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  • 1.
    Aalto, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cloning and characterization of genes encoding proteins involved in the terminal stage of vesicular traffic in the yeast Saccharomyces cerevisiae1995In: VTT publication 255, Technical research centre of Finland, Espoo, Vol. 255Other (Other scientific)
  • 2.
    Abdulrahman, Hazha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mach, Aaron
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Does photographic documentation of the position of the recording electrodes decrease motor amplitude variation in electroneurography?2009Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    It is known that there is an intraindividual amplitude variation in motor electroneurography when the same person is examined at different times. This variation affects the evaluation the status of the patient. The aim of this study was to investigate if the intraindividual amplitude variation decreased by photographing the electrode position, that later is used in the follow-up study. Twenty test persons were examined by four laboratory scientists. The nerves that were examined were median, ulnar, peroneal and tibial nerve. At the first examination the laboratory scientists used method guidelines and took photographs of the electrode position. The photographs were then used in the follow-up. The results showed that there was an indication of decreased of the intraindividual amplitude variation when photographic documentation was used instead of method guidelines.

  • 3. Abramsson, Alexandra
    et al.
    Kurup, Sindhulakshmi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Yamada, Shuhei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindblom, Per
    Schallmeiner, Edith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ledin, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ringvall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kjellén, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bondjers, Göran
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gerhardt, Holger
    Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development2007In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 21, no 3, p. 316-331Article in journal (Refereed)
    Abstract [en]

    During vascular development, endothelial platelet-derived growth factor B (PDGF-B) is critical for pericyte recruitment. Deletion of the conserved C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment in vivo, suggesting a potential role for heparan sulfate (HS) in PDGF-BB function during vascular development. We studied the participation of HS chains in pericyte recruitment using two mouse models with altered HS biosynthesis. Reduction of N-sulfation due to deficiency in N-deacetylase/N-sulfotransferase-1 attenuated PDGF-BB binding in vitro, and led to pericyte detachment and delayed pericyte migration in vivo. Reduced N-sulfation also impaired PDGF-BB signaling and directed cell migration, but not proliferation. In contrast, HS from glucuronyl C5-epimerase mutants, which is extensively N- and 6-O-sulfated, but lacks 2-O-sulfated L-iduronic acid residues, retained PDGF-BB in vitro, and pericyte recruitment in vivo was only transiently delayed. These observations were supported by in vitro characterization of the structural features in HS important for PDGF-BB binding. We conclude that pericyte recruitment requires HS with sufficiently extended and appropriately spaced N-sulfated domains to retain PDGF-BB and activate PDGF receptor β (PDGFRβ) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.

  • 4.
    Abrink, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, E
    Hellman, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Demethylation of ERV3, anendogenous retrovirus regulating a krüppel related zinc finger gene H-plk,in several human cell lines arrested during early monocyte development.1998In: DNA and Cell Biology, Vol. 17, p. 27-Article in journal (Refereed)
  • 5.
    Abrink, Magnus
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Erik
    Department of Genetics and Pathology.
    Gobl, Anders
    Department of Medical Sciences.
    Hellman, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Expression of lactoferrin in the kidney:implications for innate immunity and iron metabolism2000In: Kidney Int, Vol. 57, p. 2004-Article in journal (Refereed)
  • 6.
    Acar, Binnaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Phylogenetic characterization of equine influenza viruses from Swedish outbreaks from 1979 to 20012011Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Introduction: Equine influenza virus, an influenza type A virus, belongs to the family of Orthomyxoviridae. Equine influenza is a major cause of respiratory disease in horses and outbreaks have severe economical repercussions for the horse industry. It is considered to be endemic in Sweden and between 1997 and 2006 there have been around 10 to 40 outbreaks every year. The objective of this study was to do a phylogenetic characterization of equine influenza outbreaks that occurred in Sweden during a twenty year period.

    Methods: The haemagglutinin and neuraminidase gene of 14 samples and the complete genome of three samples collected over the span of 20 years were sequenced. The viral RNA were extracted, amplified with OneStep RT-PCR and sequenced.

    Results & Discussion: The phylogenetic tree and deduced amino acid sequence of HA1 illustrated that different lineages of equine influenza virus has circulated simultaneously in the Swedish horse population. The isolates mainly belonged to pre-divergence-, Eurasian- and American lineages. To characterize equine influenza viruses is important for vaccine strain selection, to fully understand the disease and how the virus evolves. 

  • 7.
    Adler, Marlen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mechanisms and Dynamics of Carbapenem Resistance in Escherichia coli2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The emergence of extended spectrum β-lactamase (ESBL) producing Enterobacteriaceae worldwide has led to an increased use of carbapenems and may drive the development of carbapenem resistance. Existing mechanisms are mainly due to acquired carbapenemases or the combination of ESBL-production and reduced outer membrane permeability. The focus of this thesis was to study the development of carbapenem resistance in Escherichia coli in the presence and absence of acquired β-lactamases. To this end we used the resistance plasmid pUUH239.2 that caused the first major outbreak of ESBL-producing Enterobacteriaceae in Scandinavia.

    Spontaneous carbapenem resistance was strongly favoured by the presence of the ESBL-encoding plasmid and different mutational spectra and resistance levels arose for different carbapenems. Mainly, loss of function mutations in the regulators of porin expression caused reduced influx of antibiotic into the cell and in combination with amplification of β-lactamase genes on the plasmid this led to high resistance levels. We further used a pharmacokinetic model, mimicking antibiotic concentrations found in patients during treatment, to test whether ertapenem resistant populations could be selected even at these concentrations. We found that resistant mutants only arose for the ESBL-producing strain and that an increased dosage of ertapenem could not prevent selection of these resistant subpopulations. In another study we saw that carbapenem resistance can even develop in the absence of ESBL-production. We found mutants in export pumps and the antibiotic targets to give high level resistance albeit with high fitness costs in the absence of antibiotics. In the last study, we used selective amplification of β-lactamases on the pUUH239.2 plasmid by carbapenems to determine the cost and stability of gene amplifications. Using mathematical modelling we determined the likelihood of evolution of new gene functions in this region. The high cost and instability of the amplified state makes de novo evolution very improbable, but constant selection of the amplified state may balance these factors until rare mutations can establish a new function.

