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  • 101.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Proteomics to Understand the Degenerative Matter2014Inngår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 75, s. S10-S10Artikkel i tidsskrift (Annet vitenskapelig)
  • 102.
    Bergström, Rosita
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Evolutionsbiologi.
    Savary, Katia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Morén, Anita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Guibert, Sylvain
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Evolutionsbiologi.
    Heldin, Carl-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Ohlsson, Rolf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Evolutionsbiologi.
    Moustakas, Aristidis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Transforming growth factor β promotes complexes between Smad proteins and the CCCTC-binding factor on the H19 imprinting control region chromatin2010Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, nr 26, s. 19727-19737Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Whether signal transduction pathways regulate epigenetic states in response to environmental cues remains poorly understood. We demonstrate here that Smad3, signaling downstream of transforming growth factor beta, interacts with the zinc finger domain of CCCTC-binding factor (CTCF), a nuclear protein known to act as "the master weaver of the genome." This interaction occurs via the Mad homology 1 domain of Smad3. Although Smad2 and Smad4 fail to interact, an alternatively spliced form of Smad2 lacking exon 3 interacts with CTCF. CTCF does not perturb well established transforming growth factor beta gene responses. However, Smads and CTCF co-localize to the H19 imprinting control region (ICR), which emerges as an insulator in cis and regulator of transcription and replication in trans via direct CTCF binding to the ICR. Smad recruitment to the ICR requires intact CTCF binding to this locus. Smad2/3 binding to the ICR requires Smad4, which potentially provides stability to the complex. Because the CTCF-Smad complex is not essential for the chromatin insulator function of the H19 ICR, we propose that it can play a role in chromatin cross-talk organized by the H19 ICR.

  • 103.
    Bergström, Sven
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Zückert, Wolfram R
    Structure, function and biogenesis of the Borrelia cell envelope2010Inngår i: Borrelia, molecular biology, host interactions and pathogenesis / [ed] Eds DS Samuels and JD Radolf, Norfolk, UK: Caister Academic Press , 2010, s. 139-166Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 104.
    Bergström, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Modeling Neural Stem Cell and Glioma Biology2013Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis is focused on neural stem cell (NSC) and glioma biology. I discuss how NSCs interact with extracellular matrix (ECM) proteins in the stem cell niche, and investigate the consequences of deregulated Platelet-derived growth factor (PDGF) signaling for embryonic NSCs in transgenic mice. Furthermore I present cell cultures of human glioblastoma multiforme (GBM) that models human disease, taking into account the heterogeneity of GBM. Finally, interactions between brain tumors and mast cells are studied using the glioma cultures.

    In paper I, the importance of NSC interactions with the ECM in the stem cell niche during development is discussed. Contacts between NSCs and the ECM in the subventricular zone (SVZ) are emerging as important regulatory mechanisms. We show that early postnatal neural stem and progenitor cells (NSPC) attach to collagen I, and that the adhesion is explained by higher expression of collagen receptor integrins compared to adult NSPC. Further, blood vessels in the SVZ express collagen I, indicating a possible functional relationship.

    Growth factors, e.g. PDGF, regulate NSC proliferation and differentiation. Aberrant activation of growth factor signaling pathways also plays a role in brain tumor formation. Paper II demonstrates that transgenic mice expressing PDGF-B at high levels in embryonic NSCs displayed mild neurological defects but no hyperplasia or brain tumors. This suggests that a high level of PDGF is not sufficient to induce brain tumors from NSCs without further mutations.

    Paper III presents a novel panel of human glioma stem cell (GSC) lines from GBM that display NSC markers in vitro and form secondary orthotopic tumors in vivo. GBM has recently been categorized in molecular subclasses and we demonstrate, for the first time, that these subclasses can be retained in vitro by stem cell culture conditions. We have thus generated models for research and drug development aiming at a focused treatment depending on GBM subtype.

    Interactions with the immune system are integral parts of tumorigenesis. Mast cells are found in glioma and in paper IV we demonstrate that the grade-dependent infiltration of mast cells is in part mediated by macrophage migration inhibitory factor and phosphorylation of STAT5.

     

     

  • 105.
    Bett, Bernard
    et al.
    Int Livestock Res Inst, Nairobi, Kenya..
    Said, Mohammed Y.
    Int Livestock Res Inst, Nairobi, Kenya..
    Sang, Rosemary
    Kenya Govt Med Res Ctr, Nairobi, Kenya..
    Bukachi, Salome
    Univ Nairobi, Inst Anthropol Gender & African Studies, Nairobi, Kenya..
    Wanyoike, Salome
    Minist Agr, Dept Vet Serv, Nairobi, Kenya..
    Kifugo, Shem C.
    Int Livestock Res Inst, Nairobi, Kenya..
    Otieno, Fredrick
    Int Livestock Res Inst, Nairobi, Kenya..
    Ontiri, Enoch
    Int Livestock Res Inst, Nairobi, Kenya..
    Njeru, Ian
    Kenyatta Natl Hosp, Minist Publ Hlth & Sanitat, Div Dis Surveillance & Response, Nairobi, Kenya..
    Lindahl, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Int Livestock Res Inst, Nairobi, Kenya.;Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Grace, Delia
    Int Livestock Res Inst, Nairobi, Kenya..
    Effects of flood irrigation on the risk of selected zoonotic pathogens in an arid and semi-arid area in the eastern Kenya2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 5, artikkel-id e0172626Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To investigate the effects of irrigation on land cover changes and the risk of selected zoonotic pathogens, we carried out a study in irrigated, pastoral and riverine areas in the eastern Kenya. Activities implemented included secondary data analyses to determine land use and land cover (LULC) changes as well as human, livestock and wildlife population trends; entomological surveys to characterize mosquitoes population densities and species distribution by habitat and season; and serological surveys in people to determine the risk of Rift Valley fever virus (RVFV), West Nile fever virus (WNV), dengue fever virus (DFV), Leptospira spp. and Brucella spp. Results demonstrate a drastic decline in vegetation cover over R approximate to 25 years particularly in the irrigated areas where cropland increased by about 1,400% and non-farm land (under closed trees, open to closed herbaceous vegetation, bushlands and open trees) reduced by 30-100%. The irrigated areas had high densities of Aedes mcintoshi, Culexspp. and Mansonia spp. (important vectors for multiple arboviruses) during the wet and dry season while pastoral areas had high densities of Ae. tricholabis specifically in the wet season. The seroprevalences of RVFV, WNV and DFV were higher in the irrigated compared to the pastoral areas while those for Leptospira spp and Brucella spp. were higher in the pastoral compared to the irrigated areas. It is likely that people in the pastoral areas get exposed to Leptospira spp by using water fetched from reservoirs that are shared with livestock and wildlife, and to Brucella spp. by consuming raw or partially cooked animal source foods such as milk and meat. This study suggests that irrigation increases the risk of mosquito-borne infections while at the same time providing a protective effect against zoonotic pathogens that thrive in areas with high livestock population densities.

  • 106.
    Beven, Laure
    et al.
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Charenton, Claire
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Dautant, Alain
    Univ Bordeaux, Bordeaux, France ; IBMC, CNRS, Bordeaux, France.
    Bouyssou, Guillaume
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Labroussaa, Fabien
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Sköllermo, Anna
    KTH, Skolan för bioteknologi (BIO), Proteomik. KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Persson, Anja
    KTH, Skolan för bioteknologi (BIO), Proteomik. KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Blanchard, Alain
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Sirand-Pugnet, Pascal
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Specific Evolution of F-1-Like ATPases in Mycoplasmas2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 6, s. e38793-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    F1F0 ATPases have been identified in most bacteria, including mycoplasmas which have very small genomes associated with a host-dependent lifestyle. In addition to the typical operon of eight genes encoding genuine F1F0 ATPase (Type 1), we identified related clusters of seven genes in many mycoplasma species. Four of the encoded proteins have predicted structures similar to the alpha, beta, gamma and e subunits of F-1 ATPases and could form an F-1-like ATPase. The other three proteins display no similarity to any other known proteins. Two of these proteins are probably located in the membrane, as they have three and twelve predicted transmembrane helices. Phylogenomic studies identified two types of F-1-like ATPase clusters, Type 2 and Type 3, characterized by a rapid evolution of sequences with the conservation of structural features. Clusters encoding Type 2 and Type 3 ATPases were assumed to originate from the Hominis group of mycoplasmas. We suggest that Type 3 ATPase clusters may spread to other phylogenetic groups by horizontal gene transfer between mycoplasmas in the same host, based on phylogeny and genomic context. Functional analyses in the ruminant pathogen Mycoplasma mycoides subsp. mycoides showed that the Type 3 cluster genes were organized into an operon. Proteomic analyses demonstrated that the seven encoded proteins were produced during growth in axenic media. Mutagenesis and complementation studies demonstrated an association of the Type 3 cluster with a major ATPase activity of membrane fractions. Thus, despite their tendency toward genome reduction, mycoplasmas have evolved and exchanged specific F-1-like ATPases with no known equivalent in other bacteria. We propose a model, in which the F-1-like structure is associated with a hypothetical X-0 sector located in the membrane of mycoplasma cells.

  • 107.
    Bhushan, Shashi
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kuhn, Claus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Berglund, Anna-Karin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Roth, Christian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Glaser, Elzbieta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The role of the N-terminal domain of chloroplast targeting peptides in organellar protein import and miss-sorting2006Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, nr 16, s. 3966-3972Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have analysed 385 mitochondrial and 567 chloroplastic signal sequences of proteins found in the organellar proteomes of Arabidopsis thaliana. Despite overall similarities, the first 16 residues of transit peptides differ remarkably. To test the hypothesis that the N-terminally truncated transit peptides would redirect chloroplastic precursor proteins to mitochondria, we studied import of the N-terminal deletion mutants of ELIP, PetC and Lhcb2.1. The results show that the deletion mutants were neither imported into chloroplasts nor miss-targeted to mitochondria in vitro and in vivo, showing that the entire transit peptide is necessary for correct targeting as well as miss-sorting.

