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  • 1.
    Forsberg, Ulf
    et al.
    Umeå university.
    Jonsson, Per
    Umeå university.
    Stegmayr, Christofer
    Umeå university.
    Jonsson, Fredrik
    Umeå university.
    Nilsson, Bo
    Uppsala university.
    Nilsson Ekdahl, Kristina
    Uppsala university.
    Stegmayr, Bernd
    Umeå university.
    A high blood level in the venous chamber and a wet-stored dialyzer help to reduce exposure for microemboli during hemodialysis2013In: Hemodialysis International, ISSN 1492-7535, E-ISSN 1542-4758, Vol. 17, no 4, p. 612-617Article in journal (Refereed)
    Abstract [en]

    During hemodialysis (HD), microemboli develop in the blood circuit of the apparatus. These microemboli can pass through the venous chamber and enter into the patient's circulation. The aim of this study was to investigate whether it is possible to reduce the risk for exposure of microemboli by altering of the treatment mode. Twenty patients on chronic HD were randomized to a prospective cross-over study of three modes of HD: (a) a dry-stored dialyzer (F8HPS, Fresenius, steam sterilized) with a low blood level in the venous chamber (DL), (b) the same dialyzer as above, but with a high level in the venous chamber (DH), and (c) a wet-stored dialyzer (Rexeed, Asahi Kasei Medical, gamma sterilized) with a high blood level (WH). Microemboli measurements were obtained in a continuous fashion during 180 minutes of HD for all settings. A greater number of microemboli were detected during dialysis with the setting DL vs. WH (odds ratio [OR] 4.07, 95% confidence interval [CI] 4.03-4.11, P<0.0001) and DH vs. WH (OR 1.18, 95% CI 1.17-1.19, P<0.0001) and less for DH vs. DL (OR 0.290, 95% CI 0.288-0.2930.288-0.293, P<0.0001). These data indicate that emboli exposure was least when using WH, greater with DH, and most with DL. This study shows that using a high blood level in the venous chamber and wet-stored dialyzers may reduce the number of microemboli.

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  • 2.
    Nilsson, Per H.
    et al.
    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.
    Magnusson, Peetra U
    Uppsala University.
    Qu, Hongchang
    University of Pennsylvania, USA.
    Iwata, Hiroo
    Kyoto University, Japan.
    Ricklin, Daniel
    University of Pennsylvania, USA.
    Hong, Jaan
    Uppsala University.
    Lambris, John D
    University of Pennsylvania, USA.
    Nilsson, Bo
    Uppsala University.
    Teramura, Yuji
    Uppsala University;Kyoto University, Japan.
    Autoregulation of thromboinflammation on biomaterial surfaces by a multicomponent therapeutic coating2013In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 4, p. 985-994Article in journal (Refereed)
    Abstract [en]

    Activation of the thrombotic and complement systems is the main recognition and effector mechanisms in the multiple adverse biological responses triggered when biomaterials or therapeutic cells come into blood contact. We have created a surface which is auto-protective to human innate immunity by combining three fundamentally different strategies, all developed by us previously, which have been shown to induce substantial, but incomplete hemocompatibility when used separately. In summary, we have conjugated a factor H-binding peptide; and an ADP-degrading enzyme; using a PEG linker on both material and cellular surfaces. When exposed to human whole blood, factor H was specifically recruited to the modified surfaces and inhibited complement attack. In addition, activation of platelets and coagulation was efficiently attenuated, by degrading ADP. Thus, by inhibiting thromboinflammation using a multicomponent approach, we have created a hybrid surface with the potential to greatly reduce incompatibility reactions involving biomaterials and transplantation.

  • 3.
    Suriyanarayanan, Subramanian
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Petrone, Luigi
    Linköping University.
    Ederth, Thomas
    Linköping University.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Biotinyl moiety-selective polymer films with highly ordered macropores2013In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 49, no 46, p. 5274-5276Article in journal (Refereed)
    Abstract [en]

    Macroporous polymer films with long-range uniformity and biotinyl-moiety selective recognition sites have been developed. A hierarchical molecular imprinting strategy afforded significant enhancements in quartz crystal microbalance (QCM) sensitivities towards biotinylated compounds.

