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  • 201. Kaempfer, Peter
    et al.
    Matthews, Holly
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Glaeser, Stefanie P.
    Martin, Karin
    Lodders, Nicole
    Faye, Ingrid
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Elizabethkingia anophelis sp nov., isolated from the midgut of the mosquito Anopheles gambiae2011In: International Journal of Systematic and Evolutionary Microbiology, ISSN 1466-5026, E-ISSN 1466-5034, Vol. 61, p. 2670-2675Article in journal (Refereed)
    Abstract [en]

    The taxonomic position, growth characteristics and antibiotic resistance properties of a slightly yellow-pigmented bacterial strain, designated R26(T), isolated from the midgut of the mosquito Anopheles gambiae, were studied. The isolate produced rod-shaped cells, which stained Gram-negative. The bacterium had two growth optima at 30-31 degrees C and 37 degrees C. Strain R26(T) demonstrated natural antibiotic resistance to ampicillin, chloramphenicol, kanamycin, streptomycin and tetracycline. 16S rRNA gene sequence analysis revealed that the isolate showed 98.6% sequence similarity to that of Elizabethkingia meningoseptica ATCC 13253(T) and 98.2 % similarity to that of Elizabethkingia miricola GTC 862(T). The major fatty acids of strain R26(T) were iso-C(15:0), iso-C(17:0) 3-OH and summed feature 4 (iso-C(15:0) 2-OH and/or C(16:1)omega 7c/t. Strain R26(T) contained only menaquinone MK-6 and showed a complex polar lipid profile consisting of diphosphatidylglycerol, phosphatidylinositol, an unknown phospholipid and unknown polar lipids and glycolipids. DNA-DNA hybridization experiments with E. meningoseptica CCUG 214(T) (=ATCC 13253(T)) and E. miricola KCTC 12492(T) (=GTC 862(T)) gave relatedness values of 34.5 % (reciprocal 41.5 %) and 35.0 % (reciprocal 25.7 %), respectively. DNA-DNA hybridization results and some differentiating biochemical properties indicate that strain R26T represents a novel species, for which the name Elizabethkingia anophelis sp. nov. is proposed. The type strain is R26(T) (=CCUG 60038(T) =CCM 7804(T)).

  • 202.
    Kamat, Nasir
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Genotoxic effects of systemic chemotherapy in cancer patients - Microsatellite instability, loss of heterozygosity and expression of mismatch repair genes2011Licentiate thesis, monograph (Other academic)
  • 203.
    Kamat, Nasir
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Khidhir, Mohammed A.
    Jaloudi, Mohammed
    Hussain, Sabir
    Alashari, Mouied M.
    Al Qawasmeh, Khaled H.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study2012In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, p. 373-Article in journal (Refereed)
    Abstract [en]

    Background: The aim of the study was to evaluate potential chemotherapy-induced microsatellite instability, loss of heterozygosity, loss of expression in mismatch repair proteins and associations with clinical findings in breast cancer patients, especially resistance to chemotherapy and/or development of other tumors in the four years following chemotherapy treatment. Methods: A comprehensive study of chemotherapy-related effects with a follow-up period of 48 months post treatment was conducted. A total of 369 peripheral blood samples were collected from 123 de novo breast cancer patients. Microsatellite instability and loss of heterozygosity in five commonly used marker loci (including Tp53-Alu of the tumor suppressor gene TP53) were analyzed in blood samples. Sampling was conducted on three occasions; 4-5 weeks prior to the first chemotherapy session (pre-treatment), to serve as a baseline, followed by two consecutive draws at 12 weeks intervals from the first collection. Mismatch repair protein expression was evaluated in cancer tissues using immunohistochemistry for three mismatch-repair related proteins. Results: A total of 70.7% of the patients showed microsatellite instability for at least one locus, including 18.6% marked as high-positive and 52.1% as low-positive; 35.8% showed loss of heterozygosity in addition to microsatellite instability, while 29.3% exhibited microsatellite stability. The following incidence rates for microsatellite instability and loss of heterozygosity were detected: 39.1% positive for Tp53-Alu, 31.1% for locus Mfd41, and 25.3% for locus Mfd28. A higher occurrence of loss of heterozygosity was noted with alleles 399 and 404 of Tp53-Alu. The mismatch repair protein expression analysis showed that the chemotherapy caused a loss of 29.3% in hMLH1 expression, and 18.7% and 25.2% loss in hMSH2 and P53 expression, respectively. A strong correlation between low or deficient hMSH2 protein expression and occurrence of mismatch repair/loss of heterozygosity events in Mfd41, Tp53-Alu, and Mfd28 was evident. A significant association between mismatch repair/loss of heterozygosity and incidence of secondary tumors was also established. Conclusion: Our results suggest that microsatellite instability, loss of heterozygosity, and deficiency in mismatch repair may serve as early prognostic factors for potential chemotherapy-related side effects in breast cancer patients.

  • 204. Kaneko, Takashi
    et al.
    Goldman, William E.
    Mellroth, Peter
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Steiner, Håkan
    Fukase, Koichi
    Kusumoto, Shoichi
    Harley, William
    Fox, Alvin
    Golenbock, Douglas
    Silverman, Neal
    Monomeric and Polymeric Gram-Negative Peptidoglycan but Not Purified LPS Stimulate the Drosophila IMD Pathway2004In: Immunity, ISSN 1074-7613, Vol. 20, no 5, p. 637-649Article in journal (Refereed)
  • 205.
    Karlsson, Jenny
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Peptidoglycan regulation of Drosophila immunity2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Innate immunity is an ancient defense system that distinguishes between self and non self and is present in both vertebrates and invertebrates. Peptidoglycan (PGN), a cell wall component shared by both gram-negative and gram-positive bacteria, is the major recognition molecule for the detection of bacteria in Drosophila. Peptidoglycan Recognition Proteins (PGRPs) are conserved from insect to mammals and bind PGN with high affinity. In Drosophila, distinct PGRPs provide essential signals upstream of the Toll and Imd pathways. This thesis concerns the recognition of PGN by PGRPs and the expression of antibacterial peptides from the Imd pathway.

    The PGRP-LC locus encodes three splice forms, a, x, and y. PGRP-LCx and PGRP-LCa form heterodimers in the presence of monomeric PGN. We propose a model for activation of Imd where PGRP-LCx binds to monomeric PGN leading to dimerization with PGRP-LCa and activation of the Imd pathway. With polymeric PGN, PGRP-LCx dimers activate the Imd pathway.

    Drosophila PGRP-SC1B has amidase activity and cleaves the PGN lactamyl bond between the glycan strand and the peptide. The digested material is less immunogenic than intact PGN or PGN digested by egg white lysozyme. We suggest PGRP-SC1B to be a scavenger of immunogenic PGN. Amino acid sequence homology predicts six of the Drosophila PGRPs as well as two vertebrate PGRPs to be amidases. Murine PGRP-L is expressed in the liver and was shown to have PGN degrading activity. We found that an earlier purified human serum amidase is in fact identical to PGRP-L.

    Although PGN is a potential trigger of the insect immune system, the actual detection of PGN in vivo poses problems. In gram-negative bacteria, PGN is covered by an outer membrane. Using a cell line approach we demonstrate that bacteria can be recognized by the Imd pathway without the need of phagocytosis or contact between bacteria and cells. Instead growing bacteria release immune eliciting fragments of PGN nature.