    In my studies I observed the influence of β-lactamases on carbapenem resistance and saw that amplification of these genes would further contribute to resistance. The rapid disappearance of amplified arrays of resistance genes in the absence of antibiotic selection may lead to the underestimation of gene amplification as clinical resistance mechanism. Amplification of β-lactamase genes is an important stepping-stone and might lead to the evolution of new resistance genes.

    List of papers
    1. Influence of acquired β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli
    Open this publication in new window or tab >>Influence of acquired β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli
    2013 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 1, p. 51-59Article in journal (Refereed) Published
    Abstract [en]

    Objectives: To investigate the influence of plasmid-borne β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli and the fitness costs associated with resistance. Methods: Stepwise selection of carbapenem-resistant mutants with or without the extended-spectrum β-lactamase (ESBL)-encoding plasmid pUUH239.2 was performed. Mutation rates and mutational pathways to resistance were determined. In vitro-selected and constructed mutants were characterized regarding the MICs of the carbapenems, porin expression profiles, growth rates and the presence of mutations in the porins ompC/ompF and their regulatory genes. The influence of the plasmid-encoded β-lactamases TEM-1, OXA-1 and CTX-M-15 on resistance development was determined. Results: Results show that E. coli readily developed reduced carbapenem susceptibility and clinical resistance levels by a combination of porin loss and increased β-lactamase expression, especially towards ertapenem. All tested β-lactamases (CTX-M-15, TEM-1 and OXA-1) contributed to reduced carbapenem susceptibility in the absence of porin expression. However, complete loss of porin expression conferred a 20% fitness cost on the bacterial growth rate. Increased β-lactamase expression through spontaneous gene amplification on the plasmid was a major resistance factor. Conclusions: Plasmid-encoded β-lactamases, including non-ESBL enzymes, have a strong influence on the frequency and resistance level of spontaneous carbapenem-resistant mutants. The fitness cost associated with the loss of OmpC/OmpF in E. coli most likely reduces the survivability of porin mutants and could explain why they have not emerged as a clinical problem in this species.

    Keywords
    Fitness cost, Gene amplification, Mutations, Plasmids
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-192026 (URN)10.1093/jac/dks368 (DOI)000312646300010 ()
    Available from: 2013-01-24 Created: 2013-01-15 Last updated: 2017-12-06Bibliographically approved
    2. Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model
    Open this publication in new window or tab >>Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model
    Show others...
    2013 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 6, p. 1319-1326Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES:

    Ertapenem resistance is increasing in Enterobacteriaceae. The production of extended-spectrum β-lactamases (ESBLs) and reduced expression of outer membrane porins are major mechanisms of resistance in ertapenem-resistant Klebsiella pneumoniae. Less is known of ertapenem resistance in Escherichia coli. The aim of this study was to explore the impact of ESBL production in E. coli on the antibacterial activity of ertapenem.

    METHODS:

    Two E. coli strains, with and without ESBL production, were exposed to ertapenem in vitro for 48 h at concentrations simulating human pharmacokinetics with conventional and higher dosages.

    RESULTS:

    Isolates with non-susceptibility to ertapenem (MICs 0.75-1.5 mg/L) were detected after five of nine time-kill experiments with the ESBL-producing strain. All of these isolates had ompR mutations, which reduce the expression of outer membrane porins OmpF and OmpC. Higher dosage did not prevent selection of porin-deficient subpopulations. No mutants were detected after experiments with the non-ESBL-producing strain. Compared with other experiments, experiments with ompR mutants detected in endpoint samples showed significantly less bacterial killing after the second dose of ertapenem. Impaired antibacterial activity against E. coli with ESBL production and ompR mutation was also demonstrated in time-kill experiments with static antibiotic concentrations.

    CONCLUSIONS:

    The combination of ESBL production and porin loss in E. coli can result in reduced susceptibility to ertapenem. Porin-deficient subpopulations frequently emerged in ESBL-producing E. coli during exposure to ertapenem at concentrations simulating human pharmacokinetics. Inappropriate use of ertapenem should be avoided to minimize the risk of selection of ESBL-producing bacteria with reduced susceptibility to carbapenems.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-197878 (URN)10.1093/jac/dkt044 (DOI)000319468900016 ()23478794 (PubMedID)
    Available from: 2013-04-05 Created: 2013-04-05 Last updated: 2017-12-06Bibliographically approved
    3. Combinations of mutations in envZ, ftsI, mrdA, acrB and acrR can cause high-level carbapenem resistance in Escherichia coli
    Open this publication in new window or tab >>Combinations of mutations in envZ, ftsI, mrdA, acrB and acrR can cause high-level carbapenem resistance in Escherichia coli
    2016 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 5, p. 1188-1198Article in journal (Refereed) Published
    Abstract [en]

    The worldwide spread of ESBL-producing Enterobacteriaceae has led to an increased use of carbapenems, the group of beta-lactams with the broadest spectrum of activity. Bacterial resistance to carbapenems is mainly due to acquired carbapenemases or a combination of ESBL production and reduced drug influx via loss of outer-membrane porins. Here, we have studied the development of carbapenem resistance in Escherichia coli in the absence of beta-lactamases. We selected mutants with high-level carbapenem resistance through repeated serial passage in the presence of increasing concentrations of meropenem or ertapenem for similar to 60 generations. Isolated clones were whole-genome sequenced, and the order in which the identified mutations arose was determined in the passaged populations. Key mutations were reconstructed, and bacterial growth rates of populations and isolated clones and resistance levels to 23 antibiotics were measured. High-level resistance to carbapenems resulted from a combination of downstream effects of envZ mutation and target mutations in AcrAB-TolC-mediated drug export, together with PBP genes [mrdA (PBP2) after meropenem exposure or ftsI (PBP3) after ertapenem exposure]. Our results show that antibiotic resistance evolution can occur via several parallel pathways and that new mechanisms may appear after the most common pathways (i.e. beta-lactamases and loss of porins) have been eliminated. These findings suggest that strategies to target the most commonly observed resistance mechanisms might be hampered by the appearance of previously unknown parallel pathways to resistance.