  • 4.
    Sengottaiyan, Palanivelu
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Petrlova, Jitka
    Lund university.
    Lagerstedt, Jens
    Lund university.
    Ruiz-Pavon, Lorena
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Budamagunta, Madhu
    University of California, USA.
    Voss, John
    University of California, USA.
    Persson, Bengt L.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Characterization of the biochemical and biophysical properties of the Saccharomyces cerevisiae phosphate transporter Pho892013In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 436, no 3, p. 551-556Article in journal (Refereed)
    Abstract [en]

    In Saccharomyces cerevisiae, Pho89 mediates a cation-dependent transport of Pi across the plasma membrane. This integral membrane protein belongs to the Inorganic Phosphate Transporter (PiT) family, a group that includes the mammalian Na+/Pi cotransporters Pit1 and Pit2. Here we report that the Pichia pastoris expressed recombinant Pho89 was purified in the presence of Foscholine-12 and functionally reconstituted into proteoliposomes with a similar substrate specificity as observed in an intact cell system. The alpha-helical content of the Pho89 protein was estimated to 44%. EPR analysis showed that purified Pho89 protein undergoes conformational change upon addition of substrate. 

  • 5.
    Nicholls, Ian A.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Olsson, Gustaf D.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rosengren, Annika M.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Computational Strategies for the Design and Study of Molecularly Imprinted Materials2013In: Industrial & Engineering Chemistry Research, ISSN 0888-5885, E-ISSN 1520-5045, Vol. 52, no 39, p. 13900-13909Article in journal (Refereed)
    Abstract [en]

    The need for materials with predetermined ligand-selectivities for use in sensing and separation technologies, e.g. membranes and chromatography, has driven the development of molecularly imprinted polymer science and technology. Over recent years, the need to develop robust predictive tools capable of handling the complexity of molecular imprinting systems has become apparent The current status of the use of in silica techniques in molecular imprinting is here presented, and we highlight areas where new developments are contributing to improvements in the rational design of molecularly imprinted polymers.

  • 6.
    Rosengren, Annika M.
    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.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Consequences of morphology on molecularly imprinted polymer-ligand recognition2013In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 14, no 1, p. 1207-1217Article in journal (Refereed)
    Abstract [en]

    The relationship between molecularly imprinted polymer (MIP) morphology and template-rebinding over a series of warfarin-imprinted methacrylic acid co(ethylene dimethacrylate) polymers has been explored. Detailed investigations of the nature of template recognition revealed that an optimal template binding was obtained with polymers possessing a narrow population of pores (~3–4 nm) in the mesopore size range. Importantly, the warfarin-polymer rebinding analyses suggest strategies for regulating ligand binding capacity and specificity through variation of the degree of cross-linking, where polymers prepared with a lower degree of cross-linking afford higher capacity though non-specific in character. In contrast, the co-existence of specific and non-specific binding was found in conjunction with higher degrees of cross-linking and resultant meso- and macropore size distributions.

  • 7.
    Bäck, Jennie
    et al.
    Uppsala University.
    Lood, Christian
    Skåne University Hospital;Lund University.
    Bengtsson, Anders A.
    Skåne University Hospital;Lund University.
    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 products are new potential biomarkers to evaluate the risk of thrombotic events in systemic lupus erythematosus2013In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 15, no 6, article id R206Article in journal (Refereed)
    Abstract [en]

