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  • 151.
    Asplund, T
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Brinck, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Briskin, M.J.
    Heldin, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Partial purification and characterization of hyaluronan synthesizing activity from a human glioma cell line1998In: Biochim Biophys Acta, Vol. 1380, p. 377-Article in journal (Refereed)
  • 152.
    Assadian, Farzaneh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN USA..
    Kamel, Wael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Expression profile of Epstein-Barr virus and human adenovirus small RNAs in tonsillar B and T lymphocytes2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0177275Article in journal (Refereed)
    Abstract [en]

    We have used high-throughput small RNA sequencing to characterize viral small RNA expression in purified tonsillar B and T lymphocytes isolated from patients tested positive for Epstein-Barr virus (EBV) or human adenovirus (HAdV) infections, respectively. In the small set of patients analyzed, the expression profile of EBV and HAdV miRNAs could not distinguish between patients diagnosed with tonsillar hypertrophy or chronic/recurrent tonsillitis. The EBV miR-BART expression profile among the patients diagnosed with tonsillar diseases resembles most closely the pattern seen in EBV+ tumors (Latency II/I). The miRBARTs that appear to be absent in normal EBV infected cells are essentially all detectable in the diseased tonsillar B lymphocytes. In the EBV+ B cells we detected 44 EBV miRBARTs derived from the proposed BART precursor hairpins whereof five are not annotated in miRBase v21. One previously undetected miRNA, BART16b-5p, originates from the miR-BART16 precursor hairpin as an alternative 5 A miR-BART16 located precisely upstream of the annotated miR-BART16-5p. Further, our analysis revealed an extensive sequence variation among the EBV miRNAs with isomiRs having a constant 5 A end but alternative 3 A ends. A range of small RNAs was also detected from the terminal stem of the EBER RNAs and the 3 A part of v-snoRNA1. During a lytic HAdV infection in established cell lines the terminal stem of the viral non-coding VA RNAs are processed to highly abundant viral miRNAs (mivaRNAs). In contrast, mivaRNA expression in HAdV positive tonsillar T lymphocytes was very low. The small RNA profile further showed that the 5 A mivaRNA from VA RNAI and the 3 A mivaRNA from VA RNAII were as predicted, whereas the 3 A mivaRNA from VA RNAI showed an aberrant processing upstream of the expected Dicer cleavage site.

  • 153.
    Assadian, Farzaneh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandström, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Bondeson, Kåre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Lidian, Adnan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Distribution and Molecular Characterization of Human Adenovirus and Epstein-Barr Virus Infections in Tonsillar Lymphocytes Isolated from Patients Diagnosed with Tonsillar Diseases2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, article id e0154814Article in journal (Refereed)
    Abstract [en]

    Surgically removed palatine tonsils provide a conveniently accessible source of T and B lymphocytes to study the interplay between foreign pathogens and the host immune system. In this study we have characterised the distribution of human adenovirus (HAdV), Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) in purified tonsillar T and B cell-enriched fractions isolated from three patient age groups diagnosed with tonsillar hypertrophy and chronic/recurrent tonsillitis. HAdV DNA was detected in 93 out of 111 patients (84%), while EBV DNA was detected in 58 patients (52%). The most abundant adenovirus type was HAdV-5 (68%). None of the patients were positive for HCMV. Furthermore, 43 patients (39%) showed a co-infection of HAdV and EBV. The majority of young patients diagnosed with tonsillar hypertrophy were positive for HAdV, whereas all adult patients diagnosed with chronic/recurrent tonsillitis were positive for either HAdV or EBV. Most of the tonsils from patients diagnosed with either tonsillar hypertrophy or chronic/recurrent tonsillitis showed a higher HAdV DNA copy number in T compared to B cell-enriched fraction. Interestingly, in the majority of the tonsils from patients with chronic/recurrent tonsillitis HAdV DNA was detected in T cells only, whereas hypertrophic tonsils demonstrated HAdV DNA in both T and B cell-enriched fractions. In contrast, the majority of EBV positive tonsils revealed a preference for EBV DNA accumulation in the B cell-enriched fraction compared to T cell fraction irrespective of the patients' age.

  • 154.
    Assadian, Farzaneh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandström, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Efficient Isolation Protocol for B and T Lymphocytes from Human Palatine Tonsils2015In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, Vol. 105, article id e53374Article in journal (Refereed)
    Abstract [en]

    Palatine tonsils are a rich source of B and T lymphocytes. Here we provide an easy, efficient and rapid protocol to isolate B and T lymphocytes from human palatine tonsils. The method described has been specifically adapted for studies of the viral etiology of tonsil inflammation known as tonsillitis.

  • 155. Astrof, Sophie
    et al.
    Kirby, Andrew
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Daly, Mark
    Hynes, Richard O
    Heart development in fibronectin-null mice is governed by a genetic modifier on chromosome four2007In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 124, no 7-8, p. 551-558Article in journal (Refereed)
    Abstract [en]

    Absence of the fibronectin (FN) gene leads to early embryonic lethality in both 129S4 and C57BL/6J strains due to severe cardiovascular defects. However, heart development is arrested at different stages in these embryos depending on the genetic background. In the majority of 129S4 FN-null embryos, heart progenitors remain at their anterior bilateral positions and fail to fuse at the midline to form a heart tube. However, on the C57BL/6J genetic background, cardiac development progresses further and results in a centrally positioned and looped heart. To find factor(s) involved in embryonic heart formation and governing the extent of heart development in FN-null embryos in 129S4 and C57BL/6J strains, we performed genetic mapping and haplotype analyses. These analyses lead to identification of a significant linkage to a 1-Mbp interval on chromosome four. Microarray analysis and sequencing identified 21 genes in this region, including five that are differentially expressed between the strains, as potential modifiers. Since none of these genes was previously known to play a role in heart development, one or more of them is likely to be a novel modifier affecting cardiac development. Identification of the modifier would significantly enhance our understanding of the molecular underpinning of heart development and disease.

  • 156.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Börjesson, Stefan
    Natl Vet Inst SVA, Dept Anim Hlth & Antimicrobial Strategies, Uppsala, Sweden..
    Ny, Sofia
    Publ Hlth Agcy Sweden, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Stockholm, Sweden..
    Järhult, Josef D.
    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, Infectious Diseases.
    Byfors, Sara
    Publ Hlth Agcy Sweden, Stockholm, Sweden..
    Bonnedahl, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden.;Kalmar Cty Council, Dept Infect Dis, Kalmar, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    ESBL-producing Escherichia coli in Swedish gulls: A case of environmental pollution from humans?2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0190380Article in journal (Refereed)
    Abstract [en]

    ESBL-producing bacteria are present in wildlife and the environment might serve as a resistance reservoir. Wild gulls have been described as frequent carriers of ESBL-producing E. coli strains with genotypic characteristics similar to strains found in humans. Therefore, potential dissemination of antibiotic resistance genes and bacteria between the human population and wildlife need to be further investigated. Occurrence and characterization of ESBL-producing E. coli in Swedish wild gulls were assessed and compared to isolates from humans, livestock and surface water collected in the same country and similar time-period. Occurrence of ESBL-producing E. coli in Swedish gulls is about three times higher in gulls compared to Swedish community carriers (17% versus 5%) and the genetic characteristics of the ESBL-producing E. coli population in Swedish wild gulls and Swedish human are similar. ESBL-plasmids IncF-and IncI1-type carrying ESBL-genes blaCTX-M-15 or blaCTX-M-14 were most common in isolates from both gulls and humans, but there was limited evidence of clonal transmission. Isolates from Swedish surface water harbored similar genetic characteristics, which highlights surface waters as potential dissemination routes between wildlife and the human population. Even in a low-prevalence country such as Sweden, the occurrence of ESBL producing E. coli in wild gulls and the human population appears to be connected and the occurrence of ESBL-producing E. coli in Swedish gulls is likely a case of environmental pollution.