    National Category
    Biochemistry and Molecular Biology Microbiology
    Identifiers
    urn:nbn:se:uu:diva-221428 (URN)10.1093/jac/dkv475 (DOI)000376291300008 ()26869688 (PubMedID)
    Funder
    Swedish Research Council Formas, 2013-5476-25194-9EU, European Research Council, 282004
    Available from: 2014-03-31 Created: 2014-03-31 Last updated: 2017-12-05Bibliographically approved
    4. High Fitness Costs and Instability of Gene Duplications Reduce Rates of Evolution of New Genes by Duplication-Divergence Mechanisms
    Open this publication in new window or tab >>High Fitness Costs and Instability of Gene Duplications Reduce Rates of Evolution of New Genes by Duplication-Divergence Mechanisms
    Show others...
    2014 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 31, no 6, p. 1526-1535Article in journal (Refereed) Published
    Abstract [sv]

    An important mechanism for generation of new genes is by duplication-divergence of existing genes. Duplication-divergence includes several different sub-models, such as subfunctionalization where after accumulation of neutral mutations the original function is distributed between two partially functional and complementary genes, and neofunctionalization where a new function evolves in one of the duplicated copies while the old function is maintained in another copy. The likelihood of these mechanisms depends on the longevity of the duplicated state, which in turn depends on the fitness cost and genetic stability of the duplications. Here, we determined the fitness cost and stability of defined gene duplications/amplifications on a low copy number plasmid. Our experimental results show that the costs of carrying extra gene copies are substantial and that each additional kbp of DNA reduces fitness by approximately 0.15%. Furthermore, gene amplifications are highly unstable and rapidly segregate to lower copy numbers in absence of selection. Mathematical modelling shows that the fitness costs and instability strongly reduces the likelihood of both sub- and neofunctionalization, but that these effects can be off-set by positive selection for novel beneficial functions.

    National Category
    Microbiology Biochemistry and Molecular Biology Genetics
    Identifiers
    urn:nbn:se:uu:diva-221431 (URN)10.1093/molbev/msu111 (DOI)000337067400019 ()
    Available from: 2014-03-31 Created: 2014-03-31 Last updated: 2017-12-05Bibliographically approved
  • 8.
    Adler, Marlen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anjum, Mehreen
    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.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Combinations of mutations in envZ, ftsI, mrdA, acrB and acrR can cause high-level carbapenem resistance in Escherichia coli2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 5, p. 1188-1198Article in journal (Refereed)
    Abstract [en]

    The worldwide spread of ESBL-producing Enterobacteriaceae has led to an increased use of carbapenems, the group of beta-lactams with the broadest spectrum of activity. Bacterial resistance to carbapenems is mainly due to acquired carbapenemases or a combination of ESBL production and reduced drug influx via loss of outer-membrane porins. Here, we have studied the development of carbapenem resistance in Escherichia coli in the absence of beta-lactamases. We selected mutants with high-level carbapenem resistance through repeated serial passage in the presence of increasing concentrations of meropenem or ertapenem for similar to 60 generations. Isolated clones were whole-genome sequenced, and the order in which the identified mutations arose was determined in the passaged populations. Key mutations were reconstructed, and bacterial growth rates of populations and isolated clones and resistance levels to 23 antibiotics were measured. High-level resistance to carbapenems resulted from a combination of downstream effects of envZ mutation and target mutations in AcrAB-TolC-mediated drug export, together with PBP genes [mrdA (PBP2) after meropenem exposure or ftsI (PBP3) after ertapenem exposure]. Our results show that antibiotic resistance evolution can occur via several parallel pathways and that new mechanisms may appear after the most common pathways (i.e. beta-lactamases and loss of porins) have been eliminated. These findings suggest that strategies to target the most commonly observed resistance mechanisms might be hampered by the appearance of previously unknown parallel pathways to resistance.

  • 9.
    Adler, Marlen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anjum, Mehreen
    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.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Influence of acquired β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli2013In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 1, p. 51-59Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate the influence of plasmid-borne β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli and the fitness costs associated with resistance. Methods: Stepwise selection of carbapenem-resistant mutants with or without the extended-spectrum β-lactamase (ESBL)-encoding plasmid pUUH239.2 was performed. Mutation rates and mutational pathways to resistance were determined. In vitro-selected and constructed mutants were characterized regarding the MICs of the carbapenems, porin expression profiles, growth rates and the presence of mutations in the porins ompC/ompF and their regulatory genes. The influence of the plasmid-encoded β-lactamases TEM-1, OXA-1 and CTX-M-15 on resistance development was determined. Results: Results show that E. coli readily developed reduced carbapenem susceptibility and clinical resistance levels by a combination of porin loss and increased β-lactamase expression, especially towards ertapenem. All tested β-lactamases (CTX-M-15, TEM-1 and OXA-1) contributed to reduced carbapenem susceptibility in the absence of porin expression. However, complete loss of porin expression conferred a 20% fitness cost on the bacterial growth rate. Increased β-lactamase expression through spontaneous gene amplification on the plasmid was a major resistance factor. Conclusions: Plasmid-encoded β-lactamases, including non-ESBL enzymes, have a strong influence on the frequency and resistance level of spontaneous carbapenem-resistant mutants. The fitness cost associated with the loss of OmpC/OmpF in E. coli most likely reduces the survivability of porin mutants and could explain why they have not emerged as a clinical problem in this species.

  • 10.
    Adler, Marlen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anjum, Mehreen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berg, Otto, G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Andersson, Dan I.
    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.
    High Fitness Costs and Instability of Gene Duplications Reduce Rates of Evolution of New Genes by Duplication-Divergence Mechanisms2014In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 31, no 6, p. 1526-1535Article in journal (Refereed)
    Abstract [sv]

    An important mechanism for generation of new genes is by duplication-divergence of existing genes. Duplication-divergence includes several different sub-models, such as subfunctionalization where after accumulation of neutral mutations the original function is distributed between two partially functional and complementary genes, and neofunctionalization where a new function evolves in one of the duplicated copies while the old function is maintained in another copy. The likelihood of these mechanisms depends on the longevity of the duplicated state, which in turn depends on the fitness cost and genetic stability of the duplications. Here, we determined the fitness cost and stability of defined gene duplications/amplifications on a low copy number plasmid. Our experimental results show that the costs of carrying extra gene copies are substantial and that each additional kbp of DNA reduces fitness by approximately 0.15%. Furthermore, gene amplifications are highly unstable and rapidly segregate to lower copy numbers in absence of selection. Mathematical modelling shows that the fitness costs and instability strongly reduces the likelihood of both sub- and neofunctionalization, but that these effects can be off-set by positive selection for novel beneficial functions.

