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  • 1.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala university, Sweden.
    Fromell, Karin
    Uppsala university, Sweden.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Teramura, Yuji
    Uppsala university, Sweden;Univ Tokyo, Japan.
    Nilsson, Bo
    Uppsala university, Sweden.
    A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity2019In: Science and Technology of Advanced Materials, ISSN 1468-6996, E-ISSN 1878-5514, Vol. 20, no 1, p. 688-698Article, review/survey (Refereed)
    Abstract [en]

    In this review article, we focus on activation of the soluble components of the innate immune system triggered by nonbiological compounds and stress variances in activation due to the difference in size between nanoparticles (NPs) and larger particles or bulk material of the same chemical and physical composition. We then discuss the impact of the so-called protein corona which is formed on the surface of NPs when they come in contact with blood or other body fluids. For example, NPs which bind inert proteins, proteins which are prone to activate the contact system (e.g., factor XII), which may lead to clotting and fibrin formation or the complement system (e.g., IgG or C3), which may result in inflammation and vascular damage. Furthermore, we describe a whole blood model which we have developed to monitor activation and interaction between different components of innate immunity: blood protein cascade systems, platelets, leukocytes, cytokine generation, which are induced by NPs. Finally, we describe our own studies on innate immunity system activation induced by three fundamentally different species of NPs (two types of engineered NPs and diesel NPs) as demonstrator of the utility of an initial determination of the composition of the protein corona formed on NPs exposed to ethylenediaminetetraacetic acid (EDTA) plasma and subsequent analysis in our whole blood model. [GRAPHICS] .

  • 2.
    Todde, Guido
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Activation and Inactivation of the FLT3 Kinase: Pathway Intermediates and the Free Energy of Transition2019In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 123, no 26, p. 5385-5394Article in journal (Refereed)
    Abstract [en]

    The aberrant expression of kinases is often associated with pathologies such as cancer and autoimmune diseases. Like other types of enzymes, kinases can adopt active and inactive states, where a shift toward more stable active state often leads to disease. Dozens of kinase inhibitors are, therefore, used as drugs. Most of these bind to either the inactive or active state. In this work, we study the transitions between these two states in FLT3, an important drug target in leukemias. Kinases are composed of two lobes (N- and C-terminal lobes) with the catalytic site in-between. Through projection of the largest motions obtained through molecular dynamics (MD) simulations, we show that each of the end-states (active or inactive) already possess the ability for transition as the two lobes rotate which initiates the transition. A targeted simulation approach known as essential dynamics sampling (EDS) was used to speed up the transition between the two protein states. Coupling the EDS to implicit-solvent MD was performed to estimate the free energy barriers of the transitions. The activation energies were found in good agreement with previous estimates obtained for other kinases. Finally, we identified FLT3 intermediates that assumed configurations that resemble that of the c-Src nonreceptor tyrosine kinase. The intermediates show better binding to the drug ponatinib than c-Src and the inactive state of FLT3. This suggests that targeting intermediate states can be used to explain the drug-binding patterns of kinases and for rational drug design.

  • 3.
    Johansson, Ulrika
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. KTH Royal Instute of Technology, Sweden;Uppsala University, Sweden.
    Widhe, Mona
    KTH Royal Instute of Technology, Sweden.
    Shalaly, Nancy Dekki
    KTH Royal Instute of Technology, Sweden.
    Arregui, Irene Linares
    KTH Royal Instute of Technology, Sweden.
    Nileback, Linnea
    KTH Royal Instute of Technology, Sweden.
    Tasiopoulos, Christos Panagiotis
    KTH Royal Instute of Technology, Sweden.
    Åstrand, Carolina
    KTH Royal Instute of Technology, Sweden.
    Berggren, Per-Olof
    Karolinska Institutet, Sweden;Karolinska University Hospital, Sweden.
    Gasser, Christian
    KTH Royal Instute of Technology, Sweden.
    Hedhammar, My
    KTH Royal Instute of Technology, Sweden.
    Assembly of functionalized silk together with cells to obtain proliferative 3D cultures integrated in a network of ECM-like microfibers2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, p. 1-13, article id 6291Article in journal (Refereed)
    Abstract [en]

    Tissues are built of cells integrated in an extracellular matrix (ECM) which provides a three-dimensional (3D) microfiber network with specific sites for cell anchorage. By genetic engineering, motifs from the ECM can be functionally fused to recombinant silk proteins. Such a silk protein, FN-silk, which harbours a motif from fibronectin, has the ability to self-assemble into networks of microfibers under physiological-like conditions. Herein we describe a method by which mammalian cells are added to the silk solution before assembly, and thereby get uniformly integrated between the formed microfibers. In the resulting 3D scaffold, the cells are highly proliferative and spread out more efficiently than when encapsulated in a hydrogel. Elongated cells containing filamentous actin and defined focal adhesion points confirm proper cell attachment to the FN-silk. The cells remain viable in culture for at least 90 days. The method is also scalable to macro-sized 3D cultures. Silk microfibers formed in a bundle with integrated cells are both strong and extendable, with mechanical properties similar to that of artery walls. The described method enables differentiation of stem cells in 3D as well as facile co-culture of several different cell types. We show that inclusion of endothelial cells leads to the formation of vessel-like structures throughout the tissue constructs. Hence, silk-assembly in presence of cells constitutes a viable option for 3D culture of cells integrated in a ECM-like network, with potential as base for engineering of functional tissue.

  • 4.
    Zhao, Fei
    et al.
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Afonso, Sara
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Lindner, Susanne
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Hartmann, Andrea
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Loeschmann, Ina
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Nilsson, Bo
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linneaus Ctr Bomat Chem, Kalmar, Sweden..
    Weber, Lutz T.
    Univ Hosp Cologne, Germany.
    Habbig, Sandra
    Univ Hosp Cologne, Germany.
    Schalk, Gesa
    Univ Hosp Cologne, Germany.
    Kirschfink, Michael
    Heidelberg Univ, Germany.
    Zipfel, Peter F.
    Leibniz Inst Nat Prod Res & Infect Biol, Germany;Friedrich Schiller Univ Jena, Germany.
    Skerka, Christine
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    C3-Glomerulopathy Autoantibodies Mediate Distinct Effects on Complement C3-and C5-Convertases2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, p. 1-14, article id 1030Article in journal (Refereed)
    Abstract [en]

    C3 glomerulopathy (C3G) is a severe kidney disease, which is caused by defective regulation of the alternative complement pathway. Disease pathogenesis is heterogeneous and is caused by both autoimmune and genetic factors. Here we characterized IgG autoantibodies derived from 33 patients with autoimmune C3 glomerulopathy. Serum antibodies from all 33 patients as well as purified IgGs bound to the in vitro assembled C3-convertase. Noteworthy, two groups of antibodies were identified: group 1 with strong (12 patients) and group 2 with weak binding C3-convertase autoantibodies (22 patients). C3Nef, as evaluated in a standard C3Nef assay, was identified in serum from 19 patients, which included patients from group 1 as well as group 2. The C3-convertase binding profile was independent of C3Nef. Group 1 antibodies, but not the group 2 antibodies stabilized the C3-convertase, and protected the enzyme from dissociation by Factor H. Also, only group 1 antibodies induced C3a release. However, both group 1 and group 2 autoantibodies bound to the C5-convertase and induced C5a generation, which was inhibited by monoclonal anti-C5 antibody Eculizumab in vitro. In summary, group 1 antibodies are composed of C3Nef and C5Nef antibodies and likely over-activate the complement system, as seen in hemolytic assays. Group 2 antibodies show predominantly C5Nef like activities and stabilize the C5 but not the C3-convertase. Altogether, these different profiles not only reveal a heterogeneity of the autoimmune forms of C3G (MPGN), they also show that in diagnosis of C3G not all autoimmune forms are identified and thus more vigorous autoantibody testing should be performed.

  • 5.
    Todde, Guido
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Conformational modifications induced by internal tandem duplications on the FLT3 kinase and juxtamembrane domains2019In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 21, p. 18467-18476Article in journal (Refereed)
  • 6.
    Kathiravan, Suppan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Suriyanarayanan, Subramanian
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Electrooxidative Amination of sp2 C–H Bonds: Coupling of Amines with Aryl Amides via Copper Catalysis2019In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 21, no 7, p. 1968-1972Article in journal (Refereed)
    Abstract [en]

    Metal-catalyzed cross-coupling reactions are among the most important transformations in organic synthesis. However, the use of C−H activation for sp2 C−N bond formation remains one of the major challenges in the field of crosscoupling chemistry. Described herein is the first example of the synergistic combination of copper catalysis and electrocatalysis for aryl C−H amination under mild reaction conditions in an atom-and step-economical manner with the liberation of H2 as the sole and benign byproduct.