  • 157.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Mourkas, Evangelos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England.
    Meric, Guillaume
    Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England.
    Pascoe, Ben
    Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England;MRC CLIMB Consortium, Bath, Avon, England.
    Wang, Helen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Waldenström, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden.
    Sheppard, Samuel K.
    Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England;MRC CLIMB Consortium, Bath, Avon, England.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Ellström, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    The Potential of Isolation Source to Predict Colonization in Avian Hosts: A Case Study in Campylobacter jejuni Strains From Three Bird Species2018In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 9, article id 591Article in journal (Refereed)
    Abstract [en]

    Campylobacter jejuni is the primary cause of bacterial gastroenteritis worldwide, infecting humans mostly through consumption of contaminated poultry. C. jejuni is common in the gut of wild birds, and shows distinct strain-specific association to particular bird species. This contrasts with farm animals, in which several genotypes co-exist. It is unclear if the barriers restricting transmission between host species of such specialist strains are related to environmental factors such as contact between host species, bacterial survival in the environment, etc., or rather to strain specific adaptation to the intestinal environment of specific hosts. We compared colonization dynamics in vivo between two host-specific C. jejuni from a song thrush (ST-1304 complex) and a mallard (ST-995), and a generalist strain from chicken (ST-21 complex) in a wild host, the mallard (Anas platyrhynchos). In 18-days infection experiments, the song thrush strain showed only weak colonization and was cleared from all birds after 10 days, whereas both mallard and chicken strains remained stable. When the chicken strain was given 4 days prior to co-infection of the same birds with a mallard strain, it was rapidly outcompeted by the latter. In contrast, when the mallard strain was given 4 days prior to co-infection with the chicken strain, the mallard strain remained and expansion of the chicken strain was delayed. Our results suggest strain-specific differences in the ability of C. jejuni to colonize mallards, likely associated with host origin. This difference might explain observed host association patterns in C. jejuni from wild birds.

  • 158.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ramey, Andrew M.
    Gustafsson Hall, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Järhult, Josef
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Börjesson, Stefan
    Bonnedahl, Jonas
    Increased prevalence of antibiotic resistant E. coli in gulls sampled in Southcentral Alaska is associated with urban environments2016In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 6, no 1, article id 32334Article in journal (Refereed)
    Abstract [en]

    Background : Antibiotic-resistant bacteria pose challenges to healthcare delivery systems globally; however, limited information is available regarding the prevalence and spread of such bacteria in the environment. The aim of this study was to compare the prevalence of antibiotic-resistant bacteria in large-bodied gulls ( Larus spp.) at urban and remote locations in Southcentral Alaska to gain inference into the association between antibiotic resistance in wildlife and anthropogenically influenced habitats. Methods : Escherichia coli was cultured ( n 115 isolates) from fecal samples of gulls (n 160) collected from a remote location, Middleton Island, and a more urban setting on the Kenai Peninsula. Results : Screening of E. coli from fecal samples collected from glaucous-winged gulls ( Larus glaucescens )at Middleton Island revealed 8% of isolates were resistant to one or more antibiotics and 2% of the isolates were resistant to three or more antibiotics. In contrast, 55% of E. coli isolates derived from fecal samples collected from large-bodied gulls (i.e. glaucous, herring [ Larus argentatus ], and potentially hybrid gulls) on the Kenai Peninsula were resistant to one or more antibiotics and 22% were resistant to three or more antibiotics. In addition, total of 16% of the gull samples from locations on the Kenai Peninsula harbored extended-spectrum cephalosporin-resistant E. coli isolates (extended-spectrum beta-lactamases [ESBL] and plasmid-encoded AmpC [pAmpC]), in contrast to Middleton Island where no ESBL- or pAmpC-producing isolates were detected. Conclusion : Our findings indicate that increased prevalence of antibiotic resistance is associated with urban environments in Southcentral Alaska and presumably influenced by anthropogenic impacts. Further investigation is warranted to assess how migratory birds may maintain and spread antimicrobial-resistant bacteria of relevance to human and animal health.

  • 159.
    Augustsson, Mirja
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Co-localization of the astrocytic proteins Mts1 and clusterin in CNS injury2005Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    In the case of injury to the CNS, different proteins act to repair and protect cells in the brain and spinal cord. In the present study, we looked at dorsal root injury and hypoglossal nerve avulsion and transection. Here we studied for the first time the expression of Parkin in these types of injuries. However the antibodies against Parkin used here have not been able to detect Parkin in the injuries examined, neither with fluorescence or using DAB. The roles of Mts1, GFAP, and clusterin after injury have been investigated earlier, but their co-localization in the same cells was first shown in this study in the hypoglossal nucleus with immunohisto-chemical methods. These results may also be of value in the process of finding an effective treatment for neurodegenerative disorders such as ALS.

  • 160.
    Aveskogh, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evidence for an early appearance of modern postswitch isotypes in mammalian evolution: cloning of IgE, IgG and IgA from the marsupial Monodelphis domestica.1998In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 28, no 9, p. 2738-2750Article in journal (Refereed)
    Abstract [en]

    In birds, reptiles and amphibians the IgY isotype exhibits the functional characteristics of both of IgG and IgE. Hence, the gene for IgY most likely duplicated some time during early mammalian evolution and formed the ancestor of present day IgG and IgE. To address the question of when IgY duplicated and formed two functionally distinct isotypes, and to study when IgG and IgA lost their second constant domains, we have examined the Ig expression in a non-placental mammal, the marsupial Monodelphis domestica (grey short-tailed opossum). Screening of an opossum spleen cDNA library revealed the presence of all three isotypes in marsupials. cDNA clones encoding the entire constant regions of opossum IgE (epsilon chain), IgG (gamma chain) and IgA (alpha chain) were isolated, and their nucleotide sequences were determined. A comparative analysis of the amino acid sequences for IgY, IgA, IgE and IgG from various animal species showed that opossum IgE, IgG and IgA on the phylogenetic tree form branches clearly separated from their eutherian counterparts. However, they still conform to the general structure found in eutherian IgE, IgG and IgA. Our findings indicate that all the major evolutionary changes in the Ig isotype repertoire, and in basic Ig structure that have occurred since the evolutionary separation of mammals from the early reptile lineages, occurred prior to the evolutionary separation of marsupials and placental mammals.

  • 161.
    Aveskogh, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evidence for an early appearence ofmodern post switch isotypes in mammalian evolution: Cloning of IgE, IgGand IgA from the marsupial Monodelphis domestica1998In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 28, no 9, p. 2738-2750Article in journal (Refereed)
    Abstract [en]

    In birds, reptiles and amphibians the IgY isotype exhibits the functional characteristics of both of IgG and IgE. Hence, the gene for IgY most likely duplicated some time during early mammalian evolution and formed the ancestor of present day IgG and IgE. To address the question of when IgY duplicated and formed two functionally distinct isotypes, and to study when IgG and IgA lost their second constant domains, we have examined the Ig expression in a non-placental mammal, the marsupial Monodelphis domestica (grey short-tailed opossum). Screening of an opossum spleen cDNA library revealed the presence of all three isotypes in marsupials. cDNA clones encoding the entire constant regions of opossum IgE (ϵ chain), IgG (γ chain) and IgA (α chain) were isolated, and their nucleotide sequences were determined. A comparative analysis of the amino acid sequences for IgY, IgA, IgE and IgG from various animal species showed that opossum IgE, IgG and IgA on the phylogenetic tree form branches clearly separated from their eutherian counterparts. However, they still conform to the general structure found in eutherian IgE, IgG and IgA. Our findings indicate that all the major evolutionary changes in the Ig isotype repertoire, and in basic Ig structure that have occurred since the evolutionary separation of mammals from the early reptile lineages, occurred prior to the evolutionary separation of marsupials and placental mammals.

