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  • 51.
    Akusjärvi, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stevenin, J
    Remodelling of the host cell RNA splicing machinery during an adenovirusinfection2003In: Current Topics in Microbiology and Immunology, ISSN 0070-217X, E-ISSN 2196-9965, Vol. 272, p. 253-286Article in journal (Refereed)
    Abstract [en]

    Adenovirus makes extensive use of RNA splicing to produce a complex set of spliced mRNAs during virus replication. All transcription units, except pIX and IVa2, encode multiple alternatively spliced mRNAs. The accumulation of viral mRNAs is subjected to a temporal regulation, a mechanism that ensures that proteins that are needed at certain stages of the viral life cycle are produced. The complex interaction between host cell RNA splicing factors and viral regulatory elements has been studied intensely during the last decade. Such studies have begun to produce a picture of how adenovirus remodels the host cell RNA splicing machinery to orchestrate the shift from the early to the late profile of viral mRNA accumulation. Recent progress has to a large extent focused on the mechanisms regulating E1A and L1 alternative splicing. Here we will review the current knowledge of cis-acting sequence element, trans-acting factors and mechanisms controlling E1A and L1 alternative splicing.

  • 52. Albert, F. W.
    et al.
    Hodges, E.
    Jensen, J. D.
    Besnier, F.
    Xuan, Z.
    Rooks, M.
    Bhattacharjee, A.
    Brizuela, L.
    Good, J. M.
    Green, R. E.
    Burbano, H. A.
    Plyusnina, I. Z.
    Trut, L.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Schoeneberg, T.
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Hannon, G. J.
    Pääbo, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Targeted resequencing of a genomic region influencing tameness and aggression reveals multiple signals of positive selection2011In: Heredity, ISSN 0018-067X, E-ISSN 1365-2540, Vol. 107, no 3, p. 205-214Article in journal (Refereed)
    Abstract [en]

    The identification of the causative genetic variants in quantitative trait loci (QTL) influencing phenotypic traits is challenging, especially in crosses between outbred strains. We have previously identified several QTL influencing tameness and aggression in a cross between two lines of wild-derived, outbred rats (Rattus norvegicus) selected for their behavior towards humans. Here, we use targeted sequence capture and massively parallel sequencing of all genes in the strongest QTL in the founder animals of the cross. We identify many novel sequence variants, several of which are potentially functionally relevant. The QTL contains several regions where either the tame or the aggressive founders contain no sequence variation, and two regions where alternative haplotypes are fixed between the founders. A re-analysis of the QTL signal showed that the causative site is likely to be fixed among the tame founder animals, but that several causative alleles may segregate among the aggressive founder animals. Using a formal test for the detection of positive selection, we find 10 putative positively selected regions, some of which are close to genes known to influence behavior. Together, these results show that the QTL is probably not caused by a single selected site, but may instead represent the joint effects of several sites that were targets of polygenic selection.

  • 53. Albert, Frank W.
    et al.
    Carlborg, Örjan
    SLU.
    Plyusnina, Irina
    Besnier, Francois
    Hedwig, Daniela
    Lautenschläger, Susann
    Lorenz, Doreen
    McIntosh, Jenny
    Neumann, Christof
    Richter, Henning
    Zeising, Claudia
    Kozhemyakina, Rimma
    Shchepina, Olesya
    Kratzsch, Jürgen
    Trut, Lyudmila
    Teupser, Daniel
    Thiery, Joachim
    Schöneberg, Torsten
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pääbo, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Genetic architecture of tameness in a rat model of animal domestication2009In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 182, no 2, p. 541-554Article in journal (Refereed)
    Abstract [en]

    A common feature of domestic animals is tameness - i.e., they tolerate and are unafraid of human presence and handling. To gain insight into the genetic basis of tameness and aggression, we studied an intercross between two lines of rats (Rattus norvegicus) selected over >60 generations for increased tameness and increased aggression against humans, respectively. We measured 45 traits, including tameness and aggression, anxiety-related traits, organ weights, and levels of serum components in >700 rats from an intercross population. Using 201 genetic markers, we identified two significant quantitative trait loci (QTL) for tameness. These loci overlap with QTL for adrenal gland weight and for anxiety-related traits and are part of a five-locus epistatic network influencing tameness. An additional QTL influences the occurrence of white coat spots, but shows no significant effect on tameness. The loci described here are important starting points for finding the genes that cause tameness in these rats and potentially in domestic animals in general.

  • 54.
    Albinsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Laboratory of Clinical Microbiology, Uppsala University Hospital, Uppsala.
    Vene, Sirkka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. The Public Health Agency of Sweden, Solna.
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Department of Infectious diseases, Eskilstuna.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rönnberg, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Laboratory of Clinical Microbiology, Uppsala University Hospital .
    Distinction between serological responses following tick-borne encephalitis virus (TBEV) infection vs vaccination, Sweden 20172018In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 23, no 3, p. 2-7, article id 17-00838Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) is an important European vaccine-preventable pathogen. Discrimination of vaccine-induced antibodies from those elicited by infection is important. We studied anti-TBEV IgM/IgG responses, including avidity and neutralisation, by multiplex serology in 50 TBEV patients and 50 TBEV vaccinees. Infection induced antibodies reactive to both whole virus (WV) and non-structural protein 1 (NS1) in 48 clinical cases, whereas 47 TBEV vaccinees had WV, but not NS1 antibodies, enabling efficient discrimination of infection/vaccination.

  • 55.
    Albrecht, Lisa M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Antibiotic Resistance: Selection in the Presence of Metals and Antimicrobials2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The external environment is complex: Antibiotics, metals and antimicrobials do not exist in isolation but in mixtures. Human activities such as animal husbandry, fertilization of agricultural fields and human medicine release high amounts these compounds into the environment. The work in this thesis contributes to our understanding of how the selection of bacterial antibiotic resistance can be facilitated by the pollution by metals and antimicrobials. We show that low levels of antibiotics, metals and combinations thereof can lead to the selection of chromosomally encoded antibiotic resistance genes as well as a multidrug resistance plasmid. The underlying genetic and cellular mechanisms of selection identified relate to mutational changes in a plasmid-encoded metal resistance operon, and metal-associated increases in cellular membrane permeability. We further show that exposure to quaternary ammonium compounds can result in cross-resistance to antibiotics following genetic changes in genes related to efflux, membrane synthesis and transcription/translation. Taken together, the work in this thesis suggests that the stewardship of antibiotics should include prudent use of metals and antimicrobials. 

