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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.
    Abdalaal, Hind
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala.
    Deciphering molecular mechanisms in the evolution of new functions2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The evolution of new genes and functions is considered to be a major contributor to biological diversity in organisms. Through de novo origination, “duplication and divergence”, and horizontal gene transfer, organisms can acquire new genetic material that can evolve to perform novel functions. In this thesis, we investigate how functional trade-offs, “gene duplication and amplification”, and neutral divergence contribute to the emergence of a new function from a preexisting gene.

     In Paper i, we investigated the ability of Salmonella enterica to compensate for the loss of peptide release factor 1 (RFI) and the potential of peptide release factor 2 (RF2) to gain a new function to replace RFI. The amplification of RF2 and accumulated mutations within RF2 were the main evolutionary routes by which the fitness cost was restored. However, further characterization of the evolved RF2 showed a toxic effect to the cell due to the termination on tryptophan codon (UGG). This evolutionary trade-off - which we named “collateral toxicity” - might present a serious barrier for evolving an efficient RF2 to replace RF1.

    In Paper ii, we determined whether we could evolve a generalist enzyme with two functions (HisA + TrpF) from the specialist enzyme HisA, which can only synthesize histidine. In a previous study, we showed that HisA evolved a TrpF activity through strong trade-off trajectories. Here, we developed a selection scheme in which we constantly selected for keeping the original function (HisA), while intermittently selecting for the new function (TrpF). Our results showed that all evolved lineages shared the same “stepping stone” mutations in the hisA gene, which enabled them to grow well in the absence of both histidine and tryptophan. Additional accumulated mutations in the hisA gene gave the strains an increased ability to grow without both amino acids, indicating that the HisA enzyme evolved to be an efficient generalist.  

    In Paper iii, we explored how differences between diverged orthologs influence evolvability. We generated artificial orthologs using a random mutagenesis approach. First, we screened for orthologs with a lower HisA activity and then selected for orthologs with a higher HisA activity; these steps were repeated in alternating rounds. We then tested the ability of each ortholog to evolve  TrpF activity. As expected, the orthologs showed varying abilities to evolve the new function. In particular, orthologs with higher HisA activity levels showed both a higher potential to evolve the new function and a higher TrpF activity when they acquired the new function. 

    List of papers
    1. Collateral toxicity limits the evolution of bacterial Release Factor 2 towards total omnipotence
    Open this publication in new window or tab >>Collateral toxicity limits the evolution of bacterial Release Factor 2 towards total omnipotence
    Show others...
    2020 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 37, no 10, p. 2918-2930Article in journal (Refereed) Published
    Abstract [en]

    When new genes evolve through modification of existing genes, there are often trade-offs between the new and original functions, making gene duplication and amplification necessary to buffer deleterious effects on the original function. We have used experimental evolution of a bacterial strain lacking peptide release factor 1 (RF1) in order to study how peptide release factor 2 (RF2) evolves to compensate the loss of RF1. As expected, amplification of the RF2-encoding gene prfB to high copy number was a rapid initial response, followed by the appearance of mutations in RF2 and other components of the translation machinery. Characterization of the evolved RF2 variants by their effects on bacterial growth rate, reporter gene expression, and in vitro translation termination reveals a complex picture of reduced discrimination between the cognate and near cognate stop codons and highlight a functional trade-off that we term “collateral toxicity”. We suggest that this type of trade-off may be a more serious obstacle in new gene evolution than the more commonly discussed evolutionary trade-offs between “old” and “new” functions of a gene, as it cannot be overcome by gene copy number changes. Further, we suggest a model for how RF2 autoregulation responds not only to alterations in the demand for RF2 activity, but also for RF1 activity.

    Place, publisher, year, edition, pages
    Oxford University Press (OUP), 2020
    National Category
    Evolutionary Biology Microbiology Biochemistry and Molecular Biology
    Research subject
    Biology with specialization in Molecular Evolution
    Identifiers
    urn:nbn:se:uu:diva-410852 (URN)10.1093/molbev/msaa129 (DOI)000593115800011 ()32437534 (PubMedID)
    Note

    The two first authors contributed equally to this work.

    Available from: 2020-05-22 Created: 2020-05-22 Last updated: 2023-06-21Bibliographically approved
    2. Intermittent selection directs evolution of a specialist enzyme to become a generalist
    Open this publication in new window or tab >>Intermittent selection directs evolution of a specialist enzyme to become a generalist
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    A mutation that introduces a new enzymatic function can be accompanied by a trade-off between the original function and the new function. We previously tested the evolutionary trajectories of Salmonella enterica HisA enzyme (catalyze the fourth step in histidine biosynthesis) towards TrpF activity (catalyze the third step in tryptophan biosynthesis). The majority of the mutations that introduced TrpF activity led to a complete loss of detectable HisA activity. In the rare hisA mutants that kept HisA activity, HisA activity was lost when selecting for mutations that improved TrpF activity. However, some natural HisA orthologs had dual (HisA and TrpF) activities, which has evolved from a specialist HisA.

    The present study was designed to investigate whether Salmonella enterica HisA can evolve into a generalist (HisA+TrpF) enzyme, despite the strong trade-off between the original function and the new function. Therefore, we allowed trpF-deleted Salmonella enterica with or without a mutator phenotype to evolve in a low concentration of tryptophan. This allowed it to grow for a few generations in relaxed selection, which was followed by several days of strong selection (tryptophan depletion). In this setup, it was never lethal to not have TrpF activity, but it would be lethal to lose HisA activity.

    These cycled lineages circumvented the tryptophan starvation by loss of function in the tryptophan biosynthesis pathway or by accumulating mutations in hisA gene. The accumulated mutations introduced bifunctionality to the hisA alleles, which was more common in the lineages with the mutator phenotype. These alleles became increasingly efficient in performing both functions when evolved further using the same conditions. Our results indicate that it is possible to evolve an efficient generalist HisA when we use a selection condition that is more likely to occur in nature (a fluctuating environment).

     

     

    National Category
    Biological Sciences
    Research subject
    Biology with specialization in Microbiology; Biology with specialization in Molecular Evolution
    Identifiers
    urn:nbn:se:uu:diva-423324 (URN)
    Available from: 2020-10-25 Created: 2020-10-25 Last updated: 2020-10-25
    3. Evolvability of orthologous genes
    Open this publication in new window or tab >>Evolvability of orthologous genes
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The divergence of orthologous genes is usually attributed to the slow and steady accumulation of neutral or nearly neutral mutations. It is known that present-day orthologous genes have a common ancestor and still perform the same function with about the same performance. Natural orthologs differ from each other not only in sequence, but also in physical properties such as their tolerance of mutations and their potential to evolve new functions. However, we currently have a poor understanding of how mutations that accumulate during the sequence divergence of orthologous genes affect their evolvability.

    In this study, we generated a library of laboratory-evolved orthologous genes for studying how mutations and combinations of mutations (deleterious and compensatory mutations) affect evolvability. We simulated what could happen during the divergence of orthologous genes where fixation of a deleterious mutation is followed by a compensatory mutation. We have subjected one of histidine biosynthetic genes hisA from Salmonella enterica to alternating rounds of weak selection (by random mutagenesis through error-prone PCR subsequent screens for partial loss of hisA function) followed by strong purifying selection (another round of random mutagenesis and subsequent selection for restored hisA function).

    The diverging lineages were tested for their ability to evolve TrpF activity and were compared with the WT hisA using a fluctuation test. Our results confirmed that orthologous enzymes had differing abilities to evolve the new function. The HisA orthologs with restored function had evolved adaptive genotypes with higher TrpF activity. We suggest that these orthologs may have a higher stability, which is known to increase evolutionary potential by increasing the tolerance for the otherwise destabilizing mutations that confer the new function.