  • 11.
    Adolfsson, Päivi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Ek, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Umb Carlsson, Öie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    The challenges for registered dietitians working with food related health promotion for people with IDD in Sweden.2018Conference paper (Refereed)
  • 12.
    Adolfsson, Päivi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. Centrum för forskning om funktionshinder, Centre for Disability research.
    Ek, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Umb Carlsson, Öie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    The challenges for registered dietitians working with food related health promotion for people with IDD in Sweden.2018Conference paper (Refereed)
  • 13.
    Adolfsson, Päivi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Research in Disability and Habilitation.
    Ekman, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Umb-Carlsson, Öie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Research in Disability and Habilitation.
    Challenges for registered dietitians working with food related health promotion for adults with IDD in supported housing2018In: JARID: Journal of applied research in intellectual disabilities, ISSN 1360-2322, E-ISSN 1468-3148, Vol. 31, no 4, p. 621-621Article in journal (Other academic)
  • 14.
    Advani, Jayshree
    et al.
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India;Manipal Acad Higher Educ, Manipal, Karnataka, India.
    Verma, Renu
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India.
    Chatterjee, Oishi
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India;Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India;Amrita Vishwa Vidyapeetham, Sch Biotechnol, Kollam, India.
    Balaya, Rex Devasahayam Arokia
    Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Najar, Mohd Altaf
    Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Ravishankara, Namitha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. MS Ramaiah Inst Technol, Dept Biotechnol, Bangalore, Karnataka, India.
    Suresh, Sneha
    MS Ramaiah Inst Technol, Dept Biotechnol, Bangalore, Karnataka, India;Univ Massachusetts Lowell, Dept Biol Sci, Lowell, MA USA.
    Pachori, Praveen Kumar
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India.
    Gupta, Umesh D.
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India.
    Pinto, Sneha M.
    Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Chauhan, Devendra S.
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India.
    Tripathy, Srikanth Prasad
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India;Natl Inst Res TB, Madras, Tamil Nadu, India.
    Gowda, Harsha
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India.
    Prasad, T. S. Keshava
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India;Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Rise of Clinical Microbial Proteogenomics: A Multiomics Approach to Nontuberculous Mycobacterium-The Case of Mycobacterium abscessus UC222018In: Omics, ISSN 1536-2310, E-ISSN 1557-8100Article in journal (Refereed)
    Abstract [en]

    Nontuberculous mycobacterial (NTM) species present a major challenge for global health with serious clinical manifestations ranging from pulmonary to skin infections. Multiomics research and its applications toward clinical microbial proteogenomics offer veritable potentials in this context. For example, the Mycobacterium abscessus, a highly pathogenic NTM, causes bronchopulmonary infection and chronic pulmonary disease. The rough variant of the M. abscessus UC22 strain is extremely virulent and causes lung upper lobe fibrocavitary disease. Although several whole-genome next-generation sequencing studies have characterized the genes in the smooth variant of M. abscessus, a reference genome sequence for the rough variant was generated only recently and calls for further clinical applications. We carried out whole-genome sequencing and proteomic analysis for a clinical isolate of M. abscessus UC22 strain obtained from a pulmonary tuberculosis patient. We identified 5506 single-nucleotide variations (SNVs), 63 insertions, and 76 deletions compared with the reference genome. Using a high-resolution LC-MS/MS-based approach (liquid chromatography tandem mass spectrometry), we obtained protein coding evidence for 3601 proteins, representing 71% of the total predicted genes in this genome. Application of proteogenomic approach further revealed seven novel protein-coding genes and enabled refinement of six computationally derived gene models. We also identified 30 variant peptides corresponding to 16 SNVs known to be associated with drug resistance. These new observations offer promise for clinical applications of microbial proteogenomics and next-generation sequencing, and provide a resource for future global health applications for NTM species.

  • 15.
    Afshari Kashanian, Elisa
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Detection of celery (Apium graveolens) in food with Real-Time PCR2006Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Directive EC 2003/89/EC of the European Parliament and of the Council states that certain

    ingredients and products derived there of known to cause allergen reactions must always be

    declared. Furthermore labelling is mandatory irrespective of the amount included. The National

    Food Administration therefore needs methods for monitoring the presence of allergens in food.

    Methods already exist for most of the allergens on the EU-list, but an operational method for

    celery (Apium graveolens) is missing.

    A specific DNA-method was developed, based on TaqMan Real-Time PCR with the celery

    mannitol dehydrogenase gene as target sequence. The analysis was started with homogenisation

    of the sample followed by extraction of DNA. The Real-Time PCR method was shown to be

    specific for celery, producing a 113 bp fragment with two celery varieties and negative results

    with other closely selected species commonly present together with celery in food products (12

    samples). The detection limit was 2-20 pg DNA, which corresponds to 1-7 haploid genome

    copies. When evaluated with model samples of celery in meat, a detection limit of less than

    0,01 % was determined. When used to analyse food products from the market, six out of seven

    products declared to contain celery were correctly identified as positive.

  • 16. Agler, Caryline
    et al.
    Nielsen, Dahlia M.
    Urkasemsin, Ganokon
    Singleton, Andrew
    Tonomura, Noriko
    Sigurdsson, Snaevar
    Tang, Ruqi
    Linder, Keith
    Arepalli, Sampath
    Hernandez, Dena
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van de Leemput, Joyce
    Motsinger-Reif, Alison
    O'Brien, Dennis P.
    Bell, Jerold
    Harris, Tonya
    Steinberg, Steven
    Olby, Natasha J.
    Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB242014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 2, p. e1003991-Article in journal (Refereed)
    Abstract [en]

    Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia. Author Summary Neurodegenerative diseases are one of the most important causes of decline in an aging population. An important subset of these diseases are known as the hereditary ataxias, familial neurodegenerative diseases that affect the cerebellum causing progressive gait disturbance in both humans and dogs. We identified a mutation in RAB24, a gene associated with autophagy, in Old English Sheepdogs and Gordon Setters with hereditary ataxia. Autophagy is a process by which cell proteins and organelles are removed and recycled and its critical role in maintenance of the continued health of cells is becoming clear. We evaluated the brains of affected dogs and identified accumulations of autophagosomes within the cerebellum, suggesting a defect in the autophagy pathway. Our results suggest that a defect in the autophagy pathway results in neuronal death in a naturally occurring disease in dogs. The autophagy pathway should be investigated in human hereditary ataxia and may represent a therapeutic target in neurodegenerative diseases.