  • 108.
    Bhushan, Shashi
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Pavlov, Pavel F
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rudhe, Charlotta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Glaser, Elzbieta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    In vitro and in vivo methods to study protein import into plant mitochondria.2007Inngår i: Methods Mol Biol, ISSN 1064-3745, Vol. 390, s. 131-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Plant mitochondria contain about 1000 proteins, 90-99% of which in different plant species are nuclear encoded, synthesized on cytosolic polyribosomes, and imported into the organelle. Most of the nuclear-encoded proteins are synthesized as precursors containing an N-terminal extension called a presequence or targeting peptide that directs the protein to the mitochondria. Here we describe in vitro and in vivo methods to study mitochondrial protein import in plants. In vitro synthesized precursor proteins can be imported in vitro into isolated mitochondria (single organelle import). However, missorting of chloroplast precursors in vitro into isolated mitochondria has been observed. A novel dual import system for simultaneous import of proteins into isolated mitochondria and chloroplasts followed by reisolation of the organelles is superior over the single import system as it abolishes the mistargeting. Precursor proteins can also be imported into the mitochondria in vivo using an intact cellular system. In vivo approaches include import of transiently expressed fusion constructs containing a presequence or a full-length precursor protein fused to a reporter gene, most commonly the green fluorescence protein (GFP) in protoplasts or in an Agrobacterium-mediated system in intact tobacco leaves.

  • 109.
    Biasiotto, Roberta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Akusjärvi, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Regulation of Human Adenovirus Alternative RNA Splicing by the Adenoviral L4-33K and L4-22K Proteins2015Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 16, nr 2, s. 2893-2912Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Adenovirus makes extensive use of alternative RNA splicing to produce a complex set of spliced viral mRNAs. Studies aimed at characterizing the interactions between the virus and the host cell RNA splicing machinery have identified three viral proteins of special significance for the control of late viral gene expression: L4-33K, L4-22K, and E4-ORF4. L4-33K is a viral alternative RNA splicing factor that controls L1 alternative splicing via an interaction with the cellular protein kinases Protein Kinase A (PKA) and DNA-dependent protein kinase (DNA-PK). L4-22K is a viral transcription factor that also has been implicated in the splicing of a subset of late viral mRNAs. E4-ORF4 is a viral protein that binds the cellular protein phosphatase IIA (PP2A) and controls Serine/Arginine (SR)-rich protein activity by inducing SR protein dephosphorylation. The L4-33K, and most likely also the L4-22K protein, are highly phosphorylated in vivo. Here we will review the function of these viral proteins in the post-transcriptional control of adenoviral gene expression and further discuss the significance of potential protein kinases phosphorylating the L4-33K and/or L4-22K proteins.

  • 110.
    Biava, Pier M.
    et al.
    Scientific Institute of Research and Care Multimedica, Milano, Italy.
    Canaider, Silvia
    Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy; National Institute of Biostructures and Biosystems, Bologna, Italy.
    Facchin, Federica
    Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy; National Institute of Biostructures and Biosystems, Bologna, Italy.
    Bianconi, Eva
    Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy; National Institute of Biostructures and Biosystems, Bologna, Italy.
    Ljungberg, Liza
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Rotilio, Domenico
    Department of Haematology, Ospedali Riuniti BMM, Reggio Calabria, Italy.
    Burigana, Fabio
    Associazione Medicina e Complessità (AMEC), Trieste, Italy.
    Ventura, Carlo
    Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy; National Institute of Biostructures and Biosystems, Bologna, Italy; Stem Wave Institute for Tissue Healing (SWITH), Gruppo Villa Maria (GVM) Care & Research - Ettore Sansavini Health Science Foundation, Lugo (Ravenna), Italy.
    Stem Cell Differentiation Stage Factors from Zebrafish Embryo: A Novel Strategy to Modulate the Fate of Normal and Pathological Human (Stem) Cells2015Inngår i: Current Pharmaceutical Biotechnology, ISSN 1389-2010, E-ISSN 1873-4316, Vol. 16, nr 9, s. 782-792Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In spite of the growing body of evidence on the biology of the Zebrafish embryo and stem cells, including the use of Stem Cell Differentiation Stage Factors (SCDSFs) taken from Zebrafish embryo to impact cancer cell dynamics, comparatively little is known about the possibility to use these factors to modulate the homeostasis of normal human stem cells or to modulate the behavior of cells involved in different pathological conditions. In the present review we recall in a synthetic way the most important researches about the use of SCDSFs in reprogramming cancer cells and in modulating the high speed of multiplication of keratinocytes which is characteristic of some pathological diseases like psoriasis. Moreover we add here the results about the capability of SCDSFs in modulating the homeostasis of human adipose-derived stem cells (hASCs) isolated from a fat tissue obtained with a novel-non enzymatic method and device. In addition we report the data not yet published about a first protein analysis of the SCDSFs and about their role in a pathological condition like neurodegeneration.

  • 111.
    Bivik Stadler, Caroline
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Genetic pathways controlling CNS development: The role of Notch signaling in regulating daughter cell proliferation in Drosophila2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The human central nervous system (CNS) displays the greatest cellular diversity of any organ system, consisting of billions of neurons, of numerous cell sub-types, interconnected in a vast network. Given this enormous complexity, decoding the genetic programs controlling the multistep process of CNS development remains a major challenge. While great progress has been made with respect to understanding sub-type specification, considerably less is known regarding how the generation of the precise number of each sub-type is controlled.

    The aim of this thesis was to gain deeper knowledge into the regulatory programs controlling cell specification and proliferation. To address these questions I have studied the Drosophila embryonic CNS as a model system, to thereby be able to investigate the genetic mechanisms at high resolution. Despite the different size and morphology between the Drosophila and the mammalian CNS, the lineages of their progenitors share similarity. Importantly for this thesis, both species progenitors show elaborate variations in their proliferation modes, either giving rise to daughters that can directly differentiate into neurons or glia (type 0), divide once (type I), or multiple times (type II).

    The studies launched off with a comprehensive chemical forward genetic screen, for the very last born cell in the well-studied lineage of progenitor NB5-6T: the Ap4 neuron, which expresses the neuropeptide FMRFa. NB5-6T is a powerful model to use, because it undergoes a programmed type I>0 daughter cell proliferation switch. An FMRF-eGFP transgenic reporter was utilized as readout for successful terminal differentiation of Ap4/FMRFa and thereby proper lineage progression of the ∼20 cells generated. The strongest mutants were mapped to genes with both known and novel essential functions e.g., spatial and temporal patterning, cell cycle control, cell specification and chromatin modification. Subsequently, we focused on some of the genes that showed a loss of function phenotype with an excess of lineage cells. We found that Notch is critical for the type I>0 daughter cell proliferation switch in the NB5-6T lineage and globally as well. When addressing the broader relevance of these findings, and to further decipher the Notch pathway, we discovered that selective groups of E(spl) genes is controlling the switch in a close interplay with four key cell cycle factors: Cyclin E, String, E2F and Dacapo, in most if not all embryonic progenitors. The Notch mediation of the switch is likely to be by direct transcriptional regulation. Furthermore, another gene identified in the screen, sequoia, was investigated. The analysis revealed that sequoia is also controlling the daughter cell switch in the CNS, and this partly through context dependent interactions with the Notch pathway.

    Taken together, the findings presented in this thesis demonstrate that daughter cell proliferation switches in Drosophila neural lineages are genetically programmed, and that Notch contributes to the triggering of these events. Given that early embryonic processes is frequently shown to be evolutionary conserved, you can speculate that changeable daughter proliferation programs could be applied to mammals, and contribute to a broader understanding of proliferation processes in humans as well.

     

  • 112. Bjorklund, Geir
    et al.
    Stejskal, Vera
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Urbina, Mauricio A.
    Dadar, Maryam
    Chirumbolo, Salvatore
    Mutter, Joachim
    Metals and Parkinson's Disease: Mechanisms and Biochemical Processes2018Inngår i: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 25, nr 19, s. 2198-2214Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Genetic background accounts for only 5 to 10% of the reported cases of Parkinson's disease (PD), while the remaining cases are of unknown etiology. It is believed that environmental factors may be involved in the causality of a large proportion of PD cases. Several PD genes are activated by xenobiotic exposure, and a link between pesticide exposure and PD has been demonstrated. Many epidemiological studies have shown an association between PD and exposure to metals such as mercury, lead, manganese, copper, iron, aluminum, bismuth, thallium, and zinc. This review explores the biological effects, the pathogenetic processes, genetic susceptibilities to metals as well as examining future strategies for PD treatment, such as chelation therapy.

  • 113. Bjornsdottir, Halla
    et al.
    Rudin, Agnes Dahlstrand
    Klose, Felix P.
    Elmwall, Jonas
    Welin, Amanda
    Stylianou, Marios
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Christenson, Karin
    Urban, Constantin F.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsman, Huamei
    Dahlgren, Claes
    Karlsson, Anna
    Bylund, Johan
    Phenol-soluble Modulin α Peptide Toxins from aggressive Staphylococcus aureus induce rapid Formation of neutrophil extracellular Traps through a reactive Oxygen species-independent Pathway2017Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, artikkel-id 257Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neutrophils have the ability to capture and kill microbes extracellularly through the formation of neutrophil extracellular traps (NETs). These are DNA and protein structures that neutrophils release extracellularly and are believed to function as a defense mechanism against microbes. The classic NET formation process, triggered by, e.g., bacteria, fungi, or by direct stimulation of protein kinase C through phorbol myristate acetate, is an active process that takes several hours and relies on the production of reactive oxygen species (ROS) that are further modified by myeloperoxidase (MPO). We show here that NET-like structures can also be formed by neutrophils after interaction with phenol-soluble modulin alpha (PSM alpha) that are cytotoxic membrane-disturbing peptides, secreted from community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). The PSMa-induced NETs contained the typical protein markers and were able to capture microbes. The PSMa-induced NET structures were disintegrated upon prolonged exposure to DNase-positive S. aureus but not on exposure to DNase-negative Candida albicans. Opposed to classic NETosis, PSMa-triggered NET formation occurred very rapidly, independently of ROS or MPO, and was also manifest at 4 degrees C. These data indicate that rapid NETs release may result from cytotoxic membrane disturbance by PSMa peptides, a process that may be of importance for CA-MRSA virulence.

