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Nilsson Ekdahl, KristinaORCID iD iconorcid.org/0000-0001-7888-1571
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Publications (10 of 123) Show all publications
N.Ekdahl, K., Fromell, K., Mohlin, C., Teramura, Y. & Nilsson, B. (2019). A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity. Science and Technology of Advanced Materials, 20(1), 688-698
Open this publication in new window or tab >>A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity
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2019 (English)In: Science and Technology of Advanced Materials, ISSN 1468-6996, E-ISSN 1878-5514, Vol. 20, no 1, p. 688-698Article, review/survey (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Coagulation system, complement system, contact, kallikrein system, inflammation, innate immunity, nanoparticles, protein corona, screening, toxicity, whole blood model
National Category
Pharmacology and Toxicology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-390411 (URN)10.1080/14686996.2019.1625721 (DOI)000472611100001 ()31275460 (PubMedID)
Funder
Swedish Research Council, 2016-20755-1Swedish Research Council, 2016-04519Swedish Research Council, 2018-04199
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-12Bibliographically approved
Sandholm, K., Persson, B., Skattum, L., Eggertsen, G., Nyman, D., Gunnarsson, I., . . . Nilsson Ekdahl, K. (2019). Evaluation of a Novel Immunoassay for Quantification of C1q for Clinical Diagnostic Use. Frontiers in Immunology, 10, Article ID 7.
Open this publication in new window or tab >>Evaluation of a Novel Immunoassay for Quantification of C1q for Clinical Diagnostic Use
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 7Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
C1q, immunoassays, plasma, CSF, SLE, nephritis
National Category
Rheumatology and Autoimmunity Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-376814 (URN)10.3389/fimmu.2019.00007 (DOI)000456846400001 ()
Funder
Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519
Available from: 2019-02-19 Created: 2019-02-19 Last updated: 2019-02-19Bibliographically approved
Noiri, M., Asawa, K., Okada, N., Kodama, T., Murayama, Y., Inoue, Y., . . . Teramura, Y. (2019). Modification of human MSC surface with oligopeptide-PEG-lipids for selective binding to activated endothelium. Journal of Biomedical Materials Research. Part A, 107(8), 1779-1792
Open this publication in new window or tab >>Modification of human MSC surface with oligopeptide-PEG-lipids for selective binding to activated endothelium
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2019 (English)In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 107, no 8, p. 1779-1792Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
cell surface modification, E-selectin, mesenchymal stem cell (MSC), poly(ethylene glycol)-conjugated phospholipid (PEG-lipid), stroke
National Category
Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-390077 (URN)10.1002/jbm.a.36697 (DOI)000471813900020 ()30983125 (PubMedID)
Funder
Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519
Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2019-08-06Bibliographically approved
Eriksson, O., Mohlin, C., Nilsson, B. & N. Ekdahl, K. (2019). The Human Platelet as an Innate Immune Cell: Interactions Between Activated Platelets and the Complement System. Frontiers in Immunology, 10, Article ID 1590.
Open this publication in new window or tab >>The Human Platelet as an Innate Immune Cell: Interactions Between Activated Platelets and the Complement System
2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1590Article, review/survey (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
Keywords
complement, platelets, lectin pathway, disulfides, phosphorylation, thiol isomerases, innate immunity
National Category
Immunology in the medical area Immunology
Identifiers
urn:nbn:se:uu:diva-390426 (URN)10.3389/fimmu.2019.01590 (DOI)000474774200001 ()31354729 (PubMedID)
Funder
Swedish Research Council, 2015-06429Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-12Bibliographically approved
Asif, S., Asawa, K., Yuuki, I., Ishihara, K., Lindell, B., Holmgren, R., . . . Nilsson Ekdahl, K. (2019). Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models. Macromolecular Bioscience, 19(5), Article ID 1800485.
Open this publication in new window or tab >>Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models
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2019 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 19, no 5, article id 1800485Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2019
Keywords
blood compatibility, blood model systems, coagulation system, complement system, heparin coat, MPC polymer coat
National Category
Clinical Laboratory Medicine Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-374785 (URN)10.1002/mabi.201800485 (DOI)000471340300015 ()30786149 (PubMedID)
Funder
Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Note

Kazuhiko Ishihara har tillkommit som författare sedan posten lades in som manuskript.

Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-07-31Bibliographically approved
Mohlin, C., Sandholm, K., Kvanta, A., Nilsson Ekdahl, K. & Johansson, K. (2018). A model to study complement involvement in experimental retinal degeneration. Upsala Journal of Medical Sciences, 123(1), 28-42
Open this publication in new window or tab >>A model to study complement involvement in experimental retinal degeneration
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2018 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 1, p. 28-42Article in journal (Refereed) Published
Abstract [en]

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

Method and materials: The adult porcine retina was co-cultured with the spontaneously arising human retinal pigment epithelial cells-19 (ARPE-19).

