catalytic region with maintained MB0 interactions. In cellular assays, MB0 mutated c-Myc shows decreased Pin1 interaction, increased protein half-life, but lowered rates of Myc-driven transcription and cell proliferation. We propose that dynamic Pin1 recognition of MB0 contributes to the regulation of c-Myc activity in cells

  • 144.
    Helmfors, Linda
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Armstrong, Andrea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Civitelli, Livia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sandin, Linnea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Zetterberg, Henrik
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Garner, Brett
    Illawarra Health and Medical Research Institute University of Wollongong, Australia.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    A protective role of lysozyme in Alzheimer diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Alzheimer disease (AD) is a devastating neurodegenerative disorder where extracellular plaques composed of amyloid β (Aβ) peptides and neuroinflammation are some of the main hallmarks of the disease. Activated microglial cells, which are the resident macrophages in the central nervous system, are suggested to trigger the inflammation response in AD. To discover neuroinflammation biomarkers would be important to reveal the pathological mechanisms of AD and develop therapies that target inflammation mediators. Lysozyme is part of the innate immune system and is secreted from macrophages during various inflammation conditions. However, the involvement of lysozyme in AD pathology has not been explored previously. We have discovered that lysozyme is up-regulated in cerebrospinal fluid from AD patients. Cells exposed to Aβ increased the expression of lysozyme indicating that Aβ might be responsible for the upregulation of lysozyme detected in cerebrospinal fluid. In vitro studies revealed that lysozyme binds to monomeric Aβ1-42 and alters the aggregation pathway counteracting formation of toxic Aβ species. In a newly developed Drosophila model, co-expression of lysozyme with Aβ in brain neurons reduced the formation of insoluble Aβ species, prolonged the survival and improved the activity of the double transgenic flies compared to flies only expressing Aβ. Our findings identify lysozyme as a modulator of Aβ aggregation and toxicity and our discoveries has the potential to be used for development of new treatment strategies and to use lysozyme as a biomarker for AD.

  • 145.
    Helmfors, Linda
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Bergkvist, Liza
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    SAP to the rescue: Serum amyloid p component ameliorates neurological damage caused by expressing a lysozyme variant in the central nervous system of Drosophila melanogasterManuscript (preprint) (Other academic)
    Abstract [en]

    Lysozyme amyloidosis is a hereditary disease in which mutations in the gene encoding lysozyme leads to misfolding and consequently accumulation of amyloid material. To improve understanding of the processes involved we expressed human wild type (WT) lysozyme and the disease-associated variant F57I in the central nervous system (CNS) of a Drosophila melanogaster model of lysozyme amyloidosis, with and without serum amyloid p component (SAP). We found that flies expressing the amyloidogenic variant F57I in the CNS have a shorter lifespan and lower locomotor activity than flies expressing WT lysozyme or control flies, indicating that the flies’ neurological functions are impaired when F57I is expressed in the nerve cells. In addition, the Unfolded Protein Response (UPR) was upregulated in the F57I-expressing flies. However, co-expression of SAP in the CNS restored the F57I flies’ locomotor activity and lifespan. Thus, SAP has apparent ability to protect nerve cells from damage caused by F57I. Furthermore, co-expression of SAP prevented accumulation of insoluble forms of lysozyme in both WT- and F57I-expressing flies and delayed up-regulation of the UPR by 10 days in F57I flies. Our findings suggest that SAP can prevent cytotoxic effects of expressing F57I in fly CNS by retaining F57I in a soluble form and preventing crowding of misfolded F57I species in the endoplasmic reticulum.

