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  • 1.
    Chavan, Swapnil
    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.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Acute Toxicity-Supported Chronic Toxicity Prediction: A k-Nearest Neighbor Coupled Read-Across Strategy2015In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 16, no 5, p. 11659-11677Article in journal (Refereed)
    Abstract [en]

    k-nearest neighbor (k-NN) classification model was constructed for 118 RDT NEDO (Repeated Dose Toxicity New Energy and industrial technology Development Organization; currently known as the Hazard Evaluation Support System (HESS)) database chemicals, employing two acute toxicity (LD50)-based classes as a response and using a series of eight PaDEL software-derived fingerprints as predictor variables. A model developed using Estate type fingerprints correctly predicted the LD50 classes for 70 of 94 training set chemicals and 19 of 24 test set chemicals. An individual category was formed for each of the chemicals by extracting its corresponding k-analogs that were identified by k-NN classification. These categories were used to perform the read-across study for prediction of the chronic toxicity, i.e., Lowest Observed Effect Levels (LOEL). We have successfully predicted the LOELs of 54 of 70 training set chemicals (77%) and 14 of 19 test set chemicals (74%) to within an order of magnitude from their experimental LOEL values. Given the success thus far, we conclude that if the k-NN model predicts LD50classes correctly for a certain chemical, then the k-analogs of such a chemical can be successfully used for data gap filling for the LOEL. This model should support the in silico prediction of repeated dose toxicity.

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  • 2.
    Teramura, Yuji
    et al.
    University of Tokyo, Japan.
    Asif, Sana
    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.
    Cell surface engineering for regulation of immune reactions in cell therapy2015In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 865, p. 189-209Article in journal (Refereed)
    Abstract [en]

    Transplantation of the pancreatic islets of Langerhans (islets) is a promising cell therapy for treating insulin-dependent type 1 diabetes mellitus. Islet transplantation is a minimally-invasive technique involving relatively simple surgery. However, after intraportal transplantation, the transplanted islets are attacked by the recipient’s immune system, because they activate a number of systems, including coagulation, complement response, inflammation, immune rejection, and recurrence of autoimmune disease. We have developed a surface modification and microencapsulation technique that protects cells and islets with biomaterials and bioactive substances, which may be useful in clinical settings. This approach employs amphiphilic polymers, which can interact with lipid bilayer membranes, without increasing cell volume. Molecules attached to these polymers can protect transplanted cells and islets from attack by the host immune system. We expect that this surface modification technique will improve graft survival in clinical islet transplantation.

  • 3.
    Carlsson, Hanna
    et al.
    Kalmar County Hospital.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Tjernberg, Ivar
    Kalmar County Hospital.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Complement activation in asymptomatic Lyme borreliosis and neuroborreliosis2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 128-128Article in journal (Other academic)
  • 4.
    Speth, Cornelia
    et al.
    Med Univ Innsbruck, Austria.
    Rambach, Guenter
    Med Univ Innsbruck, Austria.
    Wuerzner, Reinhard
    Med Univ Innsbruck, Austria.
    Lass-Floerl, Cornelia
    Med Univ Innsbruck, Austria.
    Kozarcanin, Huda
    Uppsala University.
    Hamad, Osama A.
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Complement and platelets: Mutual interference in the immune network2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 108-118Article, review/survey (Refereed)
    Abstract [en]

    In recent years, the view of platelets has changed from mere elements of hemostasis to immunological multitaskers. They are connected in manifold ways to other cellular and humoral components of the immune network, one of which is the complement system, a potent player in soluble innate immunity. Our article reviews the crucial and complex interplay between platelets and complement, focusing on mutual regulation of these two interaction partners by their respective molecular mechanisms. Furthermore, the putative relevance of these processes to infectious diseases, inflammatory conditions, and autoimmune disorders, as well as the treatment of patients with biomaterials is highlighted. (C) 2015 Elsevier Ltd. All rights reserved.

  • 5.
    Aeinehband, Shahin
    et al.
    Karolinska Institutet.
    Lindblom, Rickard P. F.
    Karolinska Institutet.
    Al Nimer, Faiez
    Karolinska Institutet.
    Vijayaraghavan, Swetha
    Karolinska Institutet.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Khademi, Mohsen
    Karolinska Institutet.
    Olsson, Tomas
    Karolinska Institutet.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Darreh-Shori, Taher
    Karolinska Institutet.
    Piehl, Fredrik
    Karolinska Institutet.
    Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 4, article id e0122048Article in journal (Refereed)
    Abstract [en]

    Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genomewide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with >= 9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

  • 6.
    Mohlin, Camilla
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Johansson, Kjell
    Örebro University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Complement factor involvement during experimental AMD2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 163-163Article in journal (Other academic)
  • 7.
    Biglarnia, Alireza
    et al.
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Complement interception across humoral incompatibility in solid organ transplantation: a clinical perspective2015In: Immune Responses to Biosurfaces / [ed] John D. Lambris, Kristina Nilsson-Ekdahl, Daniel Ricklin, Bo Nilsson, Springer, 2015, p. 211-233Chapter in book (Refereed)
    Abstract [en]

    The humoral barrier in transplant biology is the result of preformed donor-specific antibodies (DSAs), directed either against human leukocyte antigens (HLA) or non-HLA antigens such as blood group (ABO) molecules. The term "sensitization" applies to patients carrying these antibodies. Transplantation is widely accepted as a life-saving opportunity for patients with terminal end-organ disease. However, in sensitized patients, transplant outcome is hampered by antibody-mediated rejection (AMR) as a consequence of DSA exposure. Furthermore, sensitized patients have limited access to "matched" organs from the both living and deceased donor pool.Considering the crucial role of the complement system in the pathophysiology of AMR and the availability of complement intervention therapeutics, there is a growing interest in complement-targeting strategies. This review highlights the emerging importance of monitoring and modulation of the complement system in the context of enabling transplantation across humoral incompatibility in sensitized recipients with preformed anti-HLA or natural anti-ABO antibodies. It also discusses the significance of the complement system in the induction of accommodation and further emphasizes current and future perspectives of novel complement therapeutics.

