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  • 51.
    Nevalainen, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology. nina.nevalainen@diagrad.umu.se.
    Af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Gerhardt, G A
    Department of Anatomy, Neurobiology, and Neurology, University of Kentucky Medical Center, Lexington, KY, USA.
    Strömberg, Iingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Serotonergic nerve fibers in l-DOPA-derived dopamine release and dyskinesia2014In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 260, p. 73-86Article in journal (Refereed)
    Abstract [en]

    The 5-HT (5-hydroxytryptamine) system has been assigned a key role in the development of 3,4-dihydroxyphenyl-l-alanine (l-DOPA)-induced dyskinesia, mainly due to 5-HT neuronal ability to decarboxylate l-DOPA into dopamine. Nevertheless, knowledge of l-DOPA-induced events that could lead to development of dyskinesias are limited and therefore the present work has evaluated (i) the role of the 5-HT system in l-DOPA-derived dopamine synthesis when dopamine neurons are present, (ii) l-DOPA-induced effects on striatal dopamine release and clearance, and on 5-HT nerve fiber density, and (iii) the behavioral outcome of altered 5-HT transmission in dyskinetic rats. Chronoamperometric recordings demonstrated attenuated striatal l-DOPA-derived dopamine release (∼30%) upon removal of 5-HT nerve fibers in intact animals. Interestingly, four weeks of daily l-DOPA treatment yielded similar-sized dopamine peak amplitudes in intact animals as found after a 5-HT-lesion. Moreover, chronic l-DOPA exposure attenuated striatal 5-HT nerve fiber density in the absence of dopamine nerve terminals. Furthermore, fluoxetine-induced altered 5-HT transmission blocked dyskinetic behavior via action on 5-HT1A receptors. Taken together, the results indicate a central role for the 5-HT system in l-DOPA-derived dopamine synthesis and in dyskinesia, and therefore potential l-DOPA-induced deterioration of 5-HT function might reduce l-DOPA efficacy as well as promote the upcoming of motor side effects.

  • 52.
    Nordborg, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis and modifications of materials for separation science2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis deals with the preparation of materials for use in separation science and their surface modification by grafting. The overall aim is the preparation of diverse materials by combination of a set of developed tools.

    Included in the thesis is the synthesis of monolithic media using non-traditional crosslinkers, the characterization of their porous properties and initial testing in reversed-phase chromatographic separation of proteins. The preparation of a library of short polymer chains, telomers, with varied functionality and their characterization is reported. Included in the characterization is the gradient polymer elution chromatography of selected telomers on a monolithic column in capillary format. The technique shows promise as a tool for monitoring of polymerization processes and for the separation of telomers with similar size but different functionalities or characteristics.

    Finally, the combination of polymeric support materials and the prepared telomer library is used in surface modification. Surface modification is performed onto activated surfaces via a “grafting to” approach. One example is shown, the surface modification of epoxy-modified divinylbenzene particles by attachment of telomer chains introducing ion-exchange functionality. The material is tested for the separation of proteins, in ion-exchange chromatography mode.

  • 53.
    Norlin, Rikard
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Juhlin, Lars
    Swedish Defence Research Agency, Division of NBC-Defence, Department of Threat Assessment, Umeå.
    Lind, Per
    Swedish Defence Research Agency, Division of NBC-Defence, Department of Threat Assessment, Umeå.
    Trogen, Lars
    Swedish Defence Research Agency, Division of NBC-Defence, Department of Threat Assessment, Umeå.
    a-Haloenamines as reagents for the conversion of phosphorus oxyacids to their halogenated analogues2005In: Synthesis (Stuttgart), ISSN 0039-7881, E-ISSN 1437-210X, no 11, p. 1765-1770Article in journal (Refereed)
    Abstract [en]

    Phosphorus oxyacids are converted to their halogenated analogues under mild conditions. α-Haloenamines are shown to be effective halogen transfer reagents affording good to high yields of the desired products at reaction times, in some cases, less than one minute.

  • 54.
    Norlin, Rikard
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Lindberg, Gösta
    Swedish Defence Research Agency, NBC-protection Division, Umeå .
    Synthesis of 14C Sarin2003In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 6, p. 599-604Article in journal (Refereed)
    Abstract [en]

    Synthetic routes for the synthesis of [14C] sarin and related nerve agents are described. Triethyl phosphite and [14C] methyl iodide are reacted in the Michaelis-Arbusov reaction to produce diethyl methyl phosphonate which is converted to methylphosphonic acid by hydrolysis. After chlorination and subsequent fluorination the final product is formed by reaction with the appropriate alcohol.

  • 55.
    Norén, Katarina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Coordination Chemistry of Monocarboxylate and Aminocarboxylate Complexes at the Water/Goethite Interface2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is a summary of five papers with focus on adsorption processes of various monocarboxylates and aminocarboxylates at the water/goethite interface. Interaction of organic acids at the water/mineral interfaces are of importance in biogeochemical processes, since such processes have potential to alter mobility and bioavailability of the acids and metal ions.

    In order to determine the coordination chemistry of acetate, benzoate, cyclohexanecarboxylate, sarcosine, MIDA (methyliminediacetic acid), EDDA (ethylenediamine-N,N’-diacetic acid) and EDTA (ethylenediamine-N,N’-tetraacetic acid) upon adsorption to the goethite (alpha-FeOOH) surface, a combination of quantitative measurements with attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) was utilized.

    Over the pH range studied here (pH 3- 9) all ligands, except for sarcosine, have been found to form surface complexes with goethite. In general, theses were characterized as outer sphere surface complexes i.e. with no direct interaction with surface Fe(III) metal ions. Furthermore, two types of different outer-sphere complexes were identified, the solvent-surface hydration-separated ion pair, and hydration-shared ion pair. For the monocarboxylate surface complexes distinction between these two could be made. At high pH values the solvent-surface hydration-separated ion pair was the predominating complex, while at low pH the surface complex is stabilized through the formation of strong hydrogen bonds with the goethite surface. However, it was not possible to clearly separate between the two outer-sphere complexes for coordination of the aminocarboxylates with the surface of goethite. Additionally, EDDA also formed an inner-sphere surface complex at high pH values. The EDDA molecule was suggested to coordinate to the surface by forming a five membered ring with an iron at the goethite surface, through the amine and carboxylate groups.

    Contrary to the other ligands studied, EDTA significantly induced dissolution of goethite. Some of the dissolved iron, in the form of the highly stable FeEDTA- solution complex, was indicated to re-adsorb to the mineral surface as a ternary complex. Similar ternary surface complexes were also found in the Ga(III)EDTA/goethite system, and quantitative and spectroscopic studies on adsorption of Ga(III) in presence and absence of EDTA showed that EDTA considerably effects speciation of gallium at goethite surface.

    The collective results in this thesis show that the affinity of these ligands for the surface of goethite is primarily governed by their chemical composition and structure, and especially important are the types, numbers and relative position of functional groups within the molecular structure.