  • 162.
    Avril, Alexis
    et al.
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst EEMiS, SE-39182 Kalmar, Sweden..
    Grosbois, Vladimir
    CIRAD, Campus Int Baillarguet, F-34398 Montpellier, France..
    Latorre-Margalef, Neus
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst EEMiS, SE-39182 Kalmar, Sweden.;Univ Georgia, Southeeastern Cooperat Wildlife Dis Study, Coll Vet Med, Dept Populat Hlth, Athens, GA 30602 USA..
    Gaidet, Nicolas
    CIRAD, Campus Int Baillarguet, F-34398 Montpellier, France..
    Tolf, Conny
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst EEMiS, SE-39182 Kalmar, Sweden..
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Waldenström, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst EEMiS, SE-39182 Kalmar, Sweden..
    Capturing individual-level parameters of influenza A virus dynamics in wild ducks using multistate models2016In: Journal of Applied Ecology, ISSN 0021-8901, E-ISSN 1365-2664, Vol. 53, no 4, p. 1289-1297Article in journal (Refereed)
    Abstract [en]

    Disease prevalence in wildlife is governed by epidemiological parameters (infection and recovery rates) and response to infection, both of which vary within and among individual hosts. Studies quantifying these individual-scale parameters and documenting their source of variation in wild hosts are fundamental for predicting disease dynamics. Such studies do not exist for the influenza A virus (IAV), despite its strong impact on the global economy and public health. Using capture-recaptures of 3500 individual mallards Anas platyrhynchos during seven migration seasons at a stopover site in southern Sweden, we provide the first empirical description of the individual-based mechanisms of IAV dynamics in a wild reservoir host. For most years, prevalence and risk of IAV infection peaked at a single time during the autumn migration season, but the timing, shape and intensity of the infection curve showed strong annual heterogeneity. In contrast, the seasonal pattern of recovery rate only varied in intensity across years. Adults and juveniles displayed similar seasonal patterns of infection and recovery each year. However, compared to adults, juveniles experienced twice the risk of becoming infected, whereas recovery rates were similar across age categories. Finally, we did not find evidence that infection influenced the timing of emigration.Synthesis and applications. Our study provides robust empirical estimates of epidemiological parameters for predicting influenza A virus (IAV) dynamics. However, the strong annual variation in infection curves makes forecasting difficult. Prevalence data can provide reliable surveillance indicators as long as they catch the variation in infection risk. However, individual-based monitoring of infection is required to verify this assumption in areas where surveillance occurs. In this context, monitoring of captive sentinel birds kept in close contact with wild birds is useful. The fact that infection does not impact the timing of migration underpins the potential for mallards to spread viruses rapidly over large geographical scales. Hence, we strongly encourage IAV surveillance with a multistate capture-recapture approach along the entire migratory flyway of mallards.

  • 163. Awano, Tomoyuki
    et al.
    Johnson, Gary S.
    Wade, Claire M.
    Katz, Martin L.
    Johnson, Gayle C.
    Taylor, Jeremy F.
    Perloski, Michele
    Biagi, Tara
    Baranowska, Izabella
    Long, Sam
    March, Philip A.
    Olby, Natasha J.
    Shelton, G. Diane
    Khan, Shahnawaz
    O'Brien, Dennis P.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Coates, Joan R.
    Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 8, p. 2794-2799Article in journal (Refereed)
    Abstract [en]

    Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.

  • 164. Axelman, Elena
    et al.
    Henig, Israel
    Crispel, Yonatan
    Attias, Judith
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Brenner, Benjamin
    Vlodavsky, Israel
    Nadir, Yona
    Novel peptides that inhibit heparanase activation of the coagulation system2014In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 112, no 3, p. 466-477Article in journal (Refereed)
    Abstract [en]

    Heparanase is implicated in cell invasion, tumour metastasis and angiogenesis. It forms a complex and enhances the activity of the blood coagulation initiator tissue factor (IF). We describe new peptides derived from the solvent accessible surface of TF pathway inhibitor 2 (TFPI-2) that inhibit the heparanase procoagulant activity. Peptides were evaluated in vitro by measuring activated coagulation factor X levels and co-immunoprecipitation. Heparanase protein and/or lipopolysaccharide (LPS) were injected intra-peritoneally and inhibitory peptides were injected subcutaneously in mouse models. Plasma was analysed by ELISA for thrombin-antithrombin complex (TAT), D-dimer as markers of coagulation activation, and interleukin 6 as marker of sepsis severity. Peptides 5, 6, 7, 21 and 22, at the length of 11-14 amino acids, inhibited heparanase procoagulant activity but did not affect IF activity. Injection of newly identified peptides 5, 6 and 7 significantly decreased or abolished TAT plasma levels when heparanase or LPS were pre-injected, and inhibited clot formation in an inferior vena cava thrombosis model. To conclude, the solvent accessible surface of TFPI-2 first Kunitz domain is involved in TF/heparanase complex inhibition. The newly identified peptides potentially attenuate activation of the coagulation system induced by heparanase or LPS without predisposing to significant bleeding tendency.

  • 165.
    Axelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ratnakumar, Abhirami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arendt, Maja Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maqbool, Khurram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Perloski, Michele
    Liberg, Olof
    Arnemo, Jon M.
    Hedhammar, Ake
    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 genomic signature of dog domestication reveals adaptation to a starch-rich diet2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 495, no 7441, p. 360-364Article in journal (Refereed)
    Abstract [en]

    The domestication of dogs. was an important episode in the development of human civilization. The precise timing and location of this event is debated(1-5) and little is known about the genetic changes that accompanied the transformation of ancient wolves into domestic dogs. Here we conduct whole-genome resequencimg of dogs and wolves to identify 3.8 million genetic variants used to identify 36 genomic regions that probably represent targets for selection during dog domestication. Nineteen of these regions contain genes important in brain function, eight of which belong to nervous system development pathways and potentially underlie behavioural changes central to dog domestication(6). Ten genes with key roles in starch digestion and fat metabolism also show signals of selection. We identify candidate mutations in key genes and provide functional support for an increased starch digestion in dogs relative to wolves. Our results indicate that novel adaptations allowing the early ancestors of modern dogs to thrive on a diet rich in starch, relative to the carnivorous diet of wolves, constituted a crucial step in the early domestication of dogs.

  • 166.
    Axelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ratnakumar, Abhirami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ponting, Chris P.
    Univ Oxford, MRC Funct Genom Unit, Dept Physiol Anat & Genet, Oxford OX1 3QX, England.
    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. Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA 02139 USA.
    Death of PRDM9 coincides with stabilization of the recombination landscape in the dog genome2011In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 22, no 1, p. 51-63Article in journal (Refereed)
    Abstract [en]

    Analysis of diverse eukaryotes has revealed that recombination events cluster in discrete genomic locations known as hotspots. In humans, a zinc-finger protein, PRDM9, is believed to initiate recombination in >40% of hotspots by binding to a specific DNA sequence motif. However, the PRDM9 coding sequence is disrupted in the dog genome assembly, raising questions regarding the nature and control of recombination in dogs. By analyzing the sequences of PRDM9 orthologs in a number of dog breeds and several carnivores, we show here that this gene was inactivated early in canid evolution. We next use patterns of linkage disequilibrium using more than 170,000 SNP markers typed in almost 500 dogs to estimate the recombination rates in the dog genome using a coalescent-based approach. Broad-scale recombination rates show good correspondence with an existing linkage-based map. Significant variation in recombination rate is observed on the fine scale, and we are able to detect over 4000 recombination hotspots with high confidence. In contrast to human hotspots, 40% of canine hotspots are characterized by a distinct peak in GC content. A comparative genomic analysis indicates that these peaks are present also as weaker peaks in the panda, suggesting that the hotspots have been continually reinforced by accelerated and strongly GC biased nucleotide substitutions, consistent with the long-term action of biased gene conversion on the dog lineage. These results are consistent with the loss of PRDM9 in canids, resulting in a greater evolutionary stability of recombination hotspots. The genetic determinants of recombination hotspots in the dog genome may thus reflect a fundamental process of relevance to diverse animal species.