     

    National Category
    Biological Sciences
    Research subject
    Biology with specialization in Microbiology
    Identifiers
    urn:nbn:se:uu:diva-423416 (URN)
    Available from: 2020-10-25 Created: 2020-10-25 Last updated: 2020-10-25
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  • 3.
    Abdalaal, Hind
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University.
    Näsvall, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evolvability of orthologous genesManuscript (preprint) (Other academic)
    Abstract [en]

    The divergence of orthologous genes is usually attributed to the slow and steady accumulation of neutral or nearly neutral mutations. It is known that present-day orthologous genes have a common ancestor and still perform the same function with about the same performance. Natural orthologs differ from each other not only in sequence, but also in physical properties such as their tolerance of mutations and their potential to evolve new functions. However, we currently have a poor understanding of how mutations that accumulate during the sequence divergence of orthologous genes affect their evolvability.

    In this study, we generated a library of laboratory-evolved orthologous genes for studying how mutations and combinations of mutations (deleterious and compensatory mutations) affect evolvability. We simulated what could happen during the divergence of orthologous genes where fixation of a deleterious mutation is followed by a compensatory mutation. We have subjected one of histidine biosynthetic genes hisA from Salmonella enterica to alternating rounds of weak selection (by random mutagenesis through error-prone PCR subsequent screens for partial loss of hisA function) followed by strong purifying selection (another round of random mutagenesis and subsequent selection for restored hisA function).

    The diverging lineages were tested for their ability to evolve TrpF activity and were compared with the WT hisA using a fluctuation test. Our results confirmed that orthologous enzymes had differing abilities to evolve the new function. The HisA orthologs with restored function had evolved adaptive genotypes with higher TrpF activity. We suggest that these orthologs may have a higher stability, which is known to increase evolutionary potential by increasing the tolerance for the otherwise destabilizing mutations that confer the new function.

     

  • 4.
    Abdalaal, Hind
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala university.
    Näsvall, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Intermittent selection directs evolution of a specialist enzyme to become a generalistManuscript (preprint) (Other academic)
    Abstract [en]

    A mutation that introduces a new enzymatic function can be accompanied by a trade-off between the original function and the new function. We previously tested the evolutionary trajectories of Salmonella enterica HisA enzyme (catalyze the fourth step in histidine biosynthesis) towards TrpF activity (catalyze the third step in tryptophan biosynthesis). The majority of the mutations that introduced TrpF activity led to a complete loss of detectable HisA activity. In the rare hisA mutants that kept HisA activity, HisA activity was lost when selecting for mutations that improved TrpF activity. However, some natural HisA orthologs had dual (HisA and TrpF) activities, which has evolved from a specialist HisA.

    The present study was designed to investigate whether Salmonella enterica HisA can evolve into a generalist (HisA+TrpF) enzyme, despite the strong trade-off between the original function and the new function. Therefore, we allowed trpF-deleted Salmonella enterica with or without a mutator phenotype to evolve in a low concentration of tryptophan. This allowed it to grow for a few generations in relaxed selection, which was followed by several days of strong selection (tryptophan depletion). In this setup, it was never lethal to not have TrpF activity, but it would be lethal to lose HisA activity.

    These cycled lineages circumvented the tryptophan starvation by loss of function in the tryptophan biosynthesis pathway or by accumulating mutations in hisA gene. The accumulated mutations introduced bifunctionality to the hisA alleles, which was more common in the lineages with the mutator phenotype. These alleles became increasingly efficient in performing both functions when evolved further using the same conditions. Our results indicate that it is possible to evolve an efficient generalist HisA when we use a selection condition that is more likely to occur in nature (a fluctuating environment).

     

     

  • 5.
    Abdalaal, Hind
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pundir, Shreya
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Ge, Xueliang
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Sanyal, Suparna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Näsvall, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Collateral toxicity limits the evolution of bacterial Release Factor 2 towards total omnipotence2020In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 37, no 10, p. 2918-2930Article in journal (Refereed)
    Abstract [en]

    When new genes evolve through modification of existing genes, there are often trade-offs between the new and original functions, making gene duplication and amplification necessary to buffer deleterious effects on the original function. We have used experimental evolution of a bacterial strain lacking peptide release factor 1 (RF1) in order to study how peptide release factor 2 (RF2) evolves to compensate the loss of RF1. As expected, amplification of the RF2-encoding gene prfB to high copy number was a rapid initial response, followed by the appearance of mutations in RF2 and other components of the translation machinery. Characterization of the evolved RF2 variants by their effects on bacterial growth rate, reporter gene expression, and in vitro translation termination reveals a complex picture of reduced discrimination between the cognate and near cognate stop codons and highlight a functional trade-off that we term “collateral toxicity”. We suggest that this type of trade-off may be a more serious obstacle in new gene evolution than the more commonly discussed evolutionary trade-offs between “old” and “new” functions of a gene, as it cannot be overcome by gene copy number changes. Further, we suggest a model for how RF2 autoregulation responds not only to alterations in the demand for RF2 activity, but also for RF1 activity.

    Download full text (pdf)
    fulltext
  • 6.
    Abdel-Moneim, Ahmed S.
    et al.
    Taif Univ, Dept Microbiol, Coll Med, Al Taif 21944, Saudi Arabia; Beni Suef Univ, Fac Vet Med, Dept Virol, Bani Suwayf 62511, Egypt.
    Moore, Matthew D.
    Univ Massachusetts, Dept Food Sci, Amherst, MA 01003 USA.
    Naguib, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Anim Hlth Res Inst, Natl Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt.
    Romalde, Jesus L.
    Univ Santiago de Compostela, CIBUS Fac Biol, Dept Microbiol & Parasitol, Santiago De Compostela 15782, Spain.
    Söderlund-Venermo, Maria
    Univ Helsinki, Dept Virol, Helsinki 00014, Finland.
    WSV 2019: The First Committee Meeting of the World Society for Virology2020In: Virologica Sinica, ISSN 1674-0769, E-ISSN 1995-820X, Vol. 35, no 2, p. 248-252Article in journal (Other academic)
    Abstract [en]

    The World Society for Virology (WSV) was founded and incorporated as a nonprofit organization in the United States in 2017. WSV seeks to strengthen and support both virological research and virologists who conduct research of viruses that affect humans, other animals, plants, and other organisms. One of the objectives of WSV is to connect virologists worldwide and support collaboration. Fulfilling this objective, virologists from fourteen countries in North America, Europe, Africa, Asia, and the Middle East met on 25-27th August 2019 in Stockholm, Sweden at the Karolinska University Hospital for the first Committee Meeting of WSV. This meeting included compelling keynote and honorary speeches and a series of 18 scientific talks were given encompassing a diverse array of subjects within virology. Followed by the scientific session, a business session was held where multiple aspects and next steps of the society were discussed and charted out.

  • 7.
    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.