  • 7.
    Sandholm, Kerstin
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Persson, Barbro
    Uppsala University.
    Skattum, Lillemor
    Lund University.
    Eggertsen, Gösta
    Karolinska Institutet;Karolinska University Hospital.
    Nyman, Dag
    Aland Cent Hosp, Finland.
    Gunnarsson, Iva
    Karolinska Institutet;Karolinska University Hospital.
    Svenungson, Elisabet
    Karolinska Institutet;Karolinska University Hospital.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Evaluation of a Novel Immunoassay for Quantification of C1q for Clinical Diagnostic Use2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 7Article in journal (Refereed)
    Abstract [en]

    Objectives: C1q is a valuable biomarker of disease activity in systemic lupus erythematosus (SLE). The "gold standard" assay, rocket immunoelectrophoresis (RIE), is time-consuming, and thus a shift to soluble immune precipitation techniques such as nephelometry has occurred. However, quantification of C1q with these techniques has been questioned as a result of the antibody binding properties of C1q. In the present work, we have compared results using various techniques (RIE, nephelometry, and ELISA) and have developed and validated a new magnetic bead-based sandwich immunoassay (MBSI). Methods: C1q was quantified by nephelometry and the new sandwich immunoassay in 45 serum samples analyzed using RIE. C1q was also assessed in plasma using RIE and sandwich immunoassay in samples from SLE patients with nephritis (n = 69), SLE patients without nephritis (n = 310) as classified by BILAG score, and matched controls (n = 322). In addition, cerebrospinal fluid (CSF) samples from 31 patients, previously analyzed with ELISA, were also analyzed with the MBSI to test the behavior of this new assay in the lower detection range. Results: We found a strong correlation between the new MBSI, RIE, and ELISA, but not with nephelometry. The MBSI demonstrated lower levels of C1q in SLE patients than in matched controls (p < 0.0001), and patients with nephritis had lower levels than patients without nephritis (p < 0.01). Similarily, RIE showed significant differences between the patient groups (p < 0.0001). An association was also found between the levels of C1q and the SLE disease activity index (SLEDAI). Furthermore, there was good correlation between the values obtained by MBSI and ELISA, in both serum (r = 0.960) and CSF (r = 0.786), underscoring the ability of both techniques to measure low concentrations of C1q with high accuracy. Conclusion: The sandwich immunoassay correlated well with RIE, but soluble immune precipitation techniques, such as nephelometry, did not appear suitable alternatives, since C1q itself, and possibly anti-C1q antibodies, interfered with the measurements. The new sandwich immunoassay is therefore a good replacement for RIE in monitoring SLE disease activity.

  • 8.
    Gustafson, Elisabet
    et al.
    Uppsala Univ Hospital, Sweden.
    Hamad, Osama A.
    Uppsala University, Sweden.
    Deckmyn, Hans
    Katholieke Univ Leuven, Belgium.
    Barbu, Andreea
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Bo
    Uppsala University, Sweden.
    Exposure of von Willebrand Factor on Isolated Hepatocytes Promotes Tethering of Platelets to the Cell Surface2019In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 103, no 8, p. 1630-1638Article in journal (Refereed)
    Abstract [en]

    Background. Hepatocyte transplantation (Hctx) is a potentially attractive method for the treatment of acute liver failure and liver-based metabolic disorders. Unfortunately, the procedure is hampered by the instant blood-mediated inflammatory reaction (IBMIR), a thromboinflammatory response elicited by the vascular innate immune system, causing activation of the coagulation and complement systems and clearance of transplanted cells. Observations have also revealed platelets adhered to the surface of the hepatocytes (Hc). To establish Hctx as a clinical treatment, all factors that trigger IBMIR need to be identified and controlled. This work explores the expression of von Willebrand factor (VWF) on isolated Hc resulting in tethering of platelets. Methods. VWF on Hc was studied by flow cytometry, confocal microscopy, immunoblot, and real-time polymerase chain reaction. Interaction between Hc and platelets was studied in a Chandler loop model. Adhesion of platelets to the hepatocyte surface was demonstrated by flow cytometry and confocal microscopy. Results. Isolated Hc constitutively express VWF on their cell surface and mRNA for VWF was found in the cells. Hc and platelets, independently of coagulation formed complexes, were shown by antibody blocking studies to be dependent on hepatocyte-associated VWF and platelet-bound glycoprotein Ib alpha. Conclusions. VWF on isolated Hc causes, in contact with blood, adhesion of platelets, which thereby forms an ideal surface for coagulation. This phenomenon needs to be considered in hepatocyte-based reconstitution therapy and possibly even in other settings of cell transplantation.

  • 9.
    Mahajan, Rashmi
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rouhi, Mona
    Malmö University.
    Shinde, Sudhirkumar
    Malmö University.
    Bedwell, Thomas
    Univ Leicester, UK.
    Incel, Anil
    Malmö University.
    Mavliutova, Liliia
    Malmö University.
    Piletsky, Sergey
    Univ Leicester, UK.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sellergren, Börje
    Malmö University.
    Highly Efficient Synthesis and Assay of Protein-Imprinted Nanogels by Using Magnetic Templates2019In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 58, no 3, p. 727-730Article in journal (Refereed)
    Abstract [en]

    We report an approach integrating the synthesis of protein-imprinted nanogels ("plastic antibodies") with a highly sensitive assay employing templates attached to magnetic carriers. The enzymes trypsin and pepsin were immobilized on amino-functionalized solgel-coated magnetic nanoparticles (magNPs). Lightly crosslinked fluorescently doped polyacrylamide nanogels were subsequently produced by high-dilution polymerization of monomers in the presence of the magNPs. The nanogels were characterised by a novel competitive fluorescence assay employing identical protein-conjugated nanoparticles as ligands to reversibly immobilize the corresponding nanogels. Both nanogels exhibited K-d<10 pM for their respective target protein and low cross-reactivity with five reference proteins. This agrees with affinities reported for solid-phase-synthesized nanogels prepared using low-surface-area glass-bead supports. This approach simplifies the development and production of plastic antibodies and offers direct access to a practical bioassay.

  • 10.
    Noiri, Makoto
    et al.
    Univ Tokyo, Japan.
    Asawa, Kenta
    Univ Tokyo, Japan.
    Okada, Naoya
    Univ Tokyo, Japan.
    Kodama, Tomonobu
    Jikei Univ Hosp, Japan.
    Murayama, Yuichi
    Jikei Univ Hosp, Japan.
    Inoue, Yuuki
    Univ Tokyo, Japan.
    Ishihara, Kazuhiko
    Univ Tokyo, Japan.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Teramura, Yuji
    Univ Tokyo, Japan;Uppsala University, Sweden.
    Modification of human MSC surface with oligopeptide-PEG-lipids for selective binding to activated endothelium2019In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 107, no 8, p. 1779-1792Article in journal (Refereed)
    Abstract [en]

    Promising cell therapies using mesenchymal stem cells (MSCs) is proposed for stroke patients. Therefore, we aimed to efficiently accumulate human MSC (hMSC) to damaged brain area to improve the therapeutic effect using poly(ethylene glycol) (PEG)-conjugated phospholipid (PEG-lipid) carrying an oligopeptide as a ligand, specific for E-selectin which is upregulated on activated endothelial cells under hypoxia-like stroke. Here we synthesized E-selectin-binding oligopeptide (ES-bp) conjugated with PEG spacer having different molecular weights from 1 to 40 kDa. We found that ES-bp can be immobilized onto the hMSC surface through PEG-lipid without influence on cell growth and differentiation into adipocytes and osteocytes, respectively. It is also possible to control the immobilization of ES-bp on hMSC surface (<10(8) ES-bp per cell). Immobilized ES-bp can be continuously immobilized at the outside of cell membrane when PEG-lipids with PEG 5 and 40 kDa were used. In addition, the modified hMSC can specifically attach onto E-selectin-immobilized surface as a model surface of activated endothelium in human blood, indicating the sufficient number of immobilized ES-bp onto hMSC. Thus, this technique is one of the candidates for hMSC accumulation to cerebral infarction area. (c) 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1779-1792, 2019.

  • 11.
    Suriyanarayanan, Subramanian
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Olsson, Gustaf D.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Kathiravan, Suppan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Ndizeye, Natacha
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Non-Ionic Deep Eutectic Liquids: Acetamide-Urea Derived Room Temperature Solvents2019In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, no 12, article id 2857Article in journal (Refereed)
    Abstract [en]

    A family of non-ionic deep eutectic liquids has been developed based upon mixtures of solid N-alkyl derivatives of urea and acetamide that in some cases have melting points below room temperature. The eutectic behaviour and physical characteristics of a series of eleven eutectic mixtures are presented, along with a molecular dynamics study-supported hypothesis for the origin of the non-ideal mixing of these substances. Their use as solvents in applications ranging from natural product extraction to organic and polymer synthesis are demonstrated.