  • 167.
    Axemo, P
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Brauner, A
    Department of Medical Biochemistry and Microbiology.
    Pettersson, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Eriksson, L
    Department of Genetics and Pathology.
    Rwamushaija, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Bergstrom, S
    Amniotic fluid interleukins in Swedish and Mozambican pregnant women.1996In: Gynecol Obstet Invest, Vol. 41, p. 113-Article in journal (Refereed)
  • 168. Axen, A
    et al.
    Carlsson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Engstrom, Å
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bennich, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gloverin, an antibacterial protein from the immune hemolymph of Hyalophora pupae1997In: European Journal of Biochemsitry, Vol. 247, p. 614-Article in journal (Refereed)
  • 169.
    Ayllon, Fernando
    et al.
    Inst Marine Res, N-5024 Bergen, Norway..
    Kjaerner-Semb, Erik
    Inst Marine Res, N-5024 Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Furmanek, Tomasz
    Inst Marine Res, N-5024 Bergen, Norway..
    Wennevik, Vidar
    Inst Marine Res, N-5024 Bergen, Norway..
    Solberg, Monica F.
    Inst Marine Res, N-5024 Bergen, Norway..
    Dahle, Geir
    Inst Marine Res, N-5024 Bergen, Norway..
    Taranger, Geir Lasse
    Inst Marine Res, N-5024 Bergen, Norway..
    Glover, Kevin A.
    Inst Marine Res, N-5024 Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Almén, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Edvardsen, Rolf B.
    Inst Marine Res, N-5024 Bergen, Norway..
    Wargelius, Anna
    Inst Marine Res, N-5024 Bergen, Norway..
    The vgll3 Locus Controls Age at Maturity in Wild and Domesticated Atlantic Salmon (Salmo salar L.) Males2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 11, article id e1005628Article in journal (Refereed)
    Abstract [en]

    Wild and domesticated Atlantic salmon males display large variation for sea age at sexual maturation, which varies between 1-5 years. Previous studies have uncovered a genetic predisposition for variation of age at maturity with moderate heritability, thus suggesting a polygenic or complex nature of this trait. The aim of this study was to identify associated genetic loci, genes and ultimately specific sequence variants conferring sea age at maturity in salmon. We performed a genome wide association study (GWAS) using a pool sequencing approach (20 individuals per river and phenotype) of male salmon returning to rivers as sexually mature either after one sea winter (2009) or three sea winters (2011) in six rivers in Norway. The study revealed one major selective sweep, which covered 76 significant SNPs in which 74 were found in a 370 kb region of chromosome 25. Genotyping other smolt year classes of wild and domesticated salmon confirmed this finding. Genotyping domesticated fish narrowed the haplotype region to four SNPs covering 2386 bp, containing the vgll3 gene, including two missense mutations explaining 33-36% phenotypic variation. A single locus was found to have a highly significant role in governing sea age at maturation in this species. The SNPs identified may be both used as markers to guide breeding for late maturity in salmon aquaculture and in monitoring programs of wild salmon. Interestingly, a SNP in proximity of the VGLL3 gene in humans (Homo sapiens), has previously been linked to age at puberty suggesting a conserved mechanism for timing of puberty in vertebrates.

  • 170. Babiker, Hamza A.
    et al.
    Hastings, Ian M.
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Impaired fitness of drug-resistant malaria parasites: evidence and implication on drug-deployment policies2009In: Expert review of anti-infective therapy, ISSN 1478-7210, Vol. 7, no 5, p. 581-593Article, review/survey (Refereed)
    Abstract [en]

    Malaria, a leading parasitic disease, inflicts an enormous toll on human lives and is caused by protozoal parasites belonging to the genus Plasmodium. Antimalarial drugs targeting essential biochemical processes in the parasite are the primary resources for management and control. However, the parasite has established mutations, substantially reducing the efficacy of these drugs. First-line therapy is faced the with the consistent evolution of drug-resistant genotypes carrying these mutations. However, drug-resistant genotypes are likely to be less fit than the wild-type, suggesting that they might disappear by reducing the volume of drug pressure. A substantial body of epidemiological evidence confirmed that the frequency of resistant genotypes wanes when active drug selection declines. Drug selection on the parasite genome that removes genetic variation in the vicinity of drug-resistant genes (hitch-hiking) is common among resistant parasites in the field. This can further disadvantage drug-resistant strains and limit their variability in the face of a mounting immune response. Attempts to provide unequivocal evidence for the fitness cost of drug resistance have monitored the outcomes of laboratory competition experiments of deliberate mixtures of sensitive and resistant strains, in the absence of drug pressure, using isogenic clones produced either by drug selection or gene manipulation. Some of these experiments provided inconclusive results, but they all suggested reduced fitness of drug-resistant clones in the absence of drug pressure. In addition, biochemical analyses provided clearer information demonstrating that the mutation of some antimalarial-targeted enzymes lowers their activity compared with the wild-type enzyme. Here, we review current evidences for the disadvantage of drug-resistance mutations, and discuss some strategies of drug deployment to maximize the cost of resistance and limit its spread.

  • 171.
    Babina, Arianne M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Boston Coll, Dept Biol, Chestnut Hill, MA 02467 USA.
    Parker, Darren J.
    MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
    Li, Gene-Wei
    MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
    Meyer, Michelle M.
    Boston Coll, Dept Biol, Chestnut Hill, MA 02467 USA.
    Fitness advantages conferred by the L20-interacting RNA cis-regulator of ribosomal protein synthesis in Bacillus subtilis2018In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 24, no 9, p. 1133-1143Article in journal (Refereed)
    Abstract [en]

    In many bacteria, ribosomal proteins autogenously repress their own expression by interacting with RNA structures typically located in the 5'-UTRs of their mRNA transcripts. This regulation is necessary to maintain a balance between ribosomal proteins and rRNA to ensure proper ribosome production. Despite advances in noncoding RNA discovery and validation of RNA-protein regulatory interactions, the selective pressures that govern the formation and maintenance of such RNA cis-regulators in the context of an organism remain largely undetermined. To examine the impact disruptions to this regulation have on bacterial fitness, we introduced point mutations that abolish ribosomal protein binding and regulation into the RNA structure that controls expression of ribosomal proteins L20 and L35 within the Bacillus subtilis genome. Our studies indicate that removing this regulation results in reduced log phase growth, improper rRNA maturation, and the accumulation of a kinetically trapped or misassembled ribosomal particle at low temperatures, suggesting defects in ribosome synthesis. Such work emphasizes the important role regulatory RNAs play in the stoichiometric production of ribosomal components for proper ribosome composition and overall organism viability and reinforces the potential of targeting ribosomal protein production and ribosome assembly with novel antimicrobials.