    List of papers
    1. Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals
    Open this publication in new window or tab >>Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals
    Show others...
    2014 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 5, no 5, p. e01918-14-Article in journal (Refereed) Published
    Abstract [en]

    How sublethal levels of antibiotics and heavy metals select for clinically important multidrug resistance plasmids is largely unknown. Carriage of plasmids generally confers substantial fitness costs, implying that for the plasmid-carrying bacteria to be maintained in the population, the plasmid cost needs to be balanced by a selective pressure conferred by, for example, antibiotics or heavy metals. We studied the effects of low levels of antibiotics and heavy metals on the selective maintenance of a 220-kbp extended-spectrum β-lactamase (ESBL) plasmid identified in a hospital outbreak of Klebsiella pneumoniae and Escherichia coli. The concentrations of antibiotics and heavy metals required to maintain plasmid-carrying bacteria, the minimal selective concentrations (MSCs), were in all cases below (almost up to 140-fold) the MIC of the plasmid-free susceptible bacteria. This finding indicates that the very low antibiotic and heavy metal levels found in polluted environments and in treated humans and animals might be sufficiently high to maintain multiresistance plasmids. When resistance genes were moved from the plasmid to the chromosome, the MSC decreased, showing that MSC for a specific resistance conditionally depends on genetic context. This finding suggests that a cost-free resistance could be maintained in a population by an infinitesimally low concentration of antibiotic. By studying the effect of combinations of several compounds, it was observed that for certain combinations of drugs each new compound added lowered the minimal selective concentration of the others. This combination effect could be a significant factor in the selection of multidrug resistance plasmids/bacterial clones in complex multidrug environments.

    IMPORTANCE: Antibiotic resistance is in many pathogenic bacteria caused by genes that are carried on large conjugative plasmids. These plasmids typically contain multiple antibiotic resistance genes as well as genes that confer resistance to biocides and heavy metals. In this report, we show that very low concentrations of single antibiotics and heavy metals or combinations of compounds can select for a large plasmid that carries resistance to aminoglycosides, β-lactams, tetracycline, macrolides, trimethoprim, sulfonamide, silver, copper, and arsenic. Our findings suggest that the low levels of antibiotics and heavy metals present in polluted external environments and in treated animals and humans could allow for selection and enrichment of bacteria with multiresistance plasmids and thereby contribute to the emergence, maintenance, and transmission of antibiotic-resistant disease-causing bacteria.

    National Category
    Microbiology in the medical area
    Research subject
    Microbiology; Molecular Genetics
    Identifiers
    urn:nbn:se:uu:diva-235222 (URN)10.1128/mBio.01918-14 (DOI)000345459000067 ()25293762 (PubMedID)
    Available from: 2014-10-29 Created: 2014-10-29 Last updated: 2018-08-10Bibliographically approved
    2. Mutation in the Copper-Induced sil Operon Enables High-Level Silver Resistance and Silver Facilitated Co-Selection of Multidrug Resistance Plasmid
    Open this publication in new window or tab >>Mutation in the Copper-Induced sil Operon Enables High-Level Silver Resistance and Silver Facilitated Co-Selection of Multidrug Resistance Plasmid
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Human activities are responsible for an accumulation of metals in health care and agricultural environments, and plasmid-encoded metal tolerance operons enable bacteria to rapidly adapt to metal exposure under such conditions. While the mechanisms of action of many metal resistance systems have been described, there is still limited understanding of their role in co-selection of antibiotic resistance in metal-containing environments. Whether plasmid-encoded metal resistance genes confer significant selective advantages is of interest as it has implications for plasmid enrichment and the spread of plasmid-borne antibiotic resistance genes. To increase our understanding of plasmid-mediated metal resistance, we studied the sil operon and its phenotypes in E. coli during growth in the absence and presence of silver and copper. We found that the sil operon provides resistance to both silver and copper. However, it is induced by copper only, and constitutive expression due to point mutations in the two-component silS gene provides high-level silver resistance. Furthermore, we showed that a high-level silver resistant mutant could be enriched in the presence of silver. This enrichment entailed co-selection of the multidrug resistance plasmid pUUH239.2. Our results show that a copper resistance operon can provide high-level silver resistance following a single point mutation, and that the silver resistance phenotype subsequently can co-select for antibiotic resistance in the presence of silver. 

    National Category
    Other Medical Sciences not elsewhere specified
    Identifiers
    urn:nbn:se:uu:diva-356961 (URN)
    Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-10
    3. Potentiation of the Selective Effect of Antibiotics by Metal Ions
    Open this publication in new window or tab >>Potentiation of the Selective Effect of Antibiotics by Metal Ions
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Complex mixtures of antibiotics and metals are present in many environments ranging from municipal sewage to irrigation water and manure used as agricultural fertilizer. Such mixtures of drugs and metals exert unique selection pressures on local bacterial communities and could function as hotspots for enrichment of antibiotic resistance genes. The presence of metals in the environment has previously been linked to increases in tolerance to antibiotics. In this study, we investigated metal-potentiated selection of antibiotic resistant Salmonella enterica strains. Six environmentally relevant metals were examined in combinations with three different antibiotics. By performing competitions between an antibiotic resistant mutant and the isogenic wild type in each metal-antibiotic combination, we assessed the minimal selective concentration (MSC) of the antibiotic for the resistant strain. The metals silver, cadmium and mercury all exhibited potentiating effects, reducing the MSC of the antibiotic up to 5-fold as compared to in the absence of the metal. We further show that the potentiating metals increased permeability of the cellular outer membrane. These results demonstrate that the presence of a metal can decrease the concentration of an antibiotic required to select for an antibiotic resistant strain, and they indicate that this process involves metal-facilitated uptake of the antibiotic following damage to the outer membrane.

    Keywords
    Antibiotic resistance, Selection
    National Category
    Other Medical Sciences not elsewhere specified
    Identifiers
    urn:nbn:se:uu:diva-356966 (URN)
    Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-10
    4. Cross-Resistance to Antibiotics After Exposure to Qaternary Ammonium Compounds
    Open this publication in new window or tab >>Cross-Resistance to Antibiotics After Exposure to Qaternary Ammonium Compounds
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Quaternary ammonium compounds (QACs) are common antimicrobials that are used in a variety of consumer products, such as lotions, sunscreen, hair conditioners and hand sanitizers, to inhibit bacterial growth. However, it has been noted that bacteria exposed to QACs can develop resistance, and additionally, resistance to QACs has been observed to provide cross-resistance to antibiotics. In order to identify genetic adaptations for this resistance pattern, we exposed E. coli to three different QACs at sub-MIC and above-MIC concentrations, and identified genetic changes by whole genome sequencing. We found that initial adaptation, at sub-MIC levels, happened through efflux mechanisms, and that subsequent genetic changes, during above-MIC exposure, involved genes associated with the cell membranes and with transcription/translation. We also found that these genetic changes provided cross-resistance to other QACs as well as to several antibiotics.

    Keywords
    Antibiotic resistance, Antimicrobials, Cross-resistance
    National Category
    Other Medical Sciences not elsewhere specified
    Identifiers
    urn:nbn:se:uu:diva-356967 (URN)
    Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-10
  • 56.
    Albrecht, Lisa M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cross-Resistance to Antibiotics After Exposure to Qaternary Ammonium CompoundsManuscript (preprint) (Other academic)
    Abstract [en]

    Quaternary ammonium compounds (QACs) are common antimicrobials that are used in a variety of consumer products, such as lotions, sunscreen, hair conditioners and hand sanitizers, to inhibit bacterial growth. However, it has been noted that bacteria exposed to QACs can develop resistance, and additionally, resistance to QACs has been observed to provide cross-resistance to antibiotics. In order to identify genetic adaptations for this resistance pattern, we exposed E. coli to three different QACs at sub-MIC and above-MIC concentrations, and identified genetic changes by whole genome sequencing. We found that initial adaptation, at sub-MIC levels, happened through efflux mechanisms, and that subsequent genetic changes, during above-MIC exposure, involved genes associated with the cell membranes and with transcription/translation. We also found that these genetic changes provided cross-resistance to other QACs as well as to several antibiotics.