  • 56.
    Olsson, Rickard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Surface reactions on mineral particles controlling the hydrolysis of glucose phosphates2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Phosphorus (P) is an essential nutrient. A significant amount of soil P may be in the form of organophosphates. Due to the size of these compounds, hydrolysis is often required before P can be assimilated by organisms. Hydrolysis may be mediated by mineral surfaces, or catalyzed by extra cellular enzymes. Since both organophosphates and enzymes have a strong affinity for environmental particles, a study of the hydrolysis of organophosphates must focus on reactions at the water/particle interface. This thesis is a summary of four papers, discussing the adsorption, desorption, and abiotic and enzymatic hydrolysis of glucose-1-phosphate (G1P) and glucose-6-phosphate (G6P) in aqueous goethite suspensions. A new technique for simultaneous infrared and potentiometric titrations (SIPT) allowed in-situ measurements of the interfacial reactions. It was found that glucose phosphates form pH-dependent inner sphere complexes on goethite, which coordinate in a monodentate fashion, and are stabilized by hydrogen bonding. Desorption involves a change in speciation of the surface complexes, illustrating the difficulty in determining desorption rates for individual complexes. The surface mediated hydrolysis is primarily base catalyzed for G1P, and acid catalyzed for G6P. The difference is partly due to electronic factors, and partly to differences in glucose group/goethite interactions. Considerably more extensive is the hydrolysis catalyzed by an acid phosphatase (AcPase). The rate of the enzymatic hydrolysis are strongly dependent on the glucose phosphate surface coverage, showing that surface properties affect the adsorption mode of enzymes, and thus their catalytic activity. In solution, AcPase showed a greater specificity towards G6P, but this specificity was partly lost after adsorption onto goethite.

  • 57.
    Olsson, Rickard
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Giesler, Reiner
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Lindegren, Malin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Persson, Per
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Abiotic and enzymatic hydrolysis of glucose-6-phosphate on Goethite ParticlesManuscript (preprint) (Other academic)
  • 58.
    Olsson, Rickard
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Giesler, Reiner
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Loring, John
    Pacific Northwest National Laboratory.
    Persson, Per
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Enzymatic hydrolysis of organic phosphates adsorbed on mineral surfaces2012In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 46, p. 285-291Article in journal (Refereed)
    Abstract [en]

    Esters of phosphoric acid constitute a sizable fraction of the total phosphorus supply in the environment and thus play an important role in the global phosphorus cycle. Enzymatic hydrolysis of these esters to produce orthophosphate is often a required reaction preceding phosphorus uptake by plants and microorganisms. Generally, adsorption to environmental particles is assumed to limit this process. Here we show, however, that the rate of enzymatic hydrolysis of glucose-1-phosphate (G1P) adsorbed on goethite by acid phosphatase (AcPase) can be of the same order of magnitude as in aqueous solution. The surface process releases carbon to the solution whereas orthophosphate remains adsorbed on goethite. This hydrolysis reaction is strictly an interfacial process governed by the properties of the interface. A high surface concentration of substrate mediates the formation of a catalytically active layer of AcPase, and although adsorption likely reduces the catalytic efficiency of the enzyme, this reduction is almost balanced by the fact that enzyme and substrate are concentrated at the mineral surfaces. Our results suggest that mineral surfaces with appropriate surface properties can be very effective in concentrating substrates and enzymes thereby creating microchemical environments of high enzymatic activity. Hence, also strongly adsorbed molecules in soils and aquatic environments may be subjected to biodegradation by extracellular enzymes.

  • 59.
    Pedrosa-Domellöf, Fatima
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Department of Musculoskeletal Research, National Institute for Working Life, Umeå, Sweden.
    Holmgren, Ylva
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Lucas, C A
    University of Sydney.
    Hoh, J F
    University of Sydney.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Department of Musculoskeletal Research, National Institute for Working Life, Umeå, Sweden.
    Human extraocular muscles: unique pattern of myosin heavy chain expression during myotube formation2000In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 41, no 7, p. 1608-1616Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To study the myosin heavy chain composition of the human extraocular muscles (EOMs) during development.

    METHODS: EOMs from human fetuses of 8 to 22 weeks of gestation were studied with immunocytochemistry and gel electrophoresis. Antibodies specific against nine isoforms of myosin heavy chain (MyHC) were used in serial frozen sections.

    RESULTS: The developing EOMs had a delayed time course of myotube formation and a unique composition and distribution of MyHCs compared with human limb skeletal muscle. The primary myotubes coexpressed two developmental isoforms of MyHCI from the earliest stages. The third developmental MyHCI delineated the future orbital layer at 10 to 12 weeks of gestation. MyHC-slow tonic also appeared early, whereas MyHC alpha-cardiac and MyHC-extraocular, important components of adult EOM, were never detected at the gestational ages studied.

    CONCLUSIONS: The developmental features of the EOMs differed significantly from those reported for limb muscles of the corresponding ages. It is clear that the knowledge of limb muscle development does not fully apply to more specialized muscles, such as the eye muscles. The extreme complexity displayed by the EOMs probably reflects their distinct embryonic origin, innervation, and regulatory program of myogenesis.

  • 60.
    Permyakov, Eugene A.
    et al.
    (Institute for Biological Instrumentation of the Russian Academy of Sciences, Pushchino, Moscow region, Russia.
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Berliner, Lawrence J.
    Denver University, Denver, Colorado.
    Calcium Binding Lysozymes2012Book (Other academic)
  • 61. Petrelli, Riccardo
    et al.
    Meli, Maria
    Vita, Patrizia
    Torquati, Ilaria
    Ferro, Arianna
    Vodnala, Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    D'Alessandro, Natale
    Tolomeo, Manlio
    Del Bello, Fabio
    Kusumanchi, Praveen
    Franchetti, Palmarisa
    Grifantini, Mario
    Jayaram, Hiremagalur N
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Cappellacci, Loredana
    From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase: Synthesis and biological evaluation of valproic esters of 3'-C-methyladenosine2014In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 24, no 22, p. 5304-5309Article in journal (Refereed)
    Abstract [en]

    We synthesized a series of serum-stable covalently linked drugs derived from 3'-C-methyladenosine (3'-Me-Ado) and valproic acid (VPA), which are ribonucleotide reductase (RR) and histone deacetylase (HDAC) inhibitors, respectively. While the combination of free VPA and 3'-Me-Ado resulted in a clear synergistic apoptotic effect, the conjugates had lost their HDAC inhibitory effect as well as the corresponding apoptotic activity. Two of the analogs, 2',5'-bis-O-valproyl-3'-C-methyladenosine (A160) and 5'-O-valproyl-3'-C-methyladenosine (A167), showed promising cytotoxic activities against human hematological and solid cancer cell lines. A167 was less potent than A160 but had interesting features as an RR inhibitor. It inhibited RR activity by competing with ATP as an allosteric effector and concomitantly reduced the intracellular deoxyribonucleoside triphosphate (dNTP) pools. A167 represents a novel lead compound, which in contrast to previously used RR nucleoside analogs does not require intracellular kinases for its activity and therefore holds promise against drug resistant tumors with downregulated nucleoside kinases.

  • 62.
    Rojo, Maria Luisa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Fower, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Changes in cannabinoid CB(1) receptor functionality in the female rat prefrontal cortex following a high fat diet.2013In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 92, no 13, p. 757-762Article in journal (Refereed)
    Abstract [en]

    Aims: A high fat diet (HFD) has been found to affect neurotransmission in the prefrontal cortex, but the effects of this dietary regime upon the endocannabinoid system has not been studied in this brain region. In consequence, in the present study, we have investigated the effect of HFD for up to 20 weeks upon the endocannabinoid system in the prefrontal cortex of female rats.