  • 17.
    Aguda, Adeleke H.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Structural Study of the WH2 Family and Filamin: Implications for Actin Cytoskeleton Regulation2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cellular processes like motility, chemotaxis, phagocytosis and morphogenesis are dependent on the dynamic regulation of the actin cytoskeleton. This cytoskeleton system is tightly controlled by a number of diverse actin-binding proteins (ABPs) by various mechanisms described as nucleation, polymerization, capping, severing, depolymerization and sequestration. The ABPs are grouped based on sequence identity as in the Wiskott-Aldrich Syndrome protein homology domain 2 (WH2), and the calponin homology domain (CH) containing proteins.

    In this work, we elucidate the crystal structures of hybrids of gelsolin domain 1 with thymosin β4, ciboulot domain 2, and the second WH2 domain of N-WASP each bound to actin. We show that the single WH2 motif containing protein thymosin β4 in part sequesters actin by binding its pointed end via a C-terminal helix. This interaction prevents the addition of bound actin protomers to the barbed end of the filament. We propose that sequence variations in some WH2 motifs conferred F-actin binding ability to multiple repeat-containing proteins. These F-actin binding domains interact with the barbed end of a filament and the adjacent WH2 motifs are then freed to add their bound actin to the growing filament end. We demonstrate the binding of ciboulot domains 2 and 3 to both G- and F-actin and that full length ciboulot is capable of binding two actin monomers simultaneously.

    We have also cloned, expressed, purified and crystallized rod domains 14-16 from the actin crosslinking protein a-filamin. Preliminary X-ray crystallography data gives us hope that we shall be able to solve the structure of this triple domain repeat.

    List of papers
    1. Structural basis of actin sequestration by thymosin β4: implications for WH2 proteins
    Open this publication in new window or tab >>Structural basis of actin sequestration by thymosin β4: implications for WH2 proteins
    Show others...
    2004 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 23, no 18, p. 3599-608Article in journal (Refereed) Published
    Abstract [en]

    The WH2 (Wiscott-Aldridge syndrome protein homology domain 2) repeat is an actin interacting motif found in monomer sequestering and filament assembly proteins. We have stabilized the prototypical WH2 family member, thymosin-beta4 (Tbeta4), with respect to actin, by creating a hybrid between gelsolin domain 1 and the C-terminal half of Tbeta4 (G1-Tbeta4). This hybrid protein sequesters actin monomers, severs actin filaments and acts as a leaky barbed end cap. Here, we present the structure of the G1-Tbeta4:actin complex at 2 A resolution. The structure reveals that Tbeta4 sequesters by capping both ends of the actin monomer, and that exchange of actin between Tbeta4 and profilin is mediated by a minor overlap in binding sites. The structure implies that multiple WH2 motif-containing proteins will associate longitudinally with actin filaments. Finally, we discuss the role of the WH2 motif in arp2/3 activation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-94969 (URN)10.1038/sj.emboj.7600372 (DOI)15329672 (PubMedID)
    External cooperation:
    Available from: 2006-10-18 Created: 2006-10-18 Last updated: 2017-12-14Bibliographically approved
    2. The structural basis of actin interaction with multiple WH2/β thymosin motif-containing proteins
    Open this publication in new window or tab >>The structural basis of actin interaction with multiple WH2/β thymosin motif-containing proteins
    Show others...
    2006 In: Structure, Vol. 14, p. 469-76Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94970 (URN)
    Available from: 2006-10-18 Created: 2006-10-18Bibliographically approved
    3. Structural study of α-filamin repeats 14-16
    Open this publication in new window or tab >>Structural study of α-filamin repeats 14-16
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-94971 (URN)
    Available from: 2006-10-18 Created: 2006-10-18Bibliographically approved
  • 18.
    Aguda, Adeleke H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Burtnick, Leslie D
    Robinson, Robert C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The state of the filament.2005In: EMBO Rep, ISSN 1469-221X, Vol. 6, no 3, p. 220-6Article in journal (Refereed)
  • 19.
    Aguda, Adeleke, H.
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sakwe, Amos, M.
    Rask, Lars
    Robinson, Robert, C.
    Structural study of α-filamin repeats 14-16Article in journal (Refereed)
  • 20.
    Aguda, Adeleke H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xue, Bo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Irobi, Edward
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Préat, Thomas
    Robinson, Robert C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The structural basis of actin interaction with multiple WH2/beta-thymosin motif-containing proteins.2006In: Structure, ISSN 0969-2126, Vol. 14, no 3, p. 469-76Article in journal (Refereed)
  • 21.
    Aguda, Adeleke, H.
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xue, Bo
    Irobi, Edward
    Préat, Thomas
    Robinson, Robert, C.
    The structural basis of actin interaction with multiple WH2/β thymosin motif-containing proteins2006In: Structure, Vol. 14, p. 469-76Article in journal (Refereed)
  • 22.
    Aguda, Adeleke Halilu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sakwe, Amos Malle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Robinson, Robert C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Expression, crystallization and preliminary crystallographic data analysis of filamin A repeats 14-162007In: Acta Crystallographica. Section F: Structural Biology and Crystallization Communications, ISSN 1744-3091, E-ISSN 1744-3091, Vol. 63, no 4, p. 291-293Article in journal (Refereed)
    Abstract [en]

    Human filamin A is a 280 kDa protein involved in actin-filament cross-linking. It is structurally divided into an actin-binding headpiece (ABD) and a rod domain containing 24 immunoglobulin-like (Ig) repeats. A fragment of human filamin A (Ig repeats 14-16) was cloned and expressed in Escherichia coli and the purified protein was crystallized in 1.6 M ammonium sulfate, 2% PEG 1000 and 100 mM HEPES pH 7.5. The crystals diffracted to 1.95 A and belong to space group P2(1)2(1)2(1), with unit-cell parameters a = 50.63, b = 52.10, c = 98.46 A, alpha = beta = gamma = 90 degrees.