    Download full text (pdf)
    FULLTEXT01
  • 8.
    Abolhassani, Hassan
    et al.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.;Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Delavari, Samaneh
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden..
    Shokri, Sima
    Iran Univ Med Sci, Hazrat e Rasool Gen Hosp, Sch Med, Dept Pediat, Tehran, Iran..
    Bastard, Paul
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, Inst Natl Sante & Rech Med U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Du, Likun
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Zuo, Fanglei
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Hajebi, Reza
    Univ Tehran Med Sci, Dept Gen Surg, Sch Med, Sina Hosp, Tehran, Iran..
    Abolnezhadian, Farhad
    Ahvaz Jundishapur Univ Med Sci, Dept Pediat, Abuzar Childrens Hosp, Ahvaz, Iran..
    Iranparast, Sara
    Ahvaz Jundishapur Univ Med Sci, Fac Med Sci, Dept Immunol, Ahvaz, Iran..
    Modaresi, Mohammadreza
    Univ Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Div Pediat Pulm Dis, Tehran, Iran..
    Vosughimotlagh, Ahmad
    North Khorasan Univ Med Sci, Dept Pediat, Bojnurd, Iran..
    Salami, Fereshte
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Aranda-Guillen, Maribel
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden..
    Cobat, Aurelie
    Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, Inst Natl Sante & Rech Med U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Marcotte, Harold
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Zhang, Shen-Ying
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, Inst Natl Sante & Rech Med U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Zhang, Qian
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, Inst Natl Sante & Rech Med U1163, Paris, France..
    Rezaei, Nima
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Casanova, Jean-Laurent
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, Inst Natl Sante & Rech Med U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France.;Howard Hughes Med Inst, New York, NY USA..
    Kämpe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden..
    Hammarström, Lennart
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Pan-Hammarström, Qiang
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Genetic and immunologic evaluation of children with inborn errors of immunity and severe or critical COVID-192022In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 150, no 5, p. 1059-1073Article in journal (Refereed)
    Abstract [en]

    Background: Most severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals are asymptomatic or only exhibit mild disease. In about 10% of cases, the infection leads to hypoxemic pneumonia, although it is much more rare in children. Objective: We evaluated 31 young patients aged 0.5 to 19 years who had preexisting inborn errors of immunity (IEI) but lacked a molecular diagnosis and were later diagnosed with coronavirus disease 2019 (COVID-19) complications. Methods: Genetic evaluation by whole-exome sequencing was performed in all patients. SARS-CoV-2-specific antibodies, autoantibodies against type I IFN (IFN-I), and inflammatory factors in plasma were measured. We also reviewed COVID-19 disease severity/outcome in reported IEI patients. Results: A potential genetic cause of the IEI was identified in 28 patients (90.3%), including mutations that may affect IFN signaling, T- and B-cell function, the inflammasome, and the complement system. From tested patients 65.5% had detectable virus-specific antibodies, and 6.8% had autoantibodies neutralizing IFN-I. Five patients (16.1%) fulfilled the diagnostic criteria of multisystem inflammatory syndrome in children. Eleven patients (35.4%) died of COVID-19 complications. All together, at least 381 IEI children with COVID-19 have been reported in the literature to date. Although many patients with asymptomatic or mild disease may not have been reported, severe presentation of COVID-19 was observed in 23.6% of the published cases, and the mortality rate was 8.7%. Conclusions: Young patients with preexisting IEI may have higher mortality than children without IEI when infected with SARS-CoV-2. Elucidating the genetic basis of IEI patients with severe/critical COVID-19 may help to develop better strategies for prevention and treatment of severe COVID-19 disease and complications in pediatric patients.

    Download full text (pdf)
    FULLTEXT01
  • 9.
    Abolhassani, Hassan
    et al.
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge Stockholm, Sweden.;Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden..
    Bastard, Paul
    Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Materna, Marie
    Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Modaresi, Mohammadreza
    Univ Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Div Pediat Pulm Dis, Tehran, Iran..
    Du, Likun
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge Stockholm, Sweden..
    Aranda-Guillen, Maribel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sardh, Fabian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden..
    Zuo, Fanglei
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge Stockholm, Sweden..
    Zhang, Peng
    Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA..
    Marcotte, Harold
    Karolinska Univ Hosp Huddinge, Dept Lab Med, Div Clin Immunol, Karolinska Inst, Stockholm, Sweden..
    Marr, Nico
    Sidra Med, Dept Human Immunol, Doha, Qatar.;Hamad Bin Khalifa Univ, Coll Hlth & Life Sci, Doha, Qatar..
    Khan, Taushif
    Sidra Med, Dept Human Immunol, Doha, Qatar..
    Ata, Manar
    Sidra Med, Dept Human Immunol, Doha, Qatar..
    Al-Ali, Fatima
    Sidra Med, Dept Human Immunol, Doha, Qatar..
    Pescarmona, Remi
    Univ Lyon, Univ Claude Bernard, Ctr Int Rech Infectiol,ENS Lyon, Ctr Natl Rech Sci,Inserm,U1111,UMR5308,Lyon 1, Lyon, France.;Hosp Civils Lyon, Ctr Hosp Lyon Sud, Lab Immunol, Pierre Benite, France..
    Belot, Alexandre
    Univ Lyon, Univ Claude Bernard, Ctr Int Rech Infectiol,ENS Lyon, Ctr Natl Rech Sci,Inserm,U1111,UMR5308,Lyon 1, Lyon, France.;Hosp Civils Lyon, Mere Enfant, Hop Femme, Paediat Nephrol Rheumatol Dermatol, Bron, France.;Natl Reference Ctr Rheumat & Autoimmune & Syst Di, Lyon, France..
    Beziat, Vivien
    Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Zhang, Qian
    Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France..
    Casanova, Jean-Laurent
    Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France.;Univ Paris, Imagine Inst, Paris, France.;Howard Hughes Med Inst, New York, NY USA..
    Kämpe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden..
    Zhang, Shen-Ying
    Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Hammarström, Lennart
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge Stockholm, Sweden..
    Pan-Hammarström, Qiang
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge Stockholm, Sweden..
    Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome2022In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 42, no 3, p. 471-483Article in journal (Refereed)
    Abstract [en]

    Background Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive. Objectives To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C. Methods Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured. Results We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency. Conclusions Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients.

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  • 10.
    Abolhassani, Hassan
    et al.
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.;Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran.
    Vosughimotlagh, Ahmad
    North Khorasan Univ Med Sci, Dept Pediat, Bojnurd, Iran.
    Asano, Takaki
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. 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, Clinical diabetology and metabolism. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.
    Boisson, Bertrand
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, INSERM U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France.
    Delavari, Samaneh
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran.
    Bastard, Paul
    Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, INSERM U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France.
    Aranda-Guillen, Maribel
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.
    Wang, Yating
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.
    Zuo, Fanglei
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.
    Sardh, Fabian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden..
    Marcotte, Harold
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.;Karolinska Univ, Hosp Huddinge, Stockholm, Sweden.
    Du, Likun
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.
    Zhang, Shen-Ying
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA.
    Zhang, Qian
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA.
    Rezaei, Nima
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran.
    Kampe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Casanova, Jean-Laurent
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, INSERM U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France.;Howard Hughes Med Inst, New York, NY USA.
    Hammarstrom, Lennart
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.
    Pan-Hammarstrom, Qiang
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.
    X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia2022In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 42, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Background Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the mechanism underlying life-threatening COVID-19 is instrumental for disease prevention and treatment in individuals with a high risk.

    Objectives We aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI).

    Methods Serum levels of specific antibodies against the virus and autoantibodies against type I interferons (IFNs) were measured. Whole exome sequencing was performed, and the impacts of candidate gene variants were investigated. We also evaluated 247 ataxia-telangiectasia (A-T) patients in the Iranian IEI registry.

    Results We report a 7-year-old Iranian boy with a preexisting hyper IgM syndrome who developed critical COVID-19 pneumonia. IgM only specific COVID-19 immune response was detected but no autoantibodies against type I IFN were observed. A homozygous deleterious mutation in the ATM gene was identified, which together with his antibody deficiency, radiosensitivity, and neurological signs, established a diagnosis of A-T. Among the 247 A-T patients evaluated, 36 had SARS-CoV-2 infection, but all had mild symptoms or were asymptomatic except the index patient. A hemizygous deleterious mutation in the TLR7 gene was subsequently identified in the patient.