    Main methods: CB1 receptor functionality was measured using CP55,940-stimulated [S-35] GTP gamma S autoradiography. Fatty acid amide hydrolase and monoacylglycerol lipase activities were analysed in brain regions by assessing rates of [H-3] anandamide and JZL184-sensitive [H-3]2-oleoylglycerol hydrolysis, respectively.

    Key findings: In the prefrontal cortex, a significantly greater stimulation of [S-35] GTP gamma S binding by CP55,940 was seen following 4-12, but not 16-20 weeks of HFD. No significant changes were seen for the caudate-putamen, CA1-CA3 region of the hippocampus or the dentate gyrus. The increased response for the 12 week animals was not accompanied by a significant change in the receptor density, measured with [H-3]CP55,940 autoradiography. No significant changes in the activity of the endocannabinoid hydrolytic enzymes fatty acid amide or monoacylglycerol lipase were seen in the prefrontal cortex, hippocampus, amygdala or hypothalamus following either 12 or 20 weeks of HFD.

    Significance: It is concluded that HFD produces an increased CB1 receptor functionality in the prefrontal cortex of female rats. Given that the endocannabinoid system regulates neurotransmission in the prefrontal cortex, the present data would implicate this system in the disturbed prefrontal cortical activity in this region following a high fat diet.

  • 63.
    Rompikuntal, Pramod K.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Vdovikova, Svitlana
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Duperthuy, Marylise
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Johnson, Tanya L.
    Åhlund, Monika
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sandkvist, Maria
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Outer Membrane Vesicle-Mediated Export of Processed PrtV Protease from Vibrio cholerae2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0134098Article in journal (Refereed)
    Abstract [en]

    Background Outer membrane vesicles (OMVs) are known to release from almost all Gram-negative bacteria during normal growth. OMVs carry different biologically active toxins and enzymes into the surrounding environment. We suggest that OMVs may therefore be able to transport bacterial proteases into the target host cells. We present here an analysis of the Vibrio cholerae OMV-associated protease PrtV. Methodology/Principal Findings In this study, we demonstrated that PrtV was secreted from the wild type V. cholerae strain C6706 via the type II secretion system in association with OMVs. By immunoblotting and electron microscopic analysis using immunogold labeling, the association of PrtV with OMVs was examined. We demonstrated that OMV-associated PrtV was biologically active by showing altered morphology and detachment of cells when the human ileocecum carcinoma (HCT8) cells were treated with OMVs from the wild type V. cholerae strain C6706 whereas cells treated with OMVs from the prtV isogenic mutant showed no morphological changes. Furthermore, OMV-associated PrtV protease showed a contribution to bacterial resistance towards the antimicrobial peptide LL-37. Conclusion/Significance Our findings suggest that OMVs released from V. cholerae can deliver a processed, biologically active form of PrtV that contributes to bacterial interactions with target host cells.

  • 64.
    Sabouri, Nasim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Capra, John A
    Zakian, Virginia A
    The essential Schizosaccharomyces pombe Pfh1 DNA helicase promotes fork movement past G-quadruplex motifs to prevent DNA damage2014In: BMC biology, ISSN 1741-7007, Vol. 12, no 1, article id 101Article in journal (Refereed)
    Abstract [en]

    Background: G-quadruplexes (G4s) are stable non-canonical DNA secondary structures consisting of stacked arrays of four guanines, each held together by Hoogsteen hydrogen bonds. Sequences with the ability to form these structures in vitro, G4 motifs, are found throughout bacterial and eukaryotic genomes. The budding yeast Pif1 DNA helicase, as well as several bacterial Pif1 family helicases, unwind G4 structures robustly in vitro and suppress G4-induced DNA damage in S. cerevisiae in vivo.

    Results: We determined the genomic distribution and evolutionary conservation of G4 motifs in four fission yeast species and investigated the relationship between G4 motifs and Pfh1, the sole S. pombe Pif1 family helicase. Using chromatin immunoprecipitation combined with deep sequencing, we found that many G4 motifs in the S. pombe genome were associated with Pfh1. Cells depleted of Pfh1 had increased fork pausing and DNA damage near G4 motifs, as indicated by high DNA polymerase occupancy and phosphorylated histone H2A, respectively. In general, G4 motifs were underrepresented in genes. However, Pfh1-associated G4 motifs were located on the transcribed strand of highly transcribed genes significantly more often than expected, suggesting that Pfh1 has a function in replication or transcription at these sites.

    Conclusions: In the absence of functional Pfh1, unresolved G4 structures cause fork pausing and DNA damage of the sort associated with human tumors.

  • 65.
    Sandberg Hiltunen, Maria
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hjorth Alifrangis, Lene
    The Royal Danish School of Pharmacy.
    Christensen, Inge
    The Royal Danish School of Pharmacy.
    Structure-Property Model for Membrane Partitioning of Oligopeptides2000In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 43, no 1, p. 103-113Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to develop a structure-property model for membrane partitioningof oligopeptides using statistical design methods and multivariate data analysis. A set of 20tetrapeptides with optional N-methylations at residues 2 and 4 was designed by a D-optimaldesign procedure. After synthesis and purification, the membrane partitioning abilities of thepeptides were tested in two chromatographic systems with phospholipids as the stationaryphase: immobilized artificial membrane chromatography (IAM) and immobilized liposomechromatography (ILC). The relationship between these measures and three different sets ofcalculated descriptors was analyzed by partial least-squares projection to latent structures(PLS). The descriptors used were the molecular surface area, Molsurf parameters, and Volsurfparameters. All three models were of good statistical quality and supported that a largehydrogen-bonding potential and the presence of a negative charge impair membrane partitioning,whereas hydrophobic parameters promote partitioning. The findings are in accordancewith what has been found for absorption of known drugs and have implications for the designof peptide-like drugs with good oral bioavailability.

  • 66.
    Simanova, Anna A.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Loring, John S.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Persson, Per
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Formation of ternary metal-oxalate surface complexes on alpha-FeOOH particlesManuscript (preprint) (Other academic)
  • 67.
    Simanova, Anna A.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Persson, Per
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Loring, John S.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Surface reactions controlling the decomposition of DFOB in the presence of goethiteManuscript (preprint) (Other academic)
  • 68. Sjåland, Cecilie
    et al.
    Lunde, Per Kristian
    Swift, Fredrik
    Munkvik, Morten
    Ericsson, Madelene
    Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
    Lunde, Marianne
    Boye, Sigurd
    Christensen, Geir
    Ellingsen, Øyvind
    Sejersted, Ole M
    Andersson, Kristin B
    Slowed relaxation and preserved maximal force in soleus muscles of mice with targeted disruption of the Serca2 gene in skeletal muscle2011In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 589, no Pt 24, p. 6139-6155Article in journal (Refereed)
    Abstract [en]

    Sarcoplasmic reticulum Ca(2+) ATPases (SERCAs) play a major role in muscle contractility by pumping Ca(2+) from the cytosol into the sarcoplasmic reticulum (SR) Ca(2+) store, allowing muscle relaxation and refilling of the SR with releasable Ca(2+). Decreased SERCA function has been shown to result in impaired muscle function and disease in human and animal models. In this study, we present a new mouse model with targeted disruption of the Serca2 gene in skeletal muscle (skKO) to investigate the functional consequences of reduced SERCA2 expression in skeletal muscle. SkKO mice were viable and basic muscle structure was intact. SERCA2 abundance was reduced in multiple muscles, and by as much as 95% in soleus muscle, having the highest content of slow-twitch fibres (40%). The Ca(2+) uptake rate was significantly reduced in SR vesicles in total homogenates. We did not find any compensatory increase in SERCA1 or SERCA3 abundance, or altered expression of several other Ca(2+)-handling proteins. Ultrastructural analysis revealed generally well-preserved muscle morphology, but a reduced volume of the longitudinal SR. In contracting soleus muscle in vitro preparations, skKO muscles were able to fully relax, but with a significantly slowed relaxation time compared to controls. Surprisingly, the maximal force and contraction rate were preserved, suggesting that skKO slow-twitch fibres may be able to contribute to the total muscle force despite loss of SERCA2 protein. Thus it is possible that SERCA-independent mechanisms can contribute to muscle contractile function.