  • 8.
    Lindblom, Rickard P. F.
    et al.
    Karolinska Institutet;Univ Uppsala Hosp;Karolinska Univ Hosp.
    Berg, Alexander
    Karolinska Institutet.
    Ström, Mikael
    Karolinska Institutet.
    Aeinehband, Shahin
    Karolinska Institutet.
    Dominguez, Cecilia A.
    Karolinska Institutet.
    Al Nimer, Faiez
    Karolinska Institutet.
    Abdelmagid, Nada
    Karolinska Institutet.
    Heinig, Matthias
    Max Delbruck Ctr Mol Med, Germany.
    Zelano, Johan
    Karolinska Institutet.
    Harnesk, Karin
    Karolinska Institutet.
    Hubner, Norbert
    Max Delbruck Ctr Mol Med, Germany.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Diez, Margarita
    Karolinska Institutet.
    Cullheim, Staffan
    Karolinska Institutet.
    Piehl, Fredrik
    Karolinska Institutet.
    Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response2015In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 12, article id 192Article in journal (Refereed)
    Abstract [en]

    Background: Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking. Methods: Large-scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expression of complement receptor 2 (Cr2) in the spinal cord after ventral root avulsion (VRA). Expression of Cr2 in the spinal cord was studied in a separate cohort of DA and PVG rats at different time-points after VRA, and also following sciatic nerve transection (SNT) in the same strains. Consequently, Cr2(-/-) mice and Wt controls were used to further explore the role of Cr2 in the spinal cord following SNT. The in vivo experiments were complemented by astrocyte and microglia cell cultures. Results: Expression of Cr2 in naive spinal cord was low but strongly up regulated at 5-7 days after both VRA and SNT. Levels of Cr2 expression, as well as astrocyte activation, was higher in PVG rats than DA rats following both VRA and SNT. Subsequent in vitro studies proposed astrocytes as the main source of Cr2 expression. A functional role for Cr2 is suggested by the finding that transgenic mice lacking Cr2 displayed increased loss of synaptic nerve terminals following nerve injury. We also detected increased levels of soluble CR2 (sCR2) in the cerebrospinal fluid of rats following VRA. Conclusions: These results demonstrate that local expression of Cr2 in the central nervous system is part of the axotomy reaction and is suggested to modulate subsequent complement mediated effects.

  • 9.
    Asif, Sana
    et al.
    Uppsala University.
    Jonsson, Nina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Teramura, Yuji
    Univ Tokyo, Japan.
    Gustafson, Elisabet
    Univ Uppsala Hosp.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Conjugation of human recombinant CD39 to primary human hepatocytes protects against thromboinflammation2015In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 22, p. S87-S87Article in journal (Other academic)
  • 10.
    Hamad, Osama A.
    et al.
    Uppsala University.
    Mitroulis, Ioannis
    Tech Univ Dresden, Germany.
    Fromell, Karin
    Uppsala University.
    Kozarcanin, Huda
    Uppsala University.
    Chavakis, Triantafyllos
    Tech Univ Dresden, Germany.
    Ricklin, Daniel
    Univ Penn, USA.
    Lambris, John D.
    Univ Penn, USA.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD182015In: Thrombosis and Haemostasis, ISSN 0340-6245, E-ISSN 2567-689X, Vol. 114, no 6, p. 1207-1217Article in journal (Refereed)
    Abstract [en]

    Complement component C3 has a potential role in thrombotic pathologies. It is transformed, without proteolytic cleavage, into C3(H2O) upon binding to the surface of activated platelets. We hypothesise that C3(H2O) bound to activated platelets and to platelet-derived microparticles (PMPs) contributes to platelet-PMN complex (PPC) formation and to the binding of PMPs to PMNs. PAR-1 activation of platelets in human whole blood from normal individuals induced the formation of CD16(+)/CD42a(+) PPC. The complement inhibitor compstatin and a C5a receptor antagonist inhibited PPC formation by 50 %, while monoclonal antibodies to C3(H2O) or anti-CD11b inhibited PPC formation by 75-100 %. Using plasma protein-depleted blood and blood from a C3-deficient patient, we corroborated the dependence on C3, obtaining similar results after reconstitution with purified C3. By analogy with platelets, PMPs isolated from human serum were found to expose C3(H2O) and bind to PMNs. This interaction was also blocked by the anti-C3(H2O) and anti-CD11b monoclonal antibodies, indicating that C3(H2O) and CD11b are involved in tethering PMPs to PMNs. We confirmed the direct interaction between C3(H2O) and CD11b by quartz crystal microbalance analysis using purified native C3 and recombinant CD11b/CD18 and by flow cytometry using PMP and recombinant CD11b. Transfectants expressing CD11b/CD18 were also shown to specifically adhere to surface-bound C3(H2O). We have identified contact-activated C3(H2O) as a novel ligand for CD11b/CD18 that mediates PPC formation and the binding of PMPs to PMNs. Given the various roles of C3 in thrombotic reactions, this finding is likely to have important pathophysiological implications.

  • 11.
    Kathiravan, Suppan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Ghosh, Shishir
    Kings Coll London, UK.
    Hogarth, Graeme
    Kings Coll London, UK.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Copper catalysed amidation of aryl halides through chelation assistance2015In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 51, no 23, p. 4834-4837Article in journal (Refereed)
    Abstract [en]

    A copper mediated C-N bond formation for the amidation of aryl halides using 8-aminoquinoline has been developed. This strategy provides efficient access to amides bearing two contiguous heterocyclic moieties and does not require the presence of additional ligands.