    Conclusions We report a unique IEI patient with combined ATM and TLR7 deficiencies. The two genetic defects underlie A-T and critical COVID-19 in this patient, respectively.

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  • 11.
    Abozeid, Hassanein H.
    et al.
    Cairo Univ, Fac Vet Med, Dept Poultry Dis, Giza 12211, Egypt..
    Naguib, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Infectious Bronchitis Virus in Egypt: Genetic Diversity and Vaccination Strategies2020In: Veterinary Sciences, E-ISSN 2306-7381, Vol. 7, no 4, article id 204Article, review/survey (Refereed)
    Abstract [en]

    Infectious bronchitis virus (IBV) is a highly evolving avian pathogen that has increasingly imposed a negative impact on poultry industry worldwide. In the last 20 years, IBV has been continuously circulating among chicken flocks in Egypt causing huge economic losses to poultry production. Multiple IBV genotypes, namely, GI-1, GI-13, GI-16, and GI-23 have been reported in Egypt possessing different genetic and pathogenic features. Different vaccine programs are being used to control the spread of the disease in Egypt. However, the virus continues to spread and evolve where multiple IBV variants and several recombination evidence have been described. In this review, we highlight the current knowledge concerning IBV circulation, genesis, and vaccination strategies in Egypt. In addition, we analyze representative Egyptian IBV strains from an evolutionary perspective based on available data of their S1 gene. We also provide insight into the importance of surveillance programs and share our perspectives for better control of IBV circulating in Egypt.

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  • 12.
    Abramov, Sergei
    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. Kazan Fed Univ, Inst Fundamental Med & Biol, Kazan, Russia.
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Farias, Fabiana H. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Washington Univ, Genome Inst, Sch Med, St Louis, MO USA.
    Dahlqvist, Johanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wilbe, Maria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, H.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Andersson, G.
    Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ronnblom, L.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    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 risk allele A of rs200395694 associated with SLE in Swedish patients affects on MEF2D gene regulation and alternative splicing2018In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, no 12, p. A44-A44Article in journal (Other academic)
  • 13. Abramsson, Alexandra
    et al.
    Kurup, Sindhulakshmi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Yamada, Shuhei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindblom, Per
    Schallmeiner, Edith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ledin, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ringvall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kjellén, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bondjers, Göran
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gerhardt, Holger
    Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development2007In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 21, no 3, p. 316-331Article in journal (Refereed)
    Abstract [en]

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

  • 14.
    Abrink, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, E
    Hellman, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Demethylation of ERV3, anendogenous retrovirus regulating a krüppel related zinc finger gene H-plk,in several human cell lines arrested during early monocyte development.1998In: DNA and Cell Biology, Vol. 17, p. 27-Article in journal (Refereed)
  • 15.
    Abrink, Magnus
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Erik
    Department of Genetics and Pathology.
    Gobl, Anders
    Department of Medical Sciences.
    Hellman, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Expression of lactoferrin in the kidney:implications for innate immunity and iron metabolism2000In: Kidney Int, Vol. 57, p. 2004-Article in journal (Refereed)
  • 16.
    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. 

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    Phylogenetic characterization of equine influenza viruses from Swedish outbreaks from 1979 to 2001
  • 17.
    Ackermann, Paul W.
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Trauma Acute Surg & Orthopaed, S-17176 Stockholm, Sweden..
    Alim, Md Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Dept Dent Med, Stockholm, Sweden.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.
    Peterson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine. Reg Uppsala, Acad Primary Hlth Care, Uppsala, Sweden.
    Tendon pain: what are the mechanisms behind it?2023In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 23, no 1, p. 14-24Article, review/survey (Refereed)
    Abstract [en]

    Objectives

    Management of chronic tendon pain is difficult and controversial. This is due to poor knowledge of the underlying pathophysiology of chronic tendon pain, priorly known as tendinitis but now termed tendinopathy. The objective of this topical review was to synthesize evolving information of mechanisms in tendon pain, using a comprehensive search of the available literature on this topic.

    Content

    This review found no correlations between tendon degeneration, collagen separation or neovascularization and chronic tendon pain. The synthesis demonstrated that chronic tendon pain, however, is characterized by excessive nerve sprouting with ingrowth in the tendon proper, which corresponds to alterations oberserved also in other connective tissues of chronic pain conditions. Healthy, painfree tendons are devoid of nerve fibers in the tendon proper, while innervation is confined to tendon surrounding structures, such as sheaths. Chronic painful tendons exhibit elevated amounts of pain neuromediators, such as glutamate and substance p as well as up-regulated expression and excitability of pain receptors, such as the glutamate receptor NMDAR1 and the SP receptor NK1, found on ingrown nerves and immune cells. Increasing evidence indicates that mast cells serve as an important link between the peripheral nervous system and the immune systems resulting in so called neurogenic inflammation.

    Summary

    Chronic painful tendons exhibit (1) protracted ingrowth of sensory nerves (2) elevated pain mediator levels and (3) up-regulated expression and excitability of pain receptors, participating in (4) neuro-immune pathways involved in pain regulation. Current treatments that entail the highest scientific evidence to mitigate chronic tendon pain include eccentric exercises and extracorporeal shockwave, which both target peripheral neoinnervation aiming at nerve regeneration.

    Outlook

    Potential mechanism-based pharmacological treatment approaches could be developed by blocking promotors of nerve ingrowth, such as NGF, and promoting inhibitors of nerve ingrowth, like semaphorins, as well as blocking glutamate-NMDA-receptor pathways, which are prominent in chronic tendon pain.

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  • 18.
    Adel, Amany
    et al.
    Anim Hlth Res Inst, Agr Res Ctr, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Abdelmagid, Marwa A.
    Anim Hlth Res Inst, Agr Res Ctr, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Mohamed, Ahmed Abd-Elhalem
    Anim Hlth Res Inst, Agr Res Ctr, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Wasberg, Anishia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mosaad, Zienab
    Anim Hlth Res Inst, Agr Res Ctr, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Selim, Karim
    Anim Hlth Res Inst, Agr Res Ctr, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Shaaban, Asmaa
    Anim Hlth Res Inst, Agr Res Ctr, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Tarek, Mohamed
    Anim Hlth Res Inst, Agr Res Ctr, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Hagag, Naglaa M.
    Anim Hlth Res Inst, Agr Res Ctr, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ellström, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Naguib, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Anim Hlth Res Inst, Agr Res Ctr, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Genetic Variations among Different Variants of G1-like Avian Influenza H9N2 Viruses and Their Pathogenicity in Chickens2022In: Viruses, E-ISSN 1999-4915, Vol. 14, no 5, article id 1030Article in journal (Refereed)
    Abstract [en]

    Since it was first discovered, the low pathogenic avian influenza (LPAI) H9N2 subtype has established linages infecting the poultry population globally and has become one of the most prevalent influenza subtypes in domestic poultry. Several different variants and genotypes of LPAI H9N2 viruses have been reported in Egypt, but little is known about their pathogenicity and how they have evolved. In this study, four different Egyptian LPAI H9N2 viruses were genetically and antigenically characterized and compared to representative H9N2 viruses from G1 lineage. Furthermore, the pathogenicity of three genetically distinct Egyptian LPAI H9N2 viruses was assessed by experimental infection in chickens. Whole-genome sequencing revealed that the H9N2 virus of the Egy-2 G1-B lineage (pigeon-like) has become the dominant circulating H9N2 genotype in Egypt since 2016. Considerable variation in virus shedding at day 7 post-infections was detected in infected chickens, but no significant difference in pathogenicity was found between the infected groups. The rapid spread and emergence of new genotypes of the influenza viruses pinpoint the importance of continuous surveillance for the detection of novel reassortant viruses, as well as monitoring the viral evolution.