  • 69.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Achilles tendinopathy is a troublesome sports-related condition involving blood vessel ingrowth into the tendon tissue: Studies on the adjacent plantaris tendon and the peritendinous connective tissue suggest that TNF-alpha can be highly involved in the vascular and tissue changes2013In: Proceedings of the International Congress on Sports Science Research and Technology Support / [ed] Jan Cabri, Pedro Pezarat Correia, João Barreiros, SciTePress, 2013, Vol. 1, p. 45-50Conference paper (Other academic)
    Abstract [en]

    Achilles tendinopathy/tendinosis is a troublesome condition which is frequently occurring in response to sports related activities. It can lead to an ending of the sport activity. There is evidence which shows that ingrowth of blood vessels occurs from the peritendinous tissue. In well-established treatments the areas of these vessels are targeted. In Achilles tendinosis there is frequently a coalescing of the plantaris tendon with the Achilles tendon. TNF-alpha is known to be involved in blood vessel remodelling events and angiogenesis. With these facts as background, the peritendinous connective tissue located inbetween the plantaris and Achilles tendons and the plantaris tendon itself in cases with Achilles tendinosis were evaluated concerning expression of TNF-alpha and TNF receptor II (TNFRII). It was found that there were expressions of TNF-alpha in the numerous cells located in the peritendinous connective tissue and that the very frequently occurring blood vessels located in t his tissue as well as in the tendon tissue exhibited marked TNFRII reactions. The tenocytes were shown to exhibit moderate TNF-alpha reactions and very strong TNFRII reactions. The observations suggest that TNF-alpha is highly involved in the blood vessel remodelling in tendinosis and that TNF-alpha also is involved in tenocyte function.

  • 70.
    Spjut, Sara
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pudelko, Maciej
    Institut für Organische Chemie, Universität Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.
    Hartmann, Mirja
    Otto Diels Institute of Organic Chemistry, Christiana Albertina University of Kiel,Otto-Hahn-Platz 4, 24098 Kiel, Germany.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Carbamate linker strategy in solid-phase synthesis of amino-functionalized glycoconjugates for attachment to solid surfaces and investigation of protein-carbohydrate interactions2009In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 3, p. 349-57Article in journal (Refereed)
    Abstract [en]

    Amino-functionalized serine-based galactose and glucose neoglycolipids were prepared by solid-phase synthesis using a carbamate strategy for anchoring amino functionalities to a (2-fluoro-4-hydroxymethylphenoxy)acetic acid linker resin. Key synthetic steps were monitored with gel-phase 19F NMR spectroscopy. Cleavage from the solid support was performed with trifluoroacetic acid. The terminal amine of the neoglycolipids was conjugated with didecyl squarate and then immobilized in amino-functionalized microtiter plates and the glycoconjugates were successfully probed with a galactose-binding lectin.

  • 71. Steffen, Annika
    et al.
    Huerta, José-Maria
    Weiderpass, Elisabete
    Bueno-de-Mesquita, H B As
    May, Anne M
    Siersema, Peter D
    Kaaks, Rudolf
    Neamat-Allah, Jasmine
    Pala, Valeria
    Panico, Salvatore
    Saieva, Calogero
    Tumino, Rosario
    Naccarati, Alessio
    Dorronsoro, Miren
    Sánchez-Cantalejo, Emilio
    Ardanaz, Eva
    Quirós, J Ramón
    Ohlsson, Bodil
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Wallner, Bengt
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Overvad, Kim
    Halkjaer, Jytte
    Tjønneland, Anne
    Fagherazzi, Guy
    Racine, Antoine
    Clavel-Chapelon, Françoise
    Key, Tim J
    Khaw, Kay-Tee
    Wareham, Nick
    Lagiou, Pagona
    Bamia, Christina
    Trichopoulou, Antonia
    Ferrari, Pietro
    Freisling, Heinz
    Lu, Yunxia
    Riboli, Elio
    Cross, Amanda J
    Gonzalez, Carlos A
    Boeing, Heiner
    General and abdominal obesity and risk of esophageal and gastric adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 3, p. 646-657Article in journal (Refereed)
    Abstract [en]

    General obesity, as reflected by BMI, is an established risk factor for esophageal adenocarcinoma (EAC), a suspected risk factor for gastric cardia adenocarcinoma (GCC) and appears unrelated to gastric non-cardia adenocarcinoma (GNCC). How abdominal obesity, as commonly measured by waist circumference (WC), relates to these cancers remains largely unexplored. Using measured anthropometric data from 391,456 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC) study and 11 years of follow-up, we comprehensively assessed the association of anthropometric measures with risk of EAC, GCC and GNCC using multivariable proportional hazards regression. One hundred twenty-four incident EAC, 193 GCC and 224 GNCC were accrued. After mutual adjustment, BMI was unrelated to EAC, while WC showed a strong positive association (highest vs. lowest quintile HR = 1.19; 95% CI, 0.63-2.22 and HR = 3.76; 1.72-8.22, respectively). Hip circumference (HC) was inversely related to EAC after controlling for WC, while WC remained positively associated (HR = 0.35; 0.18-0.68, and HR=4.10; 1.94-8.63, respectively). BMI was not associated with GCC or GNCC. WC was related to higher risks of GCC after adjustment for BMI and more strongly after adjustment for HC (highest vs. lowest quintile HR = 1.91; 1.09-3.37, and HR = 2.23; 1.28-3.90, respectively). Our study demonstrates that abdominal, rather than general, obesity is an indisputable risk factor for EAC and also provides evidence for a protective effect of gluteofemoral (subcutaneous) adipose tissue in EAC. Our study further shows that general obesity is not a risk factor for GCC and GNCC, while the role of abdominal obesity in GCC needs further investigation.