  • 23.
    Ahlen, K
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berg, A
    Stiger, F
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tengholm, A
    Department of Medical Cell Biology.
    Siegbahn, A
    Department of Medical Sciences.
    Gylfe, E
    Department of Medical Cell Biology.
    Reed, R.K.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cell interactions with collagen matrices in vivo and in vitro depend on phosphatidylinositol 3-kinase and free cytoplasmic calcium1998In: Cell Adhesion and Communication, Vol. 5, p. 461-Article in journal (Refereed)
  • 24.
    Ahlström, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bergström, M
    Bjurling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pancreatic neuroendocrine tumors: diagnosis with PET1995In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 195, no 2, p. 333-337Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    To evaluate the use of carbon-11-labeled L-dihydroxyphenylalanine (L-DOPA) and hydroxytryptophan (5-HTP) in the diagnosis of pancreatic endocrine tumors with positron emission tomography (PET).

    MATERIALS AND METHODS:

    Twenty-two consecutive patients with clinically and biochemically verified pancreatic endocrine tumors were examined with computed tomography (CT) and PET with L-DOPA alone (n = 16) or both C-11-L-DOPA and C-11-5-HTP (n = 6).

    RESULTS:

    Tumor uptake of L-DOPA was found in 11 patients, eight of whom had metastatic disease. Heterogeneity of tracer uptake was noted among different lesions in the same patient (ie, high uptake in some lesions and low uptake in others). Results in patients examined with both L-DOPA and 5-HTP correlated well, but the uptake levels of 5-HTP were higher in two of three patients with positive findings. In two additional patients, CT enabled detection of tumors not detected at PET.

    CONCLUSION:

    The current PET technique can be a valuable complement to CT in demonstration of functional pancreatic endocrine tumors, in particular, glucagonomas, but is less useful in detection of nonfunctional tumors.

  • 25.
    Ahlström, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bergström, Mats
    Bjurling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pancreatic Neuroendocrine Tumors: Diagnosis with PET1995In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 195, no 2, p. 333-337Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    To evaluate the use of carbon-11-labeled L-dihydroxyphenylalanine (L-DOPA) and hydroxytryptophan (5-HTP) in the diagnosis of pancreatic endocrine tumors with positron emission tomography (PET).

    MATERIALS AND METHODS:

    Twenty-two consecutive patients with clinically and biochemically verified pancreatic endocrine tumors were examined with computed tomography (CT) and PET with L-DOPA alone (n = 16) or both C-11-L-DOPA and C-11-5-HTP (n = 6).

    RESULTS:

    Tumor uptake of L-DOPA was found in 11 patients, eight of whom had metastatic disease. Heterogeneity of tracer uptake was noted among different lesions in the same patient (ie, high uptake in some lesions and low uptake in others). Results in patients examined with both L-DOPA and 5-HTP correlated well, but the uptake levels of 5-HTP were higher in two of three patients with positive findings. In two additional patients, CT enabled detection of tumors not detected at PET.

    CONCLUSION:

    The current PET technique can be a valuable complement to CT in demonstration of functional pancreatic endocrine tumors, in particular, glucagonomas, but is less useful in detection of nonfunctional tumors.

  • 26.
    Ahlén, Caroline
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Outcome of patients with severe aortic stenosis – A retrospective follow-up study2008Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Aortic stenosis is the most common valvular disease in the adult population. A significant aortic stenosis is a serious condition, and if a symptomatic patient is not operated on, it may in most cases cause death. We have examined how many aortic stenoses that were diagnosed during one year, and a follow-up of the patients was also performed. We found 77 patients with significant aortic stenosis with a mean age of 76±13 years. At the time of follow-up 30 (39%) patients, aged between 29-85 years, had been surgically treated with implantation of a valve prosthesis within 2-23 months after the initial examination. At this initial examination 14 of the 30 patients who later underwent surgery had no symptoms. A coronary bypass operation was also performed on seven patients. Postoperative complications were observed in six patients, but none of them was fatal. At the initial examinations there were 26 (34%) patients with a significant aortic stenosis and symptoms who were not treated surgically. The main reason why these patients were not operated was high age, unwillingness, or severe left ventricular dysfunction. This study indicates the importance of repeated clinical and echocardiograpic examinations in patients with aortic stenosis. Almost half of the patients, that later underwent surgery, had no symptoms at the initial examination, but later developed symptoms which made surgery necessary. In one third of the patients no surgery was performed in spite of clinical symptoms.

  • 27.
    Ahlén, Karina
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ring, Patrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tomasini-Johansson, Bianca
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Holmqvist, Kristina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Magnusson, Karl-Eric
    Rubin, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Platelet-derived growth factor-BB modulates membrane mobility of beta1 integrins.2004In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 314, no 1, p. 89-96Article in journal (Refereed)
  • 28.
    Ahmed, Meftun
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Forsberg, Jens
    Department of Medical Biochemistry and Microbiology.
    Bergsten, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Protein profiling of human pancreatic islets by two-dimensional gel electrophoresis and mass spectrometry.2005In: J Proteome Res, ISSN 1535-3893, Vol. 4, no 3, p. 931-40Article in journal (Refereed)
  • 29.
    Ahmed Osman, Omneya
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Beier, Sara
    Leibniz Inst Balt Sea Res, Warnemunde, Germany..
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Interactions of Freshwater Cyanobacteria with Bacterial Antagonists2017In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 83, no 7, article id UNSP e02634Article in journal (Refereed)
    Abstract [en]