  • 12.
    Håkansson, Andreas
    et al.
    Kristianstad University.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Granfeldt, Yvonne
    Lund University.
    Diet inequality prevails among consumers interested and knowledgeable in nutrition2015In: Food & Nutrition Research, ISSN 1654-6628, E-ISSN 1654-661X, Vol. 59, article id 27601Article in journal (Refereed)
    Abstract [en]

    Previous studies have demonstrated a correlation between diet cost and adherence to nutritional recommendations among consumers in general. This has adverse effects on diet and health inequality. It could be hypothesized that consumers knowledgeable in nutrition escape this correlation

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  • 13.
    Andersson, Håkan S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Jacobsson, Erik
    Uppsala University.
    Eriksson, Camilla
    Uppsala University.
    Hedström, Martin
    Lund University.
    Seth, Henrik
    University of Gothenburg.
    McEvoy, Eric G
    Liverpool John Moores University.
    Sundberg, Per
    University of Gothenburg.
    Strand, Malin
    Swedish University of Agricultural Sciences.
    Göransson, Ulf
    Uppsala University.
    Discovery of peptide toxins in ribbon worms: challenging claims of tetrodotoxin production2015Conference paper (Other academic)
  • 14.
    Andersson, Håkan S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Jacobsson, Erik
    Uppsala University.
    Eriksson, Camilla
    Uppsala University.
    Rosengren, K. Johan
    University of Queensland, Australia.
    Andrén, Per
    Uppsala University.
    Strand, Malin
    Swedish agricultural university (SLU).
    Göransson, Ulf
    Uppsala University.
    Discovery of peptide toxins in the bootlace worm, the world's longest animal2015Conference paper (Other academic)
  • 15.
    Andersson, Håkan S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Jacobsson, Erik
    Uppsala University.
    Eriksson, Camilla
    Uppsala University.
    Hedström, Martin
    Lund University.
    Seth, Henrik
    Gothenburg University.
    McEvoy, Eric G
    Sundberg, Per
    Gothenburg University.
    Strand, Malin
    Swedish agricultural university (SLU).
    Discovery of peptide toxins in the world’s longest animal (The bootlace worm; Lineus longissimus): challenging claims of tetrodotoxin production.2015Conference paper (Other academic)
  • 16.
    Nyberg, Maria
    et al.
    Kristianstad University.
    Olsson, Viktoria
    Kristianstad University.
    Pajalic, Zada
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Kristianstad University.
    Örtman, Gerd
    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.
    Blücher, Anna
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Wendin, Karin
    Kristianstad University.
    Westergren, Albert
    Kristianstad University.
    Eating difficulties, nutrition, meal preferences and experiences among elderly - a literature overview from a Scandinavian context2015In: Journal of Food Research, ISSN 1927-0887, E-ISSN 1927-0895, Vol. 4, no 1, p. 22-37Article in journal (Refereed)
    Abstract [en]

    The risk of malnutrition increases with ageing, resulting in poorer health and higher risk of disease. Eating difficulties are important risk factors for malnutrition. Moreover, independence in relation to food and meals is highly rated by the elderly and has been associated with health and well-being. The purpose of this literature overview was to provide insights into nutritional status, food choice and preferences as well as the meal situations of home-living elderly (65+) people with motoric eating difficulties focusing on Scandinavia. The overall aim is to support independence and to prevent malnutrition. Nutritional status in the elderly was found to be negatively influenced by motoric eating difficulties including problems with manipulating food on the plate and transporting food to the mouth. Motoric eating difficulties may result in practical simplifications such as use of pre-prepared meals, less advanced cooking, and omission of certain meal constituents in order to avoid e.g. mismanagement and spillage. Eating difficulties are often accompanied by feelings of guilt and shame. Choosing smaller portions, reducing the number of eating episodes and not cooking independently have been associated with a higher risk of malnutrition. The nutritional effects of eating difficulties may be exacerbated by diminished chemosensory functions. Furthermore, both past and present food preferences should be considered in order to meet nutritional needs and meal satisfaction. Development of refined and socially accepted eating aids, in combination with tasty and nutritious products, is important in order to promote healthy and independent living among home-living elderly with motoric eating difficulties.

  • 17.
    Johri, Atul K.
    et al.
    Jawaharlal Nehru Univ, India.
    Oelmueller, Ralf
    Univ Jena, Germany.
    Dua, Meenakshi
    Jawaharlal Nehru Univ, India.
    Yadav, Vikas
    Jawaharlal Nehru Univ, India.
    Kumar, Manoj
    Jawaharlal Nehru Univ, India.
    Tuteja, Narendra
    Int Ctr Genet Engn & Biotechnol, India;Amity Univ, India.
    Varma, Ajit
    Amity Univ, India.
    Bonfante, Paola
    Univ Turin, Italy.
    Persson, Bengt L.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Stroud, Robert M.
    Univ Calif San Francisco, USA.
    Fungal association and utilization of phosphate by plants: success, limitations, and future prospects2015In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 6, article id 984Article, review/survey (Refereed)
    Abstract [en]

    Phosphorus (P) is a major macronutrient for plant health and development. The available form of P is generally low in the rhizosphere even in fertile soils. A major proportion of applied phosphate (Pi) fertilizers in the soil become fixed into insoluble, unavailable forms, which restricts crop production throughout the world. Roots possess two distinct modes of P uptake from the soil, direct and indirect uptake. The direct uptake of P is facilitated by the plant's own Pi transporters while indirect uptake occurs via mycorrhizal symbiosis, where the host plant obtains P primarily from the fungal partner, while the fungus benefits from plant-derived reduced carbon. So far, only one Pi transporter has been characterized from the mycorrhizal fungus Glomus versiforme. As arbuscular mycorrhizal fungi cannot be cultured axenically, their Pi transporter network is difficult to exploite for large scale sustainable agriculture. Alternatively, the root-colonizing endophytic fungus Piriformospora indica can grow axenically and provides strong growth-promoting activity during its symbiosis with a broad spectrum of plants. P indica contains a high affinity Pi transporter (PiPT) involved in improving Pi nutrition levels in the host plant under P limiting conditions. As P indica can be manipulated genetically, it opens new vistas to be used in P deficient fields.