  • 206.
    Karlsson, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Oldenvi, Sandra
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Daenthanasanmak, Anusara
    Steiner, Håkan
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Growing bacteria shed elicitors of Drosophila humoral immunityArticle in journal (Refereed)
    Abstract [en]

    Peptidoglycan (PGN) is a well-characterized cell wall component from bacteria that is recognized by Peptidoglycan Recognition Receptors (PGRPs) in the Drosophila immune system. It has long been a forum of debate how the immune system is able to recognize this elicitor since the PGN is hidden by the outer membrane in gram-negative bacteria and by teichoic acids in gram-positive bacteria. We show here that bacteria separated from Drosophila S2 cells by a semi permeable membrane are able to up-regulate the Imd pathway. Studies with supernatants from exponentially growning bacterial cultures show that bacteria shed elicitors in sufficient amounts to potentially induce the Imd pathway. However, when employing supernatants from bacteria in stationary phase, no stimulatory effect of the Imd pathway was detected. The elicitor effect was much reduced when the supernatans was treated with the N-acetylmuramoyl-Lalanine amidase M.mPGRP-L, which is a known scavenger of PGN. Our studies therefore indicate that bacteria in growth phase shed elicitors of PGN nature that can induce a humoral immune response in Drosophila S2 cells.

  • 207.
    Karlsson, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Oldenvi, Sandra
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Fahlander, Carina
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Daenthanasanmak, Anusara
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Steiner, Håkan
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Growing bacteria shed elicitors of Drosophila humoral immunity.2012In: Journal of innate immunity, ISSN 1662-8128, Vol. 4, no 1, p. 111-116Article in journal (Refereed)
    Abstract [en]

    It has been much debated how the Drosophila immune system can recognize bacterial peptidoglycan that is often hidden. We show that bacteria separated from Drosophila S2 cells by a semipermeable membrane can upregulate the Imd pathway. Supernatants from exponentially growing but not from stationary-phase bacterial cultures induce antimicrobial peptides. It is also made likely that the shed elicitors are of peptidoglycan nature.

  • 208. Karlsson, J.L.
    et al.
    Cardoso Palacios, Carlos
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Nilsson, A.S.
    Haggård-Ljungquist, E.
    Evolution of immunity and host chromosome integration site of P2-like coliphages2006In: Journal of bacteriology, ISSN 0021-9193, Vol. 188, no 11, p. 3923-3935Article in journal (Refereed)
  • 209. Karlsson, Joakim L
    et al.
    Cardoso-Palacios, Carlos
    Nilsson, Anders S
    Haggård-Ljungquist, Elisabeth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Evolution of immunity and host chromosome integration site of P2-like coliphages.2006In: J Bacteriol, ISSN 0021-9193, Vol. 188, no 11, p. 3923-35Article in journal (Other academic)
    Abstract [en]

    Twenty-seven video-recorded interviews, with nine patients diagnosed with schizophrenia, were analyzed using qualitative methodology. Sequences of well- and of poorly functioning communication were distinguished, and characteristic verbal and nonverbal means of communication were described. In well functioning communication the interviewer asked short open questions, explored the emotional content in the narrative, and showed nonverbal means of communication that invited social interaction. The interviewer confirmed the patient emotionally and the narrative turned into a dialogue. The patient took a more active part and the narrative became extensive and elaborated. In poorly functioning communication the conversations were often fragmented, incoherent and confusing, with long pauses. The interviewer and the patients avoided eye-contact, and the nonverbal communication that was displayed did not accompany verbal utterances, but indicated discomfort and tension instead. Either patient or interviewer were observed dominating the conversation. In order to establish well functioning communication the interviewer’s contribution, particularly the willingness to explore and pursue the emotional content in the patient’s narrative, was found to be important.

  • 210. Kondo, Natsuko
    et al.
    Takahashi, Akihisa
    Mori, Eiichiro
    Noda, Taichi
    Zdzienicka, Malgorzata Z.
    Thompson, Larry H.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Suzuki, Minoru
    Kinashi, Yuko
    Masunaga, Shinichiro
    Ono, Koji
    Hasegawa, Masatoshi
    Ohnishi, Takeo
    FANCD1/BRCA2 Plays Predominant Role in the Repair of DNA Damage Induced by ACNU or TMZ2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 5, p. e19659-Article in journal (Refereed)
    Abstract [en]

    Nimustine (ACNU) and temozolomide (TMZ) are DNA alkylating agents which are commonly used in chemotherapy for glioblastomas. ACNU is a DNA cross-linking agent and TMZ is a methylating agent. The therapeutic efficacy of these agents is limited by the development of resistance. In this work, the role of the Fanconi anemia (FA) repair pathway for DNA damage induced by ACNU or TMZ was examined. Cultured mouse embryonic fibroblasts were used: FANCA(-/-), FANCC(-/-), FANCA(-/-)C(-/-), FANCD2(-/-) cells and their parental cells, and Chinese hamster ovary and lung fibroblast cells were used: FANCD1/BRCA2mt, FANCG(-/-) and their parental cells. Cell survival was examined after a 3 h ACNU or TMZ treatment by using colony formation assays. All FA repair pathways were involved in ACNU-induced DNA damage. However, FANCG and FANCD1/BRCA2 played notably important roles in the repair of TMZ-induced DNA damage. The most effective molecular target correlating with cellular sensitivity to both ACNU and TMZ was FANCD1/BRCA2. In addition, it was found that FANCD1/BRCA2 small interference RNA efficiently enhanced cellular sensitivity toward ACNU and TMZ in human glioblastoma A172 cells. These findings suggest that the down-regulation of FANCD1/BRCA2 might be an effective strategy to increase cellular chemo-sensitization towards ACNU and TMZ.

  • 211.
    Kotova, Natalia
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Biomarkers for DNA damage in human biomonitoring2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Genomic DNA in humans is constantly exposed to different kinds of damage. Therefore, it is desirable to implement methods for detecting and measuring of inflicted body burden. Human biomonitoring (HBM) can here be a useful tool as a link between environmental exposure and disease outcome. The present thesis aims to monitor DNA damage in humans by studies on: 1) urinary thymidine dimer (T=T) as a novel biomarker (BM) of human exposure to UV-light; 2) enumeration of variants in HPRT gene in human peripheral blood lymphocytes by developing a sensitive flow cytometric (FCM) analysis; 3) the impact of dietary habits on genomic stability in vegetarians and omnivores in terms of micronuclei (MN) induction detected by FCM. Urinary T=T was quantified by a 32P-postlabeling technique, the kinetics of T=T excretion was studied and the method was validated by delivering controlled UV-doses. The major conclusion was that the amount of urinary T=T was determined by the UV dose, and hence T=T can be used as a BM of UV exposure. Moreover, a new approach for rapid and sensitive enumeration of HPRT-variants by FCM was developed. The obtained HPRT-frequencies were comparable to those previously published by others. Finally, the FCM assay for MN enumeration was applied to study effects of dietary habits in vegetarians and omnivores. The main finding was that vegetarians had significantly lower MN frequencies compared to omnivores. In summary, the applied BMs and respective methods have high sensitivity and/or throughput possibility which are important factors considered in HBM.