  • 114.
    Björkander, Sophia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hell, Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Johansson, Maria A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mata Forsberg, Manuel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Lasaviciute, Gintare
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Roos, Stefan
    Holmlund, Ulrika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Staphylococcus aureus-derived factors induce IL-10, IFN-gamma and IL-17A-expressing FOXP3(+)CD161(+) T-helper cells in a partly monocyte-dependent manner2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 22083Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Staphylococcus aureus (S. aureus) is a human pathogen as well as a frequent colonizer of skin and mucosa. This bacterium potently activates conventional T-cells through superantigens and it is suggested to induce T-cell cytokine-production as well as to promote a regulatory phenotype in T-cells in order to avoid clearance. This study aimed to investigate how S. aureus impacts the production of regulatory and pro-inflammatory cytokines and the expression of CD161 and HELIOS by peripheral CD4(+)FOXP3(+) T-cells. Stimulation of PBMC with S. aureus 161:2-cell free supernatant (CFS) induced expression of IL-10, IFN-gamma and IL-17A in FOXP3(+) cells. Further, CD161 and HELIOS separated the FOXP3(+) cells into four distinct populations regarding cytokine-expression. Monocyte-depletion decreased S. aureus 161:2-induced activation of FOXP3(+) cells while pre-stimulation of purified monocytes with S. aureus 161:2-CFS and subsequent co-culture with autologous monocyte-depleted PBMC was sufficient to mediate activation of FOXP3(+) cells. Together, these data show that S. aureus potently induces FOXP3(+) cells and promotes a diverse phenotype with expression of regulatory and pro-inflammatory cytokines connected to increased CD161-expression. This could indicate potent regulation or a contribution of FOXP3(+) cells to inflammation and repression of immune-suppression upon encounter with S. aureus.

  • 115.
    Björkblom, Benny
    et al.
    The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway ; Center for Organelle Research, University of Stavanger, Stavanger, Norway.
    Maple-Grødem, Jodi
    The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway ; Center for Organelle Research, University of Stavanger, Stavanger, Norway.
    Puno, Marc Rhyan
    Department of Molecular and Applied Biosciences, University of Westminster, London, United Kingdom.
    Odell, Mark
    Department of Molecular and Applied Biosciences, University of Westminster, London, United Kingdom.
    Larsen, Jan Petter
    The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
    Møller, Simon Geir
    The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway ; Department of Biological Sciences, St. John's University, New York, New York, USA.
    Reactive oxygen species-mediated DJ-1 monomerization modulates intracellular trafficking involving karyopherin beta 22014Inngår i: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 34, nr 16, s. 3024-3040Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in DJ-1 are a cause of recessive, early-onset Parkinson's disease (PD). Although oxidative stress and mitochondrial integrity have been implicated in PD, it is largely unknown why neurons degenerate. DJ-1 is involved in oxidative stress-mediated responses and in mitochondrial maintenance; however, its specific function remains vague. Here we show that DJ-1 exhibits neuronal dynamic intracellular trafficking, with dimeric/monomeric cycling modulated by the oxidative environment. We demonstrate that oxidative stress enhances monomerization of wild-type cytosolic DJ-1, leading to nuclear recruitment. The pathogenic DJ-1/E163K variant is unable to homodimerize but is retained in the cytosol upon wild-type DJ-1 heterodimerization. We found that this wild-type/pathogenic heterodimer is disrupted by oxidative stress, leading to DJ-1/E163K mitochondrial translocation. We further demonstrated that endogenously expressed wild-type DJ-1 is imported into neuronal nuclei as a monomer and that nucleo-cytoplasmic transport is oxidative stress mediated. We identified a novel proline-tyrosine nuclear localization signal (PY-NLS) in DJ-1, and we found that nuclear monomeric DJ-1 import is mediated by an oxidative stress-dependent interaction with karyopherin beta 2. Our study provides evidence that oxidative stress-mediated intracellular trafficking of DJ-1, mediated by dynamic DJ-1 dimeric/monomeric cycling, is implicated in PD pathogenesis.

  • 116.
    Björklund, Asa K
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Light, Sara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hedin, Linnea
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Quantitative assessment of the structural bias in protein-protein interaction assays.2008Inngår i: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 8, nr 22, s. 4657-46667Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    With recent publications of several large-scale protein-protein interaction (PPI) studies, the realization of the full yeast interaction network is getting closer. Here, we have analysed several yeast protein interaction datasets to understand their strengths and weaknesses. In particular, we investigate the effect of experimental biases on some of the protein properties suggested to be enriched in highly connected proteins. Finally, we use support vector machines (SVM) to assess the contribution of these properties to protein interactivity. We find that protein abundance is the most important factor for detecting interactions in tandem affinity purifications (TAP), while it is of less importance for Yeast Two Hybrid (Y2H) screens. Consequently, sequence conservation and/or essentiality of hubs may be related to their high abundance. Further, proteins with disordered structure are over-represented in Y2H screens and in one, but not the other, large-scale TAP assay. Hence, disordered regions may be important both in transient interactions and interactions in complexes. Finally, a few domain families seem to be responsible for a large part of all interactions. Most importantly, we show that there are method-specific biases in PPI experiments. Thus, care should be taken before drawing strong conclusions based on a single dataset.

  • 117.
    Björklund, Åsa K.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ekman, Diana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Expansion of Protein Domain Repeats2006Inngår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 2, nr 8, s. 959-970Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Many proteins, especially in eukaryotes, contain tandem repeats of several domains from the same family. These repeats have a variety of binding properties and are involved in protein-protein interactions as well as binding to other ligands such as DNA and RNA. The rapid expansion of protein domain repeats is assumed to have evolved through internal tandem duplications. However, the exact mechanisms behind these tandem duplications are not well-understood. Here, we have studied the evolution, function, protein structure, gene structure, and phylogenetic distribution of domain repeats. For this purpose we have assigned Pfam-A domain families to 24 proteomes with more sensitive domain assignments in the repeat regions. These assignments confirmed previous findings that eukaryotes, and in particular vertebrates, contain a much higher fraction of proteins with repeats compared with prokaryotes. The internal sequence similarity in each protein revealed that the domain repeats are often expanded through duplications of several domains at a time, while the duplication of one domain is less common. Many of the repeats appear to have been duplicated in the middle of the repeat region. This is in strong contrast to the evolution of other proteins that mainly works through additions of single domains at either terminus. Further, we found that some domain families show distinct duplication patterns, e. g., nebulin domains have mainly been expanded with a unit of seven domains at a time, while duplications of other domain families involve varying numbers of domains. Finally, no common mechanism for the expansion of all repeats could be detected. We found that the duplication patterns show no dependence on the size of the domains. Further, repeat expansion in some families can possibly be explained by shuffling of exons. However, exon shuffling could not have created all repeats.

  • 118.
    Blikstad, Cecilia
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Widersten, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Functional characterization of a stereospecific diol dehydrogenase, FucO, from Escherichia coli: substrate specificity, pH dependence, kinetic isotope effects and influence of solvent viscosity2010Inngår i: Journal of Molecular Catalysis B: Enzymatic, ISSN 1381-1177, E-ISSN 1873-3158, Vol. 66, nr 1-2, s. 148-155Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    FucO, (S)-1,2-propanediol oxidoreductase, from Escherichia coli is involved in the anaerobic catabolic metabolism of L-fucose and L-rhamnose, catalyzing the interconversion of lactaldehyde to propanediol. The enzyme is specific for the S-enantiomers of the diol and aldehyde suggesting stereospecificity in catalysis. We have studied the enzyme kinetics of FucO with a spectrum of putative alcohol and aldehyde substrates to map the substrate specificity space. Additionally, for a more detailed analysis of the kinetic mechanism, pH dependence of catalysis, stereochemistry in hydride transfer, deuterium kinetic isotope effect of hydride transfer and effect of increasing solvent viscosity were also analyzed. The outcome of this study can be summarized as follows: FucO is highly stereospecific with the highest E-value measured to be 320 for the S-enantiomer of 1,2-propanediol. The enzyme is strictly regiospecific for oxidation of primary alcohols. The enzyme prefers short-chained (2-4 carbons) substrates and does not act on bulkier compounds such as phenyl-substituted alcohols. FucO is an 'A-side' dehydrogenase transferring the pro-R-hydrogen of NADH to the aldehyde substrate. The deuterium KIEs of kcat and kcat/KM were 1.9 and 4.2, respectively, illustrating that hydride transfer is partially rate-limiting but also that other reaction steps contribute to rate limitation of catalysis. Combining the KIE results with the observed effects of increasing medium viscosity proposed a working model for the kinetic mechanism involving slow, rate-limiting, product release and on-pathway conformational changes in the enzyme-nucleotide complexes.

  • 119.
    Blissing, Annica
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Thiopurine S-methyltransferase - characterization of variants and ligand binding2017Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Thiopurine S-methyltransferase (TPMT) belongs to the Class I S-adenosylmethionine-dependent methyltransferase (SAM-MT) super family of structurally related proteins. Common to the members of this large protein family is the catalysis of methylation reactions using S-adenosylmethionine (SAM) as a methyl group donor, although SAM-MTs act on a wide range of different substrates and carry out numerous biologically important functions. While the natural function of TPMT is unknown, this enzyme is involved in the metabolism of thiopurines, a class of pharmaceutical substances administered in treatment of immune-related disorders. Specifically, methylation by TPMT inactivates thiopurines and their metabolic intermediates, which reduces the efficacy of clinical treatment and increases the risk of adverse side effects. To further complicate matters, TPMT is a polymorphic enzyme with over 40 naturally occurring variants known to date, most of which exhibit lowered methylation activity towards thiopurines. Consequently, there are individual variations in TPMTmediated thiopurine inactivation, and the administered dose has to be adjusted prior to clinical treatment to avoid harmful side effects.