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  • 19.
    Adel, Amany
    et al.
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Mohamed, Ahmed Abd Elhalem
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Samir, Mahmoud
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Hagag, Naglaa M.
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Erfan, Ahmed
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Said, Mahmoud
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Arafa, Abd El Satar
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Hassan, Wafaa M. M.
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    El Zowalaty, Mohamed E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Shahien, Momtaz A.
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Epidemiological and molecular analysis of circulating fowl adenoviruses and emerging of serotypes 1, 3, and 8b in Egypt2021In: Heliyon, E-ISSN 2405-8440, Vol. 7, no 12, article id e08366Article in journal (Refereed)
    Abstract [en]

    Fowl adenoviruses (FAdVs) are a large group of viruses of different serotypes. They are responsible for inclusion body hepatitis, adenoviral gizzard erosion, and hepatitis hydropericardium syndrome. The present study presents a comprehensive overview of FAdVs in Egypt, with a focus on the epidemiological features of virus serotypes across the country. We conducted molecular investigation of multiple FAdV species based on the genetic signature of hypervariable regions 1-4 in the loop1 (L1) region of the hexon gene. Epidemiologically, the Nile Delta governorates showed high positivity of FAdVs, which were more commonly found in broilers than in layers. Genetically, species D and serotype 8a/E dominated, and the findings also revealed the emergence of new FAdV serotypes 1, 3, and 8b. The comparative analysis of hypervariable regions in the L1 region of the hexon gene revealed variables specific to each virus serotype. In silico predictions of L1 region revealed variations in the molecular structure and predicted the antigenic epitopes which may affect the cross-antigenicity between the different FAdV species and serotypes.

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  • 20.
    Adler, Marlen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mechanisms and Dynamics of Carbapenem Resistance in Escherichia coli2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

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

    OBJECTIVES:

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

    METHODS:

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

    RESULTS:

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

    CONCLUSIONS:

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

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

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

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

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

    National Category
    Microbiology Biochemistry and Molecular Biology Genetics
    Identifiers
    urn:nbn:se:uu:diva-221431 (URN)10.1093/molbev/msu111 (DOI)000337067400019 ()
    Available from: 2014-03-31 Created: 2014-03-31 Last updated: 2017-12-05Bibliographically approved
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  • 21.
    Adler, Marlen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anjum, Mehreen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Combinations of mutations in envZ, ftsI, mrdA, acrB and acrR can cause high-level carbapenem resistance in Escherichia coli2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 5, p. 1188-1198Article in journal (Refereed)
    Abstract [en]

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

  • 22.
    Adler, Marlen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anjum, Mehreen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Influence of acquired β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli2013In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 1, p. 51-59Article in journal (Refereed)
    Abstract [en]

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

  • 23.
    Adler, Marlen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anjum, Mehreen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berg, Otto, G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    High Fitness Costs and Instability of Gene Duplications Reduce Rates of Evolution of New Genes by Duplication-Divergence Mechanisms2014In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 31, no 6, p. 1526-1535Article in journal (Refereed)
    Abstract [sv]

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

  • 24.
    Adolfsson, Päivi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Research in Disability and Habilitation.
    Ek, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Umb-Carlsson, Õie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Research in Disability and Habilitation.
    Dietitians’ challenges when consulting to adults with intellectual disabilities2019In: Tizard Learning Disability Review, ISSN 1359-5474, E-ISSN 2042-8782, ISSN ISSN 1359-5474,, Vol. 24, no 4, p. 153-162Article in journal (Refereed)
    Abstract [en]

    Purpose: The purpose of this paper is to investigate registered dietitians' (RDs) experiences in consulting to adults with intellectual disabilities (ID) in Sweden.

    Design/methodology/approach: A descriptive study using a study-specific web-based questionnaire was administered, comprising both multiple-choice questions with a space for comments and open-ended questions. The open-ended answers and comments from 53 respondents were analysed with systematic text condensation.

    Findings: Four categories were identified: RDs' experiences from the first meeting; explanations for late initial contact; the actions taken by RDs; and necessary measures for more sustainable nutrition care. Ten sub-categories described the challenges that RDs experience in more detail.

    Practical implications: It is necessary to provide adults with ID and their supporting staff with individually tailored nutritional information. Individuals with ID must be actively involved in lifestyle changes that affect their everyday life. The RD must be included in the interdisciplinary team supporting adults with ID. If a new practice is to be implemented, it should be compatible with the existing values of adults with ID and their staff and must be feasible to implement in the everyday life of the individual.

    Originality/value: This paper identified several barriers that should be overcome in relation to the preparation of RDs for consultation with adults with ID about nutritional health issues. A systematic structure, knowledge about nutrition and knowledge about adults with ID and their living situations are needed. An assessment instrument may meet health promotion needs and facilitate longitudinal follow-ups of nutritional problems.

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    fulltext
  • 25.
    Adolfsson, Päivi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Research in Disability and Habilitation.
    Ek, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Umb-Carlsson, Öie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Research in Disability and Habilitation.
    Challenges for registered dietitians working with food related health promotion for adults with IDD in supported housing2018Conference paper (Other academic)
  • 26.
    Adolfsson, Päivi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Hysing, Jennie
    City of Stockholm, Sweden..
    Ek, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dietitians’ endeavor to contribute to the nutritional health of children and youth with intellectual disability and autism2023In: International Journal of Developmental Disabilities, ISSN 2047-3869Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to explore the experiences of registered dietitians (RD) who consult children and youth with intellectual disability (ID) and autism. Another aim was to investigate how knowledge and working methods were transferred to RDs working with adults with ID and autism. Twenty-six RDs completed a web-based study-specific questionnaire with multiple-choice and open-ended questions. The respondents’ comments and responses to the open-ended questions were analyzed using systematic text condensation. The analyses resulted in four categories: Reachability and accessibility of RDs, Clients do not comply with RDs’ dietary advice, RD finds individual solutions and Better collaboration for better knowledge. It was noteworthy that RDs’ undergraduate education did not prepare them for clients with ID and autism. Instead, they learned by doing and from other professionals at the clinic if they collaborate with them or were part in teams around the client. The RDs reported a lack of national routines for the transition process of nutrition support from young to adult.

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    fulltext
  • 27.
    Adolfsson, Päivi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Disability Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health equity and working life.
    Umb-Carlsson, Õie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Research in Disability and Habilitation.
    Ek, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Significant others’ perspectives on experiences of meal-oriented support and diet counselling for adults with intellectual disabilities who live in supported housing2022In: International Journal of Developmental Disabilities, ISSN 2047-3869, p. 1-9Article in journal (Refereed)
    Abstract [en]

    The quality of meal-oriented support for people with intellectual disabilities is important for their health. The aim of the present study was to explore the experiences of meal-oriented support and diet counselling for adults with intellectual disabilities living in supported housing, from the perspective of housing staff and mothers. Five focus group interviews, including nine supporting staff members and nine mothers, were conducted. The interviews were analyzed using systematic text condensation. Five themes appeared; Extensive needs of the individual, Staff skills determine the food intake, Informal caregivers make up for shortage of support, Effective collaboration with a registered dietitian is needed and Responsibility of the organization state that professionalization of staff is needed. Lacking resources, such as time and nutritional knowledge, insufficient considerations of individual needs, and high staff turnover influence the meal-orientated services negatively. This study brings to the fore, staff working practices and the complexity of providing meal-oriented support for people with intellectual disabilities. Staff need skills to perform individually tailored support. This is best accomplished through effective collaboration between housing staff and relatives underpinned by knowledge from a registered dietitian. The working practices must be structured at the organizational level of the services.