  • 18.
    Rosengren-Holmberg, Jenny P.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Swedish Natl Forens Ctr, Sweden.
    Andersson, Jonas
    Univ Uppsala Hosp, Sweden.
    Smith, James R.
    Univ Portsmouth, UK.
    Alexander, Cameron
    Univ Nottingham, UK.
    Alexander, Morgan R.
    Univ Nottingham, UK.
    Tovar, Guenter
    Univ Stuttgart, Germany;Fraunhofer Inst Interfacial Engn & Biotechnol, Germany.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Uppsala Hosp, Sweden.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Heparin molecularly imprinted surfaces for the attenuation of complement activation in blood2015In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 3, no 8, p. 1208-1217Article in journal (Refereed)
    Abstract [en]

    Heparin-imprinted synthetic polymer surfaces with the ability to attenuate activation of both the complement and the coagulation system in whole blood were successfully produced. Imprinting was achieved using a template coated with heparin, a highly sulfated glycosaminoglycan known for its anticoagulant properties. The N,N'-diacryloylpiperazine-methacrylic acid copolymers were characterized using goniometry, AFM and XPS. The influence of the molecular imprinting process on morphology and template rebinding was demonstrated by radioligand binding assays. Surface hemocompatibility was evaluated using human whole blood without anticoagulants followed by measurement of complement activation markers C3a and sC5b-9 and platelet consumption as a surrogate coagulation activation marker. The observed low thrombogenicity of this copolymer combined with the attenuation of complement activation induced by the molecular imprint offer potential for the development of self-regulating surfaces with important potential clinical applications. We propose a mechanism for the observed phenomena based upon the recruitment of endogenous sulfated glycosaminoglycans with heparin-like activities.

  • 19.
    Teramura, Yuji
    et al.
    Univ Tokyo, Japan.
    Asif, Sana
    Uppsala University.
    Gustafson, Elisabet
    Univ Uppsala Hosp.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Heparinzation of cell surfaces with a heparin-binding peptide-conjugated PEG-lipid for regulation of thromboinflammation in transplantation of human MSC and hepatocyte2015In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 22, no Supplement 1, p. S70-S70, article id 561Article in journal (Other academic)
  • 20.
    Golker, Kerstin
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Bioorganic & Biophysical Chemistry Laboratory.
    Wiklander, Jesper G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rosengren, Annika M.
    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.
    Hydrogen bond diversity in the pre-polymerization stage contributes to morphology and MIP-template recognition–MAA versus MMA2015In: European Polymer Journal, ISSN 0014-3057, E-ISSN 1873-1945, Vol. 66, p. 558-568Article in journal (Refereed)
    Abstract [en]

    This report demonstrates that the diversity of hydrogen bond interactions present in molecularly imprinted polymer pre-polymerization mixtures, typically associated with binding-site heterogeneity, can also contribute to morphological characteristics that may influence polymer–template recognition. Comparisons have been made between a series of bupivacaine molecularly imprinted methacrylic acid (MAA)–ethylene glycol dimethacrylate (EGDMA) copolymers and a series of analogous methyl methacrylate (MMA)–EGDMA copolymers using comprehensive molecular dynamics studies of the respective pre-polymerization mixtures, template–polymer binding studies and detailed BET surface area and BJH porosity analyses. The role of the carboxylic acid functionality of MAA, and in particular the acidic proton, in generating morphological features conducive to analyte access (slit-like rather than ink bottle-like structures) and recognition is discussed.

  • 21.
    Huang, Shan
    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, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    iC3 generation elicited by the presence of ammonia and urea in human plasma2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 145-145Article in journal (Other academic)
  • 22.
    Lambris, John D
    et al.
    University of Pennsylvania, USA.
    Nilsson Ekdahl, KristinaUniversity of Uppsala, Sweden.Ricklin, DanielUniversity of Pennsylvania, USA.Nilsson, BoUniversity of Uppsala, Sweden.
    Immune Responses to Biosurfaces: Mechanisms and Therapeutic Interventions2015Collection (editor) (Refereed)
  • 23.
    Olsson, Viktoria
    et al.
    Kristianstad University.
    Agerhem, Hanna
    Ipsos, Sweden.
    Nyberg, Maria
    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.
    Svensson, Therése
    Kristianstad University.
    Blücher, Anna
    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.
    Westergren, Albert
    Kristianstad University.
    Wendin, Karin
    SP Technical Research Institute, Sweden ; University of Copenhagen, Denmark.
    Westin, Marie
    Kristianstad University.
    Improved everyday food for home living elderly - perception of protein and energy enrichment2015Conference paper (Refereed)
  • 24.
    Klapper, Yvonne
    et al.
    KIT, Germany.
    Maffre, Pauline
    KIT, Germany.
    Shang, Li
    KIT, Germany.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Hettler, Simon
    KIT, Germany.
    Dries, Manuel
    KIT, Germany.
    Gerthsen, Dagmar
    KIT, Germany.
    Nienhaus, G. Ulrich
    KIT, Germany;Univ Illinois, USA.
    Low affinity binding of plasma proteins to lipid-coated quantum dots as observed by in situ fluorescence correlation spectroscopy2015In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 7, no 22, p. 9980-9984Article in journal (Refereed)
    Abstract [en]

    Protein binding to lipid-coated nanoparticles has been pursued quantitatively by using fluorescence correlation spectroscopy. The binding of three important plasma proteins to lipid-enwrapped quantum dots (QDs) shows very low affinity, with an apparent dissociation coefficient in the range of several hundred micromolar. Thus, the tendency to adsorb is orders of magnitude weaker than for QDs coated with dihydrolipoic acid.

  • 25.
    Huang, Shan
    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.
    Jonsson, Nina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Anders
    Gambro Lundia AB.
    Wieslander, Anders
    Gambro Lundia AB.
    Grundström, Gunilla
    Gambro Lundia AB.
    Hancock, Viktoria
    Gambro Lundia AB.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood2015In: Clinical Kidney Journal, ISSN 2048-8505, E-ISSN 2048-8513, Vol. 8, no 1, p. 31-37Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:The use of acetate in haemodialysis fluids may induce negative effects in patients including nausea and increased inflammation. Therefore, haemodialysis fluids where acetate is substituted with citrate have recently been developed. In this study, we investigated the biocompatibility of citrate employing concentrations used in haemodialysis.

    METHODS:The effects of citrate and acetate were investigated in human whole blood in vitro under conditions promoting biomaterial-induced activation. Complement activation was measured as generation of C3a, C5a and the sC5b-9 complex, and granulocyte activation as up-regulation of CD11b expression. For the experimental set-up, a mathematical model was created to calculate the concentrations of acetate and citrate attained during haemodialysis.