     

  • 212.
    Kotova, Natalia
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Abramsson-Zetterberg, Lilianne
    Bergman, Rolf
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hartoft, Erika
    Segerbäck, Dan
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Grawé, Jan
    Vegetarians exhibit a low level of genomic instabilityManuscript (preprint) (Other academic)
  • 213.
    Kotova, Natalia
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Grawé, Jan
    Flow cytometric determination of HPRT-variantsin human peripheral blood lymphocytes2002In: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 499, no 1, p. 63-71Article in journal (Refereed)
    Abstract [en]

    Hypoxanthine guanine phosphoribosyl transferase (HPRT) deficient human peripheral blood lymphocytes are usually enumerated either by the cloning assay or by the autoradiographic short-term assay. The short-term approach presented here is based on flow cytometric (FCM) scoring of 6-thioguanine (6-TG) resistant lymphocytes. HPRT-variants are enumerated on the basis of both DNA synthesis (by use of immunofluorescent detection of incorporated 5-bromo-2-deoxyuridine, BrdU) and total DNA content (by propidium iodide (PI) incorporation) of proliferating cells, i.e. the cells must both be labelled with BrdU and reside in late-S or G(2) phase in order to be scored as a HPRT-variant. This approach is combined with a stringent discrimination of false-positive events, minimising occurrence of phenocopies or other non-specifically labelled cells that might falsely be scored as true HPRT-variants. The HPRT-variant frequency (V-f) found by the presented method varied between 0.8 x 10(-5) and 5.8 x 10(-5) for healthy male and female donors aged between 20 and 74 years. There was no significant gender difference in V-f. A strong linear correlation was found between HPRT-variant frequency and age, showing an increase of 0.56 x 10(-6) per year of age (r(2) = 0.62, P < 0.001). The frequencies of false-positive events found showed a mean of 0.22 x 10(-5) in comparison with a pooled mean V-f of 2.87 x 10(-5). There was no significant age effect on the frequency of false events (r(2) = = 0.15, P < 0.095). The method presented here may provide a rapid and sensitive alternative to the autoradiographic technique for the short-term enumeration of HPRT-variants.

  • 214.
    Kotova, Natalia
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hemminki, Kari
    Segerbäck, Dan
    Urinary Thymidine Dimer as a Marker of Total BodyBurden of UV-Inflicted DNA Damage in Humans2005In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 14, no 12, p. 2868-2872Article in journal (Refereed)
    Abstract [en]

    High levels of DNA damage are induced in human skin following exposure to UV radiation. Cyclobutane thymidine dimer (T = T) is the most common of these lesions, which are enzymatically removed as oligonucleotides from DNA and further degraded before excretion in urine. Analysis of such repair products in the urine could serve as a biomarker of total body burden of UV exposure. The aim of this study was to examine the kinetics of T = T excretion following a single tanning session in a commercial solarium and to validate the method by delivering different doses. Ten individuals used the solarium for a total of 35 sessions of body tanning. Urine was collected before UV exposure and daily thereafter (up to 5 or 11 days) and T = T was analyzed using a very sensitive and quantitative P-32-postlabeling technique combined with high-performance liquid chromatography. Following exposure, T = T levels increased dramatically and reached a peak 3 days later; afterwards, the T = T levels gradually decreased. The total amount of T = T excreted differed about 5-fold among subjects given an equal dose. A 50% excretion time was calculated using the excretion data for the first 5 days and it was found to be between 55 and 76 hours for different individuals. There was a good correlation between the amount of T = T excreted during days 1 to 5 and the delivered UV dose. Reducing exposure time to 50% lowered the amount of T = T to 47%; if half of the lamps were covered, T = T decreased to 44%. Our data show that urinary T = T could be a suitable noninvasive biomarker for UV exposure; a finding which could also be applicable to studies in children.

  • 215.
    Kotova, Natalia
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Juren, Tina
    Myohanen, Kirsi
    Cornelius, Michael
    Abramsson-Zetterberg, Lilianne
    Backman, Josefin
    Menzel, Ulrike
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Kronberg, Leif
    Vahakangas, Kirsi
    Segerback, Dan
    (32)P-HPLC analysis of N1-(2-carboxy-2-hydroxyethyl)deoxyadenosine: A DNA adduct of the acrylamide-derived epoxide glycidamide2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 207, no 1, p. 18-24Article in journal (Refereed)
    Abstract [en]

    Acrylamide (AA) is produced in many types of food products cooked or processed at high temperature. AA is metabolized to the epoxide glycidamide (GA), which can bind to deoxyguanosine and deoxyadenosine in DNA. The GA-derived N7-guanine and N3-adenine adducts are the only products which so far have been analysed in vivo. Because of previous excellent experience from analysis of adducts to N1-adenine, the aim of our study was to investigate if the N1-adenine adduct of GA could be used as a biomarker of AA exposure. A (32)P-postlabelling method was developed and tested (a) on DNA modified in vitro with GA, (b) on cells treated with GA and (c) on liver DNA from mice treated with M. The N1-adenine adduct of GA (analysed after conversion to N(6)-GA-deoxyadenosine-5'-monophosphate) was easily detected in DNA reacted with GA and in DNA from cells exposed to GA, but not in DNA from mice treated with AA. The reason for this is currently not clearly understood, but some of the possible contributing factors are discussed. The application of the method in other experimental conditions should be further pursued in order to solve this matter.

  • 216.
    Kotova, Natalia
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Vare, Daniel
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Schultz, Niklas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Gradecka Meesters, Dobrosława
    Stępnik, Maciej
    Grawé, Jan
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Genotoxicity of alcohol is linked to DNA replication-associated damage and homologous recombination repairIn: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180Article in journal (Refereed)
  • 217.
    Kotova, Natalia
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Vare, Daniel
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Schultz, Niklas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Meesters, Dobroslawa Gradecka
    Stepnik, Maciej
    Grawe, Jan
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Genotoxicity of alcohol is linked to DNA replication-associated damage and homologous recombination repair2013In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 34, no 2, p. 325-330Article in journal (Refereed)
    Abstract [en]

    Although alcohol consumption is related to increased cancer risk, its molecular mechanism remains unclear. Here, we demonstrate that an intake of 10% alcohol for 4 weeks in rats is genotoxic due to induction of micronuclei. Acetaldehyde (AA), the first product of ethanol metabolism, is believed to be responsible for DNA damage induced by alcohol. Here, we observe that AA effectively blocks DNA replication elongation in mammalian cells, resulting in DNA double-strand breaks associated with replication. AA-induced DNA damage sites colocalize with the homologous recombination (HR) repair protein RAD51. HR measured in the hypoxhantineguaninefosforibosyltransferase (HPRT) gene is effectively induced by AA and recombination defective mammalian cells are hypersensitive to AA, clearly demonstrating that HR is essential in the repair of AA-induced DNA damage. Altogether, our data indicate that alcohol genotoxicity related to AA produces replication lesions on DNA triggering HR repair.