    Download full text (pdf)
    fulltext
  • 28.
    Advani, Jayshree
    et al.
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India;Manipal Acad Higher Educ, Manipal, Karnataka, India.
    Verma, Renu
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India.
    Chatterjee, Oishi
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India;Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India;Amrita Vishwa Vidyapeetham, Sch Biotechnol, Kollam, India.
    Balaya, Rex Devasahayam Arokia
    Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Najar, Mohd Altaf
    Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Ravishankara, Namitha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. MS Ramaiah Inst Technol, Dept Biotechnol, Bangalore, Karnataka, India.
    Suresh, Sneha
    MS Ramaiah Inst Technol, Dept Biotechnol, Bangalore, Karnataka, India;Univ Massachusetts Lowell, Dept Biol Sci, Lowell, MA USA.
    Pachori, Praveen Kumar
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India.
    Gupta, Umesh D.
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India.
    Pinto, Sneha M.
    Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Chauhan, Devendra S.
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India.
    Tripathy, Srikanth Prasad
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India;Natl Inst Res TB, Madras, Tamil Nadu, India.
    Gowda, Harsha
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India.
    Prasad, T. S. Keshava
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India;Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Rise of Clinical Microbial Proteogenomics: A Multiomics Approach to Nontuberculous Mycobacterium-The Case of Mycobacterium abscessus UC222018In: Omics, ISSN 1536-2310, E-ISSN 1557-8100, Vol. 23, no 1, p. 1-16Article in journal (Refereed)
    Abstract [en]

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

  • 29.
    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.

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  • 30.
    Agelidis, Alex
    et al.
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Turturice, Benjamin A.
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Div Pulm Crit Care Sleep & Allergy, Dept Med, Chicago, IL 60612 USA..
    Suryawanshi, Rahul K.
    Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Yadavalli, Tejabhiram
    Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Jaishankar, Dinesh
    Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA.;Northwestern Univ, Dept Dermatol, Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA..
    Ames, Joshua
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Hopkins, James
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Koujah, Lulia
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Patil, Chandrashekhar D.
    Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Hadigal, Satvik R.
    Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Kyzar, Evan J.
    Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA..
    Campeau, Anaamika
    UCSD, Dept Pharmacol, La Jolla, CA USA.;UCSD, Skaggs Sch Pharm, La Jolla, CA USA..
    Wozniak, Jacob M.
    UCSD, Dept Pharmacol, La Jolla, CA USA.;UCSD, Skaggs Sch Pharm, La Jolla, CA USA..
    Gonzalez, David J.
    UCSD, Dept Pharmacol, La Jolla, CA USA.;UCSD, Skaggs Sch Pharm, La Jolla, CA USA..
    Vlodavsky, Israel
    Technion, Technion Integrated Canc Ctr TICC, Rappaport Fac Med, Haifa, Israel..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Perkins, David L.
    Univ Illinois, Div Nephrol, Dept Med, Chicago, IL 60612 USA.;Univ Illinois, Dept Surg, Chicago, IL 60612 USA..
    Finn, Patricia W.
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Div Pulm Crit Care Sleep & Allergy, Dept Med, Chicago, IL 60612 USA..
    Shukla, Deepak
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival2021In: JCI Insight, ISSN 2379-3708, Vol. 6, no 7, article id e144255Article in journal (Refereed)
    Abstract [en]

    The drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we followed heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late-stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.

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

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

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  • 32.
    Aguda, Adeleke H.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Structural Study of the WH2 Family and Filamin: Implications for Actin Cytoskeleton Regulation2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-94969 (URN)10.1038/sj.emboj.7600372 (DOI)15329672 (PubMedID)
    External cooperation:
    Available from: 2006-10-18 Created: 2006-10-18 Last updated: 2017-12-14Bibliographically approved
    2. The structural basis of actin interaction with multiple WH2/β thymosin motif-containing proteins
    Open this publication in new window or tab >>The structural basis of actin interaction with multiple WH2/β thymosin motif-containing proteins
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    2006 In: Structure, Vol. 14, p. 469-76Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94970 (URN)
    Available from: 2006-10-18 Created: 2006-10-18Bibliographically approved
    3. Structural study of α-filamin repeats 14-16
    Open this publication in new window or tab >>Structural study of α-filamin repeats 14-16
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-94971 (URN)
    Available from: 2006-10-18 Created: 2006-10-18Bibliographically approved
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  • 33.
    Aguda, Adeleke H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Burtnick, Leslie D
    Robinson, Robert C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The state of the filament.2005In: EMBO Rep, ISSN 1469-221X, Vol. 6, no 3, p. 220-6Article in journal (Refereed)
  • 34.
    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)
  • 35.
    Aguda, Adeleke H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xue, Bo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Irobi, Edward
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Préat, Thomas
    Robinson, Robert C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The structural basis of actin interaction with multiple WH2/beta-thymosin motif-containing proteins.2006In: Structure, ISSN 0969-2126, Vol. 14, no 3, p. 469-76Article in journal (Refereed)
  • 36.
    Aguda, Adeleke, H.
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xue, Bo
    Irobi, Edward
    Préat, Thomas
    Robinson, Robert, C.
    The structural basis of actin interaction with multiple WH2/β thymosin motif-containing proteins2006In: Structure, Vol. 14, p. 469-76Article in journal (Refereed)
  • 37.
    Aguda, Adeleke Halilu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sakwe, Amos Malle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Robinson, Robert C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Expression, crystallization and preliminary crystallographic data analysis of filamin A repeats 14-162007In: Acta Crystallographica. Section F: Structural Biology and Crystallization Communications, ISSN 1744-3091, E-ISSN 1744-3091, Vol. 63, no 4, p. 291-293Article in journal (Refereed)
    Abstract [en]

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

  • 38.
    Aguilar Quiñones, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Impact of Viral Geometry and Cellular Lipid Environment on Virus-Endosome Fusion Kinetics2021Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
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  • 39.
    Aguirre Rivera, Javier
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala Universitet.
    Larsson, Jimmy
    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, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Seefeldt, A. Carolin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Sanyal, Suparna
    Uppsala University, Disciplinary Domain of Science and Technology, Faculty of Science and Technology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Johansson, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Real-time measurements of aminoglycoside effects on protein synthesis in live cellsManuscript (preprint) (Other academic)
  • 40.
    Aguirre Rivera, Javier
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Larsson, Jimmy
    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, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Volkov, Ivan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Seefeldt, A. Carolin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Sanyal, Suparna
    Uppsala University, Disciplinary Domain of Science and Technology, Faculty of Science and Technology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Johansson, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Real-time measurements of aminoglycoside effects on protein synthesis in live cells2021In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 9, article id e2013315118Article in journal (Refereed)
    Abstract [en]

    The spread of antibiotic resistance is turning many of the currently used antibiotics less effective against common infections. To address this public health challenge, it is critical to enhance our understanding of the mechanisms of action of these compounds. Aminoglycoside drugs bind the bacterial ribosome, and decades of results from in vitro biochemical and structural approaches suggest that these drugs disrupt protein synthesis by inhibiting the ribosome's translocation on the messenger RNA, as well as by inducing miscoding errors. So far, however, we have sparse information about the dynamic effects of these compounds on protein synthesis inside the cell. In the present study, we measured the effect of the aminoglycosides apramycin, gentamicin, and paromomycin on ongoing protein synthesis directly in live Escherichia coli cells by tracking the binding of dye-labeled transfer RNAs to ribosomes. Our results suggest that the drugs slow down translation elongation two- to fourfold in general, and the number of elongation cycles per initiation event seems to decrease to the same extent. Hence, our results imply that none of the drugs used in this study cause severe inhibition of translocation.