    RESULTS:Citrate reduced granulocyte activation and did not induce higher complement activation compared with acetate at concentrations attained during haemodialysis. Investigating different citrate concentrations clearly showed that citrate is a potent complement inhibitor already at low concentrations, i.e. 0.25 mM, which is comparable with concentrations detected in the blood of patients during dialysis with citrate-containing fluids. Increased citrate concentration up to 6 mM further reduced the activation of C3a, C5a and sC5b-9, as well as the expression of CD11b.

    CONCLUSIONS:Our results suggest that citrate is a promising substitute for acetate for a more biocompatible dialysis, most likely resulting in less adverse effects for the patients.

  • 26.
    Cournia, Zoe
    et al.
    Academy of Athens, Greece.
    Allen, Toby W.
    University of California, USA ; RMIT University, Australia.
    Andricioaei, Ioan
    University of California, USA.
    Antonny, Bruno
    Université de Nice Sophia-Antipolis, France.
    Baum, Daniel
    Zuse Institute Berlin, Germany.
    Brannigan, Grace
    Rutgers University-Camden, USA.
    Buchete, Nicolae-Viorel
    University College Dublin, Ireland.
    Deckman, Jason T.
    University of California, USA.
    Delemotte, Lucie
    Temple University, USA.
    del Val, Coral
    University of Granada, Spain.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Gkeka, Paraskevi
    Academy of Athens, Greece.
    Hege, Hans-Christian
    Zuse Institute Berlin, Germany.
    Hénin, Jérôme
    IBPC and CNRS, France.
    Kasimova,, Marina A.
    Université de Lorraine, France ; Lomonosov Moscow State University, Russia.
    Kolocouris, Antonios
    University of Athens, Greece.
    Klein, Michael L.
    Temple University, USA.
    Khalid, Syma
    University of Southampton, UK.
    Lemieux, M. Joanne
    University of Alberta, Canada.
    Lindow, Norbert
    Zuse Institute Berlin, Germany.
    Mahua, Roy
    University of California, USA.
    Selent, Jana
    Universitat Pompeu Fabra, Spain.
    Tarek, Mounir
    Université de Lorraine, France ; CNRS SRSMC, France.
    Tofoleanu, Florentina
    University College Dublin, Ireland.
    Stefano, Vanni
    Université de Nice Sophia-Antipolis, Greece.
    Sinisa, Urban
    Johns Hopkins University School of Medicine, USA.
    Wales, David J.
    University of Cambridge, UK.
    Smith, Jeremy C.
    Oak Ridge National Laboratory, USA.
    Bondar, Ana-Nicoleta
    Freie Universität Berlin, Germany.
    Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory2015In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 248, no 4, p. 611-640Article in journal (Refereed)
    Abstract [en]

    Membrane proteins mediate processes that are fundamental for the flourishing of biological cells. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requires knowledge of how the proteins couple to their fluid, hydrated lipid membrane environment. We present here current studies in computational and experimental membrane protein biophysics, and show how they address outstanding challenges in understanding the complex environmental effects on the structure, function, and dynamics of membrane proteins.

  • 27.
    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.
    Palladium Catalyzed Vinyltrifluoromethylation of Aryl Halides through Decarboxylative Cross-Coupling with 2-(Trifluoromethyl)acrylic Acid2015In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, p. 1874-1877Article in journal (Refereed)
    Abstract [en]

    An efficient Pd-catalyzed stereoselective vinyltrifluoromethylation of aryl halides, through decarboxylative cross-coupling with 2-(trifluoromethyl)acrylic acid is described. The ready availability of the starting materials, the high level of functional group tolerance, and excellentE/Z selectivity make this protocol a safe and operationally convenient strategy for efficient synthesis of vinyltrifluoromethyl derivatives.

  • 28.
    Jacobsson, Erik
    et al.
    Uppsala University.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Strand, Malin
    Swedish agricultural university (SLU).
    Eriksson, Camilla
    Uppsala University.
    Göransson, Ulf
    Uppsala University.
    Peptide toxins from L. longissimus: extraction, biological activity, structure and production2015Conference paper (Other academic)
  • 29.
    Engberg, Anna E.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Region Skåne.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Rikshosp, Norway;Univ Oslo, Norway.
    Huang, Shan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Fromell, Karin
    Uppsala University.
    Hamad, Osama A.
    Uppsala University.
    Mollnes, Tom Eirik
    Univ Oslo, Norway;Univ Tromsö, Norway.
    Rosengren-Holmberg, Jenny P.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Swedish Natl Lab Forens Sci, Linköping.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Teramura, Yuji
    Uppsala University;Univ Tokyo, Japan.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 36, p. 55-65Article in journal (Refereed)
    Abstract [en]

    Inappropriate complement activation is often responsible for incompatibility reactions that occur when biomaterials are used. Complement activation is therefore a criterion included in legislation regarding biomaterials testing. However, no consensus is yet available regarding appropriate complement-activation-related test parameters. We examined protein adsorption in plasma and complement activation/cytokine release in whole blood incubated with well-characterized polymers. Strong correlations were found between the ratio of C4 to its inhibitor C4BP and generation of 10 (mainly pro-inflammatory) cytokines, including IL-17, IFN-gamma, and IL-6. The levels of complement activation products correlated weakly (C3a) or not at all (C5a, sC5b-9), confirming their poor predictive values. We have demonstrated a direct correlation between downstream biological effects and the proteins initially adhering to an artificial surface after contact with blood. Consequently, we propose the C4/C4BP ratio as a robust, predictor of biocompatibility with superior specificity and sensitivity over the current gold standard. (C) 2014 Elsevier Ltd. All rights reserved.