    Introduction: Patients with systemic lupus erythematosus (SLE) have persistent platelet activation and an increased risk of thrombotic events, which cannot be accounted for by traditional cardiovascular risk factors. Factor (F)XII has a potentially important role in thrombus formation and is triggered by activated platelets. We therefore asked whether the contact system is involved in inflammation and vascular disease (VD) in SLE. Methods: Fibrin clots were incubated with purified FXII or whole blood, and the activation and regulation of FXII were studied. Plasma from SLE patients with (n = 31) or without (n = 38) previous VD and from matched healthy controls (n = 68) were analyzed for the presence of complexes formed between contact system enzymes and antithrombin (AT) or C1 inhibitor (C1INH) and evaluated with regard to clinical data and laboratory parameters. Results: Fibrin clots elicited FXII activation and acted as co-factors for AT. In clotting plasma, the levels of FXIIa-AT increased, and FXIIa-C1INH decreased. A similar reciprocal relationship existed in SLE patients. FXIIa-AT was elevated in the SLE patients with a history of VD, while the corresponding levels of factor FXIIa-C1INH were significantly decreased. FXIIa-AT correlated strongly with platelet parameters. The odds ratio for VD among the SLE patients was 8.9 if they had low levels of FXIIa-C1INH, 6.1 for those with high levels of FXIIa-AT, and increased to 23.4 for those with both decreased levels of FXIIa-C1INH and increased levels of FXIIa-AT. Conclusions: Activation of FXII is elicited by fibrin during thrombotic reactions in vitro and in vivo, and fibrin acts as a heparin-like co-factor and regulates AT. Patients with SLE had altered levels of FXIIa-serpin complexes, supporting that the contact system is involved in this disease. FXIIa-serpin complexes are strongly associated with previous VD in SLE patients, suggesting that these complexes are potential biomarkers for monitoring and assessing the risk of thrombotic events in SLE.

  • 8.
    O'Mahony, John
    et al.
    Teagasc Food Research Centre, Ireland.
    Moloney, Mary
    Teagasc Food Research Centre, Ireland.
    McCormack, Martin
    Teagasc Food Research Centre, Ireland.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Mizaikoff, Boris
    University of Ulm, Germany.
    Danaher, Martin
    Teagasc Food Research Centre, Ireland.
    Design and implementation of an imprinted material for the exaction of the endocrine disruptor bisphenol A from milk2013In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 931, p. 164-169Article in journal (Refereed)
    Abstract [en]

    This paper describes the determination of bisphenol A (BPA) in milk samples, using a novel molecularly imprinted polymer. The imprinted polymer was developed using a rational design approach, and pre-polymerization interactions were investigated using molecular dynamics simulations and X-ray crystallography. A hydroquinone-imprinted polymer was used for solid phase extraction (SPE) clean-up of samples. BPA was quantified by high performance liquid chromatography (HPLC) and fluorescence (FLD) detection. Following validation, the method described was capable of determining bisphenol A in milk down to a limit of detection of 1.32 mu g kg(-1). The method was applied to a survey (n = 27) of commercial milk products; BPA was detected in one of the samples, at a level of 176 mu g kg(-1). Test results were confirmed by a parallel UHPLC-MS/MS analytical method. This demonstrates the utility of the hydroquinone-imprinted polymer for application to selective sample clean-up and analysis of bisphenol A in milk, avoiding possible detrimental affects associated with template bleeding and without the need for expensive or difficult-to-obtain template. (C) 2013 Elsevier B.V. All rights reserved.

  • 9.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Drug Resistance Missense Mutations in Cancer Are Subject to Evolutionary Constraints2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, article id e82059Article in journal (Refereed)
    Abstract [en]

    Several tumor types are sensitive to deactivation of just one or very few genes that are constantly active in the cancer cells,a phenomenon that is termed oncogene addiction'. Drugs that target the products of those oncogenes can yield a temporary relief, and even complete remission. Unfortunately, many patients receiving oncogene-targeted therapies relapse on treatment. This often happens due to somatic mutations in the oncogene (resistance mutations"). 'Compound mutations', which in the context of cancer drug resistance are defined as two or more mutations of the drug target in the same clone may lead to enhanced resistance against the most selective inhibitors. Here, it is shown that the vast majority the resistance mutations occurring in cancer patients treated with tyrosin kinase inhibitors aimed at three different proteins follow an evolutionary pathway. Using bioinforrnatic analysis tools, found that the drug-resistance mutations in the tyrosine kinase domains of Abl1, ALK and exons 20 and 21 of EGFR favour transformations to residues that can be identified in similar positions in evolutionary related proteins. The results demonstrate that evolutionary pressure shapes the mutational landscape in the case of drug-resistance somatic mutations. The constraints on the mutational landscape suggest that it may be possible to counter single drug-resistance point mutations. The observation of relatively many resistance mutations in Abl1, but not in the other genes, is explained by the fact that mutations in Abl1 tend to be biochemically conservative, whereas mutations in EGFR and ALK tend to be radical. Analysis of Abl1 compound mutations suggests that such mutations are more prevalent than hitherto reported and may be more difficult to counter. This supports the notion that such mutations may provide an escape route for targeted cancer drug resistance.