  • 57.
    Albrecht, Lisa M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Potentiation of the Selective Effect of Antibiotics by Metal IonsManuscript (preprint) (Other academic)
    Abstract [en]

    Complex mixtures of antibiotics and metals are present in many environments ranging from municipal sewage to irrigation water and manure used as agricultural fertilizer. Such mixtures of drugs and metals exert unique selection pressures on local bacterial communities and could function as hotspots for enrichment of antibiotic resistance genes. The presence of metals in the environment has previously been linked to increases in tolerance to antibiotics. In this study, we investigated metal-potentiated selection of antibiotic resistant Salmonella enterica strains. Six environmentally relevant metals were examined in combinations with three different antibiotics. By performing competitions between an antibiotic resistant mutant and the isogenic wild type in each metal-antibiotic combination, we assessed the minimal selective concentration (MSC) of the antibiotic for the resistant strain. The metals silver, cadmium and mercury all exhibited potentiating effects, reducing the MSC of the antibiotic up to 5-fold as compared to in the absence of the metal. We further show that the potentiating metals increased permeability of the cellular outer membrane. These results demonstrate that the presence of a metal can decrease the concentration of an antibiotic required to select for an antibiotic resistant strain, and they indicate that this process involves metal-facilitated uptake of the antibiotic following damage to the outer membrane.

  • 58.
    Albrecht, Lisa M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mutation in the Copper-Induced sil Operon Enables High-Level Silver Resistance and Silver Facilitated Co-Selection of Multidrug Resistance PlasmidManuscript (preprint) (Other academic)
    Abstract [en]

    Human activities are responsible for an accumulation of metals in health care and agricultural environments, and plasmid-encoded metal tolerance operons enable bacteria to rapidly adapt to metal exposure under such conditions. While the mechanisms of action of many metal resistance systems have been described, there is still limited understanding of their role in co-selection of antibiotic resistance in metal-containing environments. Whether plasmid-encoded metal resistance genes confer significant selective advantages is of interest as it has implications for plasmid enrichment and the spread of plasmid-borne antibiotic resistance genes. To increase our understanding of plasmid-mediated metal resistance, we studied the sil operon and its phenotypes in E. coli during growth in the absence and presence of silver and copper. We found that the sil operon provides resistance to both silver and copper. However, it is induced by copper only, and constitutive expression due to point mutations in the two-component silS gene provides high-level silver resistance. Furthermore, we showed that a high-level silver resistant mutant could be enriched in the presence of silver. This enrichment entailed co-selection of the multidrug resistance plasmid pUUH239.2. Our results show that a copper resistance operon can provide high-level silver resistance following a single point mutation, and that the silver resistance phenotype subsequently can co-select for antibiotic resistance in the presence of silver. 

  • 59. Alcaide, Pilar
    et al.
    Jones, Tatiana G
    Lord, Graham M
    Glimcher, Laurie H
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Arinobu, Yojiro
    Akashi, Koichi
    Paterson, Alison M
    Gurish, Michael A
    Luscinskas, Francis W
    Dendritic cell expression of the transcription factor T-bet regulates mast cell progenitor homing to mucosal tissue2007In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 204, no 2, p. 431-439Article in journal (Refereed)
    Abstract [en]

    The transcription factor T-bet was identified in CD4(+) T cells, and it controls interferon gamma production and T helper type 1 cell differentiation. T-bet is expressed in certain other leukocytes, and we recently showed (Lord, G.M., R.M. Rao, H. Choe, B.M. Sullivan, A.H. Lichtman, F.W. Luscinskas, and L.H. Glimcher. 2005. Blood. 106:3432-3439) that it regulates T cell trafficking. We examined whether T-bet influences homing of mast cell progenitors (MCp) to peripheral tissues. Surprisingly, we found that MCp homing to the lung or small intestine in T-bet(-/-) mice is reduced. This is reproduced in adhesion studies using bone marrow-derived MCs (BMMCs) from T-bet(-/-) mice, which showed diminished adhesion to mucosal addresin cellular adhesion molecule-1 (MAdCAM-1) and vascular cell adhesion molecule-1 (VCAM-1), endothelial ligands required for MCp intestinal homing. MCp, their precursors, and BMMCs do not express T-bet, suggesting that T-bet plays an indirect role in homing. However, adoptive transfer experiments revealed that T-bet expression by BM cells is required for MCp homing to the intestine. Furthermore, transfer of WT BM-derived dendritic cells (DCs) to T-bet(-/-) mice restores normal MCp intestinal homing in vivo and MCp adhesion to MAdCAM-1 and VCAM-1 in vitro. Nonetheless, T-bet(-/-) mice respond vigorously to intestinal infection with Trichinella spiralis, eliminating a role for T-bet in MC recruitment to sites of infection and their activation and function. Therefore, remarkably, T-bet expression by DCs indirectly controls MCp homing to mucosal tissues.

  • 60.
    Aldi, S.
    et al.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Eriksson, L.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Kronqvist, M.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Lengquist, M.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Folkersen, L.
    Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark..
    Perisic, L.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Grinnemo, K. H.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedin, U.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Osterholm, C.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Dual roles of heparanase in vascular calcification associated with human carotid atherosclerosis2017In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 98, no 3, p. A5-A5Article in journal (Other academic)
  • 61.
    Aldi, Silvia
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Eriksson, Linnea
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Kronqvist, Malin
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Lengquist, Mariette
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Löfling, Marie
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Folkersen, Lasse
    Tech Univ Denmark, Ctr Biol Sequence Anal, Copenhagen, Denmark.
    Matic, Ljubica P.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Maegdefessel, Lars
    Karolinska Inst, Dept Med Solna, S-17176 Stockholm, Sweden;Tech Univ Munich, Dept Vasc Surg, D-80333 Munich, Germany.
    Grinnemo, Karl-Henrik
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Österholm, C.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Hedin, Ulf
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Dual roles of heparanase in human carotid plaque calcification2019In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 283, p. 127-136Article in journal (Refereed)
    Abstract [en]

    Background and aims: Calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-beta-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of HPSE is controversial in osteogenesis and bone remodeling while it is unexplored in vascular calcification. Previously, we reported upregulation of HPSE in human carotid endarterectomies from symptomatic patients and showed correlation of HPSE expression with markers of inflammation and increased thrombogenicity. The present aim is to investigate HPSE expression in relation to genes associated with osteogenesis and osteolysis and the effect of elevated HPSE expression on calcification and osteolysis in vitro.

    Methods: Transcriptomic and immunohistochemical analyses were performed using the Biobank of Karolinska Endarterectomies (BiKE). In vitro calcification and osteolysis were analysed in human carotid smooth muscle cells overexpressing HPSE and bone marrow-derived osteoclasts from HPSE-transgenic mice respectively.

    Results: HPSE expression correlated primarily with genes coupled to osteoclast differentiation and function in human carotid atheromas. HPSE was expressed in osteoclast-like cells in atherosclerotic lesions, and HPSE-transgenic bone marrow-derived osteoclasts displayed a higher osteolytic activity compared to wild-type cells. Contrarily, human carotid SMCs with an elevated HPSE expression demonstrated markedly increased mineralization upon osteogenic differentiation.