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  • 41.
    Ahlberg, Sara
    et al.
    Int Livestock Res Inst, Dept Biosci, POB 30709, Nairobi 00100, Kenya;Univ Helsinki, Dept Food & Environm Sci, POB 66, FI-00014 Helsinki, Finland.
    Grace, Delia
    Int Livestock Res Inst, Dept Biosci, POB 30709, Nairobi 00100, Kenya.
    Kiarie, Gideon
    Mt Kenya Univ, POB 342, Thika 01000, Kenya.
    Kirino, Yumi
    Univ Miyazaki, Dept Vet Sci, 1-1 Gakuen Kibanadai Nishi, Miyazaki 8892192, Japan.
    Lindahl, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Int Livestock Res Inst, Dept Biosci, POB 30709, Nairobi 00100, Kenya;Swedish Univ Agr Sci, Dept Clin Sci, POB 7054, S-75007 Uppsala, Sweden.
    A Risk Assessment of Aflatoxin M1 Exposure in Low and Mid-Income Dairy Consumers in Kenya2018In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 10, no 9, article id 348Article in journal (Refereed)
    Abstract [en]

    Aflatoxin M-1 (AFM(1)), a human carcinogen, is found in milk products and may have potentially severe health impacts on milk consumers. We assessed the risk of cancer and stunting as a result of AFM(1) consumption in Nairobi, Kenya, using worst case assumptions of toxicity and data from previous studies. Almost all (99.5%) milk was contaminated with AFM(1). Cancer risk caused by AFM(1) was lower among consumers purchasing from formal markets (0.003 cases per 100,000) than for low-income consumers (0.006 cases per 100,000) purchasing from informal markets. Overall cancer risk (0.004 cases per 100,000) from AFM(1) alone was low. Stunting is multifactorial, but assuming only AFM(1) consumption was the determinant, consumption of milk contaminated with AFM(1) levels found in this study could contribute to 2.1% of children below three years in middle-income families, and 2.4% in low-income families, being stunted. Overall, 2.7% of children could hypothetically be stunted due to AFM(1) exposure from milk. Based on our results AFM(1) levels found in milk could contribute to an average of -0.340 height for age z-score reduction in growth. The exposure to AFM(1) from milk is 46 ng/day on average, but children bear higher exposure of 3.5 ng/kg bodyweight (bw)/day compared to adults, at 0.8 ng/kg bw/day. Our paper shows that concern over aflatoxins in milk in Nairobi is disproportionate if only risk of cancer is considered, but that the effect on stunting children might be much more significant from a public health perspective; however, there is still insufficient data on the health effects of AFM(1).

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  • 42.
    Ahlberg, Sara
    et al.
    Int Livestock Res Inst, Dept Biosci, POB 30709, Nairobi 00100, Kenya;Univ Helsinki, Dept Food & Environm Sci, POB 66, FI-00014 Helsinki, Finland.
    Randolph, Delia
    Int Livestock Res Inst, Dept Biosci, POB 30709, Nairobi 00100, Kenya.
    Okoth, Sheila
    Univ Nairobi, Sch Biol Sci, POB 30197, Nairobi 00100, Kenya.
    Lindahl, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Int Livestock Res Inst, 298 Kim Ma St, Hanoi, Vietnam;Swedish Univ Agr Sci, Dept Clin Sci, POB 7054, S-75007 Uppsala, Sweden.
    Aflatoxin Binders in Foods for Human Consumption-Can This be Promoted Safely and Ethically?2019In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 11, no 7, article id 410Article in journal (Refereed)
    Abstract [en]

    Aflatoxins continue to be a food safety problem globally, especially in developing regions. A significant amount of effort and resources have been invested in an attempt to control aflatoxins. However, these efforts have not substantially decreased the prevalence nor the dietary exposure to aflatoxins in developing countries. One approach to aflatoxin control is the use of binding agents in foods, and lactic acid bacteria (LAB) have been studied extensively for this purpose. However, when assessing the results comprehensively and reviewing the practicality and ethics of use, risks are evident, and concerns arise. In conclusion, our review suggests that there are too many issues with using LAB for aflatoxin binding for it to be safely promoted. Arguably, using binders in human food might even worsen food safety in the longer term.

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  • 43.
    Ahlen, K
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berg, A
    Stiger, F
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tengholm, A
    Department of Medical Cell Biology.
    Siegbahn, A
    Department of Medical Sciences.
    Gylfe, E
    Department of Medical Cell Biology.
    Reed, R.K.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cell interactions with collagen matrices in vivo and in vitro depend on phosphatidylinositol 3-kinase and free cytoplasmic calcium1998In: Cell Adhesion and Communication, Vol. 5, p. 461-Article in journal (Refereed)
  • 44.
    Ahlinder, J.
    et al.
    FOI, Swedish Def Res Agcy, CBRN Def & Secur, Umeå, Sweden..
    Svedberg, A-L
    Reg Norrbotten, Dept Infect Control, Luleå, Sweden..
    Nystedt, A.
    Reg Norrbotten, Dept Infect Control, Luleå, Sweden..
    Dryselius, R.
    Natl Food Agcy, Dept Biol, Uppsala, Sweden..
    Jacobsson, K.
    Natl Food Agcy, Dept Biol, Uppsala, Sweden..
    Hägglund, M.
    Clin Genom Facil, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Brindefalk, B.
    FOI, Swedish Def Res Agcy, CBRN Def & Secur, Umeå, Sweden..
    Forsman, M.
    FOI, Swedish Def Res Agcy, CBRN Def & Secur, Umeå, Sweden..
    Ottoson, J.
    Natl Food Agcy, Dept Risk & Benefit Assessment, Uppsala, Sweden..
    Troell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Natl Vet Inst, Dept Microbiol, Uppsala, Sweden..
    Use of metagenomic microbial source tracking to investigate the source of a foodborne outbreak of cryptosporidiosis2022In: FOOD AND WATERBORNE PARASITOLOGY, ISSN 2405-6766, Vol. 26, article id e00142Article in journal (Refereed)
    Abstract [en]

    Cryptosporidium is a protozoan parasite of global public health importance that causes gastroenteritis in a variety of vertebrate hosts, with many human outbreaks reported yearly, often from ingestion of contaminated water or food. Despite the major public health implications, little is typically known about sources of contamination of disease outbreaks caused by Cryptosporidium. Here, we study a national foodborne outbreak resulted from infection with Cryptosporidium parvum via romaine lettuce, with the main goal to trace the source of the parasite. To do so, we combined traditional outbreak investigation methods with molecular detection and characterization methods (i.e. PCR based typing, amplicon and shotgun sequencing) of romaine lettuce samples collected at the same farm from which the contaminated food was produced. Using 18S rRNA typing, we detected C. parvum in two out of three lettuce samples, which was supported by detections in the metagenome analysis. Microbial source tracking analysis of the lettuce samples suggested sewage water as a likely source of the contamination, albeit with some uncertainty. In addition, the high degree of overlap in bacterial species content with a public human gut microbial database corroborated the source tracking results. The combination of traditional and molecular based methods applied here is a promising tool for future source tracking investigations of food- and waterborne outbreaks of Cryptosporidium spp. and can help to control and mitigate contamination risks.