  • 72.
    Stenberg, Åsa
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Karlsson, Anna
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Feuk-Lagerstedt, Elisabeth
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Christenson, Karin
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Bylund, Johan
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Oldenborg, Anna
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Mo. , USA.
    Vesterlund, Liselotte
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology. Department of Biosciences and Nutrition at Novum, Karolinska Institute, Stockholm , Sweden.
    Matozaki, Takashi
    Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe , Japan.
    Sehlin, Janove
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Signal regulatory protein alpha is present in several neutrophil granule populations and is rapidly mobilized to the cell surface to negatively fine-tune neutrophil accumulation in inflammation2014In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 6, no 4, p. 553-560Article in journal (Refereed)
    Abstract [en]

    Signal regulatory protein alpha (SIRPα) is a cell surface glycoprotein with inhibitory functions, which may regulate neutrophil transmigration. SIRPα is mobilized to the neutrophil surface from specific granules, gelatinase granules, and secretory vesicles following inflammatory activation in vitro and in vivo. The lack of SIRPα signaling and the ability to upregulate SIRPα to the cell surface promote neutrophil accumulation during inflammation in vivo.

  • 73.
    Sundman, Ola
    Umeå University, Faculty of Science and Technology, Chemistry.
    Cation adsorption properties of substituted kraft fibres: an experimental and thermodynamic modelling study2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Acid/base and metal ion adsorption properties have been investigated for a range of chemically modified bleached Kraft fibre materials (pulps). The studies were performed via potentiometric titrations, Flame Atomic Absorbtion (and Emission) Spectroscopy, Inductively Coupled Plasma Optical Emission Spectroscopy and Extended X-ray Absorbtion Fine Structure measurements. As a result of a chemical modification procedure, the total concentration of acidic carboxylate groups in the fibre materials ranged between 43 and 590 μmol/g.

    The preferable surface potential model for modelling the ionic strength dependent acid/base properties of fibre materials with low charge densities, i.e. unmodified fully bleached Kraft fibre materials, was found to be the Basic Stern Model. For fibre materials with high total charge, ≳100 μmol/g, this model resulted in poor fits to data, and for such materials a number of Constant Capacitance Models, one at each ionic strength, must be recommended.

    With respect to metal ion adsorption, the results have indicated that the unspecific Donnan theory could correctly model the simultaneous adsorption of several metal ions, i.e. K+, Na+, Mg2+, Ca2+ and Cu2+, provided that the salt concentration in the fibre suspension is low. In suspensions of high salt concentration it was, however, found that this very same model strongly underestimated the adsorption of Ca2+ and Cu2+. Here, the Donnan model had to be complemented by specific ion exchange equilibria. These results were corroborated by spectroscopic evidence of specific interactions between Cu2+-ions and fibres. The spectroscopic indication of a complex formed between two fibre surface carboxylate groups and one Cu2+-ion, agree with the specific ion exchange model. It was therefore concluded that specific metal ionfibre interactions cannot be neglected, especially at high salt concentrations.

    The interactions occurring between the polycation GaO4Al12(OH)24(H2O)127+ and fibre materials were studied by both adsorption and spectroscopic measurements. These indicate that GaO4Al12(OH)24(H2O)127+ is surprisingly stable in fibre suspensions and that intact GaO4Al12(OH)24(H2O)127+- ions are strongly adsorbed onto the fibres. Also for this ion, specific interactions has to be considered, since the strong adsorption registered was too strong to be explained by Donnan equilibria. In the thesis, the stochiometric composition and an equilibrium constant characterising these interactions is presented.

  • 74.
    Sundqvist, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pre-metastatic decrease of CD169 expression in regional lymph nodes - The implications in prostate cancer2017Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 75.
    Sundström, Anna
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Bergdahl, Jan
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Bergdahl, M
    Public Dental Service Competence Centre of Northern Norway (TkNN), PB 2406, N-9271, Norway .
    Nilsson, Lars-Göran
    Umeå University, Faculty of Social Sciences, Centre for Population Studies (CPS).
    Cognitive status in persons with amalgam-related complaints2010In: Journal of Dental Research, ISSN 0022-0345, E-ISSN 1544-0591, Vol. 89, no 11, p. 1236-1240Article in journal (Refereed)
    Abstract [en]

    Self-reported cognitive symptoms are frequent in persons with amalgam-related complaints, but few studies have focused on their cognitive function. The aim was to examine a symptom profile and whether participants with amalgam-related complaints have cognitive deficits in comparison with control individuals. We drew 342 participants with amalgam-related complaints and 342 one-to-one matched control individuals from a longitudinal population-based study. For 81 of the participants with amalgam-related complaints and controls, data were available approximately five years before the onset of complaints, making a longitudinal analysis possible. All participants were assessed by a self-reported health questionnaire and a comprehensive cognitive test battery. The participants with amalgam-related complaints reported more symptoms, mainly musculoskeletal and neuropsychological, compared with control individuals (p < 0.001). The results revealed no significant difference between the amalgam and control group, either cross-sectionally or longitudinally, for any of the cognitive tests. These results suggest that cognitive decline is not associated with amalgam-related complaints.

  • 76.
    Svenson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Grönlund, Elisabeth
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sitaram, Raviprakash T
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length in relation to immunological parameters in patients with renal cell carcinoma2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, article id e55543Article in journal (Refereed)
    Abstract [en]

    Over the last decade, telomere length (TL) has gained attention as a potential biomarker in cancer disease. We previously reported that long blood TL was associated with a poorer outcome in patients with breast cancer and renal cell carcinoma. Based on these findings, we hypothesized that certain immunological components may have an impact on TL dynamics in cancer patients. One aim of the present study was to investigate a possible association between serum cytokines and TL of peripheral blood cells, tumors and corresponding kidney cortex, in patients with clear cell renal cell carcinoma. For this purpose, a multiplex cytokine assay was used. Correlation analysis revealed significant positive correlations between tumor TL and peripheral levels of three cytokines (IL-7, IL-8 and IL-10). In a parallel patient group with various kidney tumors, TL was investigated in whole blood and in immune cell subsets in relation to peripheral levels of regulatory T cells (Tregs). A significant positive association was found between whole blood TL and Treg levels. However, the strongest correlation was found between Tregs and TL of the T lymphocyte fraction. Thus, patients with higher Treg levels displayed longer T cell telomeres, which might reflect a suppressed immune system with fewer cell divisions and hence less telomere shortening. These results are in line with our earlier observation that long blood TL is an unfavorable prognostic factor for cancer-specific survival. In summary, we here show that immunological components are associated with TL in patients with renal cell carcinoma, providing further insight into the field of telomere biology in cancer. 

  • 77.
    Tjust, Anton
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Extraocular Muscles in Amyotrophic Lateral Sclerosis2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease of motor neurons characterized by muscle paralysis and death within 3-5 years of onset. However, due to unknown mechanisms, the extraocular muscles (EOMs) remain remarkably unaffected. The EOMs are highly specialized muscles that differ from other muscles in many respects, including innervation and satellite cells (SCs). Understanding whether these factors play a role in the relative sparing of EOMs in ALS could provide useful clues on how to slow down the progression of ALS in other muscles.

    The EOMs and limb muscles from terminal ALS patients and age-matched controls as well as the commonly used SOD1G93A ALS mouse model were studied with immunofluorescence. Antibodies against neurofilament and synaptophysin were used to identify nerves and neuromuscular junctions (NMJs); against Pax7, NCAM, MyoD, myogenin, Ki-67, dystrophin and laminin, to identify SCs and their progeny in EOMs and limb muscles. The proportion and fiber size of myofibers containing myosin heavy chain (MyHC) slow tonic and MyHC slow twitch were also determined in human EOMs.