  • 12.
    Steinz, Maarten M.
    et al.
    Karolinska Institutet, Sweden.
    Persson, Malin
    McGill University, Canada.
    Aresh, Bejan
    Stockholm University, Sweden.
    Olsson, Karl
    Karolinska Institutet, Sweden.
    Cheng, Arthur J.
    Karolinska Institutet, Sweden.
    Ahlstrand, Emma
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lilja, Mats
    Karolinska Institutet, Sweden.
    Lundberg, Tommy R.
    Karolinska Institutet, Sweden.
    Rullman, Eric
    Karolinska Institutet, Sweden.
    Ängeby Möller, Kristina
    Karolinska Institutet, Sweden.
    Sandor, Katalin
    Karolinska Institutet, Sweden.
    Ajeganova, Sofia
    Karolinska Institutet, Sweden.
    Yamada, Takashi
    Sapporo Medical University, Japan.
    Beard, Nicole
    University of Canberra, Australia.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Tavi, Pasi
    Karolinska Institutet, Sweden; University of Eastern Finland, Finland.
    Kenne, Ellinor
    Karolinska Institutet, Sweden.
    Svensson, Camilla I.
    Karolinska Institutet, Sweden.
    Rassier, Dilson E.
    McGill University, Canada.
    Karlsson, Roger
    Stockholm University, Sweden.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Gustafsson, Thomas
    Karolinska Institutet, Sweden.
    Lanner, Johanna T.
    Karolinska Institutet, Sweden.
    Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis2019In: JCI Insight, ISSN 2324-7703, Vol. 4, no 9, p. 1-16, article id e126347Article in journal (Refereed)
    Abstract [en]

    Skeletal muscle weakness in patients suffering from rheumatoid arthritis (RA) adds to their impaired working abilities and reduced quality of life. However, little molecular insight is available on muscle weakness associated with RA. Oxidative stress has been implicated in the disease pathogenesis of RA. Here we show that oxidative post-translational modifications of the contractile machinery targeted to actin result in impaired actin polymerization and reduced force production. Using mass spectrometry, we identified the actin residues targeted by oxidative 3-nitrotyrosine (3-NT) or malondialdehyde adduct (MDA) modifications in weakened skeletal muscle from mice with arthritis and patients afflicted by RA. The residues were primarily located to three distinct regions positioned at matching surface areas of the skeletal muscle actin molecule from arthritis mice and RA patients. Moreover, molecular dynamic simulations revealed that these areas, here coined “hotspots”, are important for the stability of the actin molecule and its capacity to generate filaments and interact with myosin. Together, these data demonstrate how oxidative modifications on actin promote muscle weakness in RA patients and provide novel leads for targeted therapeutic treatment to improve muscle function.

  • 13.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Simulations of Biomolecules in Electrolyte Solutions2019In: Advanced Theory and Simulations, E-ISSN 2513-0390, Vol. 2, no 4, p. 1-10, article id 1800163Article in journal (Refereed)
    Abstract [en]

    Biomolecules including proteins, lipid membranes, and nucleic acids operate at an aqueous milieu that includes solvated ions. The interactions with ions affect biomolecules in different ways depending on the nature of the solute and the type of the ions. The dynamic nature of small soluble ions makes it difficult to follow them by structural methods. Consequently, theories were developed to explain how biomolecules interact in an environment that includes electrolytes. Moreover, simulations studies are often used to study such systems at the molecular or atomistic level. The status of the field, and inparticular of simulation studies, is the subject of this progress report.

  • 14.
    Lindström, Jonathan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    de Wijn, Astrid S.
    Norwegian University of Science and Technology, Norway.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Stochastic modelling of tyrosine kinase inhibitor rotation therapy in chronic myeloid leukaemia2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, p. 1-13, article id 508Article in journal (Refereed)
    Abstract [en]

    BackgroundResistance towards targeted cancer treatments caused by single nucleotide variations is a major issue in many malignancies. Currently, there are a number of available drugs for chronic myeloid leukaemia (CML), which are overcome by different sets of mutations. The main aim of this study was to explore if it can be possible to exploit this and create a treatment protocol that outperforms each drug on its own.MethodsWe present a computer program to test different treatment protocols against CML, based on available resistance mutation growth data. The evolution of a relatively stable pool of cancer stem cells is modelled as a stochastic process, with the growth of cells expressing a tumourigenic protein (here, Abl1) and any emerging mutants determined principally by the drugs used in the therapy.ResultsThere can be some benefit to Bosutinib-Ponatinib rotation therapy even if the mutation status is unknown, whereas Imatinib-Nilotinib rotation is unlikely to improve the outcomes. Furthermore, an interplay between growth inhibition and selection effects generates a non-linear relationship between drug doses and the risk of developing resistance.ConclusionsDrug rotation therapy might be able to delay the onset of resistance in CML patients without costly ongoing observation of mutation status. Moreover, the simulations give credence to the suggestion that lower drug concentrations may achieve better results following major molecular response in CML.

  • 15.
    Georgoulia, Panagiota S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Todde, Guido
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Bjelic, Sinisa
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The catalytic activity of Abl1 single and compound mutations: Implications for the mechanism of drug resistance mutations in chronic myeloid leukaemia2019In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1863, no 4, p. 732-741Article in journal (Refereed)
    Abstract [en]

    Background

    Abl1 is a protein tyrosine kinase whose aberrant activation due to mutations is the culprit of several cancers, most notably chronic myeloid leukaemia. Several Abl1 inhibitors are used as anti-cancer drugs. Unfortunately, drug resistance limits their effectiveness. The main cause for drug resistance is mutations in the kinase domain (KD) of Abl1 that evolve in patients. The T315I mutation confers resistance against all clinically-available inhibitors except ponatinib. Resistance to ponatinib can develop by compound (double) mutations.

    Methods

    Kinetic measurements of the KD of Abl1 and its mutants were carried out to examine their catalytic activity. Specifically, mutants that lead to drug resistance against ponatinib were considered. Molecular dynamics simulations and multiple sequence analysis were used for explanation of the experimental findings.

    Results

    The catalytic efficiency of the T315I pan-resistance mutant is more than two times lower than that of the native KD. All ponatinib resistant mutations restore the catalytic efficiency of the enzyme. Two of them (G250E/T315I and Y253H/E255V) have a catalytic efficiency that is more than five times that of the native KD.

    Conclusions

    The measurements and analysis suggest that resistance is at least partially due to the development of a highly efficient kinase through subsequent mutations. The simulations highlight modifications in two structurally important regions of Abl1, the activation and phosphate binding loops, upon mutations.

    General significance

    Experimental and computational methods were used together to explain how mutations in the kinase domain of Abl1 lead to resistance against the most advanced drug currently in use to treat chronic myeloid leukaemia.

  • 16.
    Eriksson, Oskar
    et al.
    Uppsala University, Sweden.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Bo
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    The Human Platelet as an Innate Immune Cell: Interactions Between Activated Platelets and the Complement System2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, p. 1-16, article id 1590Article, review/survey (Refereed)
    Abstract [en]

    Platelets play an essential role in maintaining homeostasis in the circulatory system after an injury by forming a platelet thrombus, but they also occupy a central node in the intravascular innate immune system. This concept is supported by their extensive interactions with immune cells and the cascade systems of the blood. In this review we discuss the close relationship between platelets and the complement system and the role of these interactions during thromboinflammation. Platelets are protected from complement-mediated damage by soluble and membrane-expressed complement regulators, but they bind several complement components on their surfaces and trigger complement activation in the fluid phase. Furthermore, localized complement activation may enhance the procoagulant responses of platelets through the generation of procoagulant microparticles by insertion of sublytic amounts of C5b9 into the platelet membrane. We also highlight the role of post-translational protein modifications in regulating the complement system and the critical role of platelets in driving these reactions. In particular, modification of disulfide bonds by thiol isomerases and protein phosphorylation by extracellular kinases have emerged as important mechanisms to fine-tune complement activity in the platelet microenvironment. Lastly, we describe disorders with perturbed complement activation where part of the clinical presentation includes uncontrolled platelet activation that results in thrombocytopenia, and illustrate how complement-targeting drugs are alleviating the prothrombotic phenotype in these patients. Based on these clinical observations, we discuss the role of limited complement activation in enhancing platelet activation and consider how these drugs may provide opportunities for further dissecting the complex interactions between complement and platelets.

  • 17.
    Thorgersen, Ebbe Billmann
    et al.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Barratt-Due, Andreas
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Haugaa, Hakon
    Oslo Univ Hosp, Norway;Lovisenberg Diaconal Univ Coll, Norway.
    Harboe, Morten
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Pischke, Soren Erik
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Mollnes, Tom Eirik
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Univ Tromsö, Norway;Norwegian Univ Sci & Technol, Norway.
    The Role of Complement in Liver Injury, Regeneration, and Transplantation2019In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350Article in journal (Refereed)
    Abstract [en]

    The liver is both an immunologically complex and a privileged organ. The innate immune system is a central player, in which the complement system emerges as a pivotal part of liver homeostasis, immune responses, and crosstalk with other effector systems in both innate and adaptive immunity. The liver produces the majority of the complement proteins and is the home of important immune cells such as Kupffer cells. Liver immune responses are delicately tuned between tolerance to many antigens flowing in from the alimentary tract, a tolerance that likely makes the liver less prone to rejection than other solid organ transplants, and reaction to local injury, systemic inflammation, and regeneration. Notably, complement is a double-edged sword as activation is detrimental by inducing inflammatory tissue damage in, for example, ischemia-reperfusion injury and transplant rejection yet is beneficial for liver tissue regeneration. Therapeutic complement inhibition is rapidly developing for routine clinical treatment of several diseases. In the liver, targeted inhibition of damaged tissue may be a rational and promising approach to avoid further tissue destruction and simultaneously preserve beneficial effects of complement in areas of proliferation. Here, we argue that complement is a key system to manipulate in the liver in several clinical settings, including liver injury and regeneration after major surgery and preservation of the organ during transplantation.