    Although the clinical relevance of TPMT is well established, few studies have investigated the molecular causes of the reduced methylation activity of variant proteins. In this thesis, the results of biophysical characterization of two variant proteins, TPMT*6 (Y180F) and TPMT*8 (R215H), are presented. While the properties of TPMT*8 were indistinguishable from those of the wild-type protein, TPMT*6 was found to be somewhat destabilized. Interestingly, the TPMT*6 amino acid substitution did not affect the functionality or folding pattern of the variant protein. Therefore, the decreased in vivo functionality reported for TPMT*6 is probably caused by increased proteolytic degradation in response to the reduced stability of this protein variant, rather than loss of function.

    Also presented herein are novel methodological approaches for studies of TPMT and its variants. Firstly, the advantages of using 8-anilinonaphthalene-1-sulfonic acid (ANS) to probe TPMT tertiary structure and active site integrity are presented. ANS binds exclusively to the native state of TPMT with high affinity (KD ~ 0.2 μm) and a 1:1 ratio. The stability of TPMT was dramatically increased by binding of ANS, which was shown to co-localize with the structurally similar adenine moiety of the cofactor SAM. Secondly, an enzyme activity assay based on isothermal titration calorimetry (ITC) is presented. Using this approach, the kinetics of 6-MP and 6-TG methylation by TPMT has been characterized.

  • 120.
    Blokzijl, Andries
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. YUMAB GmbH, Rebenring 33, D-38106 Braunschweig, Germany..
    Zieba, Agata
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Hust, Michael
    Tech Univ Carolo Wilhelmina Braunschweig, Inst Biochem Biotechnol & Bioinformat, Dept Biotechnol, Spielmannstr 7, D-38106 Braunschweig, Germany..
    Schirrmann, Thomas
    Tech Univ Carolo Wilhelmina Braunschweig, Inst Biochem Biotechnol & Bioinformat, Dept Biotechnol, Spielmannstr 7, D-38106 Braunschweig, Germany.;YUMAB GmbH, Rebenring 33, D-38106 Braunschweig, Germany..
    Helmsing, Saskia
    Tech Univ Carolo Wilhelmina Braunschweig, Inst Biochem Biotechnol & Bioinformat, Dept Biotechnol, Spielmannstr 7, D-38106 Braunschweig, Germany..
    Grannas, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hertz, Ellen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Morén, Anita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Chen, Lei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Söderberg, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Moustakas, Aristidis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Dubel, Stefan
    Tech Univ Carolo Wilhelmina Braunschweig, Inst Biochem Biotechnol & Bioinformat, Dept Biotechnol, Spielmannstr 7, D-38106 Braunschweig, Germany..
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Single Chain Antibodies as Tools to Study transforming growth factor--Regulated SMAD Proteins in Proximity Ligation-Based Pharmacological Screens2016Inngår i: Molecular & cellular proteomics (online), ISSN 1535-9476, E-ISSN 1535-9484, Vol. 15, nr 6, s. 1848-1856Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The cellular heterogeneity seen in tumors, with subpopulations of cells capable of resisting different treatments, renders single-treatment regimens generally ineffective. Accordingly, there is a great need to increase the repertoire of drug treatments from which combinations may be selected to efficiently target sets of pathological processes, while suppressing the emergence of resistance mutations. In this regard, members of the TGF- signaling pathway may furnish new, valuable therapeutic targets. In the present work, we developed in situ proximity ligation assays (isPLA) to monitor the state of the TGF- signaling pathway. Moreover, we extended the range of suitable affinity reagents for this analysis by developing a set of in-vitro-derived human antibody fragments (single chain fragment variable, scFv) that bind SMAD2 (Mothers against decapentaplegic 2), 3, 4, and 7 using phage display. These four proteins are all intracellular mediators of TGF- signaling. We also developed an scFv specific for SMAD3 phosphorylated in the linker domain 3 (p179 SMAD3). This phosphorylation has been shown to inactivate the tumor suppressor function of SMAD3. The single chain affinity reagents developed in the study were fused tocrystallizable antibody fragments (Fc-portions) and expressed as dimeric IgG-like molecules having Fc domains (Yumabs), and we show that they represent valuable reagents for isPLA. Using these novel assays, we demonstrate that p179 SMAD3 forms a complex with SMAD4 at increased frequency during division and that pharmacological inhibition of cyclin-dependent kinase 4 (CDK4)(1) reduces the levels of p179SMAD3 in tumor cells. We further show that the p179SMAD3-SMAD4 complex is bound for degradation by the proteasome. Finally, we developed a chemical screening strategy for compounds that reduce the levels of p179SMAD3 in tumor cells with isPLA as a read-out, using the p179SMAD3 scFv SH544-IIC4. The screen identified two kinase inhibitors, known inhibitors of the insulin receptor, which decreased levels of p179SMAD3/SMAD4 complexes, thereby demonstrating the suitability of the recombinant affinity reagents applied in isPLA in screening for inhibitors of cell signaling.

  • 121.
    Blomfeldt, Thomas O. J.
    et al.
    KTH, Skolan för kemivetenskap (CHE), Fiber- och polymerteknologi.
    Kuktaite, Ramune
    KTH, Skolan för kemivetenskap (CHE), Fiber- och polymerteknologi.
    Johansson, Eva
    Hedenqvist, Mikael S.
    KTH, Skolan för kemivetenskap (CHE), Fiber- och polymerteknologi.
    Mechanical Properties and Network Structure of Wheat Gluten Foams2011Inngår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 12, nr 5, s. 1707-1715Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This Article reports the influence of the protein network structure on the mechanical properties of foams produced from commercial wheat gluten using freeze-drying. Foams were produced from alkaline aqueous solutions at various gluten concentrations with or without glycerol, modified with bacterial cellulose nanosized fibers, or both. The results showed that 20 wt % glycerol was sufficient for plasticization, yielding foams with low modulus and high strain recovery. It was found that when fibers were mixed into the foams, a small but insignificant increase in elastic modulus was achieved, and the foam structure became more homogeneous. SEM indicated that the compatibility between the fibers and the matrix was good, with fibers acting as bridges in the cell walls. IR spectroscopy and SE-HPLC revealed a relatively low degree of aggregation, which was highest in the presence of glycerol. Confocal laser scanning microscopy revealed distinct differences in HMW-glutenin subunits and gliadin distributions for all of the different samples.

  • 122.
    Boberg, Andreas
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Stålnacke, Alexandra
    Etvax AB, Solna, Sweden.
    Bråve, Andreas
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Hinkula, Jorma
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär virologi. Linköpings universitet, Hälsouniversitetet.
    Wahren, Britta
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Carlin, Nils
    Etvax AB, Solna, Sweden.
    Receptor binding by cholera toxin B-subunit and amino acid modification improves minimal peptide immunogenecity2012Inngår i: ISRN Molecular Biology, ISSN 2090-7907, Vol. 2012, artikkel-id 170676Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We increase our understanding of augmenting a cellular immune response, by using an HIV-1 protease-derived epitope (PR7584), and variants thereof, coupled to the C-terminal, of the B subunit of cholera toxin (CTB). Fusion proteins were used for immunizations of HLA-A0201 transgenic C57BL/6 mice. We observed different capacities to elicit a cellular immune response by peptides with additions of five to ten amino acids to the PR epitope. There was a positive correlation between the magnitude of the elicited cellular immune response and the capacity of the fusion protein to bind GM-1. This binding capacity is affected by its ability to form natural pentamers of CTB. Our results suggest that functional CTB pentamers containing a foreign amino acid-modified epitope is a novel way to overcome the limited cellular immunogenicity of minimal peptide antigens. This way of using a functional assay as readout for improved cellular immunogenicity might become highly valuable for difficult immunogens such as short peptides (epitopes).

  • 123.
    Bojmar, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Metastatic Mechanisms in Malignant Tumors2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The ultimate cause of cancer related deaths is metastasis. This thesis is about three of the main human cancers; breast, colorectal and pancreatic cancer, that together account for more than 25% of the cancer-related deaths worldwide. The focus of the thesis is the spread of cancer, metastasis, and the aim was to investigate mechanisms that can be of importance for this process. We analyzed patient samples to validate the role of epithelialto-mesenchymal transition in vivo and found regulations of many related factors. However, these changes tend to fluctuate along the metastatic process, something which makes targeting complicated. We, moreover, focused on the influence of the tumor microenvironment for metastatic spread. In pancreatic cancer, the stroma constitutes the main part of many tumors. We analyzed the crosstalk between tumor and stromal cell and focused on the mediating inflammatory factor interleukin-1 (IL-1) and regulation of microRNAs. The results showed that the most commonly mutated factor in pancreatic cancer, KRAS, associates with the expression of IL-1 and subsequent activation of stromal cells. Blocking KRAS signaling together with IL-1 blockage give a more pronounced effect on in vitro proliferation and migration of cancer cells and suggests the use of a combination therapy. The cancer-associated activation of the stroma was found to be related to changes in microRNA expression. microRNA was analyzed separately in epithelial cells and stromal cells after microdissection of matched samples of primary and secondary tumors of breast and colorectal cancers. miR-214 and miR-199a were upregulated in stroma associated with progressive tumors and in pancreatic cancer stroma we could show that their expression alters the activation of stromal cells and thereby the growth and migratory ability of associated pancreatic tumor cells. In  breast and colorectal cancers we found several common microRNAs to be up- or downregulated in line with progression. We could show that one of these candidates, miR-18a, had a prognostic value in metastatic breast cancer. To further develop these studies we analyzed this microRNA in circulating microvesicles, i.e. exosomes, and investigated their role in the preparation of a pre-metastatic niche. MicroRNAs are stable biomarkers in the circulation, especially protected in exosomes, which can moreover specifically deliver their message to recipient cells. These studies facilitate the understanding of metastatic behavior and suggest new targets to stop cancer metastasis.