  • 10.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Electrolyte Solutions and Specific Ion Effects on Interfaces2013In: Journal of Chemical Education, ISSN 0021-9584, E-ISSN 1938-1328, Vol. 90, no 8, p. 1018-1023Article in journal (Refereed)
    Abstract [en]

    Introductory general and physical chemistry courses often deal with colligative properties of solutions and do not discuss nonideal solutions in detail. Yet, a growing body of evidence reveals that even at physiological concentrations electrolyte solutions cannot be treated as ideal when a charged or partially charged solute (such as a protein) is present in the solution. In such cases, the interactions between the salt ions and the solute depend on the specific ions that constitute the electrolyte solution (specific ion effects). For example, the catalytic efficiency of an enzyme may be different in NaCl and KCl solutions. In this article, specific ion effects are reviewed from a historical perspective, and then the current state of knowledge is presented at a qualitative level that is appropriate for second-year or advanced undergraduate science students. Finally, the related nomenclature (Bjerrum ion pairs, Hofmeister series, lyotropic series, and specific ion effects) is analyzed, and some suggestions are made with respect to the terminology, to make it more accessible to students. The material is appropriate for courses where solution chemistry is discussed, for example, in physical chemistry. In addition, it may be included in the chemistry curriculum for life or pharmaceutical sciences.

  • 11.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Hong, Jaan
    Uppsala University.
    Hamad, Osama
    Uppsala University.
    Larsson, Rolf
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Evaluation of the blood compatibility of materials, cells and tissues: Basic concepts, test models and practical guidelines2013In: Complement Therapeutics / [ed] J.D. Lambris, V.M. Holers & D. Ricklin, Springer, 2013, p. 257-270Chapter in book (Refereed)
    Abstract [en]

    Medicine today uses a wide range of biomaterials, most of which make contact with blood permanently or transiently upon implantation. Contact between blood and nonbiological materials or cells or tissue of nonhematologic origin initiates activation of the cascade systems (complement, contact activation/coagulation) of the blood, which induces platelet and leukocyte activation.

    Although substantial progress regarding biocompatibility has been made, many materials and medical treatment procedures are still associated with severe side effects. Therefore, there is a great need for adequate models and guidelines for evaluating the blood compatibility of biomaterials. Due to the substantial amount of cross talk between the different cascade systems and cell populations in the blood, it is advisable to use an intact system for evaluation.

    Here, we describe three such in vitro models for the evaluation of the biocompatibility of materials and therapeutic cells and tissues. The use of different anticoagulants and specific inhibitors in order to be able to dissect interactions between the different cascade systems and cells of the blood is discussed. In addition, we describe two clinically relevant medical treatment modalities, the integration of titanium implants and transplantation of islets of Langerhans to patients with type 1 diabetes, whose mechanisms of action we have addressed using these in vitro models.

  • 12.
    Darreh-Shori, Taher
    et al.
    Karolinska Institutet.
    Vijayaraghavan, Swetha
    Karolinska Institutet.
    Aeinehband, Shahin
    Karolinska University Hospital Solna.
    Piehl, Fredrik
    Karolinska University Hospital Solna.
    Lindblom, Rickard P. F.
    Karolinska University Hospital Solna.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Långström, Bengt
    Uppsala University;Imperial College, UK;Odense University Hospital, University of Southern Denmark, Denmark.
    Almkvist, Ove
    Karolinska Institutet;Stockholm University.
    Nordberg, Agneta
    Karolinska Institutet;Karolinska University Hospital Huddinge.
    Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 11, p. 2465-2481Article in journal (Refereed)
    Abstract [en]

    Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1 beta, and tumor necrosis factor (TNF)-alpha. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1b and 21%-27% higher TNF-alpha compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low beta-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-alpha and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status. (C) 2013 Elsevier Inc. All rights reserved.