    Conclusions: We suggest that HPSE may have dual functions in vascular calcification, depending on the stage of the disease and presence of inflammatory cells. While HPSE plausibly enhances mineralization and osteogenic differentiation of vascular smooth muscle cells, it is associated with inflammation-induced osteoclast differentiation and activity in advanced atherosclerotic plaques.

  • 62.
    Alexander, Michelle
    et al.
    Univ York, York YO10 5DD, N Yorkshire, England.;Univ Aberdeen, Sch Geosci, Dept Archaeol, Aberdeen AB24 3UF, Scotland..
    Ho, Simon Y. W.
    Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia..
    Molak, Martyna
    Polish Acad Sci, Museum & Inst Zool, PL-00679 Warsaw, Poland..
    Barnett, Ross
    Palaeogen & Bioarchaeol Res Network, Res Lab Archaeol, Oxford OX1 3QY, England..
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Dorshorst, Ben
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Honaker, Christa
    Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Besnier, Francois
    Inst Marine Res, Sect Populat Genet, N-5024 Bergen, Norway..
    Wahlberg, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Dobney, Keith
    Univ Aberdeen, Sch Geosci, Dept Archaeol, Aberdeen AB24 3UF, Scotland..
    Siegel, Paul
    Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Larson, Greger
    Palaeogen & Bioarchaeol Res Network, Res Lab Archaeol, Oxford OX1 3QY, England..
    Mitogenomic analysis of a 50-generation chicken pedigree reveals a rapid rate of mitochondrial evolution and evidence for paternal mtDNA inheritance2015In: Biology Letters, ISSN 1744-9561, E-ISSN 1744-957X, Vol. 11, no 10, article id 20150561Article in journal (Refereed)
    Abstract [en]

    Mitochondrial genomes represent a valuable source of data for evolutionary research, but studies of their short-term evolution have typically been limited to invertebrates, humans and laboratory organisms. Here we present a detailed study of 12 mitochondrial genomes that span a total of 385 transmissions in a well-documented 50-generation pedigree in which two lineages of chickens were selected for low and high juvenile body weight. These data allowed us to test the hypothesis of time-dependent evolutionary rates and the assumption of strict maternal mitochondrial transmission, and to investigate the role of mitochondrial mutations in determining phenotype. The identification of a non-synonymous mutation in ND4L and a synonymous mutation in CYTB, both novel mutations in Gallus, allowed us to estimate a molecular rate of 3.13 x 10(-7) mutations/site/year (95% confidence interval 3.75 x 10(-8)-1.12 x 10(-6)). This is substantially higher than avian rate estimates based upon fossil calibrations. Ascertaining which of the two novel mutations was present in an additional 49 individuals also revealed an instance of paternal inheritance of mtDNA. Lastly, an association analysis demonstrated that neither of the point mutations was strongly associated with the phenotypic differences between the two selection lines. Together, these observations reveal the highly dynamic nature of mitochondrial evolution over short time periods.

  • 63. Alfoeldi, Jessica
    et al.
    Di Palma, Federica
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Williams, Christina
    Kong, Lesheng
    Mauceli, Evan
    Russell, Pamela
    Lowe, Craig B.
    Glor, Richard E.
    Jaffe, Jacob D.
    Ray, David A.
    Boissinot, Stephane
    Shedlock, Andrew M.
    Botka, Christopher
    Castoe, Todd A.
    Colbourne, John K.
    Fujita, Matthew K.
    Moreno, Ricardo Godinez
    ten Hallers, Boudewijn F.
    Haussler, David
    Heger, Andreas
    Heiman, David
    Janes, Daniel E.
    Johnson, Jeremy
    de Jong, Pieter J.
    Koriabine, Maxim Y.
    Lara, Marcia
    Novick, Peter A.
    Organ, Chris L.
    Peach, Sally E.
    Poe, Steven
    Pollock, David D.
    de Queiroz, Kevin
    Sanger, Thomas
    Searle, Steve
    Smith, Jeremy D.
    Smith, Zachary
    Swofford, Ross
    Turner-Maier, Jason
    Wade, Juli
    Young, Sarah
    Zadissa, Amonida
    Edwards, Scott V.
    Glenn, Travis C.
    Schneider, Christopher J.
    Losos, Jonathan B.
    Lander, Eric S.
    Breen, Matthew
    Ponting, Chris P.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The genome of the green anole lizard and a comparative analysis with birds and mammals2011In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 477, no 7366, p. 587-591Article in journal (Refereed)
    Abstract [en]

    The evolution of the amniotic egg was one of the great evolutionary innovations in the history of life, freeing vertebrates from an obligatory connection to water and thus permitting the conquest of terrestrial environments(1). Among amniotes, genome sequences are available for mammals and birds(2-4), but not for non-avian reptiles. Here we report the genome sequence of the North American green anole lizard, Anolis carolinensis. We find that A. carolinensis microchromosomes are highly syntenic with chicken microchromosomes, yet do not exhibit the high GC and low repeat content that are characteristic of avian microchromosomes(2). Also, A. carolinensis mobile elements are very young and diverse-more so than in any other sequenced amniote genome. The GC content of this lizard genome is also unusual in its homogeneity, unlike the regionally variable GC content found in mammals and birds(5). We describe and assign sequence to the previously unknown A. carolinensis X chromosome. Comparative gene analysis shows that amniote egg proteins have evolved significantly more rapidly than other proteins. An anole phylogeny resolves basal branches to illuminate the history of their repeated adaptive radiations.

  • 64. Alfoeldi, Jessica
    et al.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Comparative genomics as a tool to understand evolution and disease2013In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 23, no 7, p. 1063-1068Article in journal (Refereed)
    Abstract [en]

    When the human genome project started, the major challenge was how to sequence a 3 billion letter code in an organized and cost-effective manner. When completed, the project had laid the foundation for a huge variety of biomedical fields through the production of a complete human genome sequence, but also had driven the development of laboratory and analytical methods that could produce large amounts of sequencing data cheaply. These technological developments made possible the sequencing of many more vertebrate genomes, which have been necessary for the interpretation of the human genome. They have also enabled large-scale studies of vertebrate genome evolution, as well as comparative and human medicine. In this review, we give examples of evolutionary analysis using a wide variety of time frames-from the comparison of populations within a species to the comparison of species separated by at least 300 million years. Furthermore, we anticipate discoveries related to evolutionary mechanisms, adaptation, and disease to quickly accelerate in the coming years.

  • 65.
    Alfredsson Timmins, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Functional organisation of the cell nucleus in the fission yeast, Schizosaccharomyces pombe2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In eukaryotes the genome adopts a non-random spatial organisation, which is important for gene regulation. However, very little is known about the driving forces behind nuclear organisation. In the simple model eukaryote fission yeast, Schizosaccharomyces pombe, it has been known for a long time that transcriptionally repressed heterochromatin localise to the nuclear membrane (NM); the centromeres attaches to spindle pole body (SPB), while the telomeres are positioned at the NM on the opposite side of the nucleus compared to the SPB. Studies presented in this thesis aimed at advancing our knowledge of nuclear organisation in Schizosaccharomyces pombe.