  • 30.
    Nilsson, Bo
    et al.
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Kemper, Claudia
    King's College London, UK.
    Mollnes, Tom Eirik
    Nordland Hospital, Norway;University of Tromsø, Norway.
    Preface. 15th European Meeting on Complement in Human Disease 2015, Uppsala, Sweden.2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 1-2Article in journal (Other academic)
  • 31.
    Ricklin, Daniel
    et al.
    Univ Penn, USA.
    Sfyroera, Georgia
    Univ Penn, USA.
    Reis, Edimara
    Univ Penn, USA.
    Chen, Hui
    Univ Penn, USA.
    Wu, Emilia
    Univ Minnesota, USA.
    Kaznessis, Yiannis
    Univ Minnesota, USA.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Lambris, John D.
    Univ Penn, USA.
    Rare loss-of-function mutation in C3 provides insight into molecular and pathophysiological determinants of alternative pathway activity2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 174-174Article in journal (Other academic)
  • 32.
    Sfyroera, Georgia
    et al.
    Univ Penn, USA.
    Ricklin, Daniel
    Univ Penn, USA.
    Reis, Edimara
    Univ Penn, USA.
    Chen, Hui
    Univ Penn, USA.
    Wu, Emilia
    Univ Minnesota, USA.
    Kaznessis, Yannis
    Univ Minnesota, USA.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lambris, John
    Univ Penn, USA.
    Rare loss-of-function mutation in complement component C3 provides insight into molecular and pathophysiological determinants of complement activity2015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 194, no 7, p. 3305-3316Article in journal (Refereed)
    Abstract [en]

    The plasma protein C3 is a central element in the activation and effector functions of the complement system. A hereditary dysfunction of C3 that prevents complement activation via the alternative pathway (AP) was described previously in a Swedish family, but its genetic cause and molecular consequences have remained elusive. In this study, we provide these missing links by pinpointing the dysfunction to a point mutation in the beta-chain of C3 (c.1180T > C; p.Met(373)Thr). In the patient's plasma, AP activity was completely abolished and could only be reconstituted with the addition of normal C3. The M373T mutation was localized to the macroglobulin domain 4 of C3, which contains a binding site for the complement inhibitor compstatin and is considered critical for the interaction of C3 with the AP C3 convertase. Structural analyses suggested that the mutation disturbs the integrity of macroglobulin domain 4 and induces conformational changes that propagate into adjacent regions. Indeed, C3 M373T showed an altered binding pattern for compstatin and surface-bound C3b, and the presence of Thr(373) in either the C3 substrate or convertase-affiliated C3b impaired C3 activation and opsonization. In contrast to known gain-of-function mutations in C3, patients affected by this loss-of-function mutation did not develop familial disease, but rather showed diverse and mostly episodic symptoms. Our study therefore reveals the molecular mechanism of a relevant loss-of-function mutation in C3 and provides insight into the function of the C3 convertase, the differential involvement of C3 activity in clinical conditions, and some potential implications of therapeutic complement inhibition.

  • 33.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland.
    Pivkin, Igor
    Univ Svizzera Italiana, Switzerland ;Swiss Inst Bioinformat, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    S100A4 and its role in metastasis – computational integration of data on biological networks2015In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 11, p. 2238-2246Article in journal (Refereed)
    Abstract [en]

    Characterising signal transduction networks is fundamental to our understanding of biology. However, redundancy and different types of feedback mechanisms make it difficult to understand how variations of the network components contribute to a biological process. In silico modelling of signalling interactions therefore becomes increasingly useful for the development of successful therapeutic approaches. Unfortunately, quantitative information cannot be obtained for all of the proteins or complexes that comprise the network, which limits the usability of computational models. We developed a flexible computational framework for the analysis of biological signalling networks. We demonstrate our approach by studying the mechanism of metastasis promotion by the S100A4 protein, and suggest therapeutic strategies. The advantage of the proposed method is that only limited information (interaction type between species) is required to set up a steady-state network model. This permits a straightforward integration of experimental information where the lack of details are compensated by efficient sampling of the parameter space. We investigated regulatory properties of the S100A4 network and the role of different key components. The results show that S100A4 enhances the activity of matrix metalloproteinases (MMPs), causing higher cell dissociation. Moreover, it leads to an increased stability of the pathological state. Thus, avoiding metastasis in S100A4-expressing tumours requires multiple target inhibition. Moreover, the analysis could explain the previous failure of MMP inhibitors in clinical trials. Finally, our method is applicable to a wide range of biological questions that can be represented as directional networks.

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  • 34.
    Buetti-Dinh, Antoine
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    S100A4 and its role in metastasis – computational integration of data on biological networks2015Other (Other academic)
  • 35.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland.
    Pivkin, Igor V.
    Univ Svizzera Italiana, Switzerland ; Swiss Inst Bioinformat, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    S100A4 and its role in metastasis: simulations of knockout and amplification of epithelial growth factor receptor and matrix metalloproteinases2015In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 11, no 8, p. 2247-2254Article in journal (Refereed)
    Abstract [en]

    The calcium-binding signalling protein S100A4 enhances metastasis in a variety of cancers. Despite a wealth of data available, the molecular mechanism by which S100A4 drives metastasis is unknown. Integration of the current knowledge defies straightforward intuitive interpretation and requires computer-aided approaches to represent the complexity emerging from cross-regulating species. Here we carried out a systematic sensitivity analysis of the S100A4 signalling network in order to identify key control parameters for efficient therapeutic intervention. Our approach only requires limited details of the molecular interactions and permits a straightforward integration of the available experimental information. By integrating the available knowledge, we investigated the effects of combined inhibition of signalling pathways. Through selective knockout or inhibition of the network components, we show that the interaction between epidermal growth factor receptor (EGFR) and S100A4 modulates the sensitivity of angiogenesis development to matrix metalloproteinases (MMPs) activity. We also show that, in cells that express high EGFR, MMP inhibitors are not expected to be useful in tumours if high activity of S100A4 is present.

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  • 36.
    Olsson, Gustaf D.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Niedergall, Klaus
    Fraunhofer Inst Interfacial Engn & Biotechnol IGB, Germany.
    Bach, Monika
    Fraunhofer Inst Interfacial Engn & Biotechnol IGB, Germany;Univ Stuttgart, Germany.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Tovar, Guenter
    Fraunhofer Inst Interfacial Engn & Biotechnol IGB, Germany;Univ Stuttgart, Germany.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Simulation of imprinted emulsion prepolymerization mixtures2015In: Polymer journal, ISSN 0032-3896, E-ISSN 1349-0540, Vol. 47, no 12, p. 827-830Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to develop protocols for and evaluate the use of all-atom full system molecular dynamic (MD) simulations of emulsion systems in the development of molecularly imprinted polymers (MIPs). Here, we report on the first, to the best of our knowledge, use of all-component MD studies to simulate and evaluate MIP miniemulsion prepolymerization mixtures; in this case, the mixtures used in the synthesis of a series of MIP-nanoparticles (MIP-NPs).