  • 13.
    Karlsson, Björn C. G.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Olsson, Gustaf D.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    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.
    Henschel, Henning
    Division of Atmospheric Sciences, Department of Physics, University of Helsinki, P.O. Box 64, Helsinki, Finland.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    How warfarin’s structural diversity influences its phospholipid bilayer membrane permeation2013In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 117, no 8, p. 2384-2395Article in journal (Refereed)
    Abstract [en]

    The role of the structural diversity of the widely used anticoagulant drug warfarin on its distribution in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer membranes was investigated using a series of both restrained (umbrella sampling) and unrestrained molecular dynamics simulations. Data collected from unrestrained simulations revealed favorable positions for neutral isomers of warfarin, the open side chain form (OCO), and the cyclic hemiketal (CCO), along the bilayer normal close to the polar headgroup region and even in the relatively distant nonpolar lipid tails. The deprotonated open side chain form (DCO) was found to have lower affinity for the DOPC bilayer membrane relative to the neutral forms, with only a small fraction interacting with the membrane, typically within the polar headgroup region. The conformation of OCO inside the lipid bilayer was found to be stabilized by intramolecular hydrogen bonding thereby mimicking the structure of CCO. Differences in free energies, for positions of OCO and CCO inside the bilayer membrane, as compared to positions in the aqueous phase, were −97 and −146 kJ·mol–1. Kinetic analysis based on the computed free energy barriers reveal that warfarin will diffuse through the membranes within hours, in agreement with experimental results on warfarin’s accumulation in the plasma, thus suggesting a passive diffusion mechanism. We propose that this membrane transport may be an isomerization-driven process where warfarin adapts to the various local molecular environments encountered under its journey through the membrane. Collectively, these results improve our understanding of the influence of warfarin’s structural diversity on the drug’s distribution and bioavailability, which in turn may provide insights for developing new formulations of this important pharmaceutical to better address its narrow therapeutic window.

  • 14.
    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.
    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.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Influence of composition and morphology on template recognition in molecularly imprinted polymers2013In: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 46, no 4, p. 1408-1414Article in journal (Refereed)
    Abstract [en]

    A combination of theoretical and experimental studies has provided correlations between molecularly imprinted polymer composition, morphology, and recognition behavior obtained using a series of bupivacaine-imprinted methacrylic acid (MAA)–ethylene glycol dimethacrylate copolymers differing in molar ratios of the respective monomers. Results extracted from analysis of molecular dynamics (MD) trajectory data demonstrated that stability and frequency of interactions between bupivacaine and the monomers in the prepolymerization phase were strongly affected by minor changes in polymer composition, which in turn affected binding site affinity and heterogeneity of the imprinted polymers. Moreover, through the characterization of polymer morphology, we show that higher molar fractions of MAA resulted in polymeric materials with increased pore size, a feature that enhanced the binding capacity of the polymers. Furthermore, the results presented point at the strength of MD for predicting MIP-template binding capacity and affinity.

  • 15.
    Ahlstrand, Emma
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Spångberg, Daniel
    Uppsala University.
    Hermansson, Kersti
    Uppsala University.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Interaction energies between metal ions (Zn2+ and Cd2+) and biologically relevant ligands2013In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 113, no 23, p. 2554-2562Article in journal (Refereed)
    Abstract [en]

    Interactions between the group XII metals Zn2+ and Cd2+ and amino acid residues play an important role in biology due to the prevalence of the first and the toxicity of the second. Estimates of the interaction energies between the ions and relevant residues in proteins are however difficult to obtain. This study reports on calculated interaction energy curves for small complexes of Zn2+ or Cd2+ and amino acid mimics (acetate, methanethiolate, and imidazole) or water. Given that many applications and models (e.g., force fields, solvation models, etc.) begin with and rely on an accurate description of gas-phase interaction energies, this is where our focus lies in this study. Four density functional theory (DFT)-functionals and MP2 were used to calculate the interaction energies not only at the respective equilibrium distances but also at a relevant range of ion–ligand separation distances. The calculated values were compared with those obtained by CCSD(T). All DFT-methods are found to overestimate the magnitude of the interaction energy compared to the CCSD(T) reference values. The deviation was analyzed in terms of energy components from localized molecular orbital energy decomposition analysis scheme and is mostly attributed to overestimation of the polarization energy. MP2 shows good agreement with CCSD(T) [root mean square error (RMSE) = 1.2 kcal/mol] for the eight studied complexes at equilibrium distance. Dispersion energy differences at longer separation give rise to increased deviations between MP2 and CCSD(T) (RMSE = 6.4 kcal/mol at 3.0 Å). Overall, the results call for caution in applying DFT methods to metalloprotein model complexes even with closed-shell metal ions such as Zn2+ and Cd2+, in particular at ion–ligand separations that are longer than the equilibrium distances.