  • 18.
    Göransson, Ulf
    et al.
    Uppsala University.
    Jacobsson, Erik
    Uppsala University.
    Strand, Malin
    Swedish University of Agricultural Sciences.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The toxins of nemertean worms2019In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 11, no 2, p. 1-36, article id 120Article in journal (Refereed)
    Abstract [en]

    Most ribbon worms (phylum: Nemertea) are found in marine environments, where they act as predators and scavengers. They are characterized by an eversible proboscis that is used to hunt for prey and thick mucus covering their skin. Both proboscis and epidermal mucus mediate toxicity to predators and preys. Research into the chemical nature of the substances that render toxicity has not been extensive, but it has nevertheless led to the identification of several compounds of potential medicinal use or for application in biotechnology. This review provides a complete account of the current status of research into nemertean toxins.

  • 19.
    Asif, Sana
    et al.
    Uppsala University, Sweden.
    Asawa, Kenta
    Univ Tokyo, Japan.
    Inoue, Yuuki
    Univ Tokyo, Japan.
    Ishihara, Kazuhiko
    Univ Tokyo, Japan.
    Lindell, Björn
    Uppsala University, Sweden.
    Holmgren, Robin
    Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Ryden, Anneli
    Swedish University of Agricultural Sciences, Sweden.
    Jensen-Waern, Marianne
    Swedish University of Agricultural Sciences, Sweden.
    Teramura, Yuji
    Uppsala University, Sweden;Univ Tokyo, Japan.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Validation of an MPC Polymer Coating to Attenuate Surface-Induced Crosstalk between the Complement and Coagulation Systems in Whole Blood in In Vitro and In Vivo Models2019In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 19, no 5, article id 1800485Article in journal (Refereed)
    Abstract [en]

    Artificial surfaces that come into contact with blood induce an immediate activation of the cascade systems of the blood, leading to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Heparin coating has been used to improve hemocompatibility, and another approach is 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings. Here, the aim is to evaluate the hemocompatibility of MPC polymer coating by studying the interactions with coagulation and complement systems using human blood in vitro model and pig in vivo model. The stability of the coatings is investigated in vitro and MPC polymer-coated catheters are tested in vivo by insertion into the external jugular vein of pigs to monitor the catheters' antithrombotic properties. There is no significant activation of platelets or of the coagulation and complement systems in the MPC polymer-coated one, which was superior in hemocompatibility to non-coated matrix surfaces. The protective effect of the MPC polymer coat does not decline after incubation in human plasma for up to 2 weeks. With MPC polymer-coated catheters, it is possible to easily draw blood from pig for 4 days in contrast to the case for non-coated catheters, in which substantial clotting is seen.

  • 20.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland;Swiss Inst Bioinformat, Switzerland.
    Jensen, Rebecca
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland;Swiss Inst Bioinformat, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    A computational study of hedgehog signalling involved in basal cell carcinoma reveals the potential and limitation of combination therapy2018In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 18, no 1, p. 1-8, article id 569Article in journal (Refereed)
    Abstract [en]

    Background: The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC). SMO inhibitors are indicated for BCC patients when surgical treatment or radiation therapy are not possible. Unfortunately, SMO inhibitors are not always well tolerated due to severe side effects, and their therapeutical success is limited by resistance mutations. Methods: We investigated how common are resistance-causing mutations in two genomic databases which are not linked to BCC or other cancers, namely 1000 Genomes and ExAC. To examine the potential for combination therapy or other treatments, we further performed knowledge-based simulations of SHH signalling, in the presence or absence of SMO and PI3K/Akt inhibitors. Results: The database analysis revealed that of 18 known mutations associated with Vismodegib-resistance, three were identified in the databases. Treatment of individuals carrying such mutations is thus liable to fail a priori. Analysis of the simulations suggested that a combined inhibition of SMO and the PI3K/Akt signalling pathway may provide an effective reduction in tumour proliferation. However, the inhibition dosage of SMO and PI3K/Akt depended on the activity of phosphodiesterases (PDEs). Under high PDEs activities, SMO became the most important control node of the network. By applying PDEs inhibition, the control potential of SMO decreased and P13K appeared as a significant factor in controlling tumour proliferation. Conclusions: Our systems biology approach employs knowledge-based computer simulations to help interpret the large amount of data available in public databases, and provides application-oriented solutions for improved cancer resistance treatments.

  • 21.
    Mohlin, Camilla
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Kvanta, Anders
    Karolinska institutet.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala university.
    Johansson, Kjell
    Örebro university.
    A model to study complement involvement in experimental retinal degeneration.2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 1, p. 28-42Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The complement system (CS) plays a role in the pathogenesis of a number of ocular diseases, including diabetic retinopathy (DR), glaucoma, uveitis, and age-related macular degeneration (AMD). Given that many of the complex eye-related degenerative diseases have limited treatment opportunities, we aimed to mimic the in vivo retinal degenerative process by developing a relevant co-culture system.

    METHOD AND MATERIALS: The adult porcine retina was co-cultured with the spontaneously arising human retinal pigment epithelial cells-19 (ARPE-19).

    RESULTS: Inflammatory activity was found after culture and included migrating microglial cells, gliosis, cell death, and CS activation (demonstrated by a minor increase in the secreted anaphylotoxin C3a in co-culture). CS components, including C1q, C3, C4, soluble C5b-9, and the C5a receptor, were expressed in the retina and/or ARPE cells after culture. C1q, C3, and CS regulators such as C4 binding protein (C4BP), factor H (CFH), and factor I (CFI) were secreted after culture.

    DISCUSSION: Thus, our research indicates that this co-culturing system may be useful for investigations of the CS and its involvement in experimental neurodegenerative diseases.

  • 22.
    Orrem, Hilde L
    et al.
    Oslo University Hospital, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Oslo, Norway;Oslo University Hospital, Rikshospitalet, Norway.
    Pischke, Søren E
    Oslo University Hospital, Rikshospitalet, Norway.
    Grindheim, Guro
    Oslo University Hospital, Rikshospitalet, Norway.
    Garred, Peter
    University of Copenhagen, Denmark.
    Seljeflot, Ingebjørg
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Husebye, Trygve
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Aukrust, Pål
    University of Oslo, Norway;Oslo University Hospital, Norway.
    Yndestad, Arne
    University of Oslo, Norway;Oslo University Hospital, Norway.
    Andersen, Geir Ø
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Barratt-Due, Andreas
    Oslo University Hospital, Rikshospitalet, Norway.
    Mollnes, Tom E
    Oslo University Hospital, Rikshospitalet, Norway;University of Oslo, Norway;University of Tromsø, Norway;Norwegian University of Science and Technology, Norway.
    Acute heart failure following myocardial infarction: complement activation correlates with the severity of heart failure in patients developing cardiogenic shock.2018In: ESC Heart Failure, E-ISSN 2055-5822, Vol. 5, no 3, p. 292-301Article in journal (Refereed)
    Abstract [en]

    AIMS: Heart failure (HF) is an impending complication to myocardial infarction. We hypothesized that the degree of complement activation reflects severity of HF following acute myocardial infarction.

    METHODS AND RESULTS: The LEAF trial (LEvosimendan in Acute heart Failure following myocardial infarction) evaluating 61 patients developing HF within 48 h after percutaneous coronary intervention-treated ST-elevation myocardial infarction herein underwent a post hoc analysis. Blood samples were drawn from inclusion to Day 5 and at 42 day follow-up, and biomarkers were measured with enzyme immunoassays. Regional myocardial contractility was measured by echocardiography as wall motion score index (WMSI). The cardiogenic shock group (n = 9) was compared with the non-shock group (n = 52). Controls (n = 44) were age-matched and sex-matched healthy individuals. C4bc, C3bc, C3bBbP, and sC5b-9 were elevated in patients at inclusion compared with controls (P < 0.01). The shock group had higher levels compared with the non-shock group for all activation products except C3bBbP (P < 0.05). At Day 42, all products were higher in the shock group (P < 0.05). In the shock group, sC5b-9 correlated significantly with WMSI at baseline (r = 0.68; P = 0.045) and at Day 42 (r = 0.84; P = 0.036). Peak sC5b-9 level correlated strongly with WMSI at Day 42 (r = 0.98; P = 0.005). Circulating endothelial cell activation markers sICAM-1 and sVCAM-1 were higher in the shock group during the acute phase (P < 0.01), and their peak levels correlated with sC5b-9 peak level in the whole HF population (r = 0.32; P = 0.014 and r = 0.30; P = 0.022, respectively).

    CONCLUSIONS: Complement activation discriminated cardiogenic shock from non-shock in acute ST-elevation myocardial infarction complicated by HF and correlated with regional contractility and endothelial cell activation, suggesting a pathogenic role of complement in this condition.