    The abundance of SCs differed extensively along the length of control human EOMs, being twice as abundant in the anterior portion. Pax7-positive cells were also detected in non-traditional SC positions. EOMs from terminal ALS patients showed similar numbers of resting and activated SCs as the controls. In limb muscles of ALS patients, the number of resting and activated SCs ranged from low (similar to normal aged, sedentary individuals) to high numbers, especially in muscles with long duration of disease and varied between the upper and lower limbs. The EOMs maintained a high degree of innervation compared to hindlimb muscles of symptomatic SOD1G93A mice. MyHC slow tonic fibers were less abundant in ALS patients than in controls. The change seemed more pronounced in bulbar onset patients, and in this group of subjects only, there was a strong association between decline in MyHC slow tonic fibers and age of death. Notably, the decline in MyHC slow tonic fibers was unrelated to disease duration.

    Our data suggested that SCs play a minor role in the progression of ALS in general and in the sparing of the EOMs in particular. The generally preserved innervation in the EOMs of G93A mice may reflect distinct intrinsic properties relevant for sparing of the oculomotor system.  Even though the EOMs are relatively spared in ALS, MyHC slow tonic myofibers were selectively affected and this may reflect differences in innervation, as these fibers are multiply innervated.

  • 78. Treusch, Sebastian
    et al.
    Hamamichi, Shusei
    Goodman, Jessica L
    Matlack, Kent ES
    Chung, Chee Yeun
    Baru, Valeriya
    Shulman, Joshua M
    Parrado, Antonio
    Bevis, Brooke J
    Valastyan, Julie S
    Han, Haesun
    Lindhagen-Persson, Malin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Reiman, Eric M
    Evans, Denis A
    Bennett, David A
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Dejager, Philip L
    Tanzi, Rudolph E
    Caldwell, Kim A
    Caldwell, Guy A
    Lindquist, Susan
    Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast2011In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 334, no 6060, p. 1241-1245Article in journal (Refereed)
    Abstract [en]

    Aβ (beta amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Aβ toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Aβ was previously unknown. The factors identified in yeast modified Aβ toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, Aβ impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Aβ, endocytosis, and human AD risk factors can be ascertained using yeast as a model system.

  • 79.
    Uppgård, Lise-Lott
    Umeå University, Faculty of Science and Technology, Chemistry.
    Nonionic surfactants: A multivariate study2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis technical nonionic surfactants are studied using multivariate techniques. The surfactants studied were alkyl ethoxylates (AEOs) and alkyl polyglucosides (APGs).

    The aquatic toxicity of the surfactants towards two organisms, a shrimp and a rotifer, was examined. The specified effect was lethality, LC50, as indicated by immobilisation. In a comparative study, the LC50 values obtained were used to develop two different types of model. In the log P model the toxicity was correlated to log P alone, while in the multivariate model several physicochemical variables, including log P, were correlated to the toxicity. The multivariate model gave smaller prediction errors than the log P model.

    Further, the change in reactivity when a surfactant mixture was added to dissolving pulp under alkaline conditions was studied, using the amount of residual cellulose as a measure of the reactivity. Ten AEO/APG mixtures were tested, and the mixture with greatest potential was studied in more detail. An optimum in the amount of added surfactant was found that seems to coincide, according to surface tension measurements, with the CMC.

  • 80.
    Uppgård, Lise-Lott
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindgren, Åsa
    Akzo Nobel Surface Chemistry AB, Stenungsund, Sweden.
    Sjöström, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wold, Svante
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Multivariate quantitative structure-activity relationships for the aquatic toxicity of technical nonionic surfactants2000In: Journal of Surfactants and Detergents, ISSN 1097-3958 (Print) 1558-9293 (Online), Vol. 3, no 1, p. 33-41Article in journal (Refereed)
    Abstract [en]

    The aquatic toxicity of 36 technical nonionic surfactants (ethoxylated fatty alcohols) was examined toward two freshwater animal species, the fairy shrimp Thamnocephalus playtyurus and the rotifer Brachionus calyciflorus. Responses of the two species to the surfactants were generally similar. A multivariate-quantitative structure-activity relationship (M-QSAR) model was developed from the data. The M-QSAR model consisted of a partial least squares model with three components and explained 92.4% of the response variance and had a predictive capability of 89.1%. The most important physicochemical variables for the M-QSAR model were the number of carbon atoms in the longest chain of the surfactant hydrophobe (redC), the molecular hydrophobicity (log P), the number of carbon atoms in the hydrophobe (C), the hydrophilic-lipophilic balance according to Davis (Davis), the critical packing parameter with respect to whether the hydrophobe was branched or not (redCPP), and the critical micelle concentration. Surfactant toxicity tended to increase with increasing alkyl chain lengths.

  • 81.
    Uppgård, Lise-Lott
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjöström, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wold, Svante
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Multivariate quantitative structure-activity relationships for the aquatic toxicity of alkyl polyglucosides2000In: Tenside Surfactants Detergents:, Vol. 37, no 2, p. 131-8Article in journal (Refereed)
    Abstract [en]

    The aquatic toxicity of 34 alkyl polyglucosides (APGs) towards two fresh-water species, Thamnocephalus platyurus and Brachionus calyciflorus were studied. The toxicity tests were performed using so-called toxkits, and for each surfactant the results are presented as (10)log (mean LC50) values. The toxicity data were combined with physico-chemical data for the APGs, and a Multivariate Quantitative Structure-Activity Relationship (M-QSAR) model was calculated. Partial Least Squares (PLS) regression was used to develop the M-QSAR model. The resulting linear M-QSAR model explained 93.6% of the variance in the biological response and had a predictability of 86.6% according to cross-validation. The physico-chemical properties with the strongest influences on the toxicity of the surfactants were the critical micelle concentration (c.m.c.), wetting, contact angle, and number of carbon atoms in their hydrophobic parts (C and redC).

  • 82.
    Wallner, Fredrik K
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Boström, Dan
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics, Energy Technology and Thermal Process Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis and evaluation of 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid as a linker in solid-phase synthesis monitored by gel-phase 19F NMR spectroscopy2007In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 5, p. 2464-2471Article in journal (Refereed)
    Abstract [en]

    Gel-phase 19F NMR spectroscopy is a useful monitoring technique for solid-phase organic chemistry due to the high information content it delivers and swift acquisition times, using standard NMR spectrometers. This paper describes the synthesis of the novel linker 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid in 29% yield over seven steps, using nucleophilic aromatic substitutions on 2,4,5-trifluorobenzonitrile as key steps. Following standard solid-phase synthesis a peptide could be cleaved from the linker using 20% TFA in CH2Cl2 in 30 minutes, in contrast to a previously described monoalkoxy linker that requires 90% TFA in water at elevated temperature. A resin-bound peptide could be successfully glycosylated using only two equivalents of a thioglycoside donor, activated with N-iodosuccinimide and trifluoromethanesulfonic acid, and subsequent cleavage and deprotection gave the target glycopeptide. Direct glycosylation of the linker itself followed by mild acidic cleavage gave a fully protected hemiacetal for further chemical manipulation.

  • 83.
    Wiberg, Jörgen
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mechanisms controlling DNA damage survival and mutation rates in budding yeast2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    All living organisms are made of cells, within which genetic information is stored on long strands of deoxyribonucleic acid (DNA). The DNA encodes thousands of different genes and provides the blueprint for all of the structures and activities occurring within the cell. The building blocks of DNA are the four deoxyribonucleotides, dATP, dGTP, dTTP, and dCTP, which are collectively referred to as dNTPs.