  • 16.
    Bergman, Ingrid-Maria
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Aarhus University, Denmark.
    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.
    Okumura, Naohiko
    Institute of Society for Techno-innovation of Agriculture, Japan.
    Uenishi, Hirohide
    National Institute of Agrobiological Sciences, Japan.
    Guldbrandtsen, Bernt
    Aarhus University, Denmark.
    Essler, Sabine
    Univ of Veterinary Medicine, Austria.
    Knoll, Ales
    Mendel University, Czech Republic.
    Heegaard, Peter
    Technical University of Denmark, Denmark.
    Edfors, Inger
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Juul-Madsen, Helle
    Aarhus University, Denmark.
    MBL1 genotypes in wild boar populations from Sweden, Austria, the Czech Republic and Japan2013In: International Journal of Immunogenetics, ISSN 1744-3121, E-ISSN 1744-313X, Vol. 40, no 2, p. 131-139Article in journal (Refereed)
    Abstract [en]

    The single nucleotide polymorphism (SNP) G949T in the mannose-binding lectin (MBL) 1 gene has been associated with low MBL-A concentration in serum and detected at different frequencies in various European pig populations. However, the origin of this SNP is not known. Part of the MBL1 gene was sequenced in 12 wild boar/Large White crossbred pigs from the second backcross (BC 2) generation in a family material originating from two wild boar x Large White intercrosses. Also, MBL-A serum concentration was measured in the entire BC 2 generation (n = 45). Furthermore, the genotypes of 68 wild boars from Sweden, Austria, the Czech Republic, and Japan were determined in regard to five previously described SNPs in MBL1. The T allele of G949T was present among the BC 2 animals. MBL-A serum concentration in the BC 2 animals showed a bimodal distribution, with one-third of the animals at levels between 0.7 and 1.6 μg mL−1 and the remaining pigs at levels around 13 μg mL−1. There was a co-variation between the presence of the T allele and low MBL-A concentration in serum. The genotyping of the wild boars revealed differences between populations. The T allele of G949T was not detected in the Austrian and Japanese samples and is thus unlikely to be an original feature of wild boars. In contrast, it was present at high frequency (0.35) among the Swedish wild boars, probably representing a founder effect. Five MBL1 haplotypes were resolved. Only two of these were present among the Japanese wild boars compared to four in each of the European populations. This difference may reflect differences in selection pressure and population history.

  • 17.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Boye, Kjetil
    Flatmark, Kjersti
    Molecular modelling and simulations in cancer research2013In: Biochimica et Biophysica Acta. CR. Reviews on Cancer, ISSN 0304-419X, E-ISSN 1879-2561, Vol. 1836, no 1, p. 1-14Article, review/survey (Refereed)
    Abstract [en]

    The complexity of cancer and the vast amount of experimental data available have made computer-aided approaches necessary. Biomolecular modelling techniques are becoming increasingly easier to use, whereas hardware and software are becoming better and cheaper. Cross-talk between theoretical and experimental scientists dealing with cancer-research from a molecular approach, however, is still uncommon. This is in contrast to other fields, such as amyloid-related diseases, where molecular modelling studies are widely acknowledged. The aim of this review paper is therefore to expose some of the more common approaches in molecular modelling to cancer scientists in simple terms, illustrating success stories while also revealing the limitations of computational studies at the molecular level.