  • 23.
    Giovannoli, Cristina
    et al.
    Univ Turin, Italy.
    Passini, Cinzia
    Univ Turin, Italy.
    Di Nardo, Fabio
    Univ Turin, Italy.
    Anfossi, Laura
    Univ Turin, Italy.
    Baggiani, Claudio
    Univ Turin, Italy.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Affinity Capillary Electrochromatography of Molecularly Imprinted Thin Layers Grafted onto Silica Capillaries Using a Surface-Bound Azo-Initiator and Living Polymerization2018In: Polymers, ISSN 2073-4360, E-ISSN 2073-4360, Vol. 10, no 2, article id 192Article in journal (Refereed)
    Abstract [en]

    Molecularly imprinted thin layers were prepared in silica capillaries by using two different surface polymerization strategies, the first using 4,4-azobis(4-cyanovaleric acid) as a surface-coupled radical initiator, and the second, S-carboxypropyl-S'-benzyltrithiocarbonate as a reversible addition-fragmentation chain transfer (RAFT) agent in combination with 2,2-azobisisobutyronitrile as a free radical initiator. The ability to generate imprinted thin layers was tested on two different polymerization systems: (i) a 4-vinylpyridine/ethylene dimethacrylate (4VP-EDMA) in methanol-water solution with 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) as a template; and (ii) methacrylic acid/ethylene dimethacrylate (MAA-EDMA) in a chloroform solution with warfarin as the template molecule. The binding properties of the imprinted capillaries were studied and compared with those of the corresponding non-imprinted polymer coated capillaries by injecting the template molecule and by measuring its migration times relative to a neutral and non-retained marker. The role of running buffer hydrophobicity on recognition was investigated by studying the influence of varying buffer acetonitrile concentration. The 2,4,5-T-imprinted capillary showed molecular recognition based on a reversed phase mechanism, with a decrease of the template recognition in the presence of higher acetonitrile content; whereas warfarin-imprinted capillaries showed a bell-shaped trend upon varying the acetonitrile percentage, illustrating different mechanisms underlying imprinted polymer-ligand recognition. Importantly, the results demonstrated the validity of affinity capillary electrochromatography (CEC) to screen the binding properties of imprinted layers.

  • 24.
    Andersson, Håkan S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala university.
    Jacobsson, Erik
    Uppsala University.
    Laborde, Quentin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rosengren, Johan
    University of Queensland, Australia.
    Strand, Malin
    Swedish University of Agricultural Sciences.
    Göransson, Ulf
    Uppsala University.
    Alpha-nemertides - a novel family of nemertean peptide neurotoxins2018Conference paper (Other academic)
    Abstract [en]

    We recently discovered a novel family of neuroactive peptides in nemerteans, which we have named alpha-nemertides (1). One of these peptides, nemertide alpha-1, has been the subject of detailed studies with regard to structure and effects. The peptide exhibits exceptional potency against a number of arthropod species. Moreover, in vitro experiments suggest that alpha-1 acts primarily on voltage-gated sodium channels, and that this action is selective for arthropods by two orders of magnitude over vertebrate species. Using transcriptomic and proteomic approaches, we have identified 10 alpha-nemertides, but this number is likely to increase. These peptides alongside with a series of mutants are currently under evaluation by our group, with the goal to improve our understanding of structure-function relationships. In addition, we are considering potential practical uses of alpha-nemertides. In this talk, I will describe the current status of this research project.

    1. E. Jacobsson et al., Peptide ion channel toxins from the bootlace worm, the longest animal on Earth. Scientific reports 8, 4596 (2018).

  • 25.
    Ahlstrand, Emma
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Buetti-Dinh, Antoine
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Universita’ della Svizzera Italiana, Switzerland;Swiss Institute of Bioinformatics, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    An interactive computer lab of the galvanic cell for students in biochemistry2018In: Biochemistry and molecular biology education, ISSN 1470-8175, E-ISSN 1539-3429, Vol. 46, no 1, p. 58-65Article in journal (Refereed)
    Abstract [en]

    We describe an interactive module that can be used to teach basic concepts in electrochemistry and thermodynamics to first year natural science students. The module is used together with an experimental laboratory and improves the students’ understanding of thermodynamic quantities such as ΔrG, ΔrH, and ΔrS that are calculated but not directly measured in the lab. We also discuss how new technologies can substitute some parts of experimental chemistry courses, and improve accessibility to course material. Cloud computing platforms such as CoCalc facilitate the distribution of computer codes and allow students to access and apply interactive course tools beyond the course's scope. Despite some limitations imposed by cloud computing, the students appreciated the approach and the enhanced opportunities to discuss study questions with their classmates and instructor as facilitated by the interactive tools. 

  • 26.
    Helin, Anu S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Aarts, Lauren
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Bususu, Isaya
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rosengren, Johan
    University of Queensland, Australia.
    Chapman, Joanne R.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Waldenström, Jonas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Antimicrobial differences between AvBDs in mallards (Anas platyrhynchos)2018Conference paper (Other academic)
  • 27.
    Huber-Lang, Markus
    et al.
    Univ Hosp Ulm, Germany.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Wiegner, Rebecca
    Univ Hosp Ulm, Germany.
    Fromell, Karin
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Auxiliary activation of the complement system and its importance for the pathophysiology of clinical conditions2018In: Seminars in Immunopathology, ISSN 1863-2297, E-ISSN 1863-2300, Vol. 40, no 1, p. 87-102Article, review/survey (Refereed)
    Abstract [en]

    Activation and regulation of the cascade systems of the blood (the complement system, the coagulation/contact activation/kallikrein system, and the fibrinolytic system) occurs via activation of zymogen molecules to specific active proteolytic enzymes. Despite the fact that the generated proteases are all present together in the blood, under physiological conditions, the activity of the generated proteases is controlled by endogenous protease inhibitors. Consequently, there is remarkable little crosstalk between the different systems in the fluid phase. This concept review article aims at identifying and describing conditions where the strict system-related control is circumvented. These include clinical settings where massive amounts of proteolytic enzymes are released from tissues, e.g., during pancreatitis or post-traumatic tissue damage, resulting in consumption of the natural substrates of the specific proteases and the available protease inhibitor. Another example of cascade system dysregulation is disseminated intravascular coagulation, with canonical activation of all cascade systems of the blood, also leading to specific substrate and protease inhibitor elimination. The present review explains basic concepts in protease biochemistry of importance to understand clinical conditions with extensive protease activation.

  • 28.
    Thomas, Anub Mathew
    et al.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Gerogianni, Alexandra
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Barratt-Due, Andreas
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    McAdam, Martin B.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Mollnes, Tom Eirik
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Complement (C5)-inhibition attenuates heme-induced inflammation in human whole blood2018In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, p. 220-220Article in journal (Other academic)
  • 29.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Università della Svizzera Italiana, Italy;Swiss Institute of Bioinformatics, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Computer simulations of the signalling network in FLT3+-acute myeloid leukaemia: indications for an optimal dosage of inhibitors against FLT3 and CDK62018In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 19, p. 1-13, article id 155Article in journal (Refereed)
    Abstract [en]

    Background

    Mutations in the FMS-like tyrosine kinase 3 (FLT3) are associated with uncontrolled cellular functions that contribute to the development of acute myeloid leukaemia (AML). We performed computer simulations of the FLT3-dependent signalling network in order to study the pathways that are involved in AML development and resistance to targeted therapies.

    Results

    Analysis of the simulations revealed the presence of alternative pathways through phosphoinositide 3 kinase (PI3K) and SH2-containing sequence proteins (SHC), that could overcome inhibition of FLT3. Inhibition of cyclin dependent kinase 6 (CDK6), a related molecular target, was also tested in the simulation but was not found to yield sufficient benefits alone.

    Conclusions

    The PI3K pathway provided a basis for resistance to treatments. Alternative signalling pathways could not, however, restore cancer growth signals (proliferation and loss of apoptosis) to the same levels as prior to treatment, which may explain why FLT3 resistance mutations are the most common resistance mechanism. Finally, sensitivity analysis suggested the existence of optimal doses of FLT3 and CDK6 inhibitors in terms of efficacy and toxicity.

  • 30.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Davoodpour, Padideh
    Uppsala University.
    Ekstrand-Hammarström, Barbro
    Swedish Defence Research Agency, Umeå.
    Fromell, Karin
    Uppsala University.
    Hamad, Osama A
    Uppsala University.
    Hong, Jaan
    Uppsala University.
    Bucht, Anders
    Swedish Defence Research Agency, Umeå;Umeå University.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Seisenbaeva, Gulaim A
    Swedish University of Agricultural Sciences (SLU).
    Kessler, Vadim G
    Swedish University of Agricultural Sciences (SLU).
    Nilsson, Bo
    Uppsala University.
    Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of α-Fe2O3 nanoparticles2018In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 14, no 3, p. 735-744Article in journal (Refereed)
    Abstract [en]

    Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. α-Fe2O3 NPs were synthesized, characterized and tested in a model for toxicity utilizing human whole blood without added anticoagulant. MALDI-TOF of the corona was performed and activation markers for plasma cascade systems (complement, contact and coagulation systems), platelet consumption and release of growth factors, MPO, and chemokine/cytokines from blood cells were analyzed. The coronas formed on the pristine α-Fe2O3 NPs contained contact system proteins and they induced massive activation of the contact (kinin/kallikrein) system, as well as thrombin generation, platelet activation, and release of two pro-angiogeneic growth factors: platelet-derived growth factor and vascular endothelial growth factor, whereas complement activation was unaffected. The α-Fe2O3 NPs exhibited a noticeable toxicity, with kinin/kallikreinactivation, which may be associated with hypotension and long-term angiogenesis in vivo, with implications for cancer, arteriosclerosis and pulmonary disease.