  • 146.
    Helmfors, Linda
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bergkvist, Liza
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Serum Amyloid P Component Ameliorates Neurological Damage Caused by Expressing a Lysozyme Variant in the Central Nervous System of Drosophila melanogaster2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, p. e0159294-Article in journal (Refereed)
    Abstract [en]

    Lysozyme amyloidosis is a hereditary disease in which mutations in the gene coding for lysozyme leads to misfolding and consequently accumulation of amyloid material. To improve understanding of the processes involved we expressed human wild type (WT) lysozyme and the disease-associated variant F57I in the central nervous system (CNS) of a Drosophila melanogaster model of lysozyme amyloidosis, with and without co-expression of serum amyloid p component (SAP). SAP is known to be a universal constituent of amyloid deposits and to associate with lysozyme fibrils. There are clear indications that SAP may play an important role in lysozyme amyloidosis, which requires further elucidation. We found that flies expressing the amyloidogenic variant F57I in the CNS have a shorter lifespan than flies expressing WT lysozyme. We also identified apoptotic cells in the brains of F57I flies demonstrating that the flies neurological functions are impaired when F57I is expressed in the nerve cells. However, co-expression of SAP in the CNS prevented cell death and restored the F57I flies lifespan. Thus, SAP has the apparent ability to protect nerve cells from damage caused by F57I. Furthermore, it was found that co-expression of SAP prevented accumulation of insoluble forms of lysozyme in both WT- and F57I-expressing flies. Our findings suggest that the F57I mutation affects the aggregation process of lysozyme resulting in the formation of cytotoxic species and that SAP is able to prevent cell death in the F57I flies by preventing accumulation of toxic F57I structures.

  • 147.
    Hennig, Janosch
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology. Helmholtz Zentrum Munchen GmbH, Germany; Technical University of Munich, Germany.
    Andrésen, Cecilia
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Museth, Anna Katrine
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology. CALTECH, CA 91125 USA.
    Lundström, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Tibell, Lena
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Local Destabilization of the Metal-Binding Region in Human Copper-Zinc Superoxide Dismutase by Remote Mutations Is a Possible Determinant for Progression of ALS2015In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 54, no 2, p. 323-333Article in journal (Refereed)
    Abstract [en]

    More than 100 distinct mutations in the gene CuZnSOD encoding human copper-zinc superoxide dismutase (CuZnSOD) have been associated with familial amyotrophic lateral sclerosis (fALS), a fatal neuronal disease. Many studies of different mutant proteins have found effects on protein stability, catalytic activity, and metal binding, but without a common pattern. Notably, these studies were often performed under conditions far from physiological. Here, we have used experimental conditions of pH 7 and 37 degrees C and at an ionic strength of 0.2 M to mimic physiological conditions as close as possible in a sample of pure protein. Thus, by using NMR spectroscopy, we have analyzed amide hydrogen exchange of the fALS-associated I113T CuZnSOD variant in its fully metalated state, both at 25 and 37 degrees C, where (15)N relaxation data, as expected, reveals that CuZnSOD I113T exists as a dimer under these conditions. The local dynamics at 82% of all residues have been analyzed in detail. When compared to the wild-type protein, it was found that I113T CuZnSOD is particularly destabilized locally at the ion binding sites of loop 4, the zinc binding loop, which results in frequent exposure of the aggregation prone outer beta-strands I and VI of the beta-barrel, possibly enabling fibril or aggregate formation. A similar study (Museth, A. K., et al. (2009) Biochemistry, 48, 8817-8829) of amide hydrogen exchange at pH 7 and 25 degrees C on the G93A variant also revealed a selective destabilization of the zinc binding loop. Thus, a possible scenario in ALS is that elevated local dynamics at the metal binding region can result in toxic species from formation of new interactions at local beta-strands.

  • 148.
    Hennig, Janosch
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    de Vries, Sjoerd J
    Utrecht University and Technical University München.
    Hennig, Klaus DM
    Gabriele-von-Bülow Gymnasium, Berlin, Germany .
    Randles, Leah
    University of Minnesota.
    Walters, Kylie J.
    University of Minnesota.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Alexandre, Alexandre MJJ
    Utrecht University.
    MTMDAT-HADDOCK: high-throughput, protein complex structure modeling based on limited proteolysis and mass spectrometry2012In: BMC Structural Biology, ISSN 1472-6807, E-ISSN 1472-6807, Vol. 12, no 29Article in journal (Refereed)
    Abstract [en]

    Background

    MTMDAT is a program designed to facilitate analysis of mass spectrometry data of proteins and biomolecular complexes that are probed structurally by limited proteolysis. This approach can provide information about stable fragments of multidomain proteins, yield tertiary and quaternary structure data, and help determine the origin of stability changes at the amino acid residue level. Here, we introduce a pipeline between MTMDAT and HADDOCK, that facilitates protein-protein complex structure probing in a high-throughput and highly automated fashion.