    Cyanobacterial and algal mass development, or blooms, have severe effects on freshwater and marine systems around the world. Many of these phototrophs produce a variety of potent toxins, contribute to oxygen depletion, and affect water quality in several ways. Coexisting antagonists, such as cyanolytic bacteria, hold the potential to suppress, or even terminate, such blooms, yet the nature of this interaction is not well studied. We isolated 31 cyanolytic bacteria affiliated with the genera Pseudomonas, Stenotrophomonas, Acinetobacter, and Delftia from three eutrophic freshwater lakes in Sweden and selected four phylogenetically diverse bacterial strains with strong-to-moderate lytic activity. To characterize their functional responses to the presence of cyanobacteria, we performed RNA sequencing (RNA-Seq) experiments on coculture incubations, with an initial predator-prey ratio of 1: 1. Genes involved in central cellular pathways, stress-related heat or cold shock proteins, and antitoxin genes were highly expressed in both heterotrophs and cyanobacteria. Heterotrophs in coculture expressed genes involved in cell motility, signal transduction, and putative lytic activity. L, D-Transpeptidase was the only significantly upregulated lytic gene in Stenotrophomonas rhizophila EK20. Heterotrophs also shifted their central metabolism from the tricarboxylic acid cycle to the glyoxylate shunt. Concurrently, cyanobacteria clearly show contrasting antagonistic interactions with the four tested heterotrophic strains, which is also reflected in the physical attachment to their cells. In conclusion, antagonistic interactions with cyanobacteria were initiated within 24 h, and expression profiles suggest varied responses for the different cyanobacteria and studied cyanolytes. IMPORTANCE Here, we present how gene expression profiles can be used to reveal interactions between bloom-forming freshwater cyanobacteria and antagonistic heterotrophic bacteria. Species-specific responses in both heterotrophs and cyanobacteria were identified. The study contributes to a better understanding of the interspecies cellular interactions underpinning the persistence and collapse of cyanobacterial blooms.

  • 30.
    Ahrén, Anna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Immunhistokemisk undersökning av paraffinbäddade celler från pleuravätska som kompletterande underlag för diagnos av cancermetastaser2005Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background. Immunohistochemistry is a useful method in the differential diagnosis between pleural mesotheliomas and metastatic adenocarcinomas in the pleura. Cytokeratin 20 and 7 have been used successfully as markers in studies determining primary location of adenocarcinomas from metastases. The current study is a complementary research of archived paraffininbedded material of cases with cancer origin. This study contributes a bigger statistical material that may facilitate the search for unknown primary site of adenocarcinoma by identification of metastatic cells in the pleura.

    Methods. Cells from the pleura taken from fifteen patients with diagnosed cancer of different types and eleven patients with cancer of unknown origin, were stained with antibodies against the tumour markers: Ber EP 4, calretinin, cytokeratin 20 and 7, estrogen receptor α, thyroid transcription factor, prostate-specific antigen and Cdx2.The staining was conducted in an automated immunohistochemical system. The staining of each kind of antibody was confirmed by a control section staining.

    Results. All control staining ended perfect The whole panel of antibodies used on mammary cancer showed the same pattern for every antibody. Of the patients with cancer of unknown origin there were four that gave the same pattern, two men and two women. The women are deceased. To make a more careful evaluation more information and clinic background is needed. The number of samples is too small to draw any statistical conclusions.

    Comment. Although the control staining was perfect the negative result of CK20 in the cases of diagnosed colon cancer was unexpected. This staining should be performed again to confirm the result. In some cases the number of cells were to few for a certain evaluation. The slides and the results of this work will be archived for further research.

  • 31. Ai, X
    et al.
    Do, AT
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lozynska, O
    Kusche-Gullberg, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Emerson CP, Jr
    QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfateproteoglycans to promote Wnt signaling.2003In: J Cell Biol, Vol. 162, p. 341-Article in journal (Refereed)
  • 32. Ai, X.
    et al.
    Kusche Gullberg, Marion
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Emerson, C.P. Jr.
    Remodeling of heparan sulfation by extracellular endosulfatases2006In: Chemistry and Biology of Heparin and Heparan Sulfate, Elsevier Science Ltd , 2006Chapter in book (Other scientific)
  • 33. Ai, Xingbin
    et al.
    Do, Anh-Tri
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kusche-Gullberg, Marion
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lu, Ke
    Emerson, Charles P
    Substrate specificity and domain functions of extracellular heparan sulfate 6-O-endosulfatases, QSulf1 and QSulf2.2006In: J Biol Chem, ISSN 0021-9258, Vol. 281, no 8, p. 4969-76Article in journal (Refereed)
  • 34. Ai, Xingbin
    et al.
    Do, Anh-Tri
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kusche-Gullberg, Marion
    Lindahl, Ulf
    Lu, Ke
    Emerson Jr, Charles P.
    Substrate Specificities and Domain Functions of Extracellular Heparan Sulfate 6-O-Endosulfatases, QSulf1 and QSulf22006In: The Journal of Biological Chemistry, ISSN 0021-9258, Vol. 281, no 8, p. 4969-4976Article in journal (Refereed)
  • 35. Ai, Xingbin
    et al.
    Do, Anh-Tri
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lozynska, Olga
    Kusche-Gullberg, Marion
    Lindahl, Ulf
    Emerson Jr, Charles P.
    QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling2003In: The Journal of Cell Biology, ISSN 0021-9525, Vol. 162, no 2, p. 341-351Article in journal (Refereed)
  • 36. Ai, Xingbin
    et al.
    Kitazawa, Toshio
    Do, Anh-Tri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kusche-Gullberg, Marion
    Labosky, Patricia A.
    Emerson, Charles P., Jr.
    SULF1 and SULF2 regulate heparan sulfate-mediated GDNF signaling for esophageal innervation2007In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 134, no 18, p. 3327-3338Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate (HS) plays an essential role in extracellular signaling during development. Biochemical studies have established that HS binding to ligands and receptors is regulated by the fine 6-O-sulfated structure of HS; however, mechanisms that control sulfated HS structure and associated signaling functions in vivo are not known. Extracellular HS 6-O-endosulfatases, SULF1 and SULF2, are candidate enzymatic regulators of HS 6-O-sulfated structure and modulate HS-dependent signaling. To investigate Sulf regulation of developmental signaling, we have disrupted Sulf genes in mouse and identified redundant functions of Sulfs in GDNF-dependent neural innervation and enteric glial formation in the esophagus, resulting in esophageal contractile malfunction in Sulf1(-/ -); Sulf2(-/ -) mice. SULF1 is expressed in GDNF-expressing esophageal muscle and SULF2 in innervating neurons, establishing their direct functions in esophageal innervation. Biochemical and cell signaling studies show that Sulfs are the major regulators of HS 6-O-desulfation, acting to reduce GDNF binding to HS and to enhance GDNF signaling and neurite sprouting in the embryonic esophagus. The functional specificity of Sulfs in GDNF signaling during esophageal innervation was established by showing that the neurite sprouting is selectively dependent on GDNF, but not on neurotrophins or other signaling ligands. These findings provide the first in vivo evidence that Sulfs are essential developmental regulators of cellular HS 6-O-sulfation for matrix transmission and reception of GDNF signal from muscle to innervating neurons.