  • 31.
    Labriere, Christophe
    et al.
    UiT Arctic Univ Norway, Norway;Univ Aberdeen, UK.
    Kondori, Nahid
    University of Gothenburg.
    Caous, Josefin Seth
    RISE Res Inst Sweden.
    Boomgaren, Marc
    UiT Arctic Univ Norway, Norway.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Hansen, Jorn H.
    UiT Arctic Univ Norway, Norway.
    Svenson, Johan
    UiT Arctic Univ Norway, Norway;RISE Res Inst Sweden.
    Development and evaluation of cationic amphiphilic antimicrobial 2,5-diketopiperazines2018In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 24, no 7, article id UNSP e3090Article in journal (Refereed)
    Abstract [en]

    Both pathogenic bacteria and fungi are developing resistance to common antimicrobial treatment at an alarming rate. To counteract this development, it is of essence to develop new classes of antimicrobial agents. One such class is antimicrobial peptides, most of which are derived from the innate immune system. In this study, a series of novel 2,5-diketopiperazines were designed, synthesized, and evaluated for their antimicrobial abilities. The compounds were designed to probe the pharmacophore dictated for short linear mimics of antimicrobial cationic peptides, and as such, the compounds contain a range of cationic and hydrophobic functionalities. Several of the prepared compounds displayed high antimicrobial activities toward bacteria and also against human pathogenic fungi. Of particular interest was the high activity toward fungal strains with an inherent increased resistance toward conventional antifungal agents. The most effective compounds displayed inhibition of Candida glabrata and Candida krusei growth at concentrations between 4 and 8 mu g/mL, which is comparable to commercial antifungal agents in use. Structure activity relationship studies revealed a similar dependence on cationic charge and the volume of the hydrophobic bulk as for linear cationic antimicrobial peptides. Finally, the hemolytic activity of selected compounds was evaluated, which revealed a potential to produce active compounds with attenuation of unwanted hemolysis. The findings highlight the potential of cyclic cationic amphiphilic peptidomimetics as a class of promising compounds for the treatment of infections caused by microorganisms with an increased resistance to conventional antimicrobial agents.

  • 32.
    Fromell, Karin
    et al.
    Uppsala University.
    Johansson, Ulrika
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Duhrkop, Claudia
    Uppsala University.
    Adler, Anna
    Uppsala University.
    Usterud, Emma
    Uppsala University.
    Hamad, Osama A.
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Generation of an alternative pathway convertase by contact-activated C3 is dependent on the conformation of C32018In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, p. 193-193Article in journal (Other academic)
  • 33.
    Ndizeye, Natacha
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Suriyanarayanan, Subramanian
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Hierarchical polymeric architectures through molecular imprinting in liquid crystalline environments2018In: European Polymer Journal, ISSN 0014-3057, E-ISSN 1873-1945, Vol. 106, p. 223-231Article in journal (Refereed)
    Abstract [en]

    The use of liquid crystalline (LC) media as sacrificial templates during the polymer synthesis has been explored. The LC-media introduce morphological features into resultant polymers which when used together with molecular imprinting can produce materials with hierarchical architectures. Bupivacaine (1) imprinted co-polymers of 2-hydroxyethylmethacrylate (HEMA) (2a) and 1,4-divinylbenzene (DVB) (3a) were synthesized using photochemical initiation in lyotrophic liquid crystalline phases of AOT (5) in water/p-xylene and Triton X-100 (6) /water systems. SEM studies revealed the impact of the LC-media on polymer morphology, with polymer brush-like structures, with bristles of ≈30 nm diameter. The polymer morphology reflects that of the hexagonal phase of the LC medium. The rebinding characteristics of polymer films were evaluated quartz crystal microbalance (QCM, under FIA conditions). The influence of the presence of imprinting-derived recognition sites in AOT (5) in water/p-xylene polymer film induced brush-like features which provided a 25-fold enhancement of sensor sensitivity. This chemosensor was shown to be selective for the local anesthetic template, bupivacaine, through studies using the structural analogues ropivacaine and mepivacaine.

  • 34.
    Steinz, Maarten
    et al.
    Karolinska Institutet.
    Malin, Persson
    Karolinska Institutet.
    Bejan, Aresh
    Stockholm University.
    Cheng, Arthur
    Karolinska Institutet.
    Ahlstrand, Emma
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Ajeganova, Sofia
    Karolinska Institutet.
    Rassier, Dilson
    McGill Univ, Canada.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Karlsson, Roger
    Stockholm University.
    Gustafsson, Thomas
    Karolinska Institutet.
    Lanner, Johanna
    Karolinska Institutet.
    Identification of oxidative hotspots on actin which promote skeletal muscle weakness in rheumatoid arthritis2018In: Free Radical Biology and Medicine, 2018, Vol. 128: Supplement 1, p. S106-, article id 247Conference paper (Refereed)
  • 35.
    Orrem, Hilde L.
    et al.
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Natl Hosp Norway, Norway;Univ Oslo, Norway;Univ Oslo, Norway.
    Pischke, Soren E.
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Kleveland, Ola
    St Olavs Hosp, Norway;Norwegian Univ Sci & Technol, Norway.
    Yndestad, Arne
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Ekholt, Karin
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Damas, Jan K.
    Norwegian Univ Sci & Technol, Norway.
    Espevik, Terje
    Norwegian Univ Sci & Technol, Norway.
    Bendz, Bjorn
    Natl Hosp Norway, Norway.
    Halvorsen, Bente
    Univ Oslo, Norway;Natl Hosp Norway, Norway.
    Gregersen, Ida
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Wiseth, Rune
    St Olavs Hosp, Norway;Norwegian Univ Sci & Technol, Norway.
    Andersen, Geir O.
    Oslo Univ Hosp, Norway.
    Ueland, Thor
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Gullestad, Lars
    Univ Oslo, Norway;Oslo Univ Hosp, Norway;Natl Hosp Norway, Norway.
    Aukrust, Pal
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Barratt-Due, Andreas
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Mollnes, Tom E.
    Natl Hosp Norway, Norway;Univ Oslo, Norway;Norwegian Univ Sci & Technol, Norway;Nordland Hosp, Norway;Univ Tromso, Norway.
    IL-6 Receptor Inhibition by Tocilizumab Attenuated Expression of C5a Receptor 1 and 2 in Non-ST-Elevation Myocardial Infarction2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2035Article in journal (Refereed)
    Abstract [en]

    Background: Elevated interleukin-6 (IL-6) and complement activation are associated with detrimental effects of inflammation in coronary artery disease (CAD). The complement anaphylatoxins C5a and C3a interact with their receptors; the highly inflammatory C5aR1, and the C5aR2 and C3aR. We evaluated the effect of the IL-6 receptor (IL-6R)-antagonist tocilizumab on the expression of the anaphylatoxin receptors in whole blood from non-ST-elevation myocardial infarction (NSTEMI) patients. Separately, anaphylatoxin receptor expression in peripheral blood mononuclear cells (PBMC) from patients with different entities of CAD was investigated. Materials and Methods: NSTEMI patients were randomized to one dose of tocilizumab (n = 28) or placebo (n = 32) and observed for 6 months. Whole blood samples drawn at inclusion, at day 2, 3 and after 6 months were used for mRNA isolation. Plasma was prepared for analysis of complement activation measured as sC5b-9 by ELISA. Furthermore, patients with different CAD entities comprising stable angina pectoris (SAP, n = 22), non-ST-elevation acute coronary syndrome (NSTE-ACS, n = 21) and ST-elevation myocardial infarction (STEMI, n = 20) were included. PBMC was isolated from blood samples obtained at admission to hospital and mRNA isolated. Anaphylatoxin-receptor-expression was analyzed with qPCR using mRNA from whole blood and PBMC, respectively. Results: Our main findings were (i) Tocilizumab decreased C5aR1 and C5aR2 mRNA expression significantly (p < 0.001) and substantially (> 50%) at day 2 and 3, whereas C3aR expression was unaffected. (ii) Tocilizumab did not affect complement activation. (iii) In analyzes of different CAD entities, C5aR1 expression was significantly increased in all CAD subgroups compared to controls with the highest level in the STEMI patients (p < 0.001). For C5aR2 and C3aR the expression compared to controls were more moderate with increased expression of C5aR2 in the STEMI group (p < 0.05) and C3aR in the NSTE-ACS group (p < 0.05). Conclusion: Expression of C5aR1 and C5aR2 in whole blood was significantly attenuated by IL-6R-inhibition in NSTEMI patients. These receptors were significantly upregulated in PBMC CAD patients with particularly high levels of C5aR1 in STEMI patients.

  • 36.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Persson, Barbro
    Uppsala University.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Skattum, Lillemor
    Lund University.
    Nilsson, Bo
    Uppsala University.
    Interpretation of Serological Complement Biomarkers in Disease2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2237Article, review/survey (Refereed)
    Abstract [en]

    Complement systemaberrations have been identified as pathophysiological mechanisms in a number of diseases and pathological conditions either directly or indirectly. Examples of such conditions include infections, inflammation, autoimmune disease, as well as allogeneic and xenogenic transplantation. Both prospective and retrospective studies have demonstrated significant complement-related differences between patient groups and controls. However, due to the low degree of specificity and sensitivity of some of the assays used, it is not always possible to make predictions regarding the complement status of individual patients. Today, there are three main indications for determination of a patient's complement status: (1) complement deficiencies (acquired or inherited); (2) disorders with aberrant complement activation; and (3) C1 inhibitor deficiencies (acquired or inherited). An additional indication is to monitor patients on complement-regulating drugs, an indication which may be expected to increase in the near future since there is now a number of such drugs either under development, already in clinical trials or in clinical use. Available techniques to study complement include quantification of: (1) individual components; (2) activation products, (3) function, and (4) autoantibodies to complement proteins. In this review, we summarize the appropriate indications, techniques, and interpretations of basic serological complement analyses, exemplified by a number of clinical disorders.