  • 37.
    Haugaard-Kedström, Linda M.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Queensland, Australia.
    Hossain, Mohammed Akhter
    Univ Melbourne, Australia.
    Daly, Norelle L
    Univ Queensland, Australia.
    Bathgate, Ross A D
    Univ Melbourne, Australia.
    Rinderknecht, Ernst
    Novartis Corp, USA.
    Wade, John D
    Univ Melbourne, Australia.
    Craik, David J
    Univ Queensland, Australia.
    Rosengren, K. Johan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Queensland, Australia.
    Solution Structure, Aggregation Behavior, and Flexibility of Human Relaxin-2.2015In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 10, no 3, p. 891-900Article in journal (Refereed)
    Abstract [en]

    Relaxin is a member of the relaxin/insulin peptide hormone superfamily and is characterized by a two-chain structure constrained by three disulfide bonds. Relaxin is a pleiotropic hormone and involved in a number of physiological and pathogenic processes, including collagen and cardiovascular regulation and tissue remodelling during pregnancy and cancer. Crystallographic and ultracentrifugation experiments have revealed that the human form of relaxin, H2 relaxin, self-associates into dimers, but the significance of this is poorly understood. Here, we present the NMR structure of a monomeric, amidated form of H2 relaxin and compare its features and behavior in solution to those of native H2 relaxin. The overall structure of H2 relaxin is retained in the monomeric form. H2 relaxin amide is fully active at the relaxin receptor RXFP1 and thus dimerization is not required for biological activity. Analysis of NMR chemical shifts and relaxation parameters identified internal motion in H2 relaxin at the pico-nanosecond and milli-microsecond time scales, which is commonly seen in other relaxin and insulin peptides and might be related to function.

  • 38.
    Elmlund, Louise
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Käck, Camilla
    Attana AB.
    Aastrup, Teodor
    Attana AB, Sweden.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Study of the Interaction of Trastuzumab and SKOV3 Epithelial Cancer Cells Using a Quartz Crystal Microbalance Sensor2015In: Sensors, E-ISSN 1424-8220, Vol. 15, no 3, p. 5884-5894Article in journal (Refereed)
    Abstract [en]

    Analytical methods founded upon whole cell-based assays are of importance in early stage drug development and in fundamental studies of biomolecular recognition. Here we have studied the binding of the monoclonal antibody trastuzumab to human epidermal growth factor receptor 2 (HER2) on human ovary adenocarcinoma epithelial cancer cells (SKOV3) using quartz crystal microbalance (QCM) technology. An optimized procedure for immobilizing the cells on the chip surface was established with respect to fixation procedure and seeding density. Trastuzumab binding to the cell decorated sensor surface was studied, revealing a mean dissociation constant, K-D, value of 7 +/- 1 nM (standard error of the mean). This study provides a new perspective on the affinity of the antibody-receptor complex presented a more natural context compared to purified receptors. These results demonstrate the potential for using whole cell-based QCM assay in drug development, the screening of HER2 selective antibody-based drug candidates, and for the study of biomolecular recognition. This real time, label free approach for studying interactions with target receptors present in their natural environment afforded sensitive and detailed kinetic information about the binding of the analyte to the target.

  • 39.
    Jonsson, Nina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Asif, Sana
    Uppsala University.
    Teramura, Yuji
    Univ Tokyo, Japan.
    Gustafson, Elisabeth
    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.
    Surface modification of primary human hepatocytes with recombinant CD39 protects against thromboinfiammation2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 149-150Article in journal (Other academic)
  • 40.
    Lundholm, Ida V
    et al.
    University of Gothenburg.
    Rodilla, Helena
    Chalmers University of Technology.
    Wahlgren, Weixiao Y.
    University of Gothenburg.
    Duelli, Annette
    University of Gothenburg.
    Bourenkov, Gleb
    European Molecular Biology Laboratory Hamburg Outstation, Germany.
    Vukusic, Josip
    Chalmers University of Technology.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Stake, Jan
    Chalmers University of Technology.
    Schneider, Thomas
    European Molecular Biology Laboratory Hamburg Outstation, Germany.
    Katona, Gergely
    University of Gothenburg.
    Terahertz radiation induces non-thermal structural changes associated with Fröhlich condensation in a protein crystal2015In: Structural Dynamics, E-ISSN 2329-7778, Vol. 2, no 5, article id 054702Article in journal (Refereed)
    Abstract [en]

    Whether long-range quantum coherent states could exist in biological systems, and beyond low-temperature regimes where quantum physics is known to be applicable, has been the subject to debate for decades. It was proposed by Fröhlich that vibrational modes within protein molecules can order and condense into a lowest-frequency vibrational mode in a process similar to Bose-Einstein condensation, and thus that macroscopic coherence could potentially be observed in biological systems. Despite the prediction of these so-called Fröhlich condensates almost five decades ago, experimental evidence thereof has been lacking. Here, we present the first experimental observation of Fröhlich condensation in a protein structure. To that end, and to overcome the challenges associated with probing low-frequency molecular vibrations in proteins(which has hampered understanding of their role in proteins' function), we combined terahertz techniques with a highly sensitive X-ray crystallographic method to visualize low-frequency vibrational modes in the protein structure of hen-egg white lysozyme. We found that 0.4 THz electromagnetic radiation induces non-thermal changes in electron density. In particular, we observed a local increase of electron density in a long α-helix motif consistent with a subtle longitudinal compression of the helix. These observed electron density changes occur at a low absorption rate indicating that thermalization of terahertz photons happens on a micro- to milli-second time scale, which is much slower than the expected nanosecond time scale due to damping of delocalized low frequency vibrations. Our analyses show that the micro- to milli-second lifetime of the vibration can only be explained by Fröhlich condensation, a phenomenon predicted almost half a century ago, yet never experimentally confirmed.