    We show that the heterochromatic mating-type region localises to the NM in the vicinity of the SPB. This positioning was completely dependent on Clr4, a histone methyl transferase crucial for the formation of heterochromatin. Additional factors important for localisation were also identified: the chromo domain protein Swi6, and the two boundary elements IR-L and IR-R surrounding this locus. We further identify two other chromo domain proteins; Chp1 and Chp2, as crucial factors for correct subnuclear localisation of this region. From these results we suggest that the boundary elements together with chromodomain proteins in balanced dosage and composition cooperate in organising the mating-type chromatin.

    Gene regulation can affect the subnuclear localisation of genes. Using nitrogen starvation in S. pombe as a model for gene induction we determined the subnuclear localisation of two gene clusters repressed by nitrogen: Chr1 and Tel1. When repressed these loci localise to the NM, and this positioning is dependent on the histone deacetylase Clr3. During induction the gene clusters moved towards the nuclear interior in a transcription dependent manner.

    The knowledge gained from work presented in this thesis, regarding nuclear organisation in the S. pombe model system, can hopefully aid to a better understanding of human nuclear organisation.

    List of papers
    1. The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast
    Open this publication in new window or tab >>The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast
    2007 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 120, no 11, p. 1935-1943Article in journal (Refereed) Published
    Abstract [en]

    The genome has a non-random spatial distribution in the cell nucleus. In Schizosaccharomyces pombe, it has been shown that the centromeres, telomeres and the mating-type region localize to the nuclear membrane (NM), the former by attaching to the spindle pole body (SPB). In addition, reporter genes inserted into these areas are transcriptionally repressed due to the formation of specialized chromatin structures. Performing live cell analysis we found that in a wild-type strain the mating-type region was positioned in the proximity of the SPB, the location where the pericentromeric heterochromatin is also found. In a strain lacking the histone methyltransferase, Clr4, crucial for the formation of heterochromatin, the mating-type region had a random localization in the nucleus. Moreover, in a strain where the two boundary elements IR-L and IR-R had been deleted the mating-type region was displaced from its position at the proximity of the SPB, but remained in the vicinity of the NM. Moreover, in all investigated strains with silencing deficiencies the distance between the mating-type region and the SPB increased. This result indicates a correlation between transcriptional derepression and displacement of the region. Two different models of how the mating-type chromatin is organized in the nucleus are discussed.

    Keywords
    fission yeast, heterochromatin, silencing, subnuclear localization
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-13023 (URN)10.1242/jcs.03457 (DOI)000246665300013 ()17504808 (PubMedID)
    Available from: 2009-08-05 Created: 2009-08-05 Last updated: 2017-12-11Bibliographically approved
    2. Chromo domain proteins in balanced dosage together with boundary elements cooperate in organising the mating-type chromatin in fission yeast
    Open this publication in new window or tab >>Chromo domain proteins in balanced dosage together with boundary elements cooperate in organising the mating-type chromatin in fission yeast
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    The chromatin in the cell nucleus has a spatial organisation. For example, in the fission yeast, Schizosaccharomyces pombe, transcriptionally repressed heterochromatin is found at the nuclear membrane (NM). The centromeres and the mating-type region localise in the proximity of the spindle pole body (SPB), while the telomeres are found on the opposite side of the nucleus in the proximity of the nucleolus. In a previous study we used the mating-type region as a model to study the driving force behind nuclear organisation. We proposed two mutually exclusive models to explain what determines the localisation of the mating-type region. The first model suggests that solely the amount of heterochromatin in the region affects the localisation, while the other model stipulates that the boundary elements together with heterochromatin formation anchor the mating-type region in the NM in the vicinity of the SPB. Here, we present data that disproves the first model. We found that in a strain expressing tripled amounts of the chromodomain protein Swi6, a structural component of heterochromatin, the mating-type region was delocalised from the proximity of the SPB. A strain deleted of the histone deacetylase clr3+ also had a delocalised mating-type locus. Interestingly, a strain with a point-mutation in clr3-735 producing an enzymatically inactive protein in normal amounts showed an intermediate phenotype. Most importantly, we identify the chromodomain proteins, Chp1 and Chp2, as crucial factors for correct subnuclear localisation of the mating-type region. We suggest that boundary elements together with chromodomain proteins in balanced dosage and composition cooperate in organising the mating-type chromatin.

    Identifiers
    urn:nbn:se:uu:diva-107280 (URN)
    Available from: 2009-08-04 Created: 2009-08-04 Last updated: 2010-01-14Bibliographically approved
    3. Reorganization of chromatin is an early response to nitrogen starvation in Schizosaccharomyces pombe
    Open this publication in new window or tab >>Reorganization of chromatin is an early response to nitrogen starvation in Schizosaccharomyces pombe
    Show others...
    2009 (English)In: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 118, no 1, p. 99-112Article in journal (Refereed) Published
    Abstract [en]

    There are several documented events of changes in subnuclear localization during gene activation. However, there are conflicting data on whether the nuclear periphery is a compartment for gene repression or activation, and whether genes are moved to the pores at the nuclear membrane (NM) or not during gene activation. Nitrogen starvation of fission yeast serves as a good model system for studying gene induction since it causes fast regulation of hundreds of genes. In this study the subnuclear localization of two gene clusters repressed by nitrogen was investigated. During normal growth conditions the gene clusters localized to the nuclear periphery at the opposite side of the nucleus as compared to the spindle pole body (SPB). This constrained localization was dependent on the histone deacetylase Clr3, known to transcriptionally repress genes in these clusters. Already 20 minutes after nitrogen depletion drastic changes in subnuclear localization of the two loci were observed, away from the NM towards the nuclear interior. At least for one of the clusters the movement was clearly transcription dependent. Data presented here illustrates how interconnected events of gene activation and nuclear reorganization are, as well as provides a suggestion of how nuclear organization might be maintained.

    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-107289 (URN)10.1007/s00412-008-0180-6 (DOI)000262504300009 ()
    Available from: 2009-08-05 Created: 2009-08-05 Last updated: 2017-12-13Bibliographically approved
  • 66.
    Alfredsson-Timmins, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Henningson, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bjerling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast2007In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 120, no 11, p. 1935-1943Article in journal (Refereed)
    Abstract [en]

    The genome has a non-random spatial distribution in the cell nucleus. In Schizosaccharomyces pombe, it has been shown that the centromeres, telomeres and the mating-type region localize to the nuclear membrane (NM), the former by attaching to the spindle pole body (SPB). In addition, reporter genes inserted into these areas are transcriptionally repressed due to the formation of specialized chromatin structures. Performing live cell analysis we found that in a wild-type strain the mating-type region was positioned in the proximity of the SPB, the location where the pericentromeric heterochromatin is also found. In a strain lacking the histone methyltransferase, Clr4, crucial for the formation of heterochromatin, the mating-type region had a random localization in the nucleus. Moreover, in a strain where the two boundary elements IR-L and IR-R had been deleted the mating-type region was displaced from its position at the proximity of the SPB, but remained in the vicinity of the NM. Moreover, in all investigated strains with silencing deficiencies the distance between the mating-type region and the SPB increased. This result indicates a correlation between transcriptional derepression and displacement of the region. Two different models of how the mating-type chromatin is organized in the nucleus are discussed.