    The key enzyme in the production of dNTPs is ribonucleotide reductase (RNR). In the budding yeast Saccharomyces cerevisiae, the concentrations of the individual dNTPs are not equal and it is primarily RNR that maintains this balance. Maintenance of the dNTP pool balance is critical for accurate DNA replication and DNA repair since elevated and/or imbalanced dNTP concentrations increase the mutation rate and can ultimately lead to genomic instability and cancer. In response to DNA damage, the overall dNTP concentration in S. cerevisiae increases. Cell survival rates increase as a result of the elevated concentration of dNTPs, but the cells also suffer from a concomitant increase in mutation rates. When the replication machinery encounters DNA damage that it cannot bypass, the replication fork stalls and recruits specialized translesion synthesis (TLS) polymerases that bypass the damage so that replication can continue. We hypothesized that elevated dNTP levels in response to DNA damage may allow the TLS polymerases to more efficiently bypass DNA damage. To explore this possibility, we deleted all known TLS polymerases in a yeast strain in which we could artificially increase the dNTP concentrations. Surprisingly, even though all TLS polymerases had been deleted, elevated dNTP concentrations led to increased cell survival after DNA damage. These results suggest that replicative DNA polymerases may be involved in the bypass of certain DNA lesions under conditions of elevated dNTPs. We confirmed this hypothesis in vitro by demonstrating that high dNTP concentrations result in an increased efficiency in the bypass of certain DNA lesions by DNA polymerase epsilon, a replicative DNA polymerase not normally associated with TLS activity.

    We asked ourselves if it would be possible to create yeast strains with imbalanced dNTP concentrations in vivo, and, if so, would these imbalances be recognized by the checkpoint control mechanisms in the cell. To address these questions, we focused on the highly conserved loop2 of the allosteric specificity site of yeast Rnr1p. We introduced several mutations into RNR1-loop2 that resulted in changes in the amino acid sequence of the protein.

    Each of the rnr1-loop2 mutation strains obtained had different levels of individual dNTPs relative to the others. Interestingly, all of the imbalanced dNTP concentrations led to increased mutation rates, but these mutagenic imbalances did not activate the S-phase checkpoint unless one or several dNTPs were present at concentrations that were too low to sustain DNA replication. We were able to use these mutant yeast strains to successfully correlate amino acid substitutions within loop2 of Rnr1p to specific ratios of dNTP concentrations in the cells. We also demonstrated that specific imbalances between the individual dNTP levels result in unique mutation spectra. These mutation spectra suggest that the mutagenesis that results from imbalanced dNTP pools is due to a decrease in fidelity of the replicative DNA polymerases at specific DNA sequences where they are more likely to make a mistake. The mutant rnr1-loop2 strains that we have created with defined dNTP pool imbalances will be of great value for in vivo studies of polymerase fidelity, translesion synthesis by specialized DNA polymerases, and lesion recognition by the DNA repair machinery.

  • 84.
    Xin, D. L.
    et al.
    Department of Surgery, University of Pennsylvania, USA.
    Hadrevi, Jenny
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Elliott, M. E.
    Department of Neurosurgery, Thomas Jefferson University, USA.
    Amin, M
    Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadephia, USA.
    Harris, M. Y.
    Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, USA.
    Barr-Gillespie, A
    College of Health Professions, Pacific University, USA.
    Barbe, M. F.
    Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, USA.
    Effectiveness of conservative interventions for sickness and pain behaviors induced by a high repetition high force upper extremity task2017In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 18, article id 36Article in journal (Refereed)
    Abstract [en]

    Background: Systemic inflammation is known to induce sickness behaviors, including decreased social interaction and pain. We have reported increased serum inflammatory cytokines in a rat model of repetitive strain injury (rats perform an upper extremity reaching task for prolonged periods). Here, we sought to determine if sickness behaviors are induced in this model and the effectiveness of conservative treatments.

    Methods: Experimental rats underwent initial training to learn a high force reaching task (10 min/day, 5 days/week for 6 weeks), with or without ibuprofen treatment (TRHF vs. TRHF + IBU rats). Subsets of trained animals went on to perform a high repetition high force (HRHF) task for 6 or 12 weeks (2 h/day, 3 days/week) without treatment, or received two secondary interventions: ibuprofen (HRHF + IBU) or a move to a lower demand low repetition low force task (HRHF-to-LRLF), beginning in task week 5. Mixed-effects models with repeated measures assays were used to assay duration of social interaction, aggression, forepaw withdrawal thresholds and reach performance abilities. One-way and two-way ANOVAs were used to assay tissue responses. Corrections for multiple comparisons were made.

    Results: TRHF + IBU rats did not develop behavioral declines or systemic increases in IL-1beta and IL-6, observed in untreated TRHF rats. Untreated HRHF rats showed social interaction declines, difficulties performing the operant task and forepaw mechanical allodynia. Untreated HRHF rats also had increased serum levels of several inflammatory cytokines and chemokines, neuroinflammatory responses (e.g., increased TNFalpha) in the brain, median nerve and spinal cord, and Substance P and neurokinin 1 immunoexpression in the spinal cord. HRHF + IBU and HRHF-to-LRLF rats showed improved social interaction and reduced inflammatory serum, nerve and brain changes. However, neither secondary treatment rescued HRHF-task induced forepaw allodynia, or completely attenuated task performance declines or spinal cord responses.

    Conclusions: These results suggest that inflammatory mechanisms induced by prolonged performance of high physical demand tasks mediate the development of social interaction declines and aggression. However, persistent spinal cord sensitization was associated with persistent behavioral indices of discomfort, despite use of conservative secondary interventions indicating the need for prevention or more effective interventions.

  • 85. Xu, Jing
    et al.
    Marsac, Remi
    Costa, Dominique
    Cheng, Wei
    Wu, Feng
    Boily, Jean-Francois
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hanna, Khalil
    Co-Binding of Pharmaceutical Compounds at Mineral Surfaces: Molecular Investigations of Dimer Formation at Goethite/Water Interfaces2017In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 51, no 15, p. 8343-8349Article in journal (Refereed)
    Abstract [en]

    The emergence of antibiotic and anti-inflammatory agents in aquatic and terrestrial systems is becoming a serious threat to human and animal health worldwide. Because pharmaceutical compounds rarely exist individually in nature, interactions between various compounds can have unforeseen effects on their binding to mineral surfaces. This work demonstrates this important possibility for the case of two typical antibiotic and anti-inflammatory agents (nalidixic acid (NA) and niflumic acid (NFA)) bound at goethite (alpha FeOOH) used as a model mineral surface. Our multidisciplinary study, which makes use of batch sorption experiments, vibration spectroscopy and periodic density functional theory calculations, reveals enhanced binding of the otherwise weakly bound NFA caused by unforeseen intermolecular interactions with mineral-bound NA. This enhancement is ascribed to the formation of a NFA NA dimer whose energetically favored formation (-0.5 eV compared to free molecules) is predominantly driven by van der Waals interactions. A parallel set of efforts also showed that no. cobinding occurred with sulfamethoxazole (SMX) because of the lack of molecular interactions with coexisting contaminants. As such, this article raises the importance of recognizing drug cobinding, and lack of cobinding, for predicting and developing policies on the fate of complex mixtures of antibiotics and anti-inflammatory agents in nature.