  • 18.
    Lard, Mercy
    et al.
    Lund University.
    ten Siethoff, Lasse
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Generosi, Johanna
    University of Copenhagen, Denmark.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Månsson, Alf
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Linke, Heiner
    Lund University.
    Nanowire Interfacing with Molecular Motors: Light Guiding and Tunneling2013Conference paper (Other academic)
  • 19.
    Suriyanarayanan, Subramanian
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lee, Hung-Hsun
    Linköping University.
    Liedberg, Bo
    Linköping University.
    Aastrup, Teodor
    Attana AB, Stockholm.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Protein-resistant hyperbranched polyethyleneimine brush surfaces2013In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 396, p. 307-315Article in journal (Refereed)
    Abstract [en]

    A novel hyperbranched polyethyleneimine (PEI) modified gold surface has been designed, fabricated, and investigated with respect to its ability to resist non-specific adsorption of proteins. The facile synthesis strategy, based on self-assembly, involves immobilization of polyethyleneimine to gold surfaces modified with 11-mercaptoundecanoic acid (MuDA) monolayers using traditional carbodiimide chemistry. The hyperbranched polymer brushes were characterized by X-ray photoelectron spectroscopy (XPS). Reflection absorption infrared spectroscopy (RAIRS) and ellipsometry measurements showed the thickness of the PEI brushes increases with adsorption solution ionic strength. Polymer brush surface concentrations can be improved from 2560 to 3880 chains/mu m(2) by changing the ionic strength of the adsorption solution (PBS) by varying NaCl concentration from 0 to 650 mM. Protein adsorption (pH 7.4) was evaluated under flow injection analysis (FIA) conditions using a quartz crystal microbalance (QCM). The PEI brushes suppress protein adsorption, for example, cytochrome C, bovine serum albumin (BSA), and ribonuclease A, to less than 0.08 mu g/cm(2) and the protein resistance increases with increasing ionic strength of the carrier solution, performance comparable to that achieved with comparable PEG-coated surfaces. The PEI brushes were exceptionally stable, with adsorption characteristics maintained after 6 months storage in aqueous conditions (pH 7.4, 25 degrees C, PBS). The potential of hyperbranched PEI structures as protein-resistant surfaces is discussed. (C) 2013 Elsevier Inc. All rights reserved.

  • 20.
    Nicholls, Ian A.
    et al.
    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.
    Golker, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Henschel, Henning
    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.
    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.
    Shoravi, Siamak
    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.
    Wikman, Susanne
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rational molecularly imprinted polymer design: theoretical and computational strategies2013In: Molecular Imprinting: Principles and Applications of Micro- and Nanostructured Polymers / [ed] Ye, L, London: Pan Stanford Publishing, 2013, p. 71-104Chapter in book (Refereed)
  • 21.
    Vijayaraghavan, Swetha
    et al.
    Karolinska Institutet.
    Karami, Azadeh
    Karolinska Institutet.
    Aeinehband, Shahin
    Karolinska Institutet.
    Behbahani, Homira
    Karolinska Institutet.
    Grandien, Alf
    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.
    Lindblom, Rickard P. F.
    Karolinska Institutet.
    Piehl, Fredrik
    Karolinska Institutet.
    Darreh-Shori, Taher
    Karolinska Institutet.
    Regulated Extracellular Choline Acetyltransferase Activity: The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, article id e65936Article in journal (Refereed)
    Abstract [en]

    Acetylcholine (ACh), the classical neurotransmitter, also affects a variety of nonexcitable cells, such as endothelia, microglia, astrocytes and lymphocytes in both the nervous system and secondary lymphoid organs. Most of these cells are very distant from cholinergic synapses. The action of ACh on these distant cells is unlikely to occur through diffusion, given that ACh is very short-lived in the presence of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), two extremely efficient ACh-degrading enzymes abundantly present in extracellular fluids. In this study, we show compelling evidence for presence of a high concentration and activity of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT) in human cerebrospinal fluid (CSF) and plasma. We show that ChAT levels are physiologically balanced to the levels of its counteracting enzymes, AChE and BuChE in the human plasma and CSF. Equilibrium analyses show that soluble ChAT maintains a steady-state ACh level in the presence of physiological levels of fully active ACh-degrading enzymes. We show that ChAT is secreted by cultured human-brain astrocytes, and that activated spleen lymphocytes release ChAT itself rather than ACh. We further report differential CSF levels of ChAT in relation to Alzheimer's disease risk genotypes, as well as in patients with multiple sclerosis, a chronic neuroinflammatory disease, compared to controls. Interestingly, soluble CSF ChAT levels show strong correlation with soluble complement factor levels, supporting a role in inflammatory regulation. This study provides a plausible explanation for the long-distance action of ACh through continuous renewal of ACh in extracellular fluids by the soluble ChAT and thereby maintenance of steady-state equilibrium between hydrolysis and synthesis of this ubiquitous cholinergic signal substance in the brain and peripheral compartments. These findings may have important implications for the role of cholinergic signaling in states of inflammation in general and in neurodegenerative disease, such as Alzheimer's disease and multiple sclerosis in particular.