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  • 41.
    Kozarcanin, Huda
    et al.
    Uppsala University.
    Lood, Christian
    Skåne Univ Hosp, Sweden;Lund Univ, Sweden.
    Munthe-Fog, Lea
    Univ Copenhagen, Denmark.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Hamad, Osama
    Uppsala University.
    Skjoedt, Mikkel-Ole
    Univ Copenhagen, Denmark.
    Bengtsson, Anders
    Skåne Univ Hosp, Sweden;Lund Univ, Sweden.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Garred, Peter
    Univ Copenhagen, 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 complement pathway serine proteases bridges the complement and the coagulation systems in thrombotic diseases2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 153-153Article in journal (Other academic)
  • 42.
    Barbu, Andreea
    et al.
    Uppsala University.
    Hamad, Osama
    Uppsala University.
    Lind, Lars
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    The role of complement factor C3 in lipid metabolism2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 101-107Article, review/survey (Refereed)
    Abstract [en]

    Abundant reports have shown that there is a strong relationship between C3 and C3a-desArg levels, adipose tissue, and risk factors for cardiovascular disease, metabolic syndrome and diabetes. The data indicate that complement components, particularly C3, are involved in lipid metabolism. The C3 fragment, C3a-desArg, functions as a hormone that has insulin-like effects and facilitates triglyceride metabolism. Adipose tissue produces and regulates the levels of complement components, which promotes generation of inflammatory initiators such as the anaphylatoxins C3a and C5a. The anaphylatoxins trigger a cyto/chemokine response in proportion to the amount of adipose tissue present, and induce inflammation and mediate metabolic effects such as insulin resistance. These observations support the concept that complement is an important participant in lipid metabolism and in obesity, contributing to the metabolic syndrome and to the low-grade inflammation associated with obesity.

  • 43.
    Nicholls, Ian A.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala Univ.
    Chavan, Swapnil
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Golker, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Bioorganic & Biophysical Chemistry Laboratory.
    Olsson, Gustaf D.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rosengren, Annika M.
    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.
    Wiklander, Jesper G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Theoretical and Computational Strategies for the Study of the Molecular Imprinting Process and Polymer Performance2015In: Advances in Biochemical Engineering, Biotechnology, ISSN 0724-6145, Vol. 150, p. 25-50Article in journal (Refereed)
    Abstract [en]

    The development of in silico strategies for the study of the molecular imprinting process and the properties of molecularly imprinted materials has been driven by a growing awareness of the inherent complexity of these systems and even by an increased awareness of the potential of these materials for use in a range of application areas. Here we highlight the development of theoretical and computational strategies that are contributing to an improved understanding of the mechanisms underlying molecularly imprinted material synthesis and performance, and even their rational design.

  • 44.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala university, Sweden.
    Teramura, Yuji
    Univ Tokyo, Japan.
    Asif, Sana
    Uppsala university, Sweden.
    Jonsson, Nina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Magnusson, Peetra
    Uppsala university, Sweden.
    Nilsson, Bo
    Uppsala university, Sweden.
    Thromboinflammation in therapeutic medicine2015In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, Vol. 865, p. 3-17Article in journal (Refereed)
    Abstract [en]

    Thromboinflammation is primarily triggered by the humoral innate immune system, which mainly consists of the cascade systems of the blood, i.e., the complement, contact/coagulation and fibrinolytic systems. Activation of these systems subsequently induces activation of endothelial cells, leukocytes and platelets, finally resulting in thrombotic and inflammatory reactions. Such reactions are triggered by a number of medical procedures, e.g., treatment with biomaterials or drug delivery devices as well as in transplantation with cells, cell clusters or whole vascularized organs. Here, we (1) describe basic mechanisms for thromboinflammation; (2) review thromboinflammatory reactions in therapeutic medicine; and (3) discuss emerging strategies to dampen thromboinflammation.

  • 45.
    Ekstrand-Hammarström, Barbro
    et al.
    Swedish Def Res Agcy, Linköping.
    Hong, Jaan
    Uppsala University.
    Davoodpour, Padideh
    Uppsala University.
    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.
    Bucht, Anders
    Umeå University.
    Nilsson, Bo
    Uppsala University.
    TiO2 nanoparticles tested in a novel screening whole human blood model of toxicity trigger adverse activation of the kallikrein system at low concentrations2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 51, p. 58-68Article in journal (Refereed)
    Abstract [en]

    There is a compelling need to understand and assess the toxicity of industrially produced nanoparticles (NPs). In order to appreciate the long-term effects of NPs, sensitive human-based screening tests that comprehensively map the NP properties are needed to detect possible toxic mechanisms. Animal models can only be used in a limited number of test applications and are subject to ethical concerns, and the interpretation of experiments in animals is also distorted by the species differences. Here, we present a novel easy-to-perform highly sensitive whole-blood model using fresh non-anticoagulated human blood, which most justly reflects complex biological cross talks in a human system. As a demonstrator of the tests versatility, we evaluated the toxicity of TiO2 NPs that are widely used in various applications and otherwise considered to have relatively low toxic properties. We show that TiO2 NPs at very low concentrations (50 ng/mL) induce strong activation of the contact system, which in this model elicits thromboinflammation. These data are in line with the finding of components of the contact system in the protein corona of the TiO2 NPs after exposure to blood. The contact system activation may lead to both thrombotic reactions and generation of bradykinin, thereby representing fuel for chronic inflammation in vivo and potentially long-term risk of autoimmunity, arteriosclerosis and cancer. These results support the notion that this novel whole-blood model represents an important contribution to testing of NP toxicity. (C) 2015 Elsevier Ltd. All rights reserved.

  • 46.
    Sandholm, Kerstin
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Wijkstrom, Elisabeth
    University Hospital, Uppsala.
    Skattum, Lillemor
    Lund University.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Validations of assays for the evaluation of C1q in inflammatory diseases and thromboinflammation2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 176-177Article in journal (Other academic)
1 - 46 of 46
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