  • 67.
    Alfredsson-Timmins, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ishida, Mayumi
    Laboratory for chromatin dynamics, Centre for Developmental Biology, Kobe, Japan.
    Nakayama, Jun-ichi
    atin dynamics, Centre for Developmental Biology, Kobe, Japan.
    Bjerling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chromo domain proteins in balanced dosage together with boundary elements cooperate in organising the mating-type chromatin in fission yeastManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    The chromatin in the cell nucleus has a spatial organisation. For example, in the fission yeast, Schizosaccharomyces pombe, transcriptionally repressed heterochromatin is found at the nuclear membrane (NM). The centromeres and the mating-type region localise in the proximity of the spindle pole body (SPB), while the telomeres are found on the opposite side of the nucleus in the proximity of the nucleolus. In a previous study we used the mating-type region as a model to study the driving force behind nuclear organisation. We proposed two mutually exclusive models to explain what determines the localisation of the mating-type region. The first model suggests that solely the amount of heterochromatin in the region affects the localisation, while the other model stipulates that the boundary elements together with heterochromatin formation anchor the mating-type region in the NM in the vicinity of the SPB. Here, we present data that disproves the first model. We found that in a strain expressing tripled amounts of the chromodomain protein Swi6, a structural component of heterochromatin, the mating-type region was delocalised from the proximity of the SPB. A strain deleted of the histone deacetylase clr3+ also had a delocalised mating-type locus. Interestingly, a strain with a point-mutation in clr3-735 producing an enzymatically inactive protein in normal amounts showed an intermediate phenotype. Most importantly, we identify the chromodomain proteins, Chp1 and Chp2, as crucial factors for correct subnuclear localisation of the mating-type region. We suggest that boundary elements together with chromodomain proteins in balanced dosage and composition cooperate in organising the mating-type chromatin.

  • 68.
    Alfredsson-Timmins, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kristell, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Henningson, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lyckman, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bjerling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Reorganization of chromatin is an early response to nitrogen starvation in Schizosaccharomyces pombe2009In: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 118, no 1, p. 99-112Article in journal (Refereed)
    Abstract [en]

    There are several documented events of changes in subnuclear localization during gene activation. However, there are conflicting data on whether the nuclear periphery is a compartment for gene repression or activation, and whether genes are moved to the pores at the nuclear membrane (NM) or not during gene activation. Nitrogen starvation of fission yeast serves as a good model system for studying gene induction since it causes fast regulation of hundreds of genes. In this study the subnuclear localization of two gene clusters repressed by nitrogen was investigated. During normal growth conditions the gene clusters localized to the nuclear periphery at the opposite side of the nucleus as compared to the spindle pole body (SPB). This constrained localization was dependent on the histone deacetylase Clr3, known to transcriptionally repress genes in these clusters. Already 20 minutes after nitrogen depletion drastic changes in subnuclear localization of the two loci were observed, away from the NM towards the nuclear interior. At least for one of the clusters the movement was clearly transcription dependent. Data presented here illustrates how interconnected events of gene activation and nuclear reorganization are, as well as provides a suggestion of how nuclear organization might be maintained.

  • 69.
    Ali, M. Z.
    et al.
    BLRI, Anim Hlth Res Div, Dhaka 1341, Bangladesh.
    Hasan, Badrul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Follow Up of Maternally Derived Antibodies Titer against Economically Important Viral Diseases of Chicken2018In: POULTRY SCIENCE JOURNAL, ISSN 2345-6604, Vol. 6, no 2, p. 149-154Article in journal (Refereed)
    Abstract [en]

    The study was conducted to know the rate of maternally derived antibodies (MDAs) transfer from parents to their offspring and declining the MDAs in their chicks at 0, 7, 14, and 21 days of age against four major poultry viruses like Newcastle disease virus (NDV), Infectious bronchitis virus (IBV), Infectious bursal diseases virus (IBDV), and Avian Reo virus (ARV). The MDAs was studied on Grandparent (GP) to Parent stock (PS), and Parent stock (PS) to broiler at 30 weeks and 50 weeks of age in Cobb-500 broiler strain chicken. The MDAs was measured from serum antibody titer by indirect ELISA test. The MDAs transfer rate against NDV from GP to PS at 50 weeks of age was higher (68.82%) than at 30 weeks of age but in case of PS to broiler it was higher (66.01%) at 30 weeks of age and its persistent rate also higher (7.96%) up to 21th days of age. Against IBV, MDAs transfer rates were higher in PS to broiler than GP to PS of both ages and highest rates were revealed in PS to broiler at 30 weeks of age as 70.72%. On the other hand, among all lines MDAs transfer rates against IBDV was higher (86.94%) in GP to PS at 30 weeks of age. For ARV, the MDAs transfer rates were highest in GP to PS in both ages than PS to broiler and within GP to PS at 50 weeks of age, it was highest (94.87%) than 30 weeks of age. Accordingly, the poultry producer may help to develop an effective vaccination schedule by considering the MDAs from above experiment.

  • 70.
    Ali, Muhammad Akhtar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Gupta, Rajesh
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjoblöm, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 25, p. 7743-7748Article in journal (Refereed)
    Abstract [en]

    The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.

  • 71.
    Ali, Muhammad Akhtar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Younis, Shady
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gupta, Rajesh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tobias Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cellsManuscript (preprint) (Other academic)
    Abstract [en]

    The transcription factor ZBED6 is a repressor of IGF2 whose action impacts development, cell proliferation and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Transcriptome analyses revealed enrichment of cell cycle-related processes among differentially expressed genes in both cell lines. Chromatin immunoprecipitation sequencing analyses displayed enrichment of ZBED6 binding at genes upregulated in ZBED6-/- knockout clones. Ten differentially expressed genes were identified as putative direct gene targets and their downregulation by ZBED6 was experimentally validated. Eight of these genes were linked to the Wnt, Hippo, TGF-b, EGFR or PI3K pathways, all involved in colorectal cancer development. Ablation of ZBED6 affected the cell cycle and led to increased growth rate of ZBED6-/- RKO cells. These observations support a role for transcriptional modulation by ZBED6 in cell cycle regulation and growth of colorectal cancers.

  • 72.
    Alim, Md Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine. Department of Molecular Medicine and Surgery, Karolinska Institutet.
    Ackermann, Paul W
    Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden.
    Eliasson, Pernilla
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Blomgran, Parmis
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Kristiansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.
    Peterson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture2017In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, no 3, p. 451-460Article in journal (Refereed)
    Abstract [en]

    The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.

  • 73.
    Alim, Md Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Grujic, Mirjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ackerman, Paul W.
    Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden.
    Kristiansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Peterson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and Biochemistry, Uppsala, Sweden.
    Glutamate Triggers the Expression of Functional Ionotropic and Metabotropic Glutamate Receptors in Mast CellsManuscript (preprint) (Other academic)
  • 74.
    Al-Jaff, Mohammed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandström, Eric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Bioinformat Infrastruct Life Sci, S-75123 Uppsala, Sweden..
    microTaboo: a general and practical solution to the k-disjoint problem2017In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 18, article id 228Article in journal (Refereed)
    Abstract [en]

    Background: A common challenge in bioinformatics is to identify short sub-sequences that are unique in a set of genomes or reference sequences, which can efficiently be achieved by k-mer (k consecutive nucleotides) counting. However, there are several areas that would benefit from a more stringent definition of "unique", requiring that these sub-sequences of length W differ by more than k mismatches (i.e. a Hamming distance greater than k) from any other sub-sequence, which we term the k-disjoint problem. Examples include finding sequences unique to a pathogen for probe-based infection diagnostics; reducing off-target hits for re-sequencing or genome editing; detecting sequence (e.g. phage or viral) insertions; and multiple substitution mutations. Since both sensitivity and specificity are critical, an exhaustive, yet efficient solution is desirable.