  • 218. Kulka, U.
    et al.
    Ainsbury, L.
    Atkinson, M.
    Barquinero, J. F.
    Barrios, L.
    Beinke, C.
    Bognar, G.
    Cucu, A.
    Darroudi, F.
    Fattibene, P.
    Gil, O.
    Gregoire, E.
    Hadjidekova, V.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Herranz, R.
    Jaworska, A.
    Lindholm, C.
    Mkacher, R.
    Moertl, S.
    Montoro, A.
    Moquet, J.
    Moreno, M.
    Ogbazghi, A.
    Oestreicher, U.
    Palitti, F.
    Pantelias, G.
    Popescu, I.
    Prieto, M. J.
    Romm, H.
    Rothkamm, K.
    Sabatier, L.
    Sommer, S.
    Terzoudi, G.
    Testa, A.
    Thierens, H.
    Trompier, F.
    Turai, I.
    Vandersickel, V.
    Vaz, P.
    Voisin, P.
    Vral, A.
    Ugletveit, F.
    Woda, C.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Realising the European Network of Biodosimetry (RENEB)2012In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 151, no 4, p. 621-625Article in journal (Refereed)
    Abstract [en]

    In Europe, a network for biological dosimetry has been created to strengthen the emergency preparedness and response capabilities in case of a large-scale nuclear accident or radiological emergency. Through the RENEB (Realising the European Network of Biodosimetry) project, 23 experienced laboratories from 16 European countries will establish a sustainable network for rapid, comprehensive and standardised biodosimetry provision that would be urgently required in an emergency situation on European ground. The foundation of the network is formed by five main pillars: (1) the ad hoc operational basis, (2) a basis of future developments, (3) an effective quality-management system, (4) arrangements to guarantee long-term sustainability and (5) awareness of the existence of RENEB. RENEB will thus provide a mechanism for quick, efficient and reliable support within the European radiation emergency management. The scientific basis of RENEB will concurrently contribute to increased safety in the field of radiation protection.

  • 219.
    Kuwae, Asaomi
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Sjölinder, Hong
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Eriksson, Jens
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Eriksson, Sara
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Chen, Yao
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    NafA negatively controls Neisseria meningitidis piliation2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, p. e21749-Article in journal (Refereed)
    Abstract [en]

    Bacterial auto-aggregation is a critical step during adhesion of N. meningitidis to host cells. The precise mechanisms and functions of bacterial auto-aggregation still remain to be fully elucidated. In this work, we characterize the role of a meningococcal hypothetical protein, NMB0995/NMC0982, and show that this protein, here denoted NafA, acts as an anti-aggregation factor. NafA was confirmed to be surface exposed and was found to be induced at a late stage of bacterial adherence to epithelial cells. A NafA deficient mutant was hyperpiliated and formed bundles of pili. Further, the mutant displayed increased adherence to epithelial cells when compared to the wild-type strain. In the absence of host cells, the NafA deficient mutant was more aggregative than the wild-type strain. The in vivo role of NafA in sepsis was studied in a murine model of meningococcal disease. Challenge with the NafA deficient mutant resulted in lower bacteremia levels and mortality when compared to the wild-type strain. The present study reveals that meningococcal NafA is an anti-aggregation factor with strong impact on the disease outcome. These data also suggest that appropriate bacterial auto-aggregation is controlled by both aggregation and anti-aggregation factors during Neisseria infection in vivo.

  • 220. Köpper, Frederik
    et al.
    Bierwirth, Cathrin
    Schön, Margarete
    Kunze, Meike
    Elvers, Ingegerd
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Kranz, Dominique
    Saini, Priyanka
    Menon, Manoj B.
    Walter, David
    Sörensen, Claus Storgaard
    Gaestel, Matthias
    Helleday, Thomas
    Schön, Michael P.
    Dobbelstein, Matthias
    Damage-induced DNA replication stalling relies on MAPK-activated protein kinase 2 activity2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 42, p. 16856-16861Article in journal (Refereed)
    Abstract [en]

    DNA damage can obstruct replication forks, resulting in replicative stress. By siRNA screening, we identified kinases involved in the accumulation of phosphohistone 2AX (gamma H2AX) upon UV irradiation-induced replication stress. Surprisingly, the strongest reduction of phosphohistone 2AX followed knockdown of the MAP kinase-activated protein kinase 2 (MK2), a kinase currently implicated in p38 stress signaling and G2 arrest. Depletion or inhibition of MK2 also protected cells from DNA damage-induced cell death, and mice deficient for MK2 displayed decreased apoptosis in the skin upon UV irradiation. Moreover, MK2 activity was required for damage response, accumulation of ssDNA, and decreased survival when cells were treated with the nucleoside analogue gemcitabine or when the checkpoint kinase Chk1 was antagonized. By using DNA fiber assays, we found that MK2 inhibition or knockdown rescued DNA replication impaired by gemcitabine or by Chk1 inhibition. This rescue strictly depended on transiesion DNA polymerases. In conclusion, instead of being an unavoidable consequence of DNA damage, alterations of replication speed and origin firing depend on MK2-mediated signaling.

  • 221.
    Lagerqvist, Anne
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Factors Influencing the Yield of Mutations Induced by Polycyclic Aromatic Hydrocarbons in Mammalian Cells2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Environmental contaminants are ubiquitously present in the urban environment, this has the implication that humans are exposed to toxic and carcinogenic chemicals. Polycyclic aromatic hydrocarbons (PAH) are one type of environmental contaminants, which are produced by combustion of organic compounds. A wide variety of different PAH areformed of which most need metabolic activation to be transformed into the ultimate carcinogenic metabolite, a reactive diol epoxide (PAH-DE) that binds to DNA. PAH induced DNA damage is occasionally removed by different repair processes.

    This thesis focuses on four PAH-DE(benzo(a)pyrene-diol-epoxide (BPDE), dibenzo(a,l)pyrene-diol-epoxide (DBPDE), dibenzo(a,h)-anthracene-diol-epoxide (DBADE) and benzo(c)phenanthrene-diol-epoxide (BPhDE)) and the role of repair of the induced adducts and their efficiency to induce mutations. The highest level of adducts per µMh was found for the two PAH-DE with fjord region conformation (DBPDE and BPhDE). The highest mutation frequency was exerted by DBPDE followed by BPDE, DBADE and BPhDE explained by differences in both nucleotide excision repair (NER) and replication fidelity. When investigating the repair efficiencies and the effect on replication fork (RF) progression we found that NER enhanced the RF progression whereas HR delayed this process. Inhibition of translesion synthesis was found to delay the RF progression in both wild-type, NER and HR deficient cells. BPDE-induced adducts were most efficiently repaired by NER, whereas DBPDE adducts were not repaired. Antioxidants were tested against PAH-DE mutagenicity and their effects were not dependent on the fjord or bay region structures but on some other property of in the individual compounds.

    All together, the results indicate that it is not possible to categorize the mutagenic potency of PAH-DE according to common structural features (bay/fjord), why these compounds need to be evaluated individually.