  • 124.
    Bojmar, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Zhang, Haiying
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Costa da Silva, Bruno
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Karlsson, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Vincent, Theresa
    Departments of Physiology and Biophysics and Cell and Developmental Biology, Weill Cornell Medical College, New York, USA / Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lyden, David
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Sandström, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome2015Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The ultimate cause of death for many cancer patients is the spread of the cancer via metastasis. Even so, there are still a lack of knowledge regarding the metastasis process. This study was performed to investigate the role of metastamirs in exosomes and their metastatic patterns. We used the well-established isogeneic murine cancer model of low metastatic 67NR cells, mimicking luminal/basal breast tumors, and highly metastatic 4T1 cells with characteristics of basal breast  tumors. We studied the exosomal properties and pre-metastatic effects in this metastasis model and compared human materials and exosomes of several other tumor types. Our data clearly demonstrated that exosomes from the highly metastatic cells home to the metastatic organs of their parental cells whereas exosomes from cells with low metastatic potential mostly located to lymph nodes. The exosome protein cargos also resembled their parental cells and potentially affects their target organs, and cells, differently. Furthermore, the exosomes from the highly metastatic cells had a more pronounced effect on tumor growth and pre-metastatic changes than the low metastatic exosomes. The microRNA-18a, a predictor of metastasis, was present to a higher extent in metastatic exosomes as compared to low metastatic exosomes, and altered the tumor progressive properties. Our findings support the role of exomirs as important players in the metastatic process, the value as biomarkers and potential therapeutic targets.

  • 125.
    Boknäs, Niklas
    et al.
    Department of Hematology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Faxälv, Lars
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Lindahl, Tomas L.
    Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Flow cytometry-based platelet function testing is predictive of symptom burden in a cohort of bleeders2018Inngår i: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, nr 5, s. 512-519Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Platelet function disorders (PFDs) are common in patients with mild bleeding disorders (MBDs), yet the significance of laboratory findings suggestive of a PFD remain unclear due to the lack of evidence for a clinical correlation between the test results and the patient phenotype. Herein, we present the results from a study evaluating the potential utility of platelet function testing using whole-blood flow cytometry in a cohort of 105 patients undergoing investigation for MBD. Subjects were evaluated with a test panel comprising two different activation markers (fibrinogen binding and P-selectin exposure) and four physiologically relevant platelet agonists (ADP, PAR1-AP, PAR4-AP, and CRP-XL). Abnormal test results were identified by comparison with reference ranges constructed from 24 healthy controls or with the fifth percentile of the entire patient cohort. We found that the abnormal test results are predictive of bleeding symptom severity, and that the greatest predictive strength was achieved using a subset of the panel, comparing measurements of fibrinogen binding after activation with all four agonists with the fifth percentile of the patient cohort (p = 0.00008, hazard ratio 8.7; 95% CI 2.5-40). Our results suggest that whole-blood flow cytometry-based platelet function testing could become a feasible alternative for the investigation of MBDs. We also show that platelet function testing using whole-blood flow cytometry could provide a clinically relevant quantitative assessment of platelet-related hemostasis.

  • 126. Bollampalli, V. P.
    et al.
    Harumi Yamashiro, L.
    Feng, X.
    Bierschenk, D.
    Gao, Y.
    Blom, Hans
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellens fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Henriques-Normark, B.
    Nylén, S.
    Rothfuchs, A. G.
    BCG Skin Infection Triggers IL-1R-MyD88-Dependent Migration of EpCAMlow CD11bhigh Skin Dendritic cells to Draining Lymph Node During CD4+ T-Cell Priming2015Inngår i: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, nr 10, artikkel-id e1005206Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The transport of antigen from the periphery to the draining lymph node (DLN) is critical for T-cell priming but remains poorly studied during infection with Mycobacterium bovis Bacille Calmette-Guérin (BCG). To address this we employed a mouse model to track the traffic of Dendritic cells (DCs) and mycobacteria from the BCG inoculation site in the skin to the DLN. Detection of BCG in the DLN was concomitant with the priming of antigen-specific CD4+ T cells at that site. We found EpCAMlow CD11bhigh migratory skin DCs to be mobilized during the transport of BCG to the DLN. Migratory skin DCs distributed to the T-cell area of the LN, co-localized with BCG and were found in close apposition to antigen-specific CD4+ T cells. Consequently, blockade of skin DC traffic into DLN dramatically reduced mycobacterial entry into DLN and muted T-cell priming. Interestingly, DC and mycobacterial entry into the DLN was dependent on IL-1R-I, MyD88, TNFR-I and IL-12p40. In addition, we found using DC adoptive transfers that the requirement for MyD88 in BCG-triggered migration was not restricted to the migrating DC itself and that hematopoietic expression of MyD88 was needed in part for full-fledged migration. Our observations thus identify a population of DCs that contribute towards the priming of CD4+ T cells to BCG infection by transporting bacilli into the DLN in an IL-1R-MyD88-dependent manner and reveal both DC-intrinsic and -extrinsic requirements for MyD88 in DC migration.

  • 127.
    Bolshakova, A.V.
    et al.
    Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia.
    Petukhova, O.A.
    Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia.
    Pinaev, G.P.
    Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia.
    Magnusson, Karl-Erik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Comparative analysis of subcellular fractionation methods for revealing a-actinin 1 and a-actinin 4 in A431 cells2009Inngår i: Cell and Tissue Biology, ISSN 1990-519X, Vol. 3, nr 2, s. 188-197Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    a-Actinin 1 and a-actinin 4 are actin-binding proteins with shared structural functions that are responsible for the regulation of several processes in the cell. Based on previous data on the different distribution of these proteins in the nucleus and cytoplasm, we have studied in detail the presence of a-actinin 1 and a-actinin 4 in subcellular fractions in the A431 cells spread on fibronectin. The detection of a-actinins in some particular fractions has been shown to depend on the method of lysis, as well as whether the preliminary low-temperature freezing of cells was used. The application of various fractionation methods has allowed us to conclude that a-actinin 4 is present in all cytoplasmic and nuclear subfractions, whereas, in addition to in the cytoplasm, a-actinin 1 can also be revealed in the nuclear envelope fraction.

  • 128.
    Bondza, Sina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Stenberg, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Björkeund, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Conjugation Effects on Antibody-Drug Conjugates: Evaluation of Interaction Kinetics in Real Time on Living Cells2014Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, nr 11, s. 4154-4163Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Antibody-drug conjugates (ADC) have shown promising effects in cancer therapy by combining the target specificity of an antibody with the toxicity of a chemotherapeutic drug. As the number of therapeutic antibodies is significantly larger than those used as ADCs, there is unused potential for more effective therapies. However, the conjugation of an additional molecule to an antibody may affect the interaction with its target, altering association rate, dissociation rate, or both. Any changes of the binding kinetics can have subsequent effects on the efficacy of the ADCs, thus the kinetics are important to monitor during ADC development and production. This paper describes a method for the analysis of conjugation effects on antibody binding to its antigen, using the instrument LigandTracer and a fluorescent monovalent anti-IgG binder denoted FIBA, which did not affect the interaction. All measurements were done in real time using living cells which naturally expressed the antigens. With this method the binding profiles of different conjugations of the therapeutic anti-EGFR antibody cetuximab and the anti-CD44v6 antibody fragment AbD15171 were evaluated and compared. Even comparatively small modifications of cetuximab altered the interaction with the epidermal growth factor receptor (EGFR). In contrast, no impact on the AbD15171-CD44v6 interaction was observed upon conjugation. This illustrates the importance to study the binding profile for each ADC combination, as it is difficult to draw any general conclusion about conjugation effects. The modification of interaction kinetics through conjugation opens up new possibilities when optimizing an antibody or an ADC, since the conjugations can be used to create a binding profile more apt for a specific clinical need.

  • 129.
    Booy, Evan P.
    et al.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Johar, Dina
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Maddika, Srilekha
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Pirzada, Hasan
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Sahib, Mickey M.
    Department of Oral Biology, University of Manitoba, Winnipeg, Canada .
    Gehrke, Iris
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Loewen, Shauna
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Louis, Sherif F.
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Kadkhoda, Kamran
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Mowat, Michael
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Monoclonal and bispecific antibodies as novel therapeutics2006Inngår i: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 54, nr 2, s. 85-101Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling through receptor kinases, which has been implicated in many human cancers and is associated with poor prognosis. Tumor growth has been shown to be decreased by interrupting this process of extensive growth factor-mediated signaling by directly targeting either the surface receptor or the ligand and thereby preventing cell survival and promoting apoptosis. Monoclonal antibodies have long been eyed as a potential new class of therapeutics targeting cancer and other diseases. Antibody-based therapy initially entered clinical practice when trastuzumab/Herceptin became the first clinically approved drug against an oncogene product as a well-established blocking reagent for tumors with hyperactivity of epidermal growth factor signaling pathways. In the first part of this review we explain basic terms related to the development of antibody-based drugs, give a brief historic perspective of the field, and also touch on topics such as the "humanization of antibodies" or creation of hybrid antibodies. The second part of the review gives an overview of the clinical usage of bispecific antibodies and antibodies "armed" with cytotoxic agents or enzymes. Further within this section, cancer-specific, site-specific, or signaling pathway-specific therapies are discussed in detail. Among other antibody-based therapeutic products, we discuss: Avastin (bevacizumab), CG76030, Theragyn (pemtumomab), daclizumab (Zenapax), TriAb, MDX-210, Herceptin (trastuzumab), panitumumab (ABX-EGF), mastuzimab (EMD-72000), Erbitux (certuximab, IMC225), Panorex (edrecolomab), STI571, CeaVac, Campath (alemtuizumab), Mylotarg (gemtuzumab, ozogamicin), and many others. The end of the review deliberates upon potential problems associated with cancer immunotherapy.