    Results: We present microTaboo, a method that allows for efficient and extensive sequence mining of unique (k-disjoint) sequences of up to 100 nucleotides in length. On a number of simulated and real data sets ranging from microbe-to mammalian-size genomes, we show that microTaboo is able to efficiently find all sub-sequences of a specified length W that do not occur within a threshold of k mismatches in any other sub-sequence. We exemplify that microTaboo has many practical applications, including point substitution detection, sequence insertion detection, padlock probe target search, and candidate CRISPR target mining.

    Conclusions: microTaboo implements a solution to the k-disjoint problem in an alignment-and assembly free manner. microTaboo is available for Windows, Mac OS X, and Linux, running Java 7 and higher, under the GNU GPLv3 license, at:https://MohammedAlJaff.github.io/microTaboo

  • 75.
    Allander, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fitness and virulence of epidemic and non-epidemic clones of extensively drug-resistant (XDR) carbapenemase-producing Klebsiella pneumoniae2018Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    The full text will be freely available from 2021-08-31 09:48
  • 76.
    Allkja, Jontana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The influence of copper on mast cell during bacterial infections2017Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    Abstract [en]

    Mast cells are innate immune cells generally known for their harmful effects, particularly their role in asthma and autoimmune diseases. However, they can also recognize pathogens and mount a response to them. Copper is essential for proper cell function and homeostasis. Research has shown that changes in copper levels can affect mast cell morphology and gene expression of many of its immune mediators. It has also been shown that the copper transporter Ctr2 plays an important role in mast cell physiology. In this project, we investigated whether the same effects can be seen when mast cells are stimulated with bacteria, namely Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). For this purpose, wild type and Ctr2 knockout mast cells were treated with different concentrations of copper for 72 hours and later co-cultured with either S. aureus or E. coli. Wild type cells were also treated with a copper chelator to investigate the effect of copper starvation. Release of IL-6 and CCL2, two common mediators released in response to bacteria, were measured by ELISA, while their gene expression was measured by qPCR. Results showed that either copper starvation or, 10 μM copper cause an increase in IL-6 and CCL2 protein levels, but have no effect on gene expression. The 10 μM copper effect was not observed in the Ctr2 knockout cells. In conclusion, not much is known about the mechanisms involved in the mast cell response to bacteria. However, it appears that copper can affect either different stages of the same pathway, or different pathways in a similar manner.

  • 77.
    Almgren, Johanna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Characterization of antibodies against mustard and development of immunological methods for the detection and quantification of mustard in foods2007Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    ABSTRACT

    Allergy to mustard has been reported for many years, in some cases as severe anaphylactic reactions. Recent studies imply that this allergy is increasing. Three major allergens have been isolated and characterised; Sin a 1 and Sin a 2 in yellow mustard (Sinapis alba), and Bra j 1 in oriental mustard (Brassica juncea). Yellow mustard and black mustard (Brassica nigra) are the most common species in Europe, whereas oriental mustard is more frequent outside Europe. Mustard plants belong to the Brassicaceae/Cruciferae family. Mustard is present as an ingredient in different foods, sauces and spices, often in small amounts. According to the European labelling directives, mustard and products thereof must always be declared. To monitor this regulation, methods need to be developed to detect mustard. Polyclonal antibodies, produced in rabbits, against yellow and black mustard were characterised with immunodiffusion, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions, and immunoblotting. Rocket-immunoelectrophoresis and enzyme-linked immunosorbent assay (ELISA) were developed for the detection and quantification of mustard protein. With indirect competitive ELISA a concentration of 156ng mustard protein per ml food extract was detected, which is more than enough to cover the lowest reported reactive doses.

  • 78.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lamichhaney, Sangeet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grant, B. Rosemary
    Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA..
    Grant, Peter R.
    Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA..
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA..
    Adaptive radiation of Darwin's finches revisited using whole genome sequencing2016In: Bioessays, ISSN 0265-9247, E-ISSN 1521-1878, Vol. 38, no 1, p. 14-20Article in journal (Refereed)
    Abstract [en]

    We recently used genome sequencing to study the evolutionary history of the Darwin's finches. A prominent feature of our data was that different polymorphic sites in the genome tended to indicate different genetic relationships among these closely related species. Such patterns are expected in recently diverged genomes as a result of incomplete lineage sorting. However, we uncovered conclusive evidence that these patterns have also been influenced by interspecies hybridisation, a process that has likely played an important role in the radiation of Darwin's finches. A major discovery was that segregation of two haplotypes at the ALX1 locus underlies variation in beak shape among the Darwin's finches, and that differences between the two haplotypes in a 240 kb region in blunt and pointed beaked birds involve both coding and regulatory changes. As we review herein, the evolution of such adaptive haplotypes comprising multiple causal changes appears to be an important mechanism contributing to the evolution of biodiversity.

  • 79. Al-Saai, Salma
    et al.
    Kheir, Amany
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Abdel-Muhsin, Abdel-Muhsin A
    Al-Ghazali, Aisha
    Nwakanma, Davis
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Babiker, Hamza A
    Distinct haplotypes of dhfr and dhps among Plasmodium falciparum isolates in an area of high level of sulfadoxine-pyrimethamine (SP) resistance in eastern Sudan2009In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 9, no 5, p. 778-783Article in journal (Refereed)
    Abstract [en]

    Typing of polymorphic microsatellites that are linked to drug resistance genes has shed light on the origin and pattern of spread of some anti-malarial drugs. Recent surveys revealed spread of a high-level pyrimethemine resistant lineage of Plasmodium falciparum, of Asian origin, across Africa. Here, we examined mutations in dihydrofolate reductase, dhfr [chromsosome 4], the dihydropteroate synthase, dhps [chromosome 8] associated with resistance to sulfadoxine-pyrimethamine (SP), and neighboring microsatellites among P. falciparum isolates in Asar village, eastern Sudan. This area lies at the fringes of malaria endemicity, where the remote P. falciparum parasites have some distinct genetic characteristics. Overall, 89% (84/94) of the examined isolates carried double mutations at dhfr (N51I and S108N), but the 59R and I164L mutations were not seen. Similarly, the majority, 43% (35/81) of the isolates carried double mutations at dhps (437G, 540E). Analysis of neighboring microsatellites revealed one major dhfr haplotype with mutations (51I, 108N) and one dhps haplotype with mutations (436S, 437G, 540E). These haplotypes differ from the major ones thought to drive resistance to SP across Africa. The resistant haplotypes of dhfr and dhps, in Asar, share some microsatellites with the wild genotypes suggesting that they were generated locally. Among isolates successfully examined, 40% shared identical haplotypes of the 2 loci, comprising a dominant resistant lineage. Undoubtedly, this lineage plays an important role in clinical failure to SP in this area.