  • 172. Bach, Anders
    et al.
    Chi, Celestine N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsen, Thomas B
    Pedersen, Søren W
    Røder, Martin U
    Pang, Gar F
    Clausen, Rasmus P
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Strømgaard, Kristian
    Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction.2008In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 20, p. 6450-9Article in journal (Refereed)
    Abstract [en]

    The protein-protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treatment of ischemic brain diseases. An undecapeptide corresponding to the C-terminal of the NMDA was used as a template for finding lead candidates for the inhibition of the PSD-95/NMDA receptor interaction. Initially, truncation and alanine scan studies were carried out, which resulted in a pentapeptide with wild-type affinity, as examined in a fluorescence polarization assay. Further examination was performed by systematic substitutions with natural and unnatural amino acids, which disclosed a tripeptide with micromolar affinity and N-methylated tetrapeptides with improved affinities. Molecular modeling studies guided further N-terminal modifications and introduction of a range of N-terminal substitutions dramatically improved affinity. The best compound, N-cyclohexylethyl-ETAV (56), demonstrated up to 19-fold lower K i value ( K i = 0.94 and 0.45 microM against PDZ1 and PDZ2 of PSD-95, respectively) compared to wild-type values, providing the most potent inhibitors of this interaction reported so far. These novel and potent inhibitors provide an important basis for development of small molecule inhibitors of the PSD-95/NMDA receptor interaction.

  • 173. Bach, Anders
    et al.
    Chi, Celestine N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pang, Gar F.
    Olsen, Lars
    Kristensen, Anders S.
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Strømgaard, Kristian
    Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95-NMDA receptor interaction2009In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 48, no 51, p. 9685-9689Article in journal (Refereed)
    Abstract [en]

    On the double: Dimerization of monomeric peptide ligands towards the PDZ domains of the protein PSD-95 (postsynaptic density 95) leads to potent inhibitors of protein-protein interactions with stability in blood plasma. Optimization of the length of the polyethylene glycol linker results in unprecedented affinity for inhibitors of the PDZ1-2 domain.

  • 174. Bach, Anders
    et al.
    Clausen, Bettina H.
    Moller, Magda
    Vestergaard, Bente
    Chi, Celestine N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Round, Adam
    Sorensen, Pernille L.
    Nissen, Klaus B.
    Kastrup, Jette S.
    Gajhede, Michael
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kristensen, Anders S.
    Lundström, Patrik
    Lambertsen, Kate L.
    Stromgaard, Kristian
    A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 9, p. 3317-3322Article in journal (Refereed)
    Abstract [en]

    Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.

  • 175.
    Backström, Ellenor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Regulation of Adenoviral Gene Expression by the L4-33K and L4-22K Proteins2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The splicing pattern during an adenovirus infection is shifted at the late phase towards using weaker splice sites, splicing out larger introns. Splicing of weak 3´ splice sites usually requires recognition of the 3´AG dinucleotide before the first catalytic step of splicing. Such splicing events are said to be AG-dependent and requires an interaction of both subunits of the cellular splicing factor U2AF with the 3´ splice site. We show that splicing of transcripts that are AG-dependent in uninfected nuclear extracts (NE) becomes AG-independent in nuclear extracts prepared form adenovirus late-infected HeLa cells (Ad-NE). Further we demonstrate that the first step in splicing of a model transcript, IgM, becomes completely U2AF-independent in Ad-NE. This finding supports our working model that 3´ splice site recognition in Ad-NE is altered, and in fact might be U2AF-independent.

    We further show that the adenovirus late protein L4-33K acts as a virus encoded alternative splicing factor. L4-33K activates splicing of both cellular and viral transcripts containing weak 3´ splice sites. This supports the hypothesis that adenovirus alter splicing during the infection to favour usage of weak, suboptimal 3´ splice sites. However, we were unable to find an alternative U2AF-related factor that could stimulate L4-33K splicing enhancer activity. Furthermore, we demonstrate that the serine residues in the C-terminal part of L4-33K are important for the splicing enhancer activity but also for its nuclear localisation.

    The adenovirus major late promoter is highly activated after the onset of viral genome replication. Protein complexes binding to downstream elements of the promoter are required for full enhancement of this promoter. We show that an L4-33K-related protein, L4-22K, stimulates transcription from the major late promoter. This stimulation is mainly via the downstream elements and does not require the viral IVa2 protein, which is a transcription factor of the major late promoter.

    List of papers
    1. Substrate-dependent differences in U2AF requirement for splicing in adenovirus-infected cell extracts.
    Open this publication in new window or tab >>Substrate-dependent differences in U2AF requirement for splicing in adenovirus-infected cell extracts.
    2005 (English)In: J Biol Chem, ISSN 0021-9258, Vol. 280, no 27, p. 25478-84Article in journal (Refereed) Published
    Keywords
    Adenoviridae/*genetics, Adenoviridae Infections/*genetics/*metabolism, Cell Extracts, Hela Cells, Humans, Immunoglobulin M/genetics, Introns/physiology, Nuclear Proteins/*metabolism, RNA Precursors/*metabolism, RNA Splice Sites/physiology, RNA Splicing/*physiology, RNA; Small Nuclear/metabolism, Research Support; Non-U.S. Gov't, Ribonucleoproteins/*metabolism
    Identifiers
    urn:nbn:se:uu:diva-80306 (URN)15899895 (PubMedID)
    Available from: 2006-05-05 Created: 2006-05-05 Last updated: 2011-01-11
    2. L4-33K, an adenovirus-encoded alternative RNA splicing factor
    Open this publication in new window or tab >>L4-33K, an adenovirus-encoded alternative RNA splicing factor
    2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 48, p. 36510-36517Article in journal (Refereed) Published
    Abstract [en]

    Splicing of the adenovirus IIIa mRNA is subjected to a strict temporal regulation during virus infection such that efficient IIIa 3' splice site usage is confined to the late phase of the infectious cycle. Here we show that the adenovirus L4-33K protein functions as a virus-encoded RNA splicing factor that preferentially activates splicing of transcripts with a weak 3' splice site sequence context, a sequence configuration that is shared by many of the late adenovirus 3' splice sites. Furthermore, we show that L4-33K activates IIIa splicing through the IIIa virus infection-dependent splicing enhancer element (3VDE). This element was previously shown to be the minimal element, both necessary and sufficient, for activation of IIIa splicing in the context of an adenovirus-infected cell. L4-33K stimulates an early step in spliceosome assembly and appears to be the only viral protein necessary to convert a nuclear extract prepared from uninfected HeLa cells to an extract with splicing properties very similar to a nuclear extract prepared from adenovirus late-infected cells. Collectively, our results suggest that L4-33K is the key viral protein required to activate the early to late switch in adenovirus major late L1 alternative splicing.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-22559 (URN)10.1074/jbc.M607601200 (DOI)000242220800006 ()17028184 (PubMedID)
    Available from: 2007-01-18 Created: 2007-01-18 Last updated: 2017-12-07Bibliographically approved
    3. Regulation of Adenovirus Late Region 1 Splicing
    Open this publication in new window or tab >>Regulation of Adenovirus Late Region 1 Splicing
    (English)Manuscript (Other academic)
    Abstract [en]

    The major late transcription unit (MLTU) produces one pre-mRNA that is processed into more than 20 cytoplasmic mRNAs by alternative polyadenylation and extensive alternative 3' splice site usage. The alternative splicing of the MLTU is temporally regulated, resulting in the expression of only one mRNA, the L1 52,55K, before the onset of viral genome replication. The L1 unit also encodes the IIIa mRNA, the expression of which is highly regulated at the level of splicing. We have previously shown that the adenoviral L4-33K protein enhances IIIa splicing via the IIIa virus infection-dependent splicing enhancer element. In this study we show that serine to glycine mutations in the tiny RS domain of the L4-33K protein retain more activity in vivo compared to results obtained previously in vitro. In addition, it is also clear that these mutations in the RS domain affect the sub-cellular localization of L4-33K. Thus, the RS domain appears to contain a nuclear localisation signal that is dependent on the serine residues. In a previous report we showed that, in extracts prepared from adenovirus-infected cells, splicing is independent of the general splicing factor U2AF. In this study we also demonstrate that none of the tested U2AF-replacement candidate proteins (PUF60, Caper α, and Caper β) collaborate with L4-33K in the activation of IIIa splicing. It has been suggested that regulation of L1 alternative splicing does not require cis-competition between the 52.55K and IIIa 3' splice sites. We find that activity of the IIIa splice site increases considerably in the absence of cis-competition with the 52,55K splice site. Interestingly, this cis-competition is not virus-specific since this observation is reproducible in a transcription unit where the β-globin 3' splice site replaces the natural 52,55K 3' splice site. We conclude that L1 alternative splicing conforms to the general rule in that it ordinarily makes use of the proximal 3' splice site (52,55K), whereas activation of distal 3' splice site usage requires active intervention. In adenovirus this intervention is achieved by production of the L4-33K protein.