  • 222.
    Lagerqvist, Anne
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Håkansson, Daniel
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Frank, Heinz
    Seidel, Albrecht
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Structural requirements for mutation formation from polycyclic aromatic hydrocarbon dihydrodiol epoxides in their interaction with food chemopreventive compounds2011In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 49, no 4, p. 879-886Article in journal (Refereed)
    Abstract [en]

    Chinese hamster V79 cells were used to investigate the protective effect of four known antimutagens present in food, chlorophyllin (CHL), ellagic acid (EA), epigallocathechingallate (EGCG) and benzylisothiocyanate (BITC), against potent mutagenic polycyclic aromatic hydrocarbon dial epoxides (PAH-DE) derived from benzo[a]pyrene (BP), dibenzo[a,h]anthracene (DBA), dibenzo[a,l]pyrene (DBP), and benzo[c]phenanthrene (BPh) known to be deposited on crops from polluted ambient air or formed during food processing. As fjord-region PAH-DE are more toxic and mutagenic than bay-region PAH-DE, we adjusted the concentrations of PAH-DE to induce approximately the same levels of adducts. The studies were performed using an assay indicating toxicity in terms of reduced cell proliferation together with the V79 Hprt assay for monitoring mutant frequencies. CHL significantly increased the survival and showed a protective effect against the mutagenicity of all PAH-DE. A significant protective effect of EA was found towards the mutagenicity of BPDE, DBPDE and BPhDE and with EGCG for BPDE and BPhDE. BITC had a slight positive effect on the mutagenicity of DBADE and BPhDE. Taken together, a novel and unexpected finding was that the antimutagenic activity could differ as much as by a factor of 7 towards four carcinogenic PAH metabolites being relatively similar in structure and genotoxic activity.

  • 223.
    Lagerqvist, Anne
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Håkansson, Daniel
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Prochaska, Gabriela
    Department of Biosciences and Nutrition, Novum, Karolinska Institute.
    Lundin, Cecilia
    Department of Biosciences and Nutrition, Novum, Karolinska Institute.
    Dreij, Kristian
    Segerbäck, Dan
    Department of Biosciences and Nutrition, Novum, Karolinska Institute.
    Jernström, Bengt
    The Institute for Environmental Medicine (IMM), Karolinska Institute.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Seidel, Albrecht
    Biochemical Institute for Environmental Carcinogens, Lurup .
    Erixon, Klaus
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Both replication bypass fidelity and repair efficiency influence the yield of mutations per target dose in intact mammalian cells induced by benzo(a)pyrene-diol-epoxide and dibenzo(a,l)-pyrene-diol-epoxide.2008In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, DNA repair, Vol. 7, no 8, p. 1202-1012Article in journal (Refereed)
    Abstract [en]

    Mutations induced by polycyclic aromatic hydrocarbons (PAH) are expected to be produced when error-prone DNA replication occurs across unrepaired DNA lesions formed by reactive PAH metabolites such as diol epoxides. The mutagenicity of the two PAH-diol epoxides (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DBPDE) was compared in nucleotide excision repair (NER) proficient and deficient hamster cell lines. We applied the 32P-postlabelling assay to analyze adduct levels and the hprt gene mutation assay for monitoring mutations. It was found that the mutagenicity per target dose was 4 times higher for DBPDE compared to BPDE in NER proficient cells while in NER deficient cells, the mutagenicity per target dose was 1.4 times higher for BPDE. In order to investigate to what extent the mutagenicity of the different adducts in NER proficient cells was influenced by repair or replication bypass, we measured the overall NER incision rate, the rate of adduct removal, the rate of replication bypass and the frequency of induced recombination in the hprt gene. The results suggest that NER of BPDE lesions are 5 times more efficient than for DBPDE lesions, in NER proficient cells. However, DBPDE adducts block replication more efficiently and also induce 6 times more recombination events in the hprt gene than adducts of BPDE, suggesting that DBPDE adducts are, to a larger extent, bypassed by homologous recombination. The results obtained here indicate that the mutagenicity of PAH is influenced not only by NER, but also by replication bypass fidelity. This has been postulated earlier based on results using in vitro enzyme assays, but is now also being recognized in terms of forward mutations in intact mammalian cells.

  • 224.
    Lagerqvist, Anne
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Håkansson, Daniel
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Lundin, Cecilia
    Prochazka, Gabriela
    Dreij, Kristian
    Segerbäck, Dan
    Jernström, Bengt
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Franke, Heinz
    Seidel, Albrecht
    Erixon, Klaus
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    DNA repair and replication influence the number of mutations per adduct of polycyclic aromatic hydrocarbons in mammalian cells2011In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 10, no 8, p. 877-886Article in journal (Refereed)
    Abstract [en]

    Polycyclic aromatic hydrocarbons (PAH) are an important class of environmental contaminants many of which require metabolic activation to DNA-reactive bay or fjord region diolepoxides (DE) in order to exert their mutagenic and carcinogenic effects. In this study, the mutagenicity of the bay region diolepoxides (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and ()-anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrodibenzo[a,h]anthracene (DBADE) and the fjord region diolepoxides ()-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]-pyrene (DBPDE) and (+/-)-anti-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]-phenanthrene (BPhDE) was compared in nucleotide excision repair (NER) proficient and deficient hamster cell lines. The (32)P-postlabelling assay was applied to analyze DNA adduct levels and the Hprt gene mutation assay for monitoring mutations. Previously, we found that the mutagenicity per adduct was four times higher for DBPDE compared to BPDE in NER proficient cells. In these same cells, the mutagenicity of DBADE and BPhDE adducts was now found to be significantly lower compared to that of BPDE. In NER deficient cells the highest mutagenicity per adduct was found for BPDE and there was a tenfold and fivefold difference when comparing the BPDE data with the DBADE and BPhDE data, respectively. In order to investigate to what extent the mutagenicity of the different adducts in NER proficient cells was influenced by repair or replication bypass, we measured the overall NER incision rate, the rate of adduct removal, the rate of replication bypass and the frequency of induced recombination in the Hprt gene. Since NER turned out to be an important pathway for the yield of mutations, we further analyzed the role of transcription coupled NER versus global genome NER. However, our data demonstrate that neither of these pathways seems to be the sole factor determining the mutation frequency of the four PAH-DE and that the differences in the repair efficiency of these compounds could not be related to the presence of a bay or fjord region in the parent PAH.

  • 225.
    Lagerqvist, Anne
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Håkansson, Daniel
    Seidel, Albrecht
    Erixon, Klaus
    Jenssen, Dag
    Replication bypass, repair efficiency and the yield of mutations per target dose of polycyclic aromatic hydrocarbons in intact mammalian cells.Manuscript (Other academic)
  • 226.
    Lagerqvist, Anne
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Håkansson, Daniel
    Seidel, Albrecht
    Erixon, Klaus
    Jenssen, Dag
    The role of the structure of polycyclic aromatic hydrocarbons for the activity of antimutagens in mammalian cells.Manuscript (Other academic)
  • 227. Lavigne, Rob
    et al.
    Darius, Paul
    Summer, Elizabeth J
    Seto, Donald
    Mahadevan, Padmanabhan
    Nilsson, Anders S
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Ackermann, Hans W
    Kropinski, Andrew M
    Classification of Myoviridae bacteriophages using protein sequence similarity.2009In: BMC microbiology, ISSN 1471-2180, Vol. 9, p. 224-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We advocate unifying classical and genomic classification of bacteriophages by integration of proteomic data and physicochemical parameters. Our previous application of this approach to the entirely sequenced members of the Podoviridae fully supported the current phage classification of the International Committee on Taxonomy of Viruses (ICTV). It appears that horizontal gene transfer generally does not totally obliterate evolutionary relationships between phages. RESULTS: CoreGenes/CoreExtractor proteome comparison techniques applied to 102 Myoviridae suggest the establishment of three subfamilies (Peduovirinae, Teequatrovirinae, the Spounavirinae) and eight new independent genera (Bcep781, BcepMu, FelixO1, HAP1, Bzx1, PB1, phiCD119, and phiKZ-like viruses). The Peduovirinae subfamily, derived from the P2-related phages, is composed of two distinct genera: the "P2-like viruses", and the "HP1-like viruses". At present, the more complex Teequatrovirinae subfamily has two genera, the "T4-like" and "KVP40-like viruses". In the genus "T4-like viruses" proper, four groups sharing >70% proteins are distinguished: T4-type, 44RR-type, RB43-type, and RB49-type viruses. The Spounavirinae contain the "SPO1-"and "Twort-like viruses." CONCLUSION: The hierarchical clustering of these groupings provide biologically significant subdivisions, which are consistent with our previous analysis of the Podoviridae.