  • 80.
    Alvarado-Vazquez, Perla Abigail
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grosick, Rachel L.
    Presbyterian Coll, Sch Pharm, Dept Pharm Practice, Clinton, SC USA.
    Moracho-Vilrriales, Carolina
    Presbyterian Coll, Sch Pharm, Dept Pharm Practice, Clinton, SC USA.
    Ward, Eileen
    Presbyterian Coll, Sch Pharm, Dept Pharm Practice, Clinton, SC USA.
    Threatt, Tiffaney
    Presbyterian Coll, Sch Pharm, Dept Pharm Practice, Clinton, SC USA.
    Romero-Sandoval, Edgar Alfonso
    Wake Forest Univ, Sch Med, Pain Mech Lab, Dept Anesthesiol, 1 Med Ctr Blvd, Winston Salem, NC 27157 USA.
    Cytokine production capabilities of human primary monocyte-derived macrophages from patients with diabetes mellitus type 2 with and without diabetic peripheral neuropathy2019In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 12, p. 69-81Article in journal (Refereed)
    Abstract [en]

    Introduction: Monocytes from patients with diabetes mellitus type 2 (DM2) are dysfunctional, persistently primed, and prone to a proinflammatory phenotype. This may alter the phenotype of their differentiation to macrophages and result in diabetic peripheral neuropathy (DPN), nerve damage, nerve sensitization, and chronic pain. We have previously demonstrated that CD163 is a molecule that promotes an anti-inflammatory cellular phenotype in human primary macrophages, but this has not been proven in macrophages from patients with DM2 or DPN. Thus, we hypothesize that macrophages from patients with DM2 or DPN display an altered proinflammatory functional phenotype related to cytokine production and that the induction of CD163 expression will promote a more homeostatic phenotype by reducing their proinflammatory responsiveness.

    Patients and methods: We tested these hypotheses in vitro using blood monocyte-derived macrophages from healthy subjects and patients with DM2 with and without DPN. Cells were incubated in the presence or the absence of 5 mu g/mL of lipopolysaccharide (LPS). The concentrations of interleuldn-10, interleukin-6, tumor necrosis factor-alpha (TNF-alpha), TGF-beta, and monocyte chemoattractant protein-1 (MCP-1) were measured using ELISA assays. Macrophages were transfected with an empty vector plasmid or a plasmid containing the CD163 gene using mannosylated polyethylenimine nanoparticles.

    Results: Our results show that nonstimulated DM2 or DPN macrophages have a constitutive primed proinflammatory state and display a deficient production of proinflammatory cytokines upon a proinflammatory challenge when compared to healthy macrophages. CD163 induction produced an anti-inflammatory phenotype in the healthy control group, and this effect was partial in DM2 or DPN macrophages.

    Conclusion: Our results suggest that diabetic macrophages adopt a complex phenotype that is only partially reversed by CD163 induction. Future experiments are focused on elucidating this differential responsiveness between healthy and diabetic macrophages.

  • 81. Alvarez-Castro, José M
    et al.
    Le Rouzic, Arnaud
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Siegel, Paul B
    Carlborg, Örjan
    Modelling of genetic interactions improves prediction of hybrid patterns: a case study in domestic fowl2012In: Genetical Research, ISSN 0016-6723, E-ISSN 1469-5073, Vol. 94, no 5, p. 255-266Article in journal (Refereed)
    Abstract [en]

    Summary A major challenge in complex trait genetics is to unravel how multiple loci and environmental factors together cause phenotypic diversity. Both first (F1) and second (F2) generation hybrids often display phenotypes that deviate from what is expected under intermediate inheritance. We have here studied two chicken F2 populations generated by crossing divergent chicken lines to assess how epistatic loci, identified in earlier quantitative trait locus (QTL) studies, contribute to hybrid deviations from the mid-parent phenotype. Empirical evidence suggests that the average phenotypes of the intercross birds tend to be lower than the midpoint between the parental means in both crosses. Our results confirm that epistatic interactions, despite a relatively small contribution to the phenotypic variance, play an important role in the deviation of hybrid phenotypes from the mid-parent values (i.e. multi-locus hybrid genotypes lead to lower rather than higher body weights). To a lesser extent, dominance also appears to contribute to the mid-parent deviation, at least in one of the crosses. This observation coincides with the hypothesis that hybridization tends to break up co-adapted gene complexes, i.e. generate Bateson-Dobzhansky-Muller incompatibilities.

  • 82. Amarger, V
    et al.
    Erlandsson, R
    Pielberg, G
    Jeon, J T
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Comparative sequence analysis of the PRKAG3 region between human and pig: evolution of repetitive sequences and potential new exons2003In: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 102, no 1-4, p. 163-172Article in journal (Refereed)
    Abstract [en]

    The PRKAG3 gene encodes the gamma3 chain of AMP-activated protein kinase (AMPK). A non-conservative missense mutation in the PRKAG3 gene causes a dominant phenotype involving abnormally high glycogen content in pig skeletal muscle. We have determined >126 kb (in 13 contigs) of porcine genomic sequence surrounding the PRKAG3 gene and the corresponding mouse region covering the gene. A comparison of these PRKAG3 sequences and the human sequence was conducted and used to predict evolutionarily conserved regions, including regulatory regions. A comparison of the human genomic sequence and a porcine BAC sequence containing the PRKAG3 gene, revealed a conserved organization and the presence of three additional genes, CYP27A1 (cytochrome P450, family 27, subfamily A, polypeptide 1), STK36 (Serine Threonine Kinase 36), and the homolog of the unidentified human mRNA KIAA0173. Interspersed repetitive elements constituted 51.4 and 38.6% of this genomic region in human and pig, respectively. We were able to reliably align 12.6 kb of orthologous repeats shared between pig and human and these showed an average sequence identity of 72.4%. Our analysis revealed that the human KIAA0173 gene harbors alternative 5' untranslated exons originating from repetitive elements. This provides an obvious example how transposable elements may affect gene evolution.

  • 83. Amemiya, Chris T.
    et al.
    Alfoeldi, Jessica
    Lee, Alison P.
    Fan, Shaohua
    Philippe, Herve
    MacCallum, Iain
    Braasch, Ingo
    Manousaki, Tereza
    Schneider, Igor
    Rohner, Nicolas
    Organ, Chris
    Chalopin, Domitille
    Smith, Jeramiah J.
    Robinson, Mark
    Dorrington, Rosemary A.
    Gerdol, Marco
    Aken, Bronwen
    Biscotti, Maria Assunta
    Barucca, Marco
    Baurain, Denis
    Berlin, Aaron M.
    Blatch, Gregory L.
    Buonocore, Francesco
    Burmester, Thorsten
    Campbell, Michael S.
    Canapa, Adriana
    Cannon, John P.
    Christoffels, Alan
    De Moro, Gianluca
    Edkins, Adrienne L.
    Fan, Lin
    Fausto, Anna Maria
    Feiner, Nathalie
    Forconi, Mariko
    Gamieldien, Junaid
    Gnerre, Sante
    Gnirke, Andreas
    Goldstone, Jared V.
    Haerty, Wilfried
    Hahn, Mark E.