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  • 1.
    Aagaard, Sunniva M. D.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Greilhuber, Johann
    University of Vienna, Department of Systematic and Evolutionary Botany.
    Zhang, Xian-Chun
    Institute of Botany,Chinese Academy of Sciences .
    Wikström, Niklas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Occurrence and evolutionary origins of polyploids in the club moss genus Diphasiastrum (Lycopodiaceae)2009In: Molecular Phylogenetics and Evolution, ISSN 1055-7903, E-ISSN 1095-9513, Vol. 52, no 3, p. 746-754Article in journal (Refereed)
    Abstract [en]

    Two polyploid taxa are commonly recognized in the genus Diphasiastrum, D. wightianum from Asia and D. zanclophyllum from South Africa and Madagascar. Here we present results from Feulgen DNA image densitometry analyses providing the first evidence for the polyploid origin of D. zanclophyllum. Reported for the first time is also data confirming that D. multispicatum and D. veitchii, representing putative parent lineages for D. wightianum, are diploids. Phylogenetic analyses of nuclear regions RPB2, LEAFY and LAMB4 reveal that putative tetraploid accessions are of allopolyploid origin. Diphasiastrum zanclophyllum shows close relationships to the North American taxon D. digitatum on the maternal side, but the paternal relationship is less clear. Two accessions from Asia, both found to be polyploid, have D. veitchii as maternal parent, whereas the paternal paralogs show relationships to D. multispicatum and D. tristachyum, respectively. None of these parental combinations have previously been hypothesized.

  • 2.
    Aagaard, Sunniva Margrethe Due
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Reticulate Evolution in Diphasiastrum (Lycopodiaceae)2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis relationships and the occurrence of reticulate evolutionary events in the club moss genus Diphasiastrum are investigated. Diphasiastrum is initially established as a monophyletic group within Lycopodiaceae using non recombinant chloroplast sequence data. Support is obtained for eight distinct parental lineages in Diphasiastrum, and relationships among the putative parent taxa in the hypothesized hybrid complexes; D. alpinum, D. complanatum, D. digitatum, D. multispicatum, D. sitchense, D. tristachyum and D. veitchii are presented.

    Feulgen DNA image densitometry data and sequence data obtained from three nuclear regions, RPB2, LEAFY and LAMB4, were used to infer the origins of three different taxa confirmed to be allopolyploid; D. zanclophyllum from South Africa, D. wightianum from Malaysia and an undescribed taxon from China. The two Asian polyploids have originated from two different hybrid combinations, D. multispicatum x D. veitchii and D. tristachyum x D. veitchii. Diphasiastrum zanclophyllum originates from a cross between D. digitatum and an unidentified diploid taxon.

    The occurrence of three homoploid hybrid combinations commonly recognized in Europe, D. alpinum x D. complanatum, D. alpinum x D. tristachyum and D. complanatum x D. tristachyum, are verified using the same three nuclear regions. Two of the three hybrid combinations are also shown to have originated from reciprocal crosses. Admixture analyses performed on an extended, dataset similarly identified predominately F1 hybrids and backcrosses. The observations and common recognition of hybrid species in the included populations are hence most likely due to frequent observations of neohybrids in hybrid zones. Reticulate patterns are, however, prominent in the presented dataset. Hence future studies addressing evolutionary and ecological questions in Diphasiastrum should emphasize the impact of gene flow between parent lineages rather than speciation as the result of hybridization.

    List of papers
    1. Resolving maternal relationships in the clubmoss genus Diphasiastrum (Lycopodiaceae)
    Open this publication in new window or tab >>Resolving maternal relationships in the clubmoss genus Diphasiastrum (Lycopodiaceae)
    2009 (English)In: Taxon, ISSN 0040-0262, E-ISSN 1996-8175, Vol. 58, no 3, p. 835-848Article in journal (Refereed) Published
    Abstract [en]

    Diphasiastrum comprises 20-30 species. In addition to a number of species with a circumboreal distribution, several island endemics and putative diploid hybrid species contribute to the diversity of the group. To assess the integrity and relationships of the recognized species, a global phylogeny of Diphasiastrum is constructed using five chloroplast regions comprising ~9000 bp. Six monophyletic groups are identified. Accessions identified as hybrid species cluster in all but one case together with one of its putative parents. Two microsatellite loci are identified, and allelic information combined with sequence information is found diagnostic for the three putative parental taxa in the Central Europe hybrid complexes. Haplotype screening is performed on six Central European populations, from where one or more putative diploid hybrid species have been reported to grow in sympatry with their parent species. The most common parental haplotypes are identified in all populations. Additional intraspecific variation, restricted to single populations, is identified in all sympatric populations at very low frequencies. Taking the low degree of sequence and microsatellite variation into consideration, the acknowledged morphological diversity in Central Europe is probably best explained by phenotypic plasticity, ancestral polymorphisms or relatively recent events of reticulate evolution.