  • 130.
    Borg, Mathias
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Study of the insulin-like peptide 3 in human platelets2009Independent thesis Advanced level (degree of Master (One Year)), 20 poäng / 30 hpOppgave
    Abstract [en]

    The insulin-like 3 peptide is autocrine/paracrine insulin-related hormone with a size of approximately 6kDa [1]. It mediates through a leucine richG-coupled receptor named LGR8. INSL3 is mainly expressed in human Leydig cells and is directly responsible for migration of the testis during the pre-natal period in maledevelopment. [2]

    INSL3 mRNA has recently been verified in human platelets whereas no mRNA has been detected for LGR8 (by Sanofi-Aventis GmbH in Frankfurt,Germany), indicating that INSL3 might be released through paracrine functions at sites of platelet adhesion and aggregation upon a vascular injury.Furthermore, has activated platelets been shown to translate essential proteins upon activation, in a term called “signal-dependent protein synthesis”.The B-Cell lymphoma-3 protein (BCL-3) is an example of such a protein [3], and there is a possibility that INSL3 might be also.

    In this thesis we wanted to detect the relaxin- like peptide 3 hormone (INSL3). (Its function, location and the timeframe of its release, when/if it issecreated in stimulated platelets).The source of platelet-derived INSL3 can be found with Western blotting and Enzyme immunoassay.

    Detection of the insulin-like 3 peptide in human platelets turned out to be a difficult challenge due to the small amount of INSL3 secretion uponplatelet activation; hence the total amount of INSL3 produced might be below detection limit.

  • 131. Borzacchiello, A
    et al.
    Mayol, L
    Ambrosio, L
    Gärskog, Ola
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Dahlqvist, Åke
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Rheological characterization of vocal folds after injection augmentation in a preliminary animal study2004Inngår i: Journal of bioactive and compatible polymers (Print), ISSN 0883-9115, E-ISSN 1530-8030, Vol. 19, nr 4, s. 331-341Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The investigation of vocal folds viscoelastic properties in an animal model (rabbit) after injection of various augmentation substances, 6 months after injection, is reported. The injected materials were: hyaluronan-based materials (Hylan B gel and Deflux(R)), cross-linked collagen (Zyplast(R)) and polytetrafluoroethylene (Teflon(R)). Rheological properties of the augmentation substances were also evaluated. The results from these animal experiments indicate that the viscoelastic properties of the vocal folds injected with Deflux(R), Zyplast(R) and Hylan B gel are similar to the healthy vocal folds (non-injected samples) used as control, thus demonstrating that these materials are good candidates for further studies aimed at restoring/preserving the vibratory capacity of the vocal folds with injection treatment in glottal insufficiency.

  • 132. Bouzenzana, Jamel
    et al.
    Pelosi, Ludovic
    Briolay, Anne
    Briolay, Jerome
    Bulone, Vincent
    KTH, Skolan för bioteknologi (BIO), Glykovetenskap.
    Identification of the first Oomycete annexin as a (1 -> 3)-beta-D-glucan synthase activator2006Inngår i: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 62, nr 2, s. 552-565Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    (1 -> 3)-beta-D-Glucans are major components of the cell walls of Oomycetes and as such they play an essential role in the morphogenesis and growth of these microorganisms. Despite the biological importance of (1 -> 3)-beta-D-glucans, their mechanisms of biosynthesis are poorly understood. Previous studies on (1 -> 3)-beta-D-glucan synthases from Saprolegnia monoica have shown that three protein bands of an apparent molecular weight of 34, 48 and 50 kDa co-purify with enzyme activity. However, none of the corresponding proteins have been identified. Here we have identified, purified, sequenced and characterized a protein from the 34 kDa band and clearly shown that it has all the biochemical properties of proteins from the annexin family. In addition, we have unequivocally demonstrated that the purified protein is an activator of (1 -> 3)-beta-D-glucan synthase. This represents a new type of function for proteins belonging to the annexin family. Two other proteins from the 48 and 50 kDa bands were identified as ATP synthase subunits, which most likely arise from contaminations by mitochondria during membrane preparation. The results, which are discussed in relation with the possible regulation mechanisms of (1 -> 3)-beta-D-glucan synthases, represent a first step towards a better understanding of cell wall polysaccharide biosynthesis in Oomycetes.

  • 133.
    Brander, Gustaf
    et al.
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Rydell, Mina
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Fernández de la Cruz, Lorena
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul S.
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Serlachius, Eva
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Perinatal risk factors in Tourette's and chronic tic disorders: a total population sibling comparison study2018Inngår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, nr 5, s. 1189-1197Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adverse perinatal events may increase the risk of Tourette's and chronic tic disorders (TD/CTD), but previous studies have been unable to control for unmeasured environmental and genetic confounding. We aimed to prospectively investigate potential perinatal risk factors for TD/CTD, taking unmeasured factors shared between full siblings into account. A population-based birth cohort, consisting of all singletons born in Sweden in 1973-2003, was followed until December 2013. A total of 3 026 861 individuals were identified, 5597 of which had a registered TD/CTD diagnosis. We then studied differentially exposed full siblings from 947 942 families; of these, 3563 families included siblings that were discordant for TD/CTD. Perinatal data were collected from the Medical Birth Register and TD/CTD diagnoses were collected from the National Patient Register, using a previously validated algorithm. In the fully adjusted models, impaired fetal growth, preterm birth, breech presentation and cesarean section were associated with a higher risk of TD/CTD, largely independent from shared family confounders and measured covariates. Maternal smoking during pregnancy was associated with risk of TD/CTD in a dose-response manner but the association was no longer statistically significant in the sibling comparison models or after the exclusion of comorbid attention-deficit/hyperactivity disorder. A dose-response relationship between the number of adverse perinatal events and increased risk for TD/CTD was also observed, with hazard ratios ranging from 1.41 (95% confidence interval (CI): 1.33-1.50) for one event to 2.42 (95% CI: 1.65-3.53) for five or more events. These results pave the way for future gene by environment interaction and epigenetic studies in TD/CTD.

  • 134.
    Branneby, Cecilia
    KTH, Skolan för bioteknologi (BIO), Biokemi.
    Exploiting enzyme promiscuity for rational design2005Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Enzymes are today well recognized in various industrial applications, being an important component in detergents, and catalysts in the production of agrochemicals, foods, pharmaceuticals, and fine chemicals. Their large use is mainly due to their high selectivity and environmental advantage, compared to traditional catalysts. Tools and techniques in molecular biology offer the possibility to screen the natural sources and engineer new enzyme activities which further increases their usefulness as catalysts, in a broader area.

    Although enzymes show high substrate and reaction selectivity many enzymes are today known to catalyze other reactions than their natural ones. This is called enzyme promiscuity. It has been suggested that enzyme promiscuity is Nature’s way to create diversity. Small changes in the protein sequence can give the enzyme new reaction specificity.

    In this thesis I will present how rational design, based on molecular modeling, can be used to explore enzyme promiscuity and to change the enzyme reaction specificity. The first part of this work describes how Candida antarctica lipase B (CALB), by a single point mutation, was mutated to give increased activity for aldol additions, Michael additions and epoxidations. The activities of these reactions were predicted by quantum chemical calculations, which suggested that a single-point mutant of CALB would catalyze these reactions. Hence, the active site of CALB, which consists of a catalytic triad (Ser, His, Asp) and an oxyanion hole, was targeted by site-directed mutagenesis and the nucleophilic serine was mutated for either glycine or alanine. Enzymes were expressed in Pichia pastoris and analyzed for activity of the different reactions. In the case of the aldol additions the best mutant showed a four-fold initial rate over the wild type enzyme, for hexanal. Also Michael additions and epoxidations were successfully catalyzed by this mutant.

    In the last part of this thesis, rational design of alanine racemase from Geobacillus stearothermophilus was performed in order to alter the enzyme specificity. Active protein was expressed in Escherichia coli and analyzed. The explored reaction was the conversion of alanine to pyruvate and 2-butanone to 2-butylamine. One of the mutants showed increased activity for transamination, compared to the wild type.

  • 135.
    Brattsand, Göran
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Nordin, Gunnar
    Isaksson, Anders
    Bjellerup, Per
    Stridsberg, Mats
    Hård, Lena
    Ankarberg Lindgren, Carina
    Becker, Charlotte
    Gustafsson, Sven
    Larsson, Kerstin
    Equalis/SFKK rekommenderar harmonisering av enheter vid hormonbestämningar -Något också för Norden?2012Inngår i: Klinisk Biokemi i Norden, ISSN 1101-2013, Vol. 24, nr 4, s. 20-27Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [sv]

    Equalis och Svensk Förening för Klinisk Kemi (SFKK) rekommenderar att de kliniska laboratorierna i Sverige använder enhetliga måttenheter vid hormonbestämningar för ökad jämförbarhet och patientsäkerhet. Vid analys i serum eller plasma med nuvarande metoder rekommenderas följande enheter:

    • Adrenokortikotropt hormon (ACTH): pmol/L

    • Insulin: mIE/L

    • Parathormon (PTH): pmol/L

    • Prolaktin: mIE/L

    • Tillväxthormon (GH): μg/L

    • Östradiol: pmol/L

    • Aldosteron: pmol/L

    • Reninkoncentration: mIE/L

  • 136. Brechmann, Nils A.
    et al.
    Eriksson, Per-Olov
    Eriksson, Kristofer
    Oscarsson, Sven
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Buijs, Jos
    Shokri, Atefeh
    Hjälm, Göran
    Chotteau, Véronique
    Pilot-scale process for magnetic bead purification of antibodies directly from non-clarified CHO cell culture2019Inngår i: Biotechnology progress (Print), ISSN 8756-7938, E-ISSN 1520-6033, Vol. 35, nr 3, artikkel-id e2775Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High capacity magnetic protein A agarose beads, LOABeads PrtA, were used in the development of a new process for affinity purification of monoclonal antibodies (mAbs) from non-clarified CHO cell broth using a pilot-scale magnetic separator. The LOABeads had a maximum binding capacity of 65 mg/mL and an adsorption capacity of 25-42 mg IgG/mL bead in suspension for an IgG concentration of 1 to 8 g/L. Pilot-scale separation was initially tested in a mAb capture step from 26 L clarified harvest. Small-scale experiments showed that similar mAb adsorptions were obtained in cell broth containing 40 x 10(6) cells/mL as in clarified supernatant. Two pilot-scale purification runs were then performed on non-clarified cell broth from fed-batch runs of 16 L, where a rapid mAb adsorption >= 96.6% was observed after 1 h. This process using 1 L of magnetic beads had an overall mAb yield of 86% and 16 times concentration factor. After this single protein A capture step, the mAb purity was similar to the one obtained by column chromatography, while the host cell protein content was very low, <10 ppm. Our results showed that this magnetic bead mAb purification process, using a dedicated pilot-scale separation device, was a highly efficient single step, which directly connected the culture to the downstream process without cell clarification. Purification of mAb directly from non-clarified cell broth without cell separation can provide significant savings in terms of resources, operation time, and equipment, compared to legacy procedure of cell separation followed by column chromatography step.