  • 86.
    Yang, Lingling
    et al.
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Di, Guohu
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Qi, Xia
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Qu, Mingli
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Wang, Yao
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Duan, Haoyun
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Xie, Lixin
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Zhou, Qingjun
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor.2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 12, p. 4262-4274Article in journal (Refereed)
    Abstract [en]

    Substance P (SP) is a neuropeptide, predominantly released from sensory nerve fibers, with a potentially protective role in diabetic corneal epithelial wound healing. However, the molecular mechanism remains unclear. We investigated the protective mechanism of SP against hyperglycemia-induced corneal epithelial wound healing defects, using type 1 diabetic mice and high glucose-treated corneal epithelial cells. Hyperglycemia induced delayed corneal epithelial wound healing, accompanied with attenuated corneal sensation, mitochondrial dysfunction, and impairments of Akt-, EGFR-, and Sirt1-activation, as well as decreased reactive oxygen species (ROS) scavenging capacity. However, SP application promoted the epithelial wound healing, the recovery of corneal sensation, the improvement of mitochondrial function, and the reactivation of Akt, EGFR and Sirt1, as well as increased ROS scavenging capacity, in both diabetic mouse corneal epithelium and high glucose-treated corneal epithelial cells. The promotion of SP on diabetic corneal epithelial healing was completely abolished by a NK-1 receptor antagonist. Moreover, the subconjunctival injection of NK-1 receptor antagonist also caused diabetic corneal pathological changes in normal mice. In conclusion, the results suggest that SP-NK-1 receptor signaling plays a critical role in the maintenance of corneal epithelium homeostasis, and that SP signaling through the NK-1 recssssseptor contributes to the promotion of diabetic corneal epithelial wound healing by rescued activation of Akt, EGFR, and Sirt1, improvement of mitochondrial function, and increased ROS scavenging capacity.

  • 87. Yousefzadeh, Matthew J
    et al.
    Wyatt, David W
    Takata, Kei-Ichi
    Mu, Yunxiang
    Hensley, Sean C
    Tomida, Junya
    Bylund, Göran O
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Doublié, Sylvie
    Johansson, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ramsden, Dale A
    McBride, Kevin M
    Wood, Richard D
    Mechanism of suppression of chromosomal instability by DNA polymerase POLQ2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 10, p. e1004654-Article in journal (Refereed)
    Abstract [en]

    Although a defect in the DNA polymerase POLQ leads to ionizing radiation sensitivity in mammalian cells, the relevant enzymatic pathway has not been identified. Here we define the specific mechanism by which POLQ restricts harmful DNA instability. Our experiments show that Polq-null murine cells are selectively hypersensitive to DNA strand breaking agents, and that damage resistance requires the DNA polymerase activity of POLQ. Using a DNA break end joining assay in cells, we monitored repair of DNA ends with long 3' single-stranded overhangs. End joining events retaining much of the overhang were dependent on POLQ, and independent of Ku70. To analyze the repair function in more detail, we examined immunoglobulin class switch joining between DNA segments in antibody genes. POLQ participates in end joining of a DNA break during immunoglobulin class-switching, producing insertions of base pairs at the joins with homology to IgH switch-region sequences. Biochemical experiments with purified human POLQ protein revealed the mechanism generating the insertions during DNA end joining, relying on the unique ability of POLQ to extend DNA from minimally paired primers. DNA breaks at the IgH locus can sometimes join with breaks in Myc, creating a chromosome translocation. We found a marked increase in Myc/IgH translocations in Polq-defective mice, showing that POLQ suppresses genomic instability and genome rearrangements originating at DNA double-strand breaks. This work clearly defines a role and mechanism for mammalian POLQ in an alternative end joining pathway that suppresses the formation of chromosomal translocations. Our findings depart from the prevailing view that alternative end joining processes are generically translocation-prone.

  • 88.
    Yu, Ji-Guo
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bonnerud, Patrik
    Department of Health Sciences, Luleå University of Technology, Luleå.
    Eriksson, Anders
    Department of Health Sciences, Luleå University of Technology, Luleå.
    Stål, Per S.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Tegner, Yelverton
    Department of Health Sciences, Luleå University of Technology, Luleå.
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Effects of long term supplementation of anabolic androgen steroids on human skeletal muscle2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e105330Article in journal (Refereed)
    Abstract [en]

    The effects of long-term (over several years) anabolic androgen steroids (AAS) administration on human skeletal muscle are still unclear. In this study, seventeen strength training athletes were recruited and individually interviewed regarding self-administration of banned substances. Ten subjects admitted having taken AAS or AAS derivatives for the past 5 to 15 years (Doped) and the dosage and type of banned substances were recorded. The remaining seven subjects testified to having never used any banned substances (Clean). For all subjects, maximal muscle strength and body composition were tested, and biopsies from the vastus lateralis muscle were obtained. Using histochemistry and immunohistochemistry (IHC), muscle biopsies were evaluated for morphology including fiber type composition, fiber size, capillary variables and myonuclei. Compared with the Clean athletes, the Doped athletes had significantly higher lean leg mass, capillary per fibre and myonuclei per fiber. In contrast, the Doped athletes had significantly lower absolute value in maximal squat force and relative values in maximal squat force (relative to lean body mass, to lean leg mass and to muscle fiber area). Using multivariate statistics, an orthogonal projection of latent structure discriminant analysis (OPLS-DA) model was established, in which the maximal squat force relative to muscle mass and the maximal squat force relative to fiber area, together with capillary density and nuclei density were the most important variables for separating Doped from the Clean athletes (regression  =  0.93 and prediction  =  0.92, p<0.0001). In Doped athletes, AAS dose-dependent increases were observed in lean body mass, muscle fiber area, capillary density and myonuclei density. In conclusion, long term AAS supplementation led to increases in lean leg mass, muscle fiber size and a parallel improvement in muscle strength, and all were dose-dependent. Administration of AAS may induce sustained morphological changes in human skeletal muscle, leading to physical performance enhancement.

  • 89.
    Åberg, Veronica
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Norman, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Westermark, Andreas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Sauer-Eriksson, Elisabeth
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Microwave-assisted decarboxylation of bicyclic 2-pyridone scaffolds and identification of A beta-peptide aggregation inhibitors2005In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 3, no 15, p. 2817-2823Article in journal (Refereed)
    Abstract [en]

    A reagent-free microwave-assisted decarboxylation procedure for carboxylic acid functionalized bicyclic 2-pyridones has been developed. This new method, based on microwave heating at 220 degrees C for 600 seconds in N-methyl pyrrolidone (NMP), proved to be practical and very efficient, resulting in decarboxylated 2-pyridones in near-quantitative yields. The decarboxylated products and the intermediate 2-pyridones in the form of carboxylic acid methyl esters and carboxylic acids were screened for their effect on A beta-peptide aggregation. Two out of the 21 2-pyridones described in this study inhibited amyloid formation of the Alzheimer A beta(1-40) peptide. The effect was seen even at a 4 : 1 ratio of 2-pyridone and monomeric A beta-peptide.

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