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  • 45.
    Ahlstrom, Christina A. A.
    et al.
    US Geol Survey, Alaska Sci Ctr, Anchorage, AK 99508 USA..
    Woksepp, Hanna
    Kalmar Cty Reg, Dept Res, Kalmar, Sweden.;Linnaeus Univ, Dept Chem & Biomed Sci, Kalmar, Sweden..
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ramey, Andrew M. M.
    US Geol Survey, Alaska Sci Ctr, Anchorage, AK 99508 USA..
    Bonnedahl, Jonas
    Linköping Univ, Dept Biomed & Clin Sci, Linköping, Sweden.;Kalmar Cty Reg, Dept Infect Dis, Kalmar, Sweden..
    Exchange of Carbapenem-Resistant Escherichia coli Sequence Type 38 Intercontinentally and among Wild Bird, Human, and Environmental Niches2023In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 89, no 6Article in journal (Refereed)
    Abstract [en]

    Carbapenem-resistant Enterobacteriaceae (CRE) are a global threat to human health and are increasingly being isolated from nonclinical settings. OXA-48-producing Escherichia coli sequence type 38 (ST38) is the most frequently reported CRE type in wild birds and has been detected in gulls or storks in North America, Europe, Asia, and Africa. The epidemiology and evolution of CRE in wildlife and human niches, however, remains unclear. We compared wild bird origin E. coli ST38 genome sequences generated by our research group and publicly available genomic data derived from other hosts and environments to (i) understand the frequency of intercontinental dispersal of E. coli ST38 clones isolated from wild birds, (ii) more thoroughly measure the genomic relatedness of carbapenem-resistant isolates from gulls sampled in Turkey and Alaska, USA, using long-read whole-genome sequencing and assess the spatial dissemination of this clone among different hosts, and (iii) determine whether ST38 isolates from humans, environmental water, and wild birds have different core or accessory genomes (e.g., antimicrobial resistance genes, virulence genes, plasmids) which might elucidate bacterial or gene exchange among niches. Our results suggest that E. coli ST38 strains, including those resistant to carbapenems, are exchanged between humans and wild birds, rather than separately maintained populations within each niche. Furthermore, despite close genetic similarity among OXA-48-producing E. coli ST38 clones from gulls in Alaska and Turkey, intercontinental dispersal of ST38 clones among wild birds is uncommon. Interventions to mitigate the dissemination of antimicrobial resistance throughout the environment (e.g., as exemplified by the acquisition of carbapenem resistance by birds) may be warranted.

    IMPORTANCE Carbapenem-resistant bacteria are a threat to public health globally and have been found in the environment as well as the clinic. Some bacterial clones are associated with carbapenem resistance genes, such as Escherichia coli sequence type 38 (ST38) and the carbapenemase gene blaOXA-48. This is the most frequently reported carbapenem-resistant clone in wild birds, though it was unclear if it circulated within wild bird populations or was exchanged among other niches. The results from this study suggest that E. coli ST38 strains, including those resistant to carbapenems, are frequently exchanged among wild birds, humans, and the environment. Carbapenem-resistant E. coli ST38 clones in wild birds are likely acquired from the local environment and do not constitute an independent dissemination pathway within wild bird populations. Management actions aimed at preventing the environmental dissemination and acquisition of antimicrobial resistance by wild birds may be warranted.

  • 46.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, Alaska Sci Ctr, 4210 Univ Dr, Anchorage, AK 99508 USA..
    Woksepp, Hanna
    Kalmar Cty Hosp, Dept Dev & Publ Hlth, S-39185 Kalmar, Sweden.;Linnaeus Univ, Dept Med & Optometry, S-39185 Kalmar, Sweden..
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mohsin, Mashkoor
    Univ Agr Faisalabad, Inst Microbiol, Faisalabad 38040, Pakistan..
    Hasan, Badrul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Anim Bacteriol Sect, Anim Bacteriol Sect Microbial Sci Pests & Dis, Bundoora, Vic, Australia..
    Muzyka, Denys
    Inst Expt & Clin Vet Med, Natl Sci Ctr, UA-61023 Kharkiv, Ukraine..
    Hernandez, Jorge
    Kalmar Cty Hosp, Dept Clin Microbiol, SE-39185 Kalmar, Sweden..
    Aguirre, Filip
    Kalmar Cty Hosp, Dept Clin Microbiol, SE-39185 Kalmar, Sweden..
    Tok, Atalay
    Uppsala Univ, Dept Med Sci, Zoonosis Sci Ctr, SE-75185 Uppsala, Sweden..
    Soderman, Jan
    Linköping Univ, Dept Clin & Expt Med, Lab Med, Linköping, Sweden..
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ramey, Andrew M.
    US Geol Survey, Alaska Sci Ctr, 4210 Univ Dr, Anchorage, AK 99508 USA..
    Bonnedahl, Jonas
    Linköping Univ, Dept Biomed & Clin Sci, S-58183 Linköping, Sweden.;Region Kalmar Cty, Dept Infect Dis, S-39185 Kalmar, Sweden..
    Genomically diverse carbapenem resistant Enterobacteriaceae fromwild birds provide insight into global patterns of spatiotemporal dissemination2022In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 824, article id 153632Article in journal (Refereed)
    Abstract [en]

    Carbapenem resistant Enterobacteriaceae (CRE) are a threat to public health globally, yet the role of the environment in the epidemiology of CRE remains elusive. Given that wild birds can acquire CRE, likely from foraging in anthropogenically impacted areas, and may aid in the maintenance and dissemination of CRE in the environment, a spatiotemporal comparison of isolates from different regions and timepoints may be useful for elucidating epidemiological information. Thus, we characterized the genomic diversity of CRE from fecal samples opportunistically collected from gulls (Larus spp.) inhabiting Alaska (USA), Chile, Spain, Turkey, and Ukraine and from black kites (Milvus migrans) sampled in Pakistan and assessed evidence for spatiotemporal patterns of dissemination. Within and among sampling locations, a high diversity of carbapenemases was found, including Klebsiella pneumoniae carbapenemase (KPC), New Delhi metallo-beta-lactamase (NDM), oxacillinase (OXA), and Verona integron Metallo beta-lactamase (VIM). Although the majority of genomic comparisons among samples did not provide evidence for spatial dissemination, we did find strong evidence for dissemination among Alaska, Spain, and Turkey. We also found strong evidence for temporal dissemination among samples collected in Alaska and Pakistan, though the majority of CRE clones were transitory and were not repeatedly detected among locations where samples were collected longitudinally. Carbapenemase-producing hypervirulent K. pneumoniae was isolated from gulls in Spain and Ukraine and some isolates harbored antimicrobial resistance genes conferring resistance to up to 10 different antibiotic classes, including colistin. Our results are consistent with local acquisition of CRE by wild birds with spatial dissemination influenced by intermediary transmission routes, likely involving humans. Furthermore, our results support the premise that anthropogenicallyassociated wild birds may be good sentinels for understanding the burden of clinically-relevant antimicrobial resistance in the local human population.

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  • 47.
    Ahlström, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bergström, M
    Bjurling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pancreatic neuroendocrine tumors: diagnosis with PET1995In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 195, no 2, p. 333-337Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

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

    MATERIALS AND METHODS:

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

    RESULTS:

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

    CONCLUSION:

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

  • 48.
    Ahlström, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bergström, Mats
    Bjurling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pancreatic Neuroendocrine Tumors: Diagnosis with PET1995In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 195, no 2, p. 333-337Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

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

    MATERIALS AND METHODS:

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

    RESULTS:

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

    CONCLUSION:

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

  • 49.
    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.

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  • 50.
    Ahlén, Karina
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ring, Patrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tomasini-Johansson, Bianca
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Holmqvist, Kristina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Magnusson, Karl-Eric
    Rubin, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Platelet-derived growth factor-BB modulates membrane mobility of beta1 integrins.2004In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 314, no 1, p. 89-96Article in journal (Refereed)
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