  • 37.
    Mohlin, Camilla
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Petrus-Reurer, Sandra
    Karolinska Institutet;Karolinska University Hospital.
    Lanner, Fredrik
    Karolinska Institutet;Karolinska University Hospital.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Norway.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Is the polarized secretion of complement factor H of importance in age-related macular degeneration?2018In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 59, no 9Article in journal (Other academic)
  • 38.
    Andersson, Håkan S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Jacobsson, Erik
    Uppsala University.
    Rosengren, Johan
    University of Queensland, Australia.
    Strand, Malin
    Swedish University of Agricultural Sciences.
    Göransson, Ulf
    Uppsala University.
    Mapping the diversity of nemertean peptide toxins2018Conference paper (Other academic)
  • 39.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Membrane-Ion Interactions2018In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 251, no 3, p. 453-460Article in journal (Refereed)
    Abstract [en]

    Biomembranes assemble and operate at the interface with electrolyte solutions. Interactions between ions in solutions and the lipid affect the membrane structure, dynamics and electrostatic potential. In this article, I review some of the experimental and computational methods that are used to study membrane-ions interactions. Experimental methods that account for membrane-ion interactions directly and indirectly are presented first. Then, studies in which molecular dynamics simulations were used to gain an understanding of membrane-ion interactions are surveyed. Finally, the current view on membrane-ion interactions and their significance is briefly discussed.

  • 40.
    Jacobsson, Erik
    et al.
    Uppsala University, Sweden.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Strand, Malin
    Swedish University of Agricultural Sciences, Sweden.
    Peigneur, Steve
    Univ Leuven, Belgium.
    Eriksson, Camilla
    Uppsala University, Sweden.
    Loden, Henrik
    Uppsala University, Sweden.
    Shariatgorji, Mohammadreza
    Uppsala University, Sweden.
    Andren, Per E.
    Uppsala University, Sweden.
    Lebbe, Eline K. M.
    Univ Leuven, Belgium.
    Rosengren, K. Johan
    Univ Queensland, Australia.
    Tytgat, Jan
    Univ Leuven, Belgium.
    Göransson, Ulf
    Uppsala University, Sweden.
    Peptide ion channel toxins from the bootlace worm, the longest animal on Earth2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 4596Article in journal (Refereed)
    Abstract [en]

    Polypeptides from animal venoms have found important uses as drugs, pharmacological tools, and within biotechnological and agricultural applications. We here report a novel family of cystine knot peptides from nemertean worms, with potent activity on voltage-gated sodium channels. These toxins, named the alpha-nemertides, were discovered in the epidermal mucus of Lineus longissimus, the 'bootlace worm' known as the longest animal on earth. The most abundant peptide, the 31-residue long alpha-1, was isolated, synthesized, and its 3D NMR structure determined. Transcriptome analysis including 17 species revealed eight alpha-nemertides, mainly distributed in the genus Lineus. alpha-1 caused paralysis and death in green crabs (Carcinus maenas) at 1 mu g/kg (similar to 300 pmol/kg). It showed profound effect on invertebrate voltage-gated sodium channels (e.g. Blattella germanica Na(v)1) at low nanomolar concentrations. Strong selectivity for insect over human sodium channels indicates that a-nemertides can be promising candidates for development of bioinsecticidal agents.

  • 41.
    Mandal, Sudip
    et al.
    Indian Inst Technol Madras, India.
    Suriyanarayanan, Subramanian
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Ramanujam, Kothandaraman
    Indian Inst Technol Madras, India.
    Selective Sensing of the Biotinyl Moiety Using Molecularly Imprinted Polyaniline Nanowires2018In: Journal of the Electrochemical Society, ISSN 0013-4651, E-ISSN 1945-7111, Vol. 165, no 14, p. B669-B678Article in journal (Refereed)
    Abstract [en]

    A chemosensor for selective recognition of biotinyl moiety has been devised using electropolymerized film and tested against selective biotinylated targets. The sensor comprises biotin molecularly imprinted polymer (MIP) polymeric nanowires, as a recognition element, overlaid on gold-coated quartz transducers. The preparation of nanostructured MIPs and reference systems have been demonstrated using electrochemical copolymerization of the stabilized complex between the template (biotin), the functional monomer (4-aminobenzoic acid), and cross-linker (aniline) and/or sacrificial biotin-modified Al2O3 membrane. Density functional theoretical studies signify formation of a stable hydrogen-bonded complex of biotin with 4-aminobenzoic acid in the pre-polymerization mixture. Scanning electron microscope studies revealed uniformly grown and densely packed polyaniline hierarchical structures. Piezoelectric microgravimetry under flow injection analysis (FIA) conditions revealed selective binding of biotin methyl ester (BtOMe, 4) (79.89 +/- 2.17 Hz/mM) with imprinted polyaniline hierarchical structures over 10 fold higher than the non-imprinted counterpart. The detection limit of the MIP is 50 nM under optimized conditions. Particularly, the sensor selectively recognizes BtOMe from structural or functional analogues, such as thiamine (4.87 +/- 0.10 Hz/mM) and pyridoxamine (12.08 +/- 0.24 Hz/mM). Importantly, the MIP hierarchical structures were shown to be selective for biotinylated targets (biotin moiety labeled cytochrome C, dextran, oxytocin and obestatin). (C) 2018 The Electrochemical Society.

  • 42.
    Orrem, Hilde L.
    et al.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Shetelig, Christian
    Univ Oslo, Norway;Oslo Univ Hosp Ulleval, Norway.
    Ueland, Thor
    Univ Oslo, Norway.;Oslo Univ Hosp, Norway;Univ Tromso, Norway.
    Limalanathan, Shanmuganathan
    Oslo Univ Hosp Ulleval, Norway;Feiring Heart Clin, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Norway.
    Husebye, Trygve
    Oslo Univ Hosp Ulleval, Norway;Univ Oslo, Norway.
    Aukrust, Pal
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Seljeflot, Ingebjorg
    Univ Oslo, Norway;Oslo Univ Hosp Ulleval, Norway.
    Hoffmann, Pavel
    Univ Oslo, Norway;Oslo Univ Hosp Ulleval, Norway.
    Eritsland, Jan
    Oslo Univ Hosp Ulleval, Norway.
    Mollnes, Tom E.
    Oslo Univ Hosp, Norway;Univ Tromso, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Norwegian Univ Sci, Norway.
    Andersen, Geir Oystein
    Oslo Univ Hosp Ulleval, Norway;Univ Oslo, Norway.
    Yndestad, Arne
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Soluble IL-1 receptor 2 is associated with left ventricular remodelling in patients with ST-elevation myocardial infarction2018In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 268, p. 187-192Article in journal (Refereed)
    Abstract [en]

    Background: The inflammatory response following myocardial infarction (MI) is prerequisite for proper healing of infarcted tissue, but can also have detrimental effects on cardiac function. Interleukin (IL)-1 alpha and IL-1 beta are potent inflammatory mediators and their bioactivity is tightly regulated by IL-1 receptor antagonist (IL-1ra) and soluble (s) IL-1 receptors (R). We aimed to examine whether levels of soluble regulators of IL-1 signalling are changed during ST-elevation MI (STEMI) and their associations with parameters of cardiac injury and ventricular remodelling. Methods: Plasma levels of IL-1Ra, sIL-1R1, sIL-1R2 and sIL-1R accessory protein (sIL-1RAcP) were measured by immunoassays in repeated samples from patients with STEMI (n = 255) and compared to healthy controls (n=65). Results: IL-1Ra, sIL-1R1 and sIL-1R2 levels were all significantly elevated after STEMI, while levels of sIL-1RAcP were lower compared to controls. sIL-1R2 levels (at different time points) correlated positively with C-reactive protein, myocardial infarct size and change in indexed left ventricular end-diastolic and end-systolic volume (LVEDVi and LVESVi) measured by cardiac MR acutely and after 4 months, and negatively with LV ejection fraction. Patients with >median levels of sIL-1R2 in the acute phase were more likely to have increased change in LVEDVi and LVESVi. Importantly, sIL-1R2 remained significantly associated with change in LVEDVi and LVESVi also after adjustment for clinical covariates. Conclusion: Levels of sIL-1R2 are independently associated with parameters of LV adverse remodelling following STEMI. (C 18 Elsevier B.V. All rights reserved.