  • 37.
    Ainhoa, Moliner Morro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Microbiology, Tumour and Cell Biology Department, Karolinska Institutet.
    Depicting the role of CD2AP during Old World alphavirus infection2017Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
  • 38.
    Akgun, Kocere Kurdé
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evaluation of Different Extraction- and Analysis Methods for Calprotectin in Feces2012Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Background Calprotectin is a protein expressed in the cytoplasm inside the neutrophile granulocytes. During inflammatory bowel disease (IBD), the neutrophile granulocytes are involved in a complex interaction at the inflammatory area where they die and release their content into the intestinal lumen. Therefore, calprotectin in stool is a suitable marker for diagnosis and measurement of the disease-activity in patients with IBD. The most commonly used method to detect calprotectin in stool is ELISA, but the process of manual preparation of stool samples is time-consuming.

    Aim The objective of the study was to evaluate an extraction method that could replace manual preparation of fecal samples and to compare different methods for measuring Calprotectin in stool using two ELISA-methods from two manufacturers and one rapidtest.

    Methods For extraction of calprotectin from stool samples we used sample collector tubes from Epitope Diagnostics and fecal preparation kits from Roche. Two different ELISA-kits for measuring calprotectin concentration in stool were compared. Measurements of calprotectin with rapid-test from Epitope Diagnostics were also performed and were compared with the two ELISA kits.

    Results The results indicate a poor correlation between two extraction methods with Sample Collector Tube and Roche preparation kit. The comparison between the two ELISA-kits showed poor correlation. Evaluation of rapid test showed 33% false negative results with a cut-off value at 50 mg/kg.

    Conclusion Evaluation of products from Epitope Diagnostics showed poor correlation with the Bühlmann ELISA and an unreliable rapid test. Therefore, none of evaluated products from Epitope Diagnostics is accurate enough to be used for clinical diagnosis in the laboratory.

  • 39. Aksaas, Anne Kristin
    et al.
    Eikvar, Sissel
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Skålhegg, Bjørn S
    Kvissel, Anne Katrine
    Protein kinase a-dependent phosphorylation of serine 119 in the proto-oncogenic serine/arginine-rich splicing factor 1 modulates its activity as a splicing enhancer protein.2011In: Genes & cancer, ISSN 1947-6027, Vol. 2, no 8, p. 841-851Article in journal (Refereed)
    Abstract [en]

    Serine/arginine-rich splicing factor 1 (SRSF1), previously designated SF2/ASF, belongs to a family of SR proteins that regulate constitutive and alternative splicing. SRSF1 expression is increased in tumors from several tissues and elicits changes in key target genes involved in tumor genesis. Several protein kinases phosphorylate SRSF1, which regulates its localization and function. It is previously reported that protein kinase A (PKA) phosphorylates SRSF1, but the importance of this modification is not well characterized. Here, we show that PKA phosphorylates SRSF1 on serine 119 in vitro. Phosphorylation of SRSF1 on this site enhanced the RNA binding capacity of SRSF1 in vivo and reduced the protein's capacity to activate splicing of the Minx transcript in vitro. We also confirm an interaction between SRSF1 and PKA Cα1 and demonstrate that this interaction is not dependent on serine 119 phosphorylation but requires active PKA Cα1. We conclude that PKA phosphorylation of SRSF1 at serine 119 regulates SFRS1-dependent RNA binding and processing but not its interaction with PKA.

  • 40.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gene expression, regulation of1995In: The Encyclopedia of Molecular Biology and Biotechnology / [ed] R. A. Meyers, VCH Publishers, New York. , 1995, p. 346-Chapter in book (Other academic)
  • 41.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gene expression, regulation of1996In: Encyclopedia of molecular biology and Molecular Medicine / [ed] R.A. Meyers, VCHPublishers, New York. , 1996, p. 364-375Chapter in book (Other academic)
  • 42.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Regulation of gene expression2000In: The Encyclopedia of Physical Science and Technology, Academic Press, San Diego , 2000, 3, Vol. 6, p. 501-517Chapter in book (Other academic)
  • 43.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Remodelling of the host cell RNA splicing machinery during an adenovirus infection1999In: Recent research developments in Virology / [ed] Pandalai, S.G., Trivandrum: Transworld Research Network , 1999, Vol. 1, p. 621-Chapter in book (Other academic)
  • 44.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjukdomsalstrande virus omskolas för att värna1996Other (Other academic)
  • 45.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Temporal regulation of adenovirus major late alternative RNA splicing2008In: Frontiers in Bioscience, ISSN 1093-9946, E-ISSN 1093-4715, Vol. 13, p. 5006-5015Article in journal (Refereed)
    Abstract [en]

    Adenovirus makes extensive use of alternative RNA splicing to produce a complex set of spliced mRNAs during replication. 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 virus life cycle are produced in a timely fashion. The complex interactions between the virus and the host cell RNA splicing machinery has been studied in detail during the last decade. These studies have resulted in the characterization of two viral proteins, E4-ORF4 and L4-33K, that adenovirus uses to remodel the host cell RNA splicing machinery. Here I will review the current knowledge of how mRNA expression from the adenovirus major late transcription unit is controlled with a particular emphasis on how cis-acting sequence element, trans-acting factors and mechanisms regulating adenovirus major late L1 alternative RNA splicing is controlled.

  • 46.
    Akusjärvi, Göran