  • 137. Breimer, Lars H
    et al.
    Nilsson, Torbjörn K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Shedded cell membrane proteins in plasma: pure waste, or informative biomarkers of pathophysiological processes?2015Inngår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 75, nr 6, s. 441-443Artikkel i tidsskrift (Annet vitenskapelig)
  • 138.
    Bridge, Eileen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Riedel, Kai-Uwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Johansson, Britt-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Spliced exons of adenovirus late RNAs colocalize with snRNP in a specific nuclear domain1996Inngår i: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 135, nr 2, s. 303-314Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Posttranscriptional steps in the production of mRNA include well characterized polyadenylation and splicing reactions, but it is also necessary to understand how RNA is transported within the nucleus from the site of its transcription to the nuclear pore, where it is translocated to the cytoplasmic compartment. Determining the localization of RNA within the nucleus is an important aspect of understanding RNA production and may provide clues for investigating the trafficking of RNA within the nucleus and the mechanism for its export to the cytoplasm. We have previously shown that late phase adenovirus-infected cells contain large clusters of snRNP and non-snRNP splicing factors; the presence of these structures is correlated with high levels of viral late gene transcription. The snRNP clusters correspond to enlarged interchromatin granules present in late phase infected cells. Here we show that polyadenylated RNA and spliced tripartite leader exons from the viral major late transcription unit are present in these same late phase snRNP-containing structures. We find that the majority of the steady state viral RNA present in the nucleus is spliced at the tripartite leader exons. Tripartite leader exons are efficiently exported from the nucleus at a time when we detect their accumulation in interchromatin granule clusters. Since the enlarged interchromatin granules contain spliced and polyadenylated RNA, we suggest that viral RNA may accumulate in this late phase structure during an intranuclear step in RNA transport.

  • 139.
    Brinck, Jonas
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    The expression and regulation of hyaluronan synthases and their role in glycosaminoglycan synthesis2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The glycosaminoglycan hyaluronan is an essential component of the extracellular matrix in all higher organisms, affecting cellular processes such as migration, proliferation and differentiation. Hyaluronan is synthesized by a plasma membrane bound hyaluronan synthase (HAS) which exists in three genetic isoforms. This thesis focuses on the understanding of the hyaluronan biosynthesis by studies on the expression and regulation of the HAS proteins.

    In order to characterize the structural and functional properties of the HAS isoforms we developed a method to solubilize HAS protein(s) while retaining enzymatic activity. The partially purified HAS protein is, most likely, not asscociated covalently with other components. Cells transfected with cDNAs for HAS1, HAS2 and HAS3 were studied and all three HAS isozymes were able to synthesize high molecular weight hyaluronan chains in intact cells. The regulation of the hyaluronan chain length involves cell specific elements as well as external stimulatory factors. HAS3 transfected cells with high hyaluronan production exhibit reduced migration capacity and reduced amounts of a cell surface hyaluronan receptor molecule (CD44) compared to wild-type cells.

    The three HAS isoforms were studied and shown to be differentially expressed and regulated in response to external stimuli. Platelet derived growth factor (PDGF-BB) and transforming growth factor (TGF-β1) are important regulators of HAS at both the transcriptional and translational level. The HAS2 isoform is the isoform most susceptible to external regulation.

    The role of the UDP-glucose dehydrogenase in mammalian glycosaminoglycan biosynthesis was assessed. The enzyme is essential for hyaluronan, heparan sulfate and chondroitin sulfate biosynthesis, but does not exert a rate-limiting effect.

  • 140.
    Brkic, Adisa
    Karlstads universitet, Fakulteten för hälsa, natur- och teknikvetenskap (from 2013).
    Litteraturstudie av senaste forskningsresultaten kring inhibition av makrofager via CSF - 1R & CCR2: - Kan det vara en möjlig väg att hämma makrofager vid cancer och därmed ge en förbättrad prognos?2016Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
  • 141. Broach, James R
    et al.
    Bharatula, Vasudha
    Chereji, Razvan
    Elfving, Nils
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Björklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Morozov, Alexandre
    The Msn2 mediated stress response: Survival based on "hedging your bet" and a dynamic interplay of transcription factor binding and nucleosome occupancy2015Inngår i: Yeast, ISSN 0749-503X, E-ISSN 1097-0061, Vol. 32, nr Suppl. 1, s. S221-S222Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Yeast cell subjected to many different stresses elicit an acute transcriptional stress response mediated by the Msn2 transcription factor, which alters expression of both a stress specific-cohort of genes as well as a common cohort of genes that changes expression in a stereotypic fashion upon exposure to any of a wide variety of stresses. We have shown by dynamic single cell analysis that stresses regulate Msn2 activity through cytoplasm to nuclear relocalization but do so in an unusual way: stresses induce increased frequency of bursts of short-lived, recurrent periods of Msn2 nuclear localization with different stresses eliciting different patterns of bursts. Moreover, genetically identical cells subject to an identical stress can behave quite differently, with some cells mounting a robust nuclear occupancy of Msn2 while others show no nuclear localization at all. We have proposed that this idiosyncratic behavior allows populations of cells to “hedge their bet” as to what will be the optimum strategy for surviving the ensuing stress. We have used computational modeling and single cell analysis to determine that bursting is a consequence of noise in the stress signaling pathways amplified by the small number of Msn2 molecules in the cell. Moreover, we have applied genome wide chromatin immunoprecipitation and nucleosome profiling to address how different stresses determine where Msn2 binds under a particular stressful conditions, and thus what genes are regulated by that stress, and how that binding affects, and is affected by, nucleosome positioning and other transcription factor binding. These results provide in vivo validation of Widon's model of indirect cooperativity of transcription factor binding, mediated by partial unwinding of nucleosomes by one transcription factor to allow access for a second transcription factor to a previously occluded binding site. Finally, we have addressed the “bet hedging” hypothesis by showing that persistence of the Msn2-mediated stress response yields cell growth arrest and have identified the targets responsible for that growth arrest. We have applied experimental evolution paradigms to address the relative fitness of cells exhibiting stochastic stress responses versus those with a uniform response. In short, our results indicate that the stress response is complex and that complexity is critical for cell survival.

  • 142. Broadbent, Kate M.
    et al.
    Broadbent, Jill C.
    Ribacke, Ulf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Wirth, Dyann
    Rinn, John L.
    Sabeti, Pardis C.
    Strand-specific RNA sequencing in Plasmodium falciparum malaria identifies developmentally regulated long non-coding RNA and circular RNA2015Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, artikkel-id 454Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The human malaria parasite Plasmodium falciparum has a complex and multi-stage life cycle that requires extensive and precise gene regulation to allow invasion and hijacking of host cells, transmission, and immune escape. To date, the regulatory elements orchestrating these critical parasite processes remain largely unknown. Yet it is becoming increasingly clear that long non-coding RNAs (lncRNAs) could represent a missing regulatory layer across a broad range of organisms. Results: To investigate the regulatory capacity of lncRNA in P. falciparum, we harvested fifteen samples from two time-courses. Our sample set profiled 56 h of P. falciparum blood stage development. We then developed and validated strand-specific, non-polyA-selected RNA sequencing methods, and pursued the first assembly of P. falciparum strand-specific transcript structures from RNA sequencing data. This approach enabled the annotation of over one thousand lncRNA transcript models and their comprehensive global analysis: coding prediction, periodicity, stage-specificity, correlation, GC content, length, location relative to annotated transcripts, and splicing. We validated the complete splicing structure of three lncRNAs with compelling properties. Non-polyA-selected deep sequencing also enabled the prediction of hundreds of intriguing P. falciparum circular RNAs, six of which we validated experimentally. Conclusions: We found that a subset of lncRNAs, including all subtelomeric lncRNAs, strongly peaked in expression during invasion. By contrast, antisense transcript levels significantly dropped during invasion. As compared to neighboring mRNAs, the expression of antisense-sense pairs was significantly anti-correlated during blood stage development, indicating transcriptional interference. We also validated that P. falciparum produces circRNAs, which is notable given the lack of RNA interference in the organism, and discovered that a highly expressed, five-exon antisense RNA is poised to regulate P. falciparum gametocyte development 1 (PfGDV1), a gene required for early sexual commitment events.

  • 143.
    Brockmann, Sarah J.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Freischmidt, Axel
    Oeckl, Patrick
    Müller, Kathrin
    Ponna, Srinivas K.
    Helferich, Anika M.
    Paone, Christoph
    Reinders, Jörg
    Kojer, Kerstin
    Orth, Michael
    Jokela, Manu
    Auranen, Mari
    Udd, Bjarne
    Hermann, Andreas
    Danzer, Karin M.
    Lichtner, Peter
    Walther, Paul
    Ludolph, Albert C.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Otto, Markus
    Kursula, Petri
    Just, Steffen
    Weishaupt, Jochen H.
    CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency2018Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, nr 4, s. 706-715Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p. R15L and p. G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p. P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p. R15L and p. G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p. R15L, but not of CHCHD10 p. G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p. G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p. P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p. R15L and p. G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.

