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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, 316-331 p.Article 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, 27- p.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, 2004- p.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.

  • 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, 1188-1198 p.Article 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, 51-59 p.Article 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, 1526-1535 p.Article 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.
    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.

  • 12. 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 1553-7404, Vol. 10, no 2, e1003991- p.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.

  • 13.
    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.

  • 14.
    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, 220-6 p.Article in journal (Refereed)
  • 15.
    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)
  • 16.
    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, 469-76 p.Article in journal (Refereed)
  • 17.
    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, 469-76 p.Article in journal (Refereed)
  • 18.
    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, 291-293 p.Article 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.

  • 19.
    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, 461- p.Article in journal (Refereed)
  • 20.
    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, 333-337 p.Article 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.

  • 21.
    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, 333-337 p.Article 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.

  • 22.
    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.

  • 23.
    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, 89-96 p.Article in journal (Refereed)
  • 24.
    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, 931-40 p.Article in journal (Refereed)
  • 25.
    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, 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.

  • 26.
    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.

  • 27. 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, 341- p.Article in journal (Refereed)
  • 28. 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)
  • 29. 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, 4969-76 p.Article in journal (Refereed)
  • 30. 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, 4969-4976 p.Article in journal (Refereed)
  • 31. 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, 341-351 p.Article in journal (Refereed)
  • 32. 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, 3327-3338 p.Article 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.

  • 33.
    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.

  • 34. 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, 841-851 p.Article 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.

  • 35.
    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, 346- p.Chapter in book (Other academic)
  • 36.
    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, 364-375 p.Chapter in book (Other academic)
  • 37.
    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, 501-517 p.Chapter in book (Other academic)
  • 38.
    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, 621- p.Chapter in book (Other academic)
  • 39.
    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)
  • 40.
    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, Vol. 13, 5006-5015 p.Article 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.

  • 41.
    Akusjärvi, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kreivi, Jan-Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Petersen-Mahrt, Svend
    Messenger RNA in Eukaryotes2007In: Encyclopedia of Life Sciences, Chichester: John Wiley , 2007, 1-8 p.Chapter in book (Other academic)
    Abstract [en]

    Posttranscriptional regulation of gene expression represents an important level at which eukaryotes can expand the coding capacity of their genomes. The concept that one gene makes one protein does not apply to higher eukaryotes. Thus, a eukaryotic cell can use alternative ribonucleic acid (RNA) splicing, alternative polyadenylation and RNA editing to produce hundreds or even several thousands of protein isoforms from a single gene.

  • 42.
    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, Vol. 272, 253-286 p.Article 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.

  • 43. 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, 205-214 p.Article 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.

  • 44. 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, 541-554 p.Article 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.

  • 45. 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, 431-439 p.Article 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.

  • 46.
    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, 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.

  • 47. 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, Vol. 477, no 7366, 587-591 p.Article 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.

  • 48. 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, 1063-1068 p.Article 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.

  • 49.
    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.

  • 50.
    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, 1935-1943 p.Article 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.

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