    Results

    A new feature of MTMDAT allows for the direct identification of residues that are involved in complex formation by comparing the mass spectra of bound and unbound proteins after proteolysis. If 3D structures of the unbound components are available, this data can be used to define restraints for data-driven docking to calculate a model of the complex. We describe here a new implementation of MTMDAT, which includes a pipeline to the data-driven docking program HADDOCK, thus streamlining the entire procedure. This addition, together with usability improvements in MTMDAT, enables high-throughput modeling of protein complexes from mass spectrometry data. The algorithm has been validated by using the protein-protein interaction between the ubiquitin-binding domain of proteasome component Rpn13 and ubiquitin. The resulting structural model, based on restraints extracted by MTMDAT from limited proteolysis and modeled by HADDOCK, was compared to the published NMR structure, which relied on twelve unambiguous intermolecular NOE interactions. The MTMDAT-HADDOCK structure was of similar quality to structures generated using only chemical shift perturbation data derived by NMR titration experiments.

    Conclusions

    The new MTMDAT-HADDOCK pipeline enables direct high-throughput modeling of protein complexes from mass spectrometry data. MTMDAT-HADDOCK can be downloaded from http://www.ifm.liu.se/chemistry/molbiotech/maria_sunnerhagens_group/mtmdat/webcitetogether with the manual and example files. The program is free for academic/non-commercial purposes.

  • 149.
    Herrmann, Uli S.
    et al.
    University of Zurich Hospital, Switzerland.
    Schuetz, Anne K.
    ETH, Switzerland.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Huang, Danzhi
    University of Zurich, Switzerland.
    Saban, Dino
    University of Zurich Hospital, Switzerland.
    Nuvolone, Mario
    University of Zurich Hospital, Switzerland.
    Li, Bei
    University of Zurich Hospital, Switzerland.
    Ballmer, Boris
    University of Zurich Hospital, Switzerland.
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Mason, Jeffrey
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Rushing, Elisabeth
    University of Zurich Hospital, Switzerland.
    Budka, Herbert
    University of Zurich Hospital, Switzerland.
    Nyström, Sofie
    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.
    Boeckmann, Anja
    University of Lyon 1, France.
    Caflisch, Amedeo
    University of Zurich, Switzerland.
    Meier, Beat H.
    ETH, Switzerland.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hornemann, Simone
    University of Zurich Hospital, Switzerland.
    Aguzzi, Adriano
    University of Zurich Hospital, Switzerland.
    Structure-based drug design identifies polythiophenes as antiprion compounds2015In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 299, p. 299ra123-Article in journal (Refereed)
    Abstract [en]

    Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrPSc, a misfolded and aggregated form of the cellular prion protein (PrPC). We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions. These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding. The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by greater than80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease.

  • 150.
    Hild Walett, Oliver
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Berlin, Emmanuel
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Johan
    Arvidsson, Sofie
    Fors, Filip
    Gavelius, Marianne
    Genander, Filip
    Granqvist, Johanna
    Lifwergren, Philip
    Sandéhn, Alexandra
    Viksten, Martin
    Wenhov, Irma
    Investigating the function of GroES with hard-to-fold proteins in vivo2019Student paper other, 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The use of molecular chaperones can increase the yield of correctly folded proteins. This is especially needed in the expression of proteins non-native to the host organism. This study set out to investigate the function of the chaperone GroES; a component in the GroE-system. The function of this chaperone has only been studied alone in vitro. Here we lay ground to further studies on GroES and its ability to act alone in vivo. GroES was expressed from a plasmid and characterized through its potential to increase the amount of correctly folded proteins. Characterization was mainly done by fluorescence spectroscopy with hard-to-fold proteins linked to fluorescent probes. Results show a very clear increase in fluorescence for most of the substrate proteins tested, indicating that GroES has a significant role in the GroE-system and perhaps outside of it.

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