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

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

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
Keywords
AMD, complement system, ocular diseases, retina, RPE
National Category
Ophthalmology
Identifiers
urn:nbn:se:uu:diva-354542 (URN)10.1080/03009734.2018.1431744 (DOI)000428060300004 ()29436895 (PubMedID)
Funder
Swedish Research CouncilStiftelsen Olle Engkvist ByggmästareMedical Research Council of Southeast Sweden (FORSS)
Available from: 2018-06-21 Created: 2018-06-21 Last updated: 2018-06-21Bibliographically approved
Huber-Lang, M., Nilsson Ekdahl, K., Wiegner, R., Fromell, K. & Nilsson, B. (2018). Auxiliary activation of the complement system and its importance for the pathophysiology of clinical conditions. Seminars in Immunopathology, 40(1), 87-102
Open this publication in new window or tab >>Auxiliary activation of the complement system and its importance for the pathophysiology of clinical conditions
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2018 (English)In: Seminars in Immunopathology, ISSN 1863-2297, E-ISSN 1863-2300, Vol. 40, no 1, p. 87-102Article, review/survey (Refereed) Published
Abstract [en]

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

Keywords
Complement system, Proteases, Protease inhibitors, Trauma
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-350204 (URN)10.1007/s00281-017-0646-9 (DOI)000424058800008 ()28900700 (PubMedID)
Funder
German Research Foundation (DFG)Swedish Research Council, 2016-01060; 2016-04519EU, FP7, Seventh Framework Programme, 602699
Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2018-05-08Bibliographically approved
Nilsson Ekdahl, K., Davoodpour, P., Ekstrand-Hammarström, B., Fromell, K., Hamad, O. A., Hong, J., . . . Nilsson, B. (2018). Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of α-Fe2O3 nanoparticles.. Nanomedicine: Nanotechnology, Biology and Medicine, 14(3), 735-744
Open this publication in new window or tab >>Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of α-Fe2O3 nanoparticles.
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2018 (English)In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 14, no 3, p. 735-744Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
α-Fe2O3, NPsContact/kallikrein system, Innate immunity
National Category
Immunology in the medical area Nano Technology
Identifiers
urn:nbn:se:uu:diva-343471 (URN)10.1016/j.nano.2017.12.008 (DOI)000429528900010 ()
Funder
Swedish Research Council, 2014-3938 2016-2075-5.1 2016-01060 2016-04519EU, FP7, Seventh Framework Programme, 602699AFA Insurance
Note

Joint and equal contribution to senior authorship by Kristina N. Ekdahl, Padideh Davoodpour and Bo Nilsson

Available from: 2018-02-27 Created: 2018-02-27 Last updated: 2018-06-08Bibliographically approved
Labriere, C., Kondori, N., Caous, J. S., Boomgaren, M., Sandholm, K., Nilsson Ekdahl, K., . . . Svenson, J. (2018). Development and evaluation of cationic amphiphilic antimicrobial 2,5-diketopiperazines. Paper presented at 7th International Meeting on Antimicrobial Peptides, AUG 25-27, 2017, Univ Copenhagen, Copenhagen, DENMARK. Journal of Peptide Science, 24(7), Article ID e3090.
Open this publication in new window or tab >>Development and evaluation of cationic amphiphilic antimicrobial 2,5-diketopiperazines
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2018 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 24, no 7, article id e3090Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
2, 5-diketopiperazine, antifungal agents, antimicrobial, Candida krusei, MRSA, structure-activity relationship
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-362848 (URN)10.1002/psc.3090 (DOI)000440144700005 ()29845683 (PubMedID)
Conference
7th International Meeting on Antimicrobial Peptides, AUG 25-27, 2017, Univ Copenhagen, Copenhagen, DENMARK
Funder
VINNOVA, 2014-01435The Research Council of Norway, ES508288
Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2018-10-15Bibliographically approved
Fromell, K., Johansson, U., Dührkop, C., Adler, A., Usterud, E., Hamad, O. A., . . . Nilsson, B. (2018). Generation of an alternative pathway convertase by contact-activated C3 is dependent on the conformation of C3. Paper presented at 27th International Complement Workshop (ICW), SEP 16-20, 2018, Santa Fe, New Mexico, USA.. Molecular Immunology, 102, 193-193
Open this publication in new window or tab >>Generation of an alternative pathway convertase by contact-activated C3 is dependent on the conformation of C3
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2018 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, p. 193-193Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2018
Keywords
Complement C3
National Category
Immunology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-365114 (URN)10.1016/j.molimm.2018.06.167 (DOI)000445313600163 ()
Conference
27th International Complement Workshop (ICW), SEP 16-20, 2018, Santa Fe, New Mexico, USA.
Available from: 2018-11-15 Created: 2018-11-15 Last updated: 2018-11-15Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-7888-1571

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