    Keyword
    Chloroplast microsatellites, Diphasiastrum, Diploid hybrid species, Lycopodium, Lycopodiaceae, Plastid phylogeny
    National Category
    Biological Sciences
    Research subject
    Systematic Botany
    Identifiers
    urn:nbn:se:uu:diva-99576 (URN)000269774900012 ()
    Available from: 2009-03-16 Created: 2009-03-16 Last updated: 2017-12-13Bibliographically approved
    2. Occurrence and evolutionary origins of polyploids in the club moss genus Diphasiastrum (Lycopodiaceae)
    Open this publication in new window or tab >>Occurrence and evolutionary origins of polyploids in the club moss genus Diphasiastrum (Lycopodiaceae)
    2009 (English)In: Molecular Phylogenetics and Evolution, ISSN 1055-7903, E-ISSN 1095-9513, Vol. 52, no 3, p. 746-754Article in journal (Refereed) Published
    Abstract [en]

    Two polyploid taxa are commonly recognized in the genus Diphasiastrum, D. wightianum from Asia and D. zanclophyllum from South Africa and Madagascar. Here we present results from Feulgen DNA image densitometry analyses providing the first evidence for the polyploid origin of D. zanclophyllum. Reported for the first time is also data confirming that D. multispicatum and D. veitchii, representing putative parent lineages for D. wightianum, are diploids. Phylogenetic analyses of nuclear regions RPB2, LEAFY and LAMB4 reveal that putative tetraploid accessions are of allopolyploid origin. Diphasiastrum zanclophyllum shows close relationships to the North American taxon D. digitatum on the maternal side, but the paternal relationship is less clear. Two accessions from Asia, both found to be polyploid, have D. veitchii as maternal parent, whereas the paternal paralogs show relationships to D. multispicatum and D. tristachyum, respectively. None of these parental combinations have previously been hypothesized.

    Keyword
    Diphasiastrum, Feulgen DNA image densitometry, Lycopodium, Lycopodiaceae, low-copy nuclear genes, phylogenies, polyploidy
    National Category
    Biological Sciences
    Research subject
    Systematic Botany
    Identifiers
    urn:nbn:se:uu:diva-99577 (URN)10.1016/j.ympev.2009.05.004 (DOI)000268265800016 ()
    Available from: 2009-03-16 Created: 2009-03-16 Last updated: 2017-12-13Bibliographically approved
    3. Reticulate phylogenetic patterns in diploid European Diphasiastrum (Lycopodiaceae).
    Open this publication in new window or tab >>Reticulate phylogenetic patterns in diploid European Diphasiastrum (Lycopodiaceae).
    (English)Manuscript (Other academic)
    Abstract [en]

    In Central Europe, three species belonging to Diphasiastrum are considered to be of homoploid hybrid origin. Diphasiastrum issleri is suggested to have originated from a cross between D. alpinum and D. complanatum, D. oellgaardii from D. alpinum and D. tristachyum, and D. zeilleri from D. complanatum and D. tristachyum. Variation at three nuclear regions and two chloroplast microsatellites verify the presence of all three putative parental combinations in Europe. Data obtained with Feulgen DNA image densitometry confirms that all specimens displaying such pattern are diploid. Also, two of three parental combinations have probably arisen repeatedly, implied by the occurrence of chloroplast haplotypes associated with different parents. The presented dataset cannot be used as argument for the existence of independent evolutionary entities hybrid origin. This is nonetheless an important first step in order to address the influence of reticulate evolutionary events in European Diphasiastrum

    Keyword
    Keywords – Diphasiastrum, homoploid hybridization, Lycopodiaceae, Lycopodium, low copy nuclear genes, phylogenies, Feulgen DNA image densitometry
    Identifiers
    urn:nbn:se:uu:diva-99578 (URN)
    Available from: 2009-03-16 Created: 2009-03-16 Last updated: 2010-01-14
    4. Homoploid hybridization in Central European Diphasiastrum (Lycopodiaceae).
    Open this publication in new window or tab >>Homoploid hybridization in Central European Diphasiastrum (Lycopodiaceae).
    (English)Manuscript (Other academic)
    Abstract [en]

    Three species of homoploid hybrid origin are commonly recognized among Central European Diphasiastrum, and reticulate evolutionary events have for a long time been acknowledged as an important factor contributing to the species count in the genus. Presented evidence obtained from molecular data has until recently been scarce and inconclusive. Recent studies have, however, documented reticulate phylogenetic patterns involving all putative parental combinations reported from Central Europe. Reciprocal crosses involving the same parental combinations have also been confirmed. In order to further explore these putative reticulate events, admixture analyses using a Bayesian approach as implemented in the program NewHybrids are conducted on an expanded dataset obtained from six Central European populations from where putative hybrid taxa are reported. A majority of the accessions included in the analