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  • 1.
    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)
  • 2.
    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).

  • 3.
    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)
  • 4.
    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. University of Kansas, USA.
    Waldenström, Jonas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Antimicrobial activity differences in reduced vs. oxidized AvBD3b peptides in mallards (Anas platyrhynchos).2017Conference paper (Other academic)
  • 5.
    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.
    Chapman, Joanne R.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Waldenström, Jonas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Bactericidal tests of mallard (Anas plathyrynchos) ß-defensin alleles2017Conference paper (Other academic)
  • 6.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Soveri, Inga
    Uppsala University.
    Hilborn, Jons
    Uppsala University.
    Fellström, Bengt
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Cardiovascular disease in haemodialysis: role of the intravascular innate immune system2017In: Nature Reviews Nephrology, ISSN 1759-5061, E-ISSN 1759-507X, Vol. 13, no 5, p. 285-296Article, review/survey (Refereed)
    Abstract [en]

    Haemodialysis is a life-saving renal replacement modality for end-stage renal disease, but this therapy also represents a major challenge to the intravascular innate immune system, which is comprised of the complement, contact and coagulation systems. Chronic inflammation is strongly associated with cardiovascular disease (CVD) in patients on haemodialysis. Biomaterial-induced contact activation of proteins within the plasma cascade systems occurs during haemodialysis and initially leads to local generation of inflammatory mediators on the biomaterial surface. The inflammation is spread by soluble activation products and mediators that are generated during haemodialysis and transported in the extracorporeal circuit back into the patient together with activated leukocytes and platelets. The combined effect is activation of the endothelium of the cardiovascular system, which loses its anti-thrombotic and anti-inflammatory properties, leading to atherogenesis and arteriosclerosis. This concept suggests that maximum suppression of the intravascular innate immune system is needed to minimize the risk of CVD in patients on haemodialysis. A potential approach to achieve this goal is to treat patients with broad-specificity systemic drugs that target more than one of the intravascular cascade systems. Alternatively, 'stealth' biomaterials that cause minimal cascade system activation could be used in haemodialysis circuits.

  • 7.
    Teramura, Yuji
    et al.
    University of Tokyo, Japan;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.
    Gustafson, Elisabet
    Uppsala University Hospital.
    Nilsson, Bo
    Uppsala University.
    Cell Adhesion Induced Using Surface Modification with Cell-Penetrating Peptide-Conjugated Poly(ethylene glycol)-Lipid: A New Cell Glue for 3D Cell-Based Structures2017In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 9, no 1, p. 244-254Article in journal (Refereed)
    Abstract [en]

    We synthesized a novel material, cell-penetrating peptide conjugated poly(ethylene glycol)-lipid (CPP-PEG-lipid), that can induce the adhesion of floating cells. Firm cell adhesion with spreading could be induced by cell surface modification with the CPP-PEG-lipids. Cell adhesion was induced by CPPs but not by any other cationic short peptides we tested. Here, we demonstrated adherence using the floating cell line CCRF-CEM as well as primary human T cells, B cells, erythrocytes, and hepatocytes. As compared to cells grown in suspension, adherent cells were more rapidly induced to attach to substrates with the cell-surface modification. The critical factor for attachment was localization of CPPs at the cell membrane by PEG-lipids with PEG > 20 kDa. These cationic CPPs on PEG chains were able to interact with substrate surfaces such as polystyrene (PS) surfaces, glass surfaces, and PS microfibers that are negatively charged, inducing firm cell adhesion and cell spreading. Also, as opposed to normal cationic peptides that interact strongly with cell membranes, CPPs were less interactive with the cell surfaces because of their cell-penetrating property, making them more available for adhering cells to the substrate surface. No effects on cell viability or cell proliferation were observed after the induction of cell adhesion. With this technique, cells could be easily immobilized onto PS microfibers, an important step in fabricating 3D cell-based structures. Cells immobilized onto 3D PS microfibers were alive, and human hepatocytes showed normal production of urea and albumin on the microfibers. This method is novel in inducing firm cell adhesion-via a one-step treatment.

  • 8.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Norway.
    Johnson, Christina
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Pischke, Soren E.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Fure, Hilde
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Landsem, Anne
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Bergseth, Grethe
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Haugaard-Kedström, Linda M.
    Univ Copenhagen, Denmark.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Brekke, Ole-Lars
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Mollnes, Tom Eirik
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Characterization of a novel whole blood model for the study of thrombin in complement activation and inflammation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 136-137Article in journal (Other academic)
  • 9.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Agmon, Noam
    Hebrew Univ Jerusalem, Israel.
    Charge Transfer in Proteins: In Celebration of Hemi Gutman's 80th Birthday2017In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 57, no 5, p. 355-356Article in journal (Other academic)
  • 10.
    Kathiravan, Suppan
    et al.
    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. Uppsala University.
    Cobalt Catalyzed, Regioselective C(sp(2))-H Activation of Amides with 1,3-Diynes2017In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 18, p. 4758-4761Article in journal (Refereed)
    Abstract [en]

    The development of a first row transition metal (cobalt)-based catalyst for the as yet unexplored CH activation-driven reaction of 1,3-diynes, themselves a functional class of interest in a range of application areas, to form isoquinolinonesan important structural motif in a number of biologically active substancesis presented. This versatile and inexpensive catalyst employs a covalently attached bidendate-directing group, 8-aminoquinoline. The template directs the CH activation and facilitates the synthesis of a wide range of alkynylated heterocycles under mild conditions and with excellent regioselectivity. This strategy provides a novel and efficient route to diverse heterocyclic frameworks as demonstrated by its late stage application in bisheterocycle syntheses.

  • 11.
    Denk, Stephanie
    et al.
    Univ Hosp Ulm, Germany.
    Neher, Miriam D.
    Univ Hosp Ulm, Germany.
    Messerer, David A. C.
    Univ Hosp Ulm, Germany.
    Wiegner, Rebecca
    Univ Hosp Ulm, Germany.
    Nilsson, Bo
    Uppsala University.
    Rittirsch, Daniel
    Univ Hosp Zurich, Switzerland.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Weckbach, Sebastian
    Ulm Univ, Germany.
    Ignatius, Anita
    Ulm Univ, Germany.
    Kalbitz, Miriam
    Univ Hosp Ulm, Germany.
    Gebhard, Florian
    Univ Hosp Ulm, Germany.
    Weiss, Manfred E.
    Univ Hosp Ulm, Germany.
    Vogt, Josef
    Ulm Univ, Germany.
    Radermacher, Peter
    Ulm Univ, Germany.
    Koehl, Joerg
    Univ Lubeck, Germany;Cincinnati Childrens Hosp Med Ctr, USA.
    Lambris, John D.
    Univ Penn, USA.
    Huber-Lang, Markus S.
    Univ Hosp Ulm, Germany.
    Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects2017In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 198, no 12, p. 4846-4854Article in journal (Refereed)
    Abstract [en]

    During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pH(i)), we propose a direct mechanistic link between complement activation and neutrophil pHi. In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pHi of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pHi. These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pHi balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.

  • 12.
    Mohlin, Camilla
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Petrus-Reurer, S.
    Karolinska Institutet;Karolinska Univ Hosp.
    Lanner, F.
    Karolinska Institutet;Karolinska Univ Hosp.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Kvanta, A.
    Karolinska Institutet.
    Nilsson, B.
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Complement system proteins in human embryonic stem cell-derived retinal pigment epithelial cells co-cultured with or without porcine retina2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 162-163Article in journal (Other academic)
  • 13.
    Ahlstrand, Emma
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Zukerman Schpector, Julio
    Universidade Federal de São Carlos, Brazil.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Computer simulations of alkali-acetate solutions: Accuracy of the forcefields in difference concentrations2017In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 147, p. 1-10, article id 194102Article in journal (Refereed)
    Abstract [en]

    When proteins are solvated in electrolyte solutions that contain alkali ions, the ions interact mostlywith carboxylates on the protein surface. Correctly accounting for alkali-carboxylate interactionsis thus important for realistic simulations of proteins. Acetates are the simplest carboxylates thatare amphipathic, and experimental data for alkali acetate solutions are available and can be comparedwith observables obtained from simulations. We carried out molecular dynamics simulations of alkali acetate solutions using polarizable and non-polarizable forcefields and examined the ionacetateinteractions. In particular, activity coefficients and association constants were studied in a range of concentrations (0.03, 0.1, and 1M). In addition, quantum-mechanics (QM) based energy decomposition analysis was performed in order to estimate the contribution of polarization, electrostatics, dispersion, and QM (non-classical) effects on the cation-acetate and cation-water interactions. Simulations of Li-acetate solutions in general overestimated the binding of Li+ and acetates. In lower concentrations, the activity coefficients of alkali-acetate solutions were too high, which is suggested to be due to the simulation protocol and not the forcefields. Energy decomposition analysis suggested that improvement of the forcefield parameters to enable accurate simulations of Li-acetate solution scan be achieved but may require the use of a polarizable forcefield. Importantly, simulations with some ion parameters could not reproduce the correct ion-oxygen distances, which calls for caution in thechoice of ion parameters when protein simulations are performed in electrolyte solutions.

  • 14.
    Gustafson, Elisabet
    et al.
    Uppsala University Hospital, Sweden.
    Asif, Sana
    Uppsala University, Sweden.
    Kozarcanin, Huda
    Uppsala University, Sweden.
    Elgue, Graciela
    Uppsala University, Sweden.
    Meurling, Staffan
    Uppsala University Hospital, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Bo
    Uppsala University, Sweden.
    Control of IBMIR Induced by Fresh and Cryopreserved Hepatocytes by Low Molecular Weight Dextran Sulfate Versus Heparin2017In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 1, p. 71-81Article in journal (Refereed)
    Abstract [en]

    Rapid destruction of hepatocytes after hepatocyte transplantation has hampered the application of this procedure clinically. The instant blood-mediated inflammatory reaction (IBMIR) is a plausible underlying cause for this cell loss. The present study was designed to evaluate the capacity of low molecular weight dextran sulfate (LMW-DS) to control these initial reactions from the innate immune system. Fresh and cryopreserved hepatocytes were tested in an in vitro whole-blood model using ABO-compatible blood. The ability to elicit IBMIR and the capacity of LMW-DS (100 mu g/ml) to attenuate the degree of activation of the cascade systems were monitored. The effect was also compared to conventional anticoagulant therapy using unfractionated heparin (1 IU/ml). Both fresh and freeze thawed hepatocytes elicited IBMIR to the same extent. LMW-DS reduced the platelet loss and maintained the cell counts at the same degree as unfractionated heparin, but controlled the coagulation and complement systems significantly more efficiently than heparin. LMW-DS also attenuated the IBMIR elicited by freeze thawed cells. Therefore, LMW-DS inhibits the cascade systems and maintains the cell counts in blood triggered by both fresh and cryopreserved hepatocytes in direct contact with ABO-matched blood. LMW-DS at a previously used and clinically applicable concentration (100 mu g/ml) inhibits IBMIR in vitro and is therefore a potential IBMIR inhibitor in hepatocyte transplantation.

  • 15.
    Karlsson, Björn C. G.
    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.
    Dilution of whisky - the molecular perspective2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 6489Article in journal (Refereed)
    Abstract [en]

    Whisky is distilled to around 70% alcohol by volume (vol-%) then diluted to about 40 vol-%, and often drunk after further slight dilution to enhance its taste. The taste of whisky is primarily associated with amphipathic molecules, such as guaiacol, but why and how dilution enhances the taste is not well understood. We carried out computer simulations of water-ethanol mixtures in the presence of guaiacol, providing atomistic details on the structure of the liquid mixture. We found that guaiacol is preferentially associated with ethanol, and, therefore, primarily found at the liquid-air interface in mixtures that contain up to 45 vol-% of ethanol. At ethanol concentrations of 59 vol-% or higher, guaiacol is increasingly surrounded by ethanol molecules and is driven to the bulk. This indicates that the taste of guaiacol in the whisky would be enhanced upon dilution prior to bottling. Our findings may apply to other flavour-giving amphipathic molecules and could contribute to optimising the production of spirits for desired tastes. Furthermore, it sheds light on the molecular structure of water-alcohol mixtures that contain small solutes, and reveals that interactions with the water may be negligible already at 89 vol-% of ethanol.

  • 16.
    Seisenbaeva, Gulaim A.
    et al.
    Swedish University of Agricultural Sciences.
    Fromell, Karin
    Uppsala University.
    Vinogradov, Vasiliy V.
    ITMO Univ Kronverksky, Russia.
    Terekhov, Aleksey N.
    Ivanovo State Med Acad, Russia.
    Pakhomov, Andrey V.
    Ivanovo State Med Acad, Russia.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Vinogradov, Vladimir V.
    ITMO Univ Kronverksky, Russia.
    Kessler, Vadim G.
    Swedish University of Agricultural Sciences.
    Dispersion of TiO2 nanoparticles improves burn wound healing and tissue regeneration through specific interaction with blood serum proteins2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 15448Article in journal (Refereed)
    Abstract [en]

    Burn wounds are one of the most important causes of mortality and especially morbidity around the world. Burn wound healing and skin tissue regeneration remain thus one of the most important challenges facing the mankind. In the present study we have addressed this challenge, applying a solution-stabilized dispersion TiO2 nanoparticles, hypothesizing that their ability to adsorb proteins will render them a strong capacity in inducing body fluid coagulation and create a protective hybrid material coating. The in vitro study of interaction between human blood and titania resulted at enhanced TiO2 concentrations in formation of rather dense gel composite materials and even at lower content revealed specific adsorption pattern initiating the cascade response, promising to facilitate the regrowth of the skin. The subsequent in vivo study of the healing of burn wounds in rats demonstrated formation of a strongly adherent crust of a nanocomposite, preventing infection and inflammation with quicker reduction of wound area compared to untreated control. The most important result in applying the TiO2 dispersion was the apparently improved regeneration of damaged tissues with appreciable decrease in scar formation and skin color anomalies.

  • 17.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Thomas, Anub Mathew
    Oslo Univ Hosp, Norway.
    Bergseth, Grethe
    Nordland Hosp, Norway.
    Gustavsen, Alice
    Oslo Univ Hosp, Norway.
    Volokhina, Elena B.
    Radboud Univ Nijmegen, Netherlands;Radboud Univ Nijmegen, Netherlands.
    van den Heuvel, Lambertus P.
    Radboud Univ Nijmegen, Netherlands;Univ Hosp Leuven, Belgium.
    Barratt-Due, Andreas
    Oslo Univ Hosp, Norway.
    Mollnes, Tom E.
    Oslo Univ Hosp, Rikshosp, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 111-114Article in journal (Refereed)
    Abstract [en]

    The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay. In the present study, we identified expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. By size exclusion chromatography of patient serum obtained before and after infusion of eculizumab, we document that the neoepitope was exposed in the fractions containing the eculizumab-C5 complexes, being positive in this actual C5a assay and negative in others. Furthermore, we confirmed that it was the eculizumab-C5 complexes that were detected in the C5a assay by adding an anti-IgG4 antibody as detection antibody. Competitive inhibition by anti-C5 antibodies localized the epitope to the C5a moiety of C5. Finally, acidification of C5, known to alter C5 conformation, induced a neoepitope reacting identical to the one we explored, in the C5a assays. These data are important for interpretation of complement analyses in patients treated with eculizumab.

  • 18.
    Suriyanarayanan, Subramanian
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Mandal, Sudip
    Indian Inst Technol Madras, India.
    Ramanujam, Kothandaraman
    Indian Inst Technol Madras, India.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Electrochemically synthesized molecularly imprinted polythiophene nanostructures as recognition elements for an aspirin-chemosensor2017In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 253, p. 428-436Article in journal (Refereed)
    Abstract [en]

    A chemosensor utilizing electro-polymerized film, as recognition element, has been devised and tested for selective determination of aspirin. The sensor consists of molecularly imprinted polymer (MIP) recognition elements electrodeposited as polymeric nanowires on gold-coated quartz resonator. A nano structures were prepared by electrochemical co-polymerization of the preformed complex between the template, aspirin, the functional monomers, 3-thienylboronic acid (3-TBA) and 3-thiopheneacetic acid (3-TAA), and thiophene, which was employed as a cross-linker. This nanostructure upon leaching aspirin serve as MIP. Polymerizations were performed in acetonitrile (MIP-org) as well as a micelle forming medium (MIP-mic). For MIP nanowire (MIP-ano) synthesis, sacrificial alumina templates were used during electro-polymerization in acetonitrile. Scanning electron microscope studies revealed compactly arranged polythiophene nanowires of uniform thickness in MIP-ano film, and MIP-mic film produced aggregated micron sized polymer structures. Density functional theoretical studies indicated a stable hydrogen bond-based complexation of aspirin by 3-TBA and 3-TAA in the pre-polymerization mixture implying that the MIP film thus prepared could selectively rebind the aspirin template. The MIP-ano-based chemosensor was sensitive towards aspirin (0.5-10 mM), over clinically relevant range (0.15-0.5 mM) under optimized FIA conditions. The sensitivity (20.62 Hz/mM) of the MIP-ano was eight and fifteen times higher than the MIP-mic (2.80 Hz/mM) and MIP-org (1.10 Hz/mM). Notably, the sensor selectively discriminates aspirin from structurally or functionally related interferants and metabolites, such as, salicylic acid, acetylsalicyloyl chloride and ibuprofen. (C) 2017 Elsevier B.V. All rights reserved.

  • 19.
    Fromell, Karin
    et al.
    Uppsala University.
    Duhrkop, Claudia
    Uppsala University.
    Johansson, Ulrika
    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.
    Forms of contact-activated C3 associated with AP convertase formation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 141-141Article in journal (Other academic)
  • 20.
    Ahlstrand, Emma
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Hermansson, Kersti
    Uppsala University.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Interaction Energies in Complexes of Zn and Amino Acids: A Comparison of Ab Initio and Force Field Based Calculations2017In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 121, no 13, p. 2643-2654Article in journal (Refereed)
    Abstract [en]

    Zinc plays important roles in structural stabilization of proteins, eniyine catalysis, and signal transduction. Many Zn binding sites are located at the interface between the protein and the cellular fluid. In aqueous solutions, Zn ions adopt an octahedral coordination, while in proteins zinc can have different coordinations, with a tetrahedral conformation found most frequently. The dynainics of Zn binding to proteins and the formation of complexes that involve Zn are dictated by interactions between Zn and its binding partners. We calculated the interaction energies between Zn and its ligands in complexes that mimic protein binding sites and in Zn complexes of water and one or two amino acid moieties, using quantum mechanics (QM) and molecular mechanics (MM). It was found that MM calculations that neglect or only approximate polarizability did not reproduce even the relative order of the QM interaction energies in these complexes. Interaction energies calculated with the CHARMM-Diode polarizable force field agreed better with the ab initio results,:although the deviations between QM and MM were still rather large (40-96 kcallmol). In order to gain further insight into Zn ligand interactions, the free energies of interaction were estimated by QM calculations with continuum solvent representation, and we performed energy decomposition analysis calculations to examine the characteristics of the different complexes. The ligand-types were found to have high impact on the relative strength of polarization and electrostatic interactions. Interestingly, ligand ligand interactions did not play a significant role in the binding of Zn. Finally) analysis of ligand exchange energies suggests that carboxylates could be exchanged with water molecules, which explains the flexibility in Zn:binding dynamics. An exchange between earboxylate (Asp/Glii) and imidazole (His) is less likely.

  • 21.
    Kathiravan, Suppan
    et al.
    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. Uppsala University.
    Monoprotected L-Amino Acid (L-MPAA), Accelerated Bromination, Chlorination, and Iodination of C(sp(2))-H Bonds by Iridium(III) Catalysis2017In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 29, p. 7031-7036Article in journal (Refereed)
    Abstract [en]

    Halogenated arenes are important structural motifs commonly found in biologically active molecules and used for a variety of transformations in organic synthesis. Herein, we report the mono-protected L-amino acid (L-MPAA) accelerated iridium(III)-catalyzed halogenation of (hetero)anilides at room temperature. This reaction constitutes the first example of an iridium(III)/L-MPAA-catalyzed general halogenation of (hetero)arenes through C(sp(2))-H activation. Furthermore, we demonstrate the potential utility of our method through its use in the synthesis of a quinolone derivative.

  • 22.
    Maganhi, Stella Hernandez
    et al.
    Federal University of São Carlos, Brazil.
    Jensen, Patrizia
    National Center for Tumor Diseases (NCT), Germany;German Cancer Research Center (DKFZ) Heidelberg, Germany.
    Caracelli, Ignez
    Federal University of São Carlos, Brazil.
    Schpector, Julio Zukerman
    Federal University of São Carlos, Brazil.
    Froehling, Stefan
    National Center for Tumor Diseases (NCT), Germany;German Cancer Research Center (DKFZ) Heidelberg, Germany ; Heidelberg University Hospital, Germany ; German Cancer Consortium (DKTK), Germany.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Palbociclib can overcome mutations in cyclin dependent kinase 6 that break hydrogen bonds between the drug and the protein2017In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 26, no 4, p. 870-879Article in journal (Refereed)
    Abstract [en]

    Inhibition of cyclin dependent kinases (CDKs) 4 and 6 prevent cells from entering the synthesis phase of the cell cycle. CDK4 and 6 are therefore important drug targets in various cancers. The selective CDK4/6 inhibitor palbociclib is approved for the treatment of breast cancer and has shown activity in a cellular model of mixed lineage leukaemia (MLL)-rearranged acute myeloid leukaemia (AML). We studied the interactions of palbociclib and CDK6 using molecular dynamics simulations. Analysis of the simulations suggested several interactions that stabilized the drug in its binding site and that were not observed in the crystal structure of the protein-drug complex. These included a hydrogen bond to His 100 that was hitherto not reported and several hydrophobic contacts. Evolutionary-based bioinformatic analysis was used to suggest two mutants, D163G and H100L that would potentially yield drug resistance, as they lead to loss of important protein-drug interactions without hindering the viability of the protein. One of the mutants involved a change in the glycine of the well-conserved DFG motif of the kinase. Interestingly, CDK6-dependent human AML cells stably expressing either mutant retained sensitivity to palbociclib, indicating that the protein-drug interactions are not affected by these. Furthermore, the cells were proliferative in the absence of palbociclib, indicating that the Asp to Gly mutation in the DFG motif did not interfere with the catalytic activity of the protein.

  • 23.
    Harboe, Morten
    et al.
    Oslo University Hospital, Norway.
    Johnson, Christina
    Oslo University Hospital, Norway.
    Nymo, Stig
    Nordland Hospital, Norway.
    Ekholt, Karin
    Oslo University Hospital, Norway.
    Schjalm, Camilla
    Oslo University Hospital, Norway.
    Lindstad, Julie K.
    Oslo University Hospital, Norway.
    Pharo, Anne
    Oslo University Hospital, Norway.
    Hellerud, Bernt Christian
    Oslo University Hospital, Norway.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Mollnes, Tom Eirik
    Oslo University Hospital, Norway ; Nordland Hospital, Norway ; University of Oslo, Norway ; University of Tromsø, Norway ; Norwegian University of Science and Technology, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo University Hospital, Norway ; University of Oslo, Norway.
    Properdin binding to complement activating surfaces depends on initial C3b deposition2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 4, p. E534-E539Article in journal (Refereed)
    Abstract [en]

    Two functions have been assigned to properdin; stabilization of the alternative convertase, C3bBb, is well accepted, whereas the role of properdin as pattern recognition molecule is controversial. The presence of nonphysiological aggregates in purified properdin preparations and experimental models that do not allow discrimination between the initial binding of properdin and binding secondary to C3b deposition is a critical factor contributing to this controversy. In previous work, by inhibiting C3, we showed that properdin binding to zymosan and Escherichia coli is not a primary event, but rather is solely dependent on initial C3 deposition. In the present study, we found that properdin in human serum bound dose-dependently to solid-phase myeloperoxidase. This binding was dependent on C3 activation, as demonstrated by the lack of binding in human serum with the C3-inhibitor compstatin Cp40, in C3-depleted human serum, or when purified properdin is applied in buffer. Similarly, binding of properdin to the surface of human umbilical vein endothelial cells or Neisseria meningitidis after incubation with human serum was completely C3-dependent, as detected by flow cytometry. Properdin, which lacks the structural homology shared by other complement pattern recognition molecules and has its major function in stabilizing the C3bBb convertase, was found to bind both exogenous and endogenous molecular patterns in a completely C3-dependent manner. We therefore challenge the view of properdin as a pattern recognition molecule, and argue that the experimental conditions used to test this hypothesis should be carefully considered, with emphasis on controlling initial C3 activation under physiological conditions.

  • 24.
    Becconi, Olga
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Cagliari, Italy.
    Ahlstrand, Emma
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Salis, Andrea
    University of Cagliari, Italy.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Protein-ion Interactions: Simulations of Bovine Serum Albumin in Physiological Solutions of NaCl, KCl and LiCl2017In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 57, no 5, p. 403-412Article in journal (Refereed)
    Abstract [en]

    Specific interactions that depend on the nature of electrolytes are observed when proteins and other molecules are studied by potentiometric, spectroscopic and theoretical methods at high salt concentrations. More recently, it became clear that such interactions may also be observed in solutions that can be described by the Debye-Hückel theory, i.e., at physiological (0.1 mol dm−3) and lower concentrations. We carried out molecular dynamics simulations of bovine serum albumin in physiological solutions at T=300 and 350 K. Analysis of the simulations revealed some differences between LiCl solutions and those of NaCl and KCl. The binding of Li+ ions to the protein was associated with a negative free energy of interaction whereas much fewer Na+ and K+ ions were associated with the protein surface. Interestingly, unlike other proteins BSA does not show a preference to Na+ over K+. Quantum chemical calculations identified a significant contribution from polarisation to the hydration of Li+ and (to a lesser degree) Na+, which may indicate that polarisable force-fields will provide more accurate results for such systems.

  • 25.
    Kathiravan, Suppan
    et al.
    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. Uppsala University.
    Rhodium(III)-catalysed, redox-neutral C(sp(2))-H alkenylation using pivalimide as a directing group with internal alkynes2017In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 58, no 1, p. 1-4Article in journal (Refereed)
    Abstract [en]

    In the presence of [RhCp*Cl(2)l(2), N-pivaloyl anilines react with internal alkynes to give the corresponding 2-alkenylpivalimides under redox neutral conditions through C-H activation. This redox neutral hydroarylation, which does not require an external organic acid, unlocks a regioselective synthetic route to 2-alkenyl anilines and is generally applicable to diversely substituted electron rich and electron poor pivalimides. (C) 2016 Elsevier Ltd. All rights reserved.

  • 26.
    Shahini, Negar
    et al.
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Michelsen, Annika E
    Oslo University Hospital, Norway;University of Oslo, 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, Norway.
    Ekholt, Karin
    University of Oslo, Norway.
    Gullestad, Lars
    University of Oslo, Norway;Oslo University Hospital, Norway.
    Broch, Kaspar
    Oslo University Hospital, Norway.
    Dahl, Christen P.
    Oslo University Hospital, Norway.
    Aukrust, Pål
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Ueland, Thor
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Mollnes, Tom Eirik
    University of Oslo, Norway;Oslo University Hospital, Norway;University of Tromsø, Norway;Norwegian University of Science and Technology, Norway.
    Yndestad, Arne
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Louwe, Mieke C.
    Oslo University Hospital, Norway;University of Oslo, Norway.
    The alternative complement pathway is dysregulated in patients with chronic heart failure2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, p. 1-10, article id 42532Article in journal (Refereed)
    Abstract [en]

    The complement system, an important arm of the innate immune system, is activated in heart failure (HF). We hypothesized that HF patients are characterized by an imbalance of alternative amplification loop components; including properdin and complement factor D and the alternative pathway inhibitor factor H. These components and the activation product, terminal complement complex (TCC), were measured in plasma from 188 HF patients and 67 age- and sex- matched healthy controls by enzyme immunoassay. Our main findings were: (i) Compared to controls, patients with HF had significantly increased levels of factor D and TCC, and decreased levels of properdin, particularly patients with advanced clinical disorder (i.e., NYHA functional class IV), (ii) Levels of factor D and properdin in HF patients were correlated with measures of systemic inflammation (i.e., C-reactive protein), neurohormonal deterioration (i.e., Nt-proBNP), cardiac function, and deteriorated diastolic function, (iii) Low levels of factor H and properdin were associated with adverse outcome in univariate analysis and for factor H, this was also seen in an adjusted model. Our results indicate that dysregulation of circulating components of the alternative pathway explain the increased degree of complement activation and is related to disease severity in HF patients.