  • 43.
    Fromell, Karin
    et al.
    Uppsala Universit.
    Duhrkop, Claudia
    Uppsala University.
    Kozarcanin, Huda
    Uppsala University.
    Johansson, Ulrika
    Uppsala University.
    Skjoedt, Mikkel-Ole
    Rigshosp, Denmark.
    Garred, Peter
    Rigshosp, Denmark.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    The lectin pathway of complement and the contact/kallikrein system are integrated2018In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, p. 151-152Article in journal (Other academic)
  • 44.
    Nyberg, Maria
    et al.
    Kristianstad University.
    Olsson, Viktoria
    Kristianstad University.
    Örtman, Gerd
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Pajalic, Zada
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Kristianstad University ; Oslo and Akershus University College of Applied Sciences, Norway.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Blücher, Anna
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lindborg, Ann-Louise
    Mälardalen University.
    Wendin, Karin
    Kristianstad University ; University of Copenhagen, Denmark ; Technical Research Institute of Sweden, Lund.
    Westergren, Albert
    Kristianstad University.
    The meal as a performance: food and meal practices beyond health and nutrition2018In: Ageing & Society, ISSN 0144-686X, E-ISSN 1469-1779, no 1, p. 83-107Article in journal (Refereed)
    Abstract [en]

    The proportion of elderly people in the population is increasing, presenting a number of new challenges in society. The purpose of this qualitative study was to in- vestigate how elderly persons with motoric eating difficulties perceive and perform their food and meal practices in everyday life. By using Goffman’s concept of performance as a theoretical framework together with Bourdieu’s thinking on habitus, a deeper understanding of food and meal practices is obtained. Semi- structured interviews were conducted with  elderly people (aged between  and  years) and meal observations were carried out with  of these people. Participants were found to manage food and meal practices by continuously adjust- ing and adapting to the new conditions arising as a result of eating difficulties. This was displayed by conscious planning of what to eat and when, avoiding certain foods and beverages, using simple eating aids, but also withdrawing socially during the meals. All these adjustments were important in order to be able to demonstrate proper food and meal behaviour, to maintain the façade and to act according to the perceived norms. As well as being a pleasurable event, food and meals were also perceived in terms of being important for maintaining health and as ‘fuel’ where the main purpose is to sustain life. This was strongly connected to the social context and the ability to enjoy food and meals with family members and friends, which appeared to be particularly crucial due to the impending risk of failing the meal performance. 

  • 45.
    Biglarnia, Ali-Reza
    et al.
    Skåne University Hospital;Lund University.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    The multifaceted role of complement in kidney transplantation2018In: Nature Reviews Nephrology, ISSN 1759-5061, E-ISSN 1759-507X, Vol. 14, no 12, p. 767-781Article, review/survey (Refereed)
    Abstract [en]

    Increasing evidence indicates an integral role for the complement system in the deleterious inflammatory reactions that occur during critical phases of the transplantation process, such as brain or cardiac death of the donor, surgical trauma, organ preservation and ischaemia-reperfusion injury, as well as in humoral and cellular immune responses to the allograft. Ischaemia is the most common cause of complement activation in kidney transplantation and in combination with reperfusion is a major cause of inflammation and graft damage. Complement also has a prominent role in antibody-mediated rejection (ABMR) owing to ABO and HL A incompatibility, which leads to devastating damage to the transplanted kidney. Emerging drugs and treatment modalities that inhibit complement activation at various stages in the complement cascade are being developed to ameliorate the damage caused by complement activation in transplantation. These promising new therapies have various potential applications at different stages in the process of transplantation, including inhibiting the destructive effects of ischaemia and/or reperfusion injury, treating ABMR, inducing accommodation and modulating the adaptive immune response.

  • 46.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Khalid, Syma
    Univ Southampton, UK.
    Aponte-Santamaria, Camilo
    Univ Los Andes, Colombia;Heidelberg Univ, Germany.
    Arutyunova, Elena
    Univ Alberta, Canada.
    Becker, Marlon
    Univ Munster, Germany.
    Boyd, Kevin J.
    Univ Connecticut, USA.
    Christensen, Mikkel
    Aarhus Univ, Denmark;Sinodanish Ctr Educ & Res, Peoples Republic of China.
    Coimbra, Joao T. S.
    Univ Porto, Portugal.
    Concilio, Simona
    Univ Salerno, Italy.
    Daday, Csaba
    Heidelberg Inst Theoret Studies, Germany.
    van Eerden, Floris J.
    Univ Groningen, Netherlands.
    Fernandes, Pedro A.
    Univ Porto, Portugal.
    Graeter, Frauke
    Heidelberg Univ, Germany;Heidelberg Inst Theoret Studies, Germany.
    Hakobyan, Davit
    Univ Munster, Germany.
    Heuer, Andreas
    Univ Munster, Germany.
    Karathanou, Konstantina
    Free Univ Berlin, Germany.
    Keller, Fabian
    Univ Munster, Germany.
    Lemieux, M. Joanne
    Univ Alberta, Canada.
    Marrink, Siewert J.
    Univ Groningen, Netherlands.
    May, Eric R.
    Univ Connecticut, USA.
    Mazumdar, Antara
    Univ Groningen, Netherlands.
    Naftalin, Richard
    Kings Coll London, UK.
    Pickholz, Monica
    Univ Buenos Aires, Argentina.
    Piotto, Stefano
    Univ Salerno, Italy.
    Pohl, Peter
    Johannes Kepler Univ Linz, Austria.
    Quinn, Peter
    Kings Coll London, UK.
    Ramos, Maria J.
    Univ Porto, Portugal.
    Schiott, Birgit
    Aarhus Univ, Denmark.
    Sengupta, Durba
    Natl Chem Lab, India.
    Sessa, Lucia
    Univ Salerno, Italy.
    Vanni, Stefano
    Univ Fribourg, Switzerland.
    Zeppelin, Talia
    Aarhus Univ, Denmark.
    Zoni, Valeria
    Univ Fribourg, Switzerland.
    Bondar, Ana-Nicoleta
    Free Univ Berlin, Germany.
    Domene, Carmen
    Univ Bath, UK;Univ Oxford, UK.
    Understanding Conformational Dynamics of Complex Lipid Mixtures Relevant to Biology2018In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 251, no 5-6, p. 609-631Article, review/survey (Refereed)
    Abstract [en]

    This is a perspective article entitled "Frontiers in computational biophysics: understanding conformational dynamics of complex lipid mixtures relevant to biology" which is following a CECAM meeting with the same name.

  • 47.
    Jönsson, Boel
    Kemivärlden Biotech.
    Jacobsson, Erik (Contributor)
    Uppsala University.
    Andersson, Håkan S. (Contributor)
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Världens längsta djur gör gift2018In: Kemivärlden Biotech/Kemisk tidskrift, ISSN 1653-5596, no 3, p. 20-21Article in journal (Other (popular science, discussion, etc.))
    Abstract [sv]

    Världens längsta djur, slemmasken långsnöre, producerar nervgifter som kan döda både krabbor och kackerlackor.

  • 48.
    Nilsson, Bo
    et al.
    Uppsala University.
    Asif, Sana
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Manell, Elin
    Swedish University of Agricultural Sciences.
    Biglarnia, Alireza
    Skåne University Hospital.
    Jensen-Waern, Marianne
    Swedish University of Agricultural Sciences.
    Teramura, Yuji
    Uppsala University;Univ Tokyo, Japan.
    A protective role of complement regulators linked to a PEG phospholipid construct in reducing ischemic reperfusion injury in transplantation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 208-208Article in journal (Other academic)
  • 49.
    Fromell, Karin
    et al.
    Uppsala University.
    Yang, Yi
    University of Gothenburg.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Berglin, Mattias
    Gothenburg University;RISE Res Inst Sweden Chem Mat & Surfaces.
    Elwing, Hans
    University of Gothenburg.
    Absence of conformational change in complement factor 3 and factor XII adsorbed to acrylate polymers is related to a high degree of polymer backbone flexibility2017In: Biointerphases, ISSN 1934-8630, E-ISSN 1559-4106, Vol. 12, no 2, article id 02D417Article in journal (Refereed)
    Abstract [en]

    In previous investigations, the authors have examined the adsorption of albumin, immunoglobulin, and fibrinogen to a series of acrylate polymers with different backbone and side-group flexibility. The authors showed that protein adsorption to acrylates with high flexibility, such as poly(lauryl methacrylate) (PLMA), tends to preserve native conformation. In the present study, the authors have continued this work by examining the conformational changes that occur during the binding of complement factor 3 (C3) and coagulation factor XII (FXII). Native C3 adsorbed readily to all solid surfaces tested, including a series of acrylate surfaces of varying backbone flexibility. However, a monoclonal antibody recognizing a "hidden" epitope of C3 (only exposed during C3 activation or denaturation) bound to the C3 on the rigid acrylate surfaces or on polystyrene (also rigid), but not to C3 on the flexible PLMA, indicating that varying degrees of conformational change had occurred with binding to different surfaces. Similarly, FXII was activated only on the rigid poly(butyl methacrylate) surface, as assessed by the formation of FXIIa-antithrombin (AT) complexes; in contrast, it remained in its native form on the flexible PLMA surface. The authors also found that water wettability hysteresis, defined as the difference between the advancing and receding contact angles, was highest for the PLMA surface, indicating that a dynamic change in the interface polymer structure may help protect the adsorbed protein from conformational changes and denaturation. (C) 2017 Author(s).

  • 50.
    Andersson, Håkan S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Jacobsson, Erik
    Uppsala University.
    Strand, Malin
    Swedish agricultural university (SLU).
    Peigneur, Steve
    University of Leuven (KU Leuven), Belgium.
    Lebbe, Eline
    University of Leuven (KU Leuven), Belgium.
    Rosengren, Johan
    University of Queensland.
    Tytgat, Jan
    University of Leuven (KU Leuven), Belgium.
    Göransson, Ulf
    Uppsala University.
    Alpha-nemertides, a novel family of marine peptide neurotoxins from ribbon worms2017Conference paper (Other academic)
12345 1 - 50 of 202
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