  • 228. Lehtiö, Lari
    et al.
    Collins, Ruairi
    van den Berg, Susanne
    Johansson, Andreas
    Dahlgren, Lars-Göran
    Hammarström, Martin
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Holmberg-Schiavone, Lovisa
    Karlberg, Tobias
    Weigelt, Johan
    Zinc binding catalytic domain of human tankyrase 1.2008In: J Mol Biol, ISSN 1089-8638, Vol. 379, no 1, p. 136-45Article in journal (Refereed)
  • 229. Lehtiö, Lari
    et al.
    Jemth, Ann-Sofie
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Collins, Ruairi
    Loseva, Olga
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Johansson, Andreas
    Markova, Natalia
    Hammarström, Martin
    Flores, Alex
    Holmberg-Schiavone, Lovisa
    Weigelt, Johan
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Schüler, Herwig
    Karlberg, Tobias
    Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3.2009In: Journal of medicinal chemistry, ISSN 1520-4804, Vol. 52, no 9, p. 3108-11Article in journal (Refereed)
    Abstract [en]

    Poly(ADP-ribose) polymerases (PARPs) activate DNA repair mechanisms upon stress- and cytotoxin-induced DNA damage, and inhibition of PARP activity is a lead in cancer drug therapy. We present a structural and functional analysis of the PARP domain of human PARP-3 in complex with several inhibitors. Of these, KU0058948 is the strongest inhibitor of PARP-3 activity. The presented crystal structures highlight key features for potent inhibitor binding and suggest routes for creating isoenzyme-specific PARP inhibitors.

  • 230. Lewinska, D
    et al.
    Palus, J
    Stepnik, M
    Dziubaltowska, E
    Beck, J
    Rydzynski, K
    Natarajan, A.T.
    Nilsson, Robert
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Micronucleus frequency in peripheral blood lymphocytes and buccal mucosa cells of copper smelter workers, with special regard to arsenic exposure2007In: International Archives of Occupational and Environmental Health, ISSN 0340-0131, E-ISSN 1432-1246, Vol. 80, no 5, p. 371-380Article in journal (Refereed)
    Abstract [en]

    Occupational exposure in copper smelters may produce various adverse health effects including cancer which, according to available epidemiologic data, is associated mainly with exposure to arsenic. Despite a number of well-documented studies reporting an increased risk of cancer among copper smelters workers, the data on genotoxic effects in this industry are scarce. In view of the above, an assessment of micronuclei (MN) frequency in peripheral blood lymphocytes and buccal epithelial cells from copper smelter workers was undertaken. Additionally, the clastogenic/aneugenic effect in lymphocytes was assessed with the fluorescence in situ hybridization (FISH). The study was conducted in three copper smelters in southwestern Poland. The subjects (n = 72) were enrolled among male workers at departments where As concentration in the air was up to at 80 μg/m3. Exposure was assessed by measurement of arsenic concentration in urine and toenail samples. The control group (n = 83) was recruited from healthy male individuals living in central Poland who did not report any exposure to known genotoxins. The results of our study showed a significant increase in MN frequency in peripheral blood lymphocytes and in buccal epithelial cells of smelter workers, compared to the controls (7.96 ± 4.28 vs. 3.47 ± 1.70 and 0.98 ± 0.76 vs. 0.50 ± 0.52, respectively). The FISH technique revealed the presence of clastogenic and aneugenic effects in peripheral blood lymphocytes in both groups. The clastogenic effect was slightly more pronounced in the smelter workers; however, the difference was not statistically significant. The mean arsenic concentrations in urine (total arsenic species) and in toenail samples in the exposed group were 54.04 ± 42.26 μg/l and 7.63 ± 7.24 μg/g, respectively, being significantly different from control group 11.01 ± 10.84 μg/l and 0.51 ± 0.05 μg/g. No correlation between As content in urine or toenail samples and the genotoxic effect was found under study.

  • 231.
    Li, Wenli
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Terenius, Olle
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hirai, Makoto
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Nilsson, Anders S
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Faye, Ingrid
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cloning, expression and phylogenetic analysis of Hemolin, from the Chinese oak silkmoth, Antheraea pernyi.2005In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 29, no 10, p. 853-64Article in journal (Refereed)
    Abstract [en]

    The Chinese oak silk moth Antheraea pernyi is an important silk producer. To understand microbial resistance of this moth, we cloned Hemolin, encoding a multifunctional immune protein belonging to the immunoglobulin superfamily, and examined the expression in gonads and fat body. The ApHemolin amino acid sequence was compared to other Hemolin sequences in order to predict functional sites. Several sites were conserved; among them a phosphate binding site, which according to 3D structure modelling does not appear in neuroglian, the phylogenetically closest related protein. In addition, two conserved KDG sequences in the C-C' loop of immunoglobulin domains 1 and 3, give rise to gamma-turns, which is a common motif in the C'-C'' loop of the hypervariable region L2 in vertebrate immunoglobulins. The comparisons also show variable regions of specific interest for future studies of hemolin and its interaction with microbial entities.

  • 232. Li, Wenli
    et al.
    Terenius, Olle
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hirai, Makoto
    Nilsson, Anders S.
    Faye, Ingrid
    Molecular characterization, immunological and phylogenetic analysis of Hemolin, in the Chinese oak silkmoth, Antheraea pernyiManuscript (Other academic)
  • 233. Liljendahl, Tove Sandberg
    et al.
    Kotova, Natalia
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Segerback, Dan
    Quantification of ultraviolet radiation induced DNA damage in the urine of Swedish adults and children following exposure to sunlight2012In: Biomarkers, ISSN 1354-750X, E-ISSN 1366-5804, Vol. 17, no 7, p. 634-641Article in journal (Refereed)
    Abstract [en]

    Context: DNA damage following exposure to ultraviolet radiation (UVR) is important in skin cancer development. The predominant photoproduct, cyclobutane thymine dimer (T=T), is repaired and excreted in the urine, where it provides a biomarker of exposure. Objective: To quantify urinary T=T levels after recreational sunlight exposure in adults and children. Methods: Average UVR doses were measured with personal dosimeters. Urinary T=T was analysed with P-32-postlabelling. Results: Background levels of T=T increased significantly following exposure to sunlight. Amounts of T=T in urine of children and adults were not significantly different after adjusting for area of skin exposed and physiological differences. UVR dose and amounts of T=T correlated for both adults and children. Conclusion: Recreational exposure to sunlight in Sweden induces levels of DNA damage, clearly detectable in urine.