  • 22.
    Engberg, Anna E.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Rikshosp, Univ Hosp, Norway.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Huang, Shan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Mollnes, T. E.
    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.
    The ratio between C4 and C4BP adsorbed to artificial materials is a new predictor for biocompatibility2013In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 56, no 3, p. 309-309Article in journal (Other academic)
  • 23.
    Olsson, Gustaf D.
    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.
    Schillinger, Eric
    Sellergren, Börje
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Theoretical Studies of 17-beta-Estradiol-Imprinted Prepolymerization Mixtures: Insights Concerning the Roles of Cross-Linking and Functional Monomers in Template Complexation and Polymerization2013In: Industrial & Engineering Chemistry Research, ISSN 0888-5885, E-ISSN 1520-5045, Vol. 52, no 39, p. 13965-13970Article in journal (Refereed)
    Abstract [en]

    In this study, computational methods were employed in efforts to elucidate physical mechanisms underlying the ligand selectivity of polymeric sorbents produced through the molecular imprinting of 17-beta-estradiol. Previous computational and experimental studies had identified candidate systems applicable to the development of synthetic polymeric receptors for the detection and possible removal of pollutants with endocrine-disrupting properties. Here we present a series of comprehensive molecular dynamics studies of candidate molecular imprinting prepolymerization systems. The results from the studies highlight the role of the cross-linker and the importance of the interplay between functionalities of the various monomers employed in template complexation. The significance of these results for future studies is discussed.

  • 24.
    Schothorst, Joep
    et al.
    Katholieke Universiteit Leuven, Belgium.
    Nag Kankipati, Harish
    Katholieke Universiteit Leuven, Belgium.
    Conrad, Michaela
    Katholieke Universiteit Leuven, Belgium.
    Samyn, Dieter R.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Van Zeebroeck, Griet
    Katholieke Universiteit Leuven, Belgium.
    Popova, Yulia
    Katholieke Universiteit Leuven, Belgium.
    Rubio-Texeira, Marta
    Katholieke Universiteit Leuven, Belgium.
    Persson, Bengt L.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Thevelein, Johan
    Katholieke Universiteit Leuven, Belgium.
    Yeast nutrient transceptors provide novel insight in the functionality of membrane transporters.2013In: Current Genetics, ISSN 0172-8083, E-ISSN 1432-0983, Vol. 59, no 4, p. 197-206Article in journal (Refereed)
    Abstract [en]

    In the yeast Saccharomyces cerevisiae several nutrient transporters have been identified that possess an additional function as nutrient receptor. These transporters are induced when yeast cells are starved for their substrate, which triggers entry into stationary phase and acquirement of a low protein kinase A (PKA) phenotype. Re-addition of the lacking nutrient triggers exit from stationary phase and sudden activation of the PKA pathway, the latter being mediated by the nutrient transceptors. At the same time, the transceptors are ubiquitinated, endocytosed and sorted to the vacuole for breakdown. Investigation of the signaling function of the transceptors has provided a new read-out and new tools for gaining insight into the functionality of transporters. Identification of amino acid residues that bind co-transported ions in symporters has been challenging because the inactivation of transport by site-directed mutagenesis is not conclusive with respect to the cause of the inactivation. The discovery of nontransported agonists of the signaling function in transceptors has shown that transport is not required for signaling. Inactivation of transport with maintenance of signaling in transceptors supports that a true proton-binding residue was mutagenised. Determining the relationship between transport and induction of endocytosis has also been challenging, since inactivation of transport by mutagenesis easily causes loss of all affinity for the substrate. The use of analogues with different combinations of transport and signaling capacities has revealed that transport, ubiquitination and endocytosis can be uncoupled in several unexpected ways. The results obtained are consistent with transporters undergoing multiple substrate-induced conformational changes, which allow interaction with different accessory proteins to trigger specific downstream events.

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