    Keywords
    Adenovirus, L4-33K, Splicing, 3VDF
    Identifiers
    urn:nbn:se:uu:diva-101308 (URN)
    Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2011-06-28
    4. Adenovirus L4-22K stimulates major late transcription by a mechanism requiring the intragenic late-specific transcription factor-binding site
    Open this publication in new window or tab >>Adenovirus L4-22K stimulates major late transcription by a mechanism requiring the intragenic late-specific transcription factor-binding site
    2010 (English)In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 151, no 2, p. 220-228Article in journal (Refereed) Published
    Abstract [en]

    The adenovirus major late promoter (MLP) generates a primary transcript that undergoes a complex pattern of regulated alternative RNA splicing and polyadenylation events. The late-specific activation of the MLP requires binding of two infected-cell specific transcription factor complexes, DEF-A and DEF-B, to the so-called DE sequence located downstream of the MLP start site. Previous studies have shown that DEF-B is a homodimer of the viral IVa2 protein and suggested that DEF-A is a heterodimer of IVa2 and an unknown protein. Here we have searched for a possible DEF-A candidate protein. The adenovirus L4-33K protein functions as a virus-encoded alternative RNA splicing factor, stimulating cytoplasmic accumulation of most late viral mRNAs. Interestingly, the L4 region also encodes for a second related protein, L4-22K, which share the 105 amino-terminal amino acids with L4-33K. Here we show that L4-22K both in vivo and in vitro stimulates transcription from the MLP in a DE sequence dependent manner. We also show that the viral pIX promoter is a natural target, activated by L4-22K. Interestingly, the position of the L4-22K DNA binding site in a promoter does not appear to be critical for function. Thus, tethering L4-22K, as a BPV E2 DNA binding domain fusion protein either to a position upstream or downstream of the MLP start site, or upstream of a minimal E1B promoter, resulted in an activation of transcription. Collectively, our results are compatible with the hypothesis that L4-22K may be the elusive component of DEF-A that partakes in activation of the MLP.

    Keywords
    Adenovirus, L4-22K, MLP, transcription, DE elements
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-101310 (URN)10.1016/j.virusres.2010.05.013 (DOI)000280210000015 ()20621673 (PubMedID)
    Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2017-12-13Bibliographically approved
  • 176.
    Backström, Ellenor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kaufmann, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lan, Xin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Adenovirus L4-22K stimulates major late transcription by a mechanism requiring the intragenic late-specific transcription factor-binding site2010In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 151, no 2, p. 220-228Article in journal (Refereed)
    Abstract [en]

    The adenovirus major late promoter (MLP) generates a primary transcript that undergoes a complex pattern of regulated alternative RNA splicing and polyadenylation events. The late-specific activation of the MLP requires binding of two infected-cell specific transcription factor complexes, DEF-A and DEF-B, to the so-called DE sequence located downstream of the MLP start site. Previous studies have shown that DEF-B is a homodimer of the viral IVa2 protein and suggested that DEF-A is a heterodimer of IVa2 and an unknown protein. Here we have searched for a possible DEF-A candidate protein. The adenovirus L4-33K protein functions as a virus-encoded alternative RNA splicing factor, stimulating cytoplasmic accumulation of most late viral mRNAs. Interestingly, the L4 region also encodes for a second related protein, L4-22K, which share the 105 amino-terminal amino acids with L4-33K. Here we show that L4-22K both in vivo and in vitro stimulates transcription from the MLP in a DE sequence dependent manner. We also show that the viral pIX promoter is a natural target, activated by L4-22K. Interestingly, the position of the L4-22K DNA binding site in a promoter does not appear to be critical for function. Thus, tethering L4-22K, as a BPV E2 DNA binding domain fusion protein either to a position upstream or downstream of the MLP start site, or upstream of a minimal E1B promoter, resulted in an activation of transcription. Collectively, our results are compatible with the hypothesis that L4-22K may be the elusive component of DEF-A that partakes in activation of the MLP.

  • 177.
    Backström, Ellenor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Törmänen, Heidi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Östberg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Regulation of Adenovirus Late Region 1 SplicingManuscript (Other academic)
    Abstract [en]

    The major late transcription unit (MLTU) produces one pre-mRNA that is processed into more than 20 cytoplasmic mRNAs by alternative polyadenylation and extensive alternative 3' splice site usage. The alternative splicing of the MLTU is temporally regulated, resulting in the expression of only one mRNA, the L1 52,55K, before the onset of viral genome replication. The L1 unit also encodes the IIIa mRNA, the expression of which is highly regulated at the level of splicing. We have previously shown that the adenoviral L4-33K protein enhances IIIa splicing via the IIIa virus infection-dependent splicing enhancer element. In this study we show that serine to glycine mutations in the tiny RS domain of the L4-33K protein retain more activity in vivo compared to results obtained previously in vitro. In addition, it is also clear that these mutations in the RS domain affect the sub-cellular localization of L4-33K. Thus, the RS domain appears to contain a nuclear localisation signal that is dependent on the serine residues. In a previous report we showed that, in extracts prepared from adenovirus-infected cells, splicing is independent of the general splicing factor U2AF. In this study we also demonstrate that none of the tested U2AF-replacement candidate proteins (PUF60, Caper α, and Caper β) collaborate with L4-33K in the activation of IIIa splicing. It has been suggested that regulation of L1 alternative splicing does not require cis-competition between the 52.55K and IIIa 3' splice sites. We find that activity of the IIIa splice site increases considerably in the absence of cis-competition with the 52,55K splice site. Interestingly, this cis-competition is not virus-specific since this observation is reproducible in a transcription unit where the β-globin 3' splice site replaces the natural 52,55K 3' splice site. We conclude that L1 alternative splicing conforms to the general rule in that it ordinarily makes use of the proximal 3' splice site (52,55K), whereas activation of distal 3' splice site usage requires active intervention. In adenovirus this intervention is achieved by production of the L4-33K protein.

  • 178.
    Backström, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Forstmeier, Wolfgang
    Schielzeth, Holger
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Mellenius, Harriet
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Nam, Kiwoong
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Bolund, Elisabeth
    Webster, Matthew T.
    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 Evolution, Genomics and Systematics, Evolutionary Biology.
    Öst, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schneider, Melanie
    Kempenaers, Bart
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    The recombination landscape of the zebra finch Taeniopygia guttata genome2010In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 20, no 4, p. 485-495Article in journal (Refereed)
    Abstract [en]

    Understanding the causes and consequences of variation in the rate of recombination is essential since this parameter is considered to affect levels of genetic variability, the efficacy of selection, and the design of association and linkage mapping studies. However, there is limited knowledge about the factors governing recombination rate variation. We genotyped 1920 single nucleotide polymorphisms in a multigeneration pedigree of more than 1000 zebra finches (Taeniopygia guttata) to develop a genetic linkage map, and then we used these map data together with the recently available draft genome sequence of the zebra finch to estimate recombination rates in 1 Mb intervals across the genome. The average zebra finch recombination rate (1.5 cM/Mb) is higher than in humans, but significantly lower than in chicken. The local rates of recombination in chicken and zebra finch were only weakly correlated, demonstrating evolutionary turnover of the recombination landscape in birds. The distribution of recombination events was heavily biased toward ends of chromosomes, with a stronger telomere effect than so far seen in any organism. In fact, the recombination rate was as low as 0.1 cM/Mb in intervals up to 100 Mb long in the middle of the larger chromosomes. We found a positive correlation between recombination rate and GC content, as well as GC-rich sequence motifs. Levels of linkage disequilibrium (LD) were significantly higher in regions of low recombination, showing that heterogeneity in recombination rates have left a footprint on the genomic landscape of LD in zebra finch populations.