  • 234.
    Lindh, Anna Renglin
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Rafii, Saeed
    Schultz, Niklas
    Cox, Angela
    Helleday, Thomas
    Mitotic defects in XRCC3 variants T241M and D213N and their relation to cancer susceptibility.2006In: Hum Mol Genet, ISSN 0964-6906, Vol. 15, no 7, p. 1217-24Article in journal (Refereed)
  • 235.
    Lindh, J. M.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Borg-Karlson, A. -K
    Faye, Ingrid
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Transstadial and horizontal transfer of bacteria within a colony of Anopheles gambiae (DipteraCulicidae) and oviposition response to bacteria-containing water:  2008In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 107, no 3, p. 242-250Article in journal (Refereed)
    Abstract [en]

    In a paratransgenic approach, genetically modified bacteria are utilized to kill the parasite in the vector gut. A critical component for paratransgenics against malaria is how transgenic bacteria can be introduced and then kept in a mosquito population. Here, we investigated transstadial and horizontal transfer of bacteria within an Anopheles gambiae mosquito colony with the focus on spiked breeding sites as a possible means of introducing bacteria to mosquitoes. A Pantoea stewartii strain, previously isolated from An. gambiae, marked with a green fluorescent protein (GFP), was introduced to mosquitoes in different life stages. The following life stages or older mosquitoes in the case of adults were screened for bacteria in their guts. In addition to P. stewartii other bacteria were isolated from the guts: these were identified by 16S rRNA sequence analysis and temporal temperature gradient gel electrophoresis (TTGE). Bacteria were transferred from larvae to pupae but not from pupae to adults. The mosquitoes were able to take up bacteria from the water they emerged from and transfer the same bacteria to the water they laid eggs in. Eliza-bethkingia meningoseptica was more often isolated from adult mosquitoes than P. stewartii. A bioassay was used to examine An. gambiae oviposition responses towards bacteria-containing solutions. The volatiles emitted from the solutions were sampled by headspace-solid phase microextraction (SPME) and identified by gas chromatography and mass spectrometry (GC-MS) analysis. P. stewartii but not E. meningoseptica mediated a positive oviposition response. The volatiles emitted by P stewartii include indole and 3-methyl-1 -butanol, which previously have been shown to affect An. gambiae mosquito behaviour. E. meningoseptica emitted indole but not 3-methyl-1 -butanol, when suspended in saline. Taken together, this indicates that it may be possible to create attractive breeding sites for distribution of genetically modified bacteria in the field in a paratransgenic approach against malaria. Further research is needed to determine if the bacteria are also transferred in the same way in nature.

  • 236.
    Lindh, J. M.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Kannaste, A.
    Knols, B. G. J.
    Faye, I.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Borg-Karlson, A. -K
    Oviposition Responses of Anopheles gambiae s.s. (Diptera Culicidae) and Identification of Volatiles from Bacteria-Containing Solutions:  2008In: Journal of medical entomology, ISSN 0022-2585, E-ISSN 1938-2928, Vol. 45, no 6, p. 1039-1049Article in journal (Refereed)
    Abstract [en]

    In this study, a dual-choice oviposition bioassay was used to screen responses of gravid An. gambiae toward 17 bacterial species, previously isolated from Anopheles gambiae s.l. (Diptera: Culicidae) midguts or oviposition sites. The 10 isolates from oviposition sites have been identified by phylogenetic analyses of their 16S rRNA genes. Eight of the 10 isolates were gram-positive, out of which six belonged to the Bacilli class. Solid phase microextraction and gas chromatography coupled to mass spectrometry (GC-MS) were used to identify the volatiles emitted From the bacterial isolates, Aromatic and aliphatic alcohols, aliphatic ketones, alkylpyrazines, dimethyl oligosulfides, and indole were among the chemical compounds identified from the headspace above bacteria-containing saline. The mosquitoes laid significantly more eggs in six of the bacteria-containing solutions compared with the sterile solution. These six bacteria did not emit any compounds in common that could explain the positive oviposition response. Instead. the bacteria were grouped according to principal component analysis (PCA) based on the relative amouts of volatile emitted. The PCA-plots facilitated the identification of 13 putative oviposition attractants for An. gambiae mosquitoes.

  • 237.
    Lindh, Jenny
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Identification of bacteria associated with malaria mosquitoes - Their characterisation and potential use2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The use of transformed bacteria to stop or kill disease-causing agents in the gut of vector insects is called paratransgenics. Two of the major steps in creating a paratransgenic Anopheles mosquito, unable to spread the Plasmodium parasites that cause malaria, are to find a bacterium suitable for the purpose and a way to introduce the transformed bacterium into mosquitoes in the field. In this project, bacteria associated with malaria mosquitoes have been identified by phylogenetic analysis of their 16S rRNA genes. First, the midgut flora of field-caught Anopheles mosquitoes was examined using two pathways, one culture dependent and one culture independent. Second, six bacterial species from an An. gambiae laboratory colony, and third, ten isolates from Anopheles oviposition sites have been identified. Altogether, 32 bacterial species, representing 16 families, seven classes and four phyla were identified. Interestingly, several of them are related to bacteria known to be symbionts in other insects. Two possible ways of introducing bacteria into mosquitoes in the field in a paratransgenic approach were investigated in a laboratory setting. It was shown that sugar solutions with or without bacteria are equally attractive to An. gambiae mosquitoes and that the mosquitoes were able to take up bacteria from the water they emerged from. These results show that it may be possible to use sugar-baits and oviposition sites for distribution of genetically modified bacteria in the field. To facilitate the distribution of the modified bacteria mosquito attractants should be used. We investigated whether the bacterial isolates identified in this project produce attractants affecting mosquito sugar-feeding or oviposition site selection. While no responses were observed from the mosquitoes towards bacteria-containing sugar solutions, seven of the 19 isolates examined mediated positive oviposition responses. In total, 13 putative oviposition attractants were identified among the volatiles emitted by the attractive bacteria.

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  • 238.
    Lindh, J.M.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Borg-Karlson, A.-K.
    Faye, I.
    Investigation of transstadial and horizontal transfer of bacteria within an Anopheles gambiae (Diptera: Culicidae) laboratory colony and oviposition response of An. gambiae to bacteria-containing waterManuscript (Other academic)
  • 239.
    Lindh, J.M.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Kännaste, A.
    Knols, B.G.J.
    Faye, I.
    Borg-Karlson, A.-K.
    Identification of volatiles and oviposition responses of Anopheles gambiae s.s. (Diptera: Culicidae) mosquitoes to solutions containing bacteria previously isolated from An. gambiae s.l. midguts or oviposition sitesManuscript (Other academic)
  • 240.
    Lindh, J.M.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Terenius, O.
    Eriksson-Gonzales, K.
    Knols, B.G.J.
    Faye, I.
    Re-introducing bacteria in mosquitoes-A method for determination of mosquito feeding preferences based on coloured sugar solutions2006In: Acta Tropica, ISSN 0001-706X, Vol. 99, no 2-3, p. 173-183Article in journal (Refereed)
  • 241.
    Lindh, J.M.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Terenius, O.
    Faye, I.
    16S rRNA gene-based identification of midgut bacteria from field-caught Anopheles gambiae sensu lato and A. funestus mosquitoes reveals new species related to known insect symbionts2005In: Applied and Environmental Microbiology, ISSN 0099-2240, Vol. 71, no 11, p. 7217-23Article in journal (Refereed)
  • 242. Lindholm, Carita
    et al.
    Stricklin, Daniela
    Jaworska, Alicja
    Koivistoinen, Armi
    Paile, Wendla
    Arvidsson, Eva
    Deperas-Standylo, Joanna
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Premature chromosome condensation (PCC) assay for dose assessment in mass casualty accidents2010In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 173, no 1, p. 71-8Article in journal (Refereed)
    Abstract [en]