  • 27.
    Golker, Kerstin
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala university.
    Olsson, Gustaf D.
    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. Uppsala University.
    The influence of a methyl substituent on molecularly imprinted polymer morphology and recognition – Acrylic acid versus methacrylic acid2017In: European Polymer Journal, ISSN 0014-3057, E-ISSN 1873-1945, Vol. 92, p. 137-149Article in journal (Refereed)
    Abstract [en]

    In this report, we have investigated factors contributing to the morphology and template recognition of bupivacaine-imprinted copolymers of methacrylic acid (MAA) and ethyleneglycol dimethacrylate (EGDMA). To this end, MAA, the most commonly used functional monomer in non-covalent molecular imprinting protocols, was compared and contrasted with the closely related acrylic acid (AA) in terms of polymer morphologies, recognition characteristics, and molecular level events in the corresponding pre-polymerization mixtures. Two series of analogous bupivacaine-imprinted EGDMA-copolymers containing increasing fractions of either AA or MAA were studied through all-component MD simulations in the pre-polymerization phase, equilibrium binding experiments on corresponding synthesized polymers and morphology characterization by N2-sorption measurements. A higher degree of hydrogen bonding frequency between respective functional monomer and bupivacaine was recorded for the mixtures containing AA compared to those containing MAA. In contrast, results from binding experiments demonstrated higher binding capacities for the polymers prepared with MAA than for those prepared with AA, which is explained by differences in polymer morphology. The surface areas and pore volumes of the AA-polymers were higher than for the MAA-polymers and the overall pore structure in the AA-polymers was ink-bottle shaped while the pores in the MAA-polymers were slit-shaped. We suggest that the methyl substituent of MAA contributes to differences in the reaction kinetics for AA and MAA during polymerization and resulted in different morphologies, in particular pore shape, which affected mass-transfer and consequently the binding qualities of the materials. © 2017 Elsevier Ltd

  • 28.
    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.
    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.
    The link between morphology and complement in ocular disease2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 84-99Article, review/survey (Refereed)
    Abstract [en]

    The complement system is a vital component of the immune-priveliged human eye that is always active at a low-grade level, preventing harmful intraocular injuries caused by accumulation of turnover products and controlling pathogens to preserve eye homeostasis and vision. The complement system is a double-edged sword that is essential for protection but may also become harmful and contribute to eye pathology. Here, we review the evidence for the involvement of complement system dysregulation in age-related macular degeneration, glaucoma, uveitis, and neuromyelitis optica, highlighting the relationship between morphogical changes and complement system protein expression and regulation in these diseases. The potential benefits of complement inhibition in age-related macular degeneration, glaucoma, uveitis, and neuromyelitis optica are abundant, as are those of further research to improve our understanding of complement-mediated injury in these diseases.

  • 29.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The molecular mechanism behind resistance of the kinase FLT3 to the inhibitor quizartinib2017In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 85, no 11, p. 2143-2152Article in journal (Refereed)
    Abstract [en]

    Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is a drug target for leukemias. Several potent inhibitors of FLT3 exist, and bind to the inactive form of the enzyme. Unfortunately, resistance due to mutations in the kinase domain of FLT3 limits the therapeutic effects of these inhibitors. As in many other cases, it is not straightforward to explain why certain mutations lead to drug resistance. Extensive fully atomistic molecular dynamics (MD) simulations of FLT3 were carried out with an inhibited form (FLT-quizartinib complex), a free (apo) form, and an active conformation. In all cases, both the wild type (wt) proteins and two resistant mutants (D835F and Y842H) were studied. Analysis of the simulations revealed that impairment of protein-drug interactions cannot explain the resistance mutations in question. Rather, it appears that the active state of the mutant forms is perturbed by the mutations. It is therefore likely that perturbation of deactivation of the protein (which is necessary for drug binding) is responsible for the reduced affinity of the drug to the mutants. Importantly, this study suggests that it is possible to explain the source of resistance by mutations in FLT3 by an analysis of unbiased MD simulations.

1 - 29 of 29
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