  • 144.
    Brockmöller, Scarlet F.
    et al.
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Bucher, Elmar
    Medical Biotechnology, VTT Technical Research Centre of Finland, University of Turku, Turku, Finland.
    Müller, Berit M.
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Budczies, Jan
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Griffin, Julian L.
    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Kallioniemi, Olli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Iljin, Kristiina
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Loibl, Sibylle
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Darb-Esfahani, Silvia
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Sinn, Bruno V.
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Klauschen, Frederick
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Prinzler, Judith
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Bangemann, Nikola
    Breast Cancer Center, Charité University Hospital, Berlin, Germany.
    Ismaeel, Fakher
    Department of Gynaecology and Obstetrics, DRK Kliniken Köpenick, Berlin, Germany; Department of Gynaecology and Obstetrics, Charité University Hospital, Berlin, Germany.
    Fiehn, Oliver
    Genome Center, University of California-Davis, Davis CA, United States.
    Dietel, Manfred
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Denkert, Carsten
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Integration of metabolomics and expression of glycerol-3-phosphate acyltransferase (GPAM) in breast cancer-link to patient survival, hormone receptor status, and metabolic profiling2012Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 11, nr 2, s. 850-60Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Changes in lipid metabolism are an important but not well-characterized hallmark of cancer. On the basis of our recent findings of lipidomic changes in breast cancer, we investigated glycerol-3-phosphate acyltransferase (GPAM), a key enzyme in the lipid biosynthesis of triacylglycerols and phospholipids. GPAM protein expression was evaluated and linked to metabolomic and lipidomic profiles in a cohort of human breast carcinomas. In addition, GPAM mRNA expression was analyzed using the GeneSapiens in silico transcriptiomics database. High cytoplasmic GPAM expression was associated with hormone receptor negative status (p = 0.013). On the protein (p = 0.048) and mRNA (p = 0.001) levels, increased GPAM expression was associated with a better overall survival. Metabolomic analysis by GC-MS showed that sn-glycerol-3-phosphate, the substrate of GPAM, was elevated in breast cancer compared to normal breast tissue. LC-MS based lipidomic analysis identified significantly higher levels of phospholipids, especially phosphatidylcholines in GPAM protein positive tumors. In conclusion, our results suggest that GPAM is expressed in human breast cancer with associated changes in the cellular metabolism, in particular an increased synthesis of phospholipids, the major structural component of cellular membranes.

  • 145.
    Bromée, Torun
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Sjödin, Paula
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Boswell, Tim
    Larsson, Tomas A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Salaneck, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Zoorob, Rima
    Mohell, Nina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Larhammar, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Neuropeptide Y-family receptors Y6 and Y7 in chicken: Cloning, pharmacological characterization, tissue distribution and conserved synteny with human chromosome region2006Inngår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, nr 9, s. 2048-2063Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The peptides of the neuropeptide Y (NPY) family exert their functions, including regulation of appetite and circadian rhythm, by binding to G-protein coupled receptors. Mammals have five subtypes, named Y1, Y2, Y4, Y5 and Y6, and recently Y7 has been discovered in fish and amphibians. In chicken we have previously characterized the first four subtypes and here we describe Y6 and Y7. The genes for Y6 and Y7 are located 1 megabase apart on chromosome 13, which displays conserved synteny with human chromosome 5 that harbours the Y6 gene. The porcine PYY radioligand bound the chicken Y6 receptor with a Kd of 0.80 ± 0.36 nm. No functional coupling was demonstrated. The Y6 mRNA is expressed in hypothalamus, gastrointestinal tract and adipose tissue. Porcine PYY bound chicken Y7 with a Kd of 0.14 ± 0.01 nm (mean ± SEM), whereas chicken PYY surprisingly had a much lower affinity, with a Ki of 41 nm, perhaps as a result of its additional amino acid at the N terminus. Truncated peptide fragments had greatly reduced affinity for Y7, in agreement with its closest relative, Y2, in chicken and fish, but in contrast to Y2 in mammals. This suggests that in mammals Y2 has only recently acquired the ability to bind truncated PYY. Chicken Y7 has a much more restricted tissue distribution than other subtypes and was only detected in adrenal gland. Y7 seems to have been lost in mammals. The physiological roles of Y6 and Y7 remain to be identified, but our phylogenetic and chromosomal analyses support the ancient origin of these Y receptor genes by chromosome duplications in an early (pregnathostome) vertebrate ancestor.

  • 146. Brosché, Mikael
    et al.
    Strid, Åke
    Örebro universitet, Institutionen för naturvetenskap.
    Molecular events following perception of ultraviolet-B radiation by plants2003Inngår i: Physiologia Plantarum: An International Journal for Plant Biology, ISSN 0031-9317, E-ISSN 1399-3054, Vol. 117, nr 1, s. 1-10Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Exposure of plants to UV-B radiation (280–320 nm) results in changes in expression of a large number of genes. Before UV-B radiation or light of other wavelengths can give rise to a cellular response, it has to be perceived by some kind of receptor, and the information transduced via a signalling pathway to the target molecules, be it proteins in the cytoplasm

    or the genetic material in the nucleus. The perception of low levels of UV-B probably occurs via a UV-B photoreceptor followed by several different signalling pathways. These pathways include second messengers such as calcium, kinases and the catalytic formation of reactive oxygen species. High levels of UV-B, on the other hand, probably cause cellular damage

    and oxidative stress, thus activating a general stress signal transduction pathway which leads to a response similar to that which occurs after pathogen attack and other stresses. Some of the genes identified so far as being regulated by UV-B encode proteins involved in the biosynthesis of protective pigments, DNA repair and antioxidative enzymes, photosynthetic genes, cell cycle genes, and stress genes induced by other types of stimuli (i.e. pathogenesis-related proteins and senescence-induced genes). In the light of the information obtained on components necessary for UV-B-induced changes in gene expression, we propose in this mini-review a working model for UV-B perception and signal transduction. This model also takes into account dosage differences for the observations, which imply a separation into UV-B-specific and more general stress signal transduction.

  • 147.
    Browning, Kathryn L.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lind, Tania
    Malmo Univ, Dept Biomed Sci & Biofilm, Malmo, Sweden.
    Maric, Selma
    Malmoe Univ, Dept Hlth & Soc, Malmo, Sweden.
    Malekkhaiat Häffner, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Fredrikson, Gunilla
    Lund Univ, Dept Clin Sci, Lund, Sweden.
    Bengtsson, Eva
    Lund Univ, Dept Clin Sci, Rochester, Sweden.
    Malmsten, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Univ Copenhagen, Dept Pharm, Copenhagen, Denmark.
    Cardenas, Marite
    Malmo Univ, Dept Biomed Sci & Biofilm, Malmo, Sweden.
    Human lipoproteins at model cell membranes: Role of the lipoprotein class on lipid dynamics2017Inngår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 253, artikkel-id 700Artikkel i tidsskrift (Annet vitenskapelig)
  • 148.
    Brändén, Magnus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Electron and proton transfer in cytochrome c oxidase2003Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This doctoral thesis describes results from studies on the mechanisms by which the enzyme cytochrome c oxidase catalyses the reduction of oxygen to water. Cytochrome c oxidase is the last integral enzyme complex of the socalled respiratory chain in the mitochondrial inner membrane (plasma membrane of bacteria). The reaction catalysed by cytochrome c oxidase produces a charge separation across the membrane by two separate mechanisms. The protons and the electrons needed to reduce oxygen to water are supplied from different sides of the membrane, and the energy released in this reaction is used by cytochrome c oxidase to pump protons against the electro-chemical gradient across the membrane. Another integral enzyme, ATP-synthase, utilises this gradient for synthesis of ATP, which in turn is used in many of the energyrequiring processes of a cell. Cytochrome c oxidase holds four redox-active metal centres that mediate electron transfer to, and reduction of the O2-molecule. One part of the thesis concerns the rates of electron transfer as well as the redox equilibrium between the metal sites (papers II and IV).

    Since the oxygen chemistry takes place in the membrane-spanning part of the enzyme it is equipped with two proton-transfer pathways that lead from the bulk solution to the active site. A second part of the thesis concerns the location of the entry-point of one of these pathways as well as the role of this pathway during the catalytic cycle (papers I and III).

    The third part of the thesis concerns the mechanism by which the enzymecouples the O2-chemistry to proton pumping (paper V).

  • 149.
    Brännström, Kristoffer
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gharibyan, Anna L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Islam, Tohidul
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Iakovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Nilsson, Lina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lee, Cheng Choo
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Sandblad, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Pamrén, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Scanning electron microscopy as a tool for evaluating morphology of amyloid structures formed on surface plasmon resonance chips2018Inngår i: Data in Brief, E-ISSN 2352-3409, Vol. 19, s. 1166-1170Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We demonstrate the use of Scanning Electron microscopy (SEM) in combination with Surface Plasmon Resonance (SPR) to probe and verify the formation of amyloid and its morphology on an SPR chip. SPR is a technique that measures changes in the immobilized weight on the chip surface and is frequently used to probe the formation and biophysical properties of amyloid structures. In this context it is of interest to also monitor the morphology of the formed structures. The SPR chip surface is made of a layer of gold, which represent a suitable material for direct analysis of the surface using SEM. The standard SPR chip used here (CM5-chip, GE Healthcare, Uppsala, Sweden) can easily be disassembled and directly analyzed by SEM. In order to verify the formation of amyloid fibrils in our experimental conditions we analyzed also in-solution produced structures by using Transmission Electron Microscopy (TEM). For further details and experimental findings, please refer to the article published in Journal of Molecular Biology, (Brännström K. et al., 2018) [1].

  • 150.
    Brännström, Kristoffer
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Islam, Tohidul
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sandblad, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    The role of histidines in amyloid β fibril assembly2017Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 591, nr 8, s. 1167-1175Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Low pH has a strong stabilising effect on the fibrillar assembly of amyloid β, which is associated with Alzheimer's disease. The stabilising effect is already pronounced at pH 6.0, suggesting that protonation of histidines might mediate this effect. Through the systematic substitution of the three native histidines in Aβ for alanines, we have evaluated their role in fibril stability. Using surface plasmon resonance, we show that at neutral pH the fibrillar forms of all His-Ala variants are destabilised by a factor of 4-12 compared to wild-type Aβ. However, none of the His-Ala Aβ variants impair the stabilising effect of the fibril at low pH.

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