    The study was undertaken to establish a dose calibration curve for a practical PCC ring assay and to apply it in a simulated mass casualty accident. The PCC assay was validated against the conventional dicentric assay. A linear relationship was established for PCC rings after (60)Co gamma irradiation with doses up to 20 Gy. In the simulated accident experiment, 62 blood samples were analyzed with both the PCC ring assay and the conventional dicentric assay, applying a triage approach. Samples received various uniform and non-uniform (10-40% partial-body) irradiations up to doses of 13 Gy. The results indicated that both assays yielded good dose estimates for the whole-body exposure scenario, although in the lower-dose range (0-6 Gy) dicentric scoring resulted in more accurate whole-body estimates, whereas PCC rings were better in the high-dose range (>6 Gy). Neither assay was successful in identifying partial-body exposures, most likely due to the low numbers of cells scored in the triage mode. In conclusion, the study confirmed that the PCC ring assay is suitable for use as a biodosimeter after whole-body exposure to high doses of radiation. However, there are limitations for its use in the triage of people exposed to high, partial-body doses.

  • 243. Lisowska, Halina
    et al.
    Deperas-Kaminska, Marta
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Parmryd, Ingela
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Cell Biology.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Radiation-induced DNA damage and repair in human gammadelta and alphabeta T-lymphocytes analysed by the alkaline comet assay.2010In: Genome integrity, ISSN 2041-9414, Vol. 1, no 1, p. 8-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: It has been shown by a number of authors that the radiosensitivity of peripheral blood mononuclear cells (PBMC) is higher in cancer patients compared to healthy donors, which is interpreted as a sign of genomic instability. PBMC are composed of different cell subpopulations which are differently radiosensitive and the difference between cancer patients and healthy donors could also be due to different composition of their PBMC pools. Gamma-delta T-lymphocytes play an important role in immunosurveillance and are promising cells for immunotherapy. Their abundance is frequently reduced in cancer patients so should their sensitivity to radiation be lower than that of other T-lymphocytes, this could, at least partly explain the low radiosensitivity of PBMC from healthy individuals compared to cancer patients. The present investigation was carried out to test this. Using the alkaline comet assay we analysed the level of DNA damage and repair in isolated gammadelta T-lymphocytes, pan T-lymphocytes and in total PBMC exposed in vitro to gamma radiation. We found no difference in the level of DNA damage and the capacity of DNA repair between the T cell populations. This is the first study that addresses the question of sensitivity to radiation of gamma-delta T-cells.

  • 244. Lisowska, Halina
    et al.
    Wegierek-Ciuk, Aneta
    Banasik-Nowak, Anna
    Braziewicz, Janusz
    Wojewodzka, Maria
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Lankoff, Anna
    The dose-response relationship for dicentric chromosomes and gamma-H2AX foci in human peripheral blood lymphocytes:  Influence of temperature during exposure and intra- and inter-individual variability of donors2013In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 89, no 3, p. 191-199Article in journal (Refereed)
    Abstract [en]

    Purpose : Hypothermia during in vitro irradiation of human peripheral blood lymphocytes (PBL) affects the level of chromosome aberrations. The molecular mechanisms of this phenomenon are not fully understood. The aim of our study was to examine the effect of hypothermia on the dose-response relationship for dicentric chromosomes and the level of gamma-H2AX (phosphorylated histone H2AX) foci. In addition, the inter- and intra-individual variability was assessed in relation to temperature. Materials and methods : PBL were kept at 0.8, 20 and 37 degrees C and then exposed to gamma-rays (from 0-3 Gy). Dicentric chromosomes were scored in first post-treatment mitoses. gamma H2AX foci were scored 15, 30, 60, 120 min and 24 h post irradiation. Results : Our results revealed that the frequency of dicentric chromosomes in cells exposed at 37 degrees C to gamma-rays was higher than after exposure at 0.8 and 20 degrees C. No effect of temperature was observed on the number of gamma-H2AX foci as well as on the intra-and inter-individual variations of the dicentric yield and the number of gamma-H2AX foci. Conclusions : Temperature at exposure to ionizing radiation has a pronounced effect on the level of cytogenetic damage but not gamma-H2AX foci.

  • 245.
    Liu, Tao
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haggård-Ljungquist, Elisabeth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The transcriptional switch of bacteriophage WPhi, a P2-related but heteroimmune coliphage.1999In: J Virol, ISSN 0022-538X, Vol. 73, no 12, p. 9816-26Article in journal (Other academic)
  • 246.
    Liu, Tao
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Renberg, Sara K
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haggård-Ljungquist, Elisabeth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Derepression of prophage P2 by satellite phage P4: cloning of the P4 epsilon gene and identification of its product.1997In: J Virol, ISSN 0022-538X, Vol. 71, no 6, p. 4502-8Article in journal (Other academic)
  • 247.
    Liu, Tao
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Renberg, Sara K
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haggård-Ljungquist, Elisabeth
    The E protein of satellite phage P4 acts as an anti-repressor by binding to the C protein of helper phage P2.1998In: Mol Microbiol, ISSN 0950-382X, Vol. 30, no 5, p. 1041-50Article in journal (Other academic)
  • 248.
    Liu, Yanfang
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haggård-Ljungquist, Elisabeth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Functional characterization of the P2 A initiator protein and its DNA cleavage site.1996In: Virology, ISSN 0042-6822, Vol. 216, no 1, p. 158-64Article in journal (Other academic)
  • 249.
    Liu, Yuanfang
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haggård-Ljungquist, Elisabeth
    Studies of bacteriophage P2 DNA replication: localization of the cleavage site of the A protein.1994In: Nucleic Acids Res, ISSN 0305-1048, Vol. 22, no 24, p. 5204-10Article in journal (Other academic)
  • 250. Loseva, Olga
    et al.
    Jemth, Ann-Sofie
    Bryant, Helen E.
    Schuler, Herwig
    Lehtio, Lari
    Karlberg, Tobias
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    PARP-3 Is a Mono-ADP-ribosylase That Activates PARP-1 in the Absence of DNA2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 11, p. 8054-8060Article in journal (Refereed)
    Abstract [en]

    The PARP-3 protein is closely related to the PARP-1 and PARP-2 proteins, which are involved in DNA repair and genome maintenance. Here, we characterized the biochemical properties of human PARP-3. PARP-3 is able to ADP-ribosylate itself as well as histone H1, a previously unknown substrate for PARP-3. PARP-3 is not activated upon binding to DNA and is a mono-ADP-ribosylase, in contrast to PARP-1 and PARP-2. PARP-3 interacts with PARP-1 and activates PARP-1 in the absence of DNA, resulting in synthesis of polymers of ADPribose. The N-terminal WGR domain of PARP-3 is involved in this activation. The functional interaction between PARP-3 and PARP-1 suggests that it may have a role in DNA repair. However, here we report that PARP-3 small interfering RNA-depleted cells are not sensitive to the topoisomerase I poison camptothecin, inducing DNA single-strand breaks, and repair these lesions as efficiently as wild-type cells. Altogether, these results suggest that the interaction between PARP-1 and PARP-3 is unrelated to DNA single-strand break repair.

2345678 201 - 250 of 476
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