  • 179.
    Backström Winquist, Ellenor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Abdurahman, Samir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tranell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindström, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tingsborg, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Schwartz, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Inefficient splicing of segment 7 and 8 mRNAs is an inherent property of influenza virus A/Brevig Mission/1918/1 (H1N1) that causes elevated expression of NS1 protein2012In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 422, no 1, p. 46-58Article in journal (Refereed)
    Abstract [en]

    Influenza A virus encodes two segments (7 and 8) that produce mRNAs that can be spliced. We have investigated if naturally occurring sequence polymorphisms in the influenza A virus family affects splicing of these viral mRNAs, as that could potentially alter the NS1/NS2- and/or M1/M2-protein ratios. We compared splicing efficiency of segment 7 and 8 mRNAs of A/Brevig Mission/1918/1 (H1N1) and A/Netherlands/178/95 (H3N2), as well as various H5N1 avian strains. Results revealed that both segment 7 and 8 mRNAs of A/Brevig Mission/1918/1 (H1N1) were inefficiently spliced compared to other influenza virus segment 7 and 8 mRNAs. This resulted in production of higher levels of functional NS1 protein, which could potentially contribute to the pathogenic properties of the A/Brevig Mission/1918/1 (H1N1). We also show that A/Brevig Mission/1918/1 (H1N1) segment 8 mRNAs responded differently to overexpression of SR proteins than A/Netherlands/178/95 (H3N2).

  • 180.
    Badrul, Hasan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Absence of vancomycin-resistant enterococci among highly ESBL-positive crows (Corvus splendens) foraging on hospital waste in Bangladesh2015In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 5, article id 29761Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Vancomycin-resistant enterococci (VRE) have emerged as a growing problem in hospitals; however, domesticated animals, poultry, and wild birds are acting as potential reservoirs. There is a knowledge gap in the Epidemiology of VRE from Bangladesh.

    METHODS:

    To study the prevalence of VRE and the mechanisms of resistance implicated among wild birds, 238 fecal samples were collected in 2010 from house crows (Corvus splendens) foraging on hospital waste in Bangladesh. Fecal samples were screened by analyzing color change in broth and screening for vanA and vanB resistant genes by PCR.

    RESULTS:

    Neither vanA nor vanB genes were detected from the fecal samples. The house crow does not seem to constitute a reservoir for VRE.

    CONCLUSION:

    The zero prevalence is an indication that foraging on hospital waste does not constitute a major risk of VRE carriage in house crows and this is the first study to focus on the prevalence of VRE from wild birds in Bangladesh.

  • 181. Bajtner, Estelle
    et al.
    Nandakumar, Kutty S
    Engström, Åke
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Holmdahl, Rikard
    Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen.2005In: Arthritis Res Ther, ISSN 1478-6362, Vol. 7, no 5, p. R1148-57Article in journal (Refereed)
  • 182. Baker, Michelle L
    et al.
    Indiviglio, Sandra
    Nyberg, April M
    Rosenberg, George H
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Miller, Robert D
    Papenfuss, Anthony T
    Analysis of a set of Australian northern brown bandicoot expressed sequence tags with comparison to the genome sequence of the South American grey short tailed opossum2007In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 8, p. 50-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Expressed sequence tags (ESTs) have been used for rapid gene discovery in a variety of organisms and provide a valuable resource for whole genome annotation. Although the genome of one marsupial, the opossum Monodelphis domestica, has now been sequenced, no EST datasets have been reported from any marsupial species. In this study we describe an EST dataset from the bandicoot, Isoodon macrourus, providing information on the transcriptional profile of the bandicoot thymus and the opportunity for a genome wide comparison between the bandicoot and opossum, two distantly related marsupial species. RESULTS: A set of 1319 ESTs was generated from sequencing randomly chosen clones from a bandicoot thymus cDNA library. The nucleic acid and deduced amino acid sequences were compared with sequences both in GenBank and the recently completed whole genome sequence of M. domestica. This study provides information on the transcriptional profile of the bandicoot thymus with the identification of genes involved in a broad range of activities including protein metabolism (24%), transcription and/or nucleic acid metabolism (10%), metabolism/energy pathways (9%), immunity (5%), signal transduction (5%), cell growth and maintenance (3%), transport (3%), cell cycle (0.7%) and apoptosis (0.5%) and a proportion of genes whose function is unknown (5.8%). Thirty four percent of the bandicoot ESTs found no match with annotated sequences in any of the public databases. Clustering and assembly of the 1319 bandicoot ESTs resulted in a set of 949 unique sequences of which 375 were unannotated ESTs. Of these, seventy one unannotated ESTs aligned to non-coding regions in the opossum, human, or both genomes, and were identified as strong non-coding RNA candidates. Eighty-four percent of the 949 assembled ESTs aligned with the M. domestica genome sequence indicating a high level of conservation between these two distantly related marsupials. CONCLUSION: This study is among the first reported marsupial EST datasets with a significant inter-species genome comparison between marsupials, providing a valuable resource for transcriptional analyses in marsupials and for future annotation of marsupial whole genome sequences.

  • 183.
    Bakkeren, Erik
    et al.
    Swiss Fed Inst Technol, Dept Biol, Inst Microbiol, Zurich, Switzerland.
    Huisman, Jana S.
    Swiss Fed Inst Technol, Inst Integrat Biol, Dept Environm Syst Sci, Zurich, Switzerland;Swiss Inst Bioinformat, Lausanne, Switzerland.
    Fattinger, Stefan A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swiss Fed Inst Technol, Dept Biol, Inst Microbiol, Zurich, Switzerland;Uppsala Univ, Sci Life Lab, Dept Med Biochem & Microbiol, Uppsala, Sweden.
    Hausmann, Annika
    Swiss Fed Inst Technol, Dept Biol, Inst Microbiol, Zurich, Switzerland.
    Furter, Markus
    Swiss Fed Inst Technol, Dept Biol, Inst Microbiol, Zurich, Switzerland.
    Egli, Adrian
    Univ Hosp Basel, Div Clin Microbiol, Basel, Switzerland;Univ Basel, Dept Biomed, Appl Microbiol Res, Basel, Switzerland.
    Slack, Emma
    Swiss Fed Inst Technol, Dept Biol, Inst Microbiol, Zurich, Switzerland;Swiss Fed Inst Technol, Inst Food Nutr & Hlth, Dept Hlth Sci & Technol, Zurich, Switzerland.
    Sellin, Mikael E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bonhoeffer, Sebastian
    Swiss Fed Inst Technol, Inst Integrat Biol, Dept Environm Syst Sci, Zurich, Switzerland.
    Regoes, Roland R.
    Swiss Fed Inst Technol, Inst Integrat Biol, Dept Environm Syst Sci, Zurich, Switzerland.
    Diard, Mederic
    Swiss Fed Inst Technol, Dept Biol, Inst Microbiol, Zurich, Switzerland;Univ Basel, Biozentrum, Basel, Switzerland.
    Hardt, Wolf-Dietrich
    Swiss Fed Inst Technol, Dept Biol, Inst Microbiol, Zurich, Switzerland.
    Salmonella persisters promote the spread of antibiotic resistance plasmids in the gut2019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 573, no 7773, p. 276-280Article in journal (Refereed)
    Abstract [en]

    The emergence of antibiotic-resistant bacteria through mutations or the acquisition of genetic material such as resistance plasmids represents a major public health issue(1,2). Persisters are subpopulations of bacteria that survive antibiotics by reversibly adapting their physiology(3-10), and can promote the emergence of antibiotic-resistant mutants(11). We investigated whether persisters can also promote the spread of resistance plasmids. In contrast to mutations, the transfer of resistance plasmids requires the co-occurrence of both a donor and a recipient bacterial strain. For our experiments, we chose the facultative intracellular entero-pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) and Escherichia coli, a common member of the microbiota(12). S. Typhimurium forms persisters that survive antibiotic therapy in several host tissues. Here we show that tissue-associated S. Typhimurium persisters represent long-lived reservoirs of plasmid donors or recipients. The formation of reservoirs of S. Typhimurium persisters requires Salmonella pathogenicity island (SPI)-1 and/or SPI-2 in gut-associated tissues, or SPI-2 at systemic sites. The re-seeding of these persister bacteria into the gut lumen enables the co-occurrence of donors with gut-resident recipients, and thereby favours plasmid transfer between various strains of Enterobacteriaceae. We observe up to 99% transconjugants within two to three days of re-seeding. Mathematical modelling shows that rare re-seeding events may suffice for a high frequency of conjugation. Vaccination reduces the formation of reservoirs of persisters after oral infection with S. Typhimurium, as well as subsequent plasmid transfer. We conclude that-even without selection for plasmid-encoded resistance genes-small reservoirs of pathogen persisters can foster the spread of promiscuous resistance plasmids in the gut.

  • 184.
    Balaban, Nathalie Q.
    et al.
    Hebrew Univ Jerusalem, Racah Inst Phys, Jerusalem, Israel.
    Helaine, Sophie
    Imperial Coll London, MRC Ctr Mol Bacteriol & Infect, London, England.
    Lewis, Kim
    Northeastern Univ, Dept Biol, Boston, MA 02115 USA.
    Ackermann, Martin
    Swiss Fed Inst Technol, Inst Biogeochem & Pollutant Dynam, Zurich, Switzerland;Eawag, Dept Environm Microbiol, Dubendorf, Switzerland.
    Aldridge, Bree
    Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Brynildsen, Mark P.
    Princeton Univ, Dept Chem & Biol Engn, Princeton, NJ 08544 USA.
    Bumann, Dirk
    Univ Basel, Biozentrum, Focal Area Infect Biol, Basel, Switzerland.
    Camilli, Andrew
    Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA.
    Collins, James J.
    MIT, Dept Biol Engn, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA;MIT, Synthet Biol Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA;Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA;Broad Inst MIT & Harvard, Cambridge, MA USA.
    Dehio, Christoph
    Univ Basel, Biozentrum, Focal Area Infect Biol, Basel, Switzerland.
    Fortune, Sarah
    Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA.
    Ghigo, Jean-Marc
    Inst Pasteur, Genet Biofilms Lab, Paris, France.
    Hardt, Wolf-Dietrich
    Swiss Fed Inst Technol, Inst Microbiol, Zurich, Switzerland.
    Harms, Alexander
    Univ Basel, Biozentrum, Focal Area Infect Biol, Basel, Switzerland.
    Heinemann, Matthias
    Univ Groningen, Groningen Biomol Sci & Biotechnol Inst, Mol Syst Biol, Groningen, Netherlands.
    Hung, Deborah T.
    Broad Inst MIT & Harvard, Cambridge, MA USA.
    Jenal, Urs
    Univ Basel, Biozentrum, Focal Area Infect Biol, Basel, Switzerland.
    Levin, Bruce R.
    Emory Univ, Dept Biol, Atlanta, GA 30322 USA.
    Michiels, Jan
    Univ Leuven, KU Leuven, Ctr Microbiol, Leuven, Belgium.
    Storz, Gisela
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Mol & Cellular Biol, Bethesda, MD USA.
    Tan, Man-Wah
    Genentech Inc, Infect Dis Dept, San Francisco, CA USA.
    Tenson, Tanel
    Univ Tartu, Inst Technol, Tartu, Estonia.
    Van Melderen, Laurence
    Univ Libre Bruxelles, Fac Sci, Brussels, Belgium.
    Zinkernagel, Annelies
    Univ Zurich, Univ Hosp Zurich, Div Infect Dis, Zurich, Switzerland.
    Definitions and guidelines for research on antibiotic persistence2019In: Nature Reviews Microbiology, ISSN 1740-1526, E-ISSN 1740-1534, Vol. 17, no 7, p. 441-448Article, review/survey (Refereed)
    Abstract [en]

    Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.

  • 185. Balaz, E.A.
    et al.
    Laurent, T.C.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    New applications for hyaluronan1998In: In:The Chemistry, Biology and Medical Applications of Hyaluronan and its Deriva- tives." (TC Laurent, ed.), Wenner-Gren Symposium , 1998, Vol. 72, p. 325-Chapter in book (Other scientific)
  • 186.
    Balciunas, D
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The Med1 subunit of the yeast mediator complex is involved in both transcriptional activation and repression [published erratum appears in Proc Natl Acad Sci U S A 1999 Mar 16;96(6):3330]1999In: Proc Natl Acad Sci U S A, Vol. 96, p. 376-Article in journal (Refereed)
  • 187.
    Balciunas, Darius
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Functional studies in yeast of cyclin C and the RNA polymerase II Mediator complex1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cyclin C belongs to a group of cyclins that are not cell cycle-regulated. It was first cloned from Drosophila and rat, but its role was not understood until the yeast cyclin C homologue Srb 11 was identified in several genetic screens for transcriptional repressors and subsequently was shown to be associated with the RNA polymerase II Mediator complex. The Mediator is a multisubunit complex that enables RNA polymerase II to respond to activators in vitro.

    In the work presented here, the yeast genes encoding cyclin C (Srb11/Gig3), its cyclin-dependent kinase (Srb10/Gig2), and a third associated protein (Srb8/Gig1) were identified in a genetic screen for negative regulators of the gluconeogenic genes. A further analysis of the cloned genes suggested that the encoded proteins function closely together.

    The Med1 subunit of the yeast Mediator complex was characterized. Evidence was found of a functional connection between Med1 and the cyclin C-dependent kinase. The expression of the GAL1 promoter is partly deregulated in cells lacking cyclin C, Med1, or another mediator subunit, Med2. This deregulated expression is seen also under derepressed non-inducing conditions, and is therefore not due to a failure of glucose repression.

    An analysis of the ability of different Mediator subunits to activate transcription when fused to a DNA binding domain indicated that Med1 and Srb7 are negatively regulated both by cyclin C and by the Sin4 subunit of the Mediator, but not by the Med2 or Gal11 subunits, even though Sin4, Med2 and Gal11 are a part of the same module within the Mediator.

    A screen was made for multicopy suppressors of disruptions in the SRB8, SRB10 and SRB11 genes. Since these disruptions lack selectable phenotypes in a wild type background, the failure of snf1 mig1 srb8/10/11 cells to grow on galactose was used to select suppressors. Four new genes were identified and named GISI-4. Evidence was obtained of a functional interaction between these genes and the RAS/cAMP pathway.

  • 188.
    Baltekin, Özden
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Boucharin, Alexis
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Elf, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Antibiotic susceptibility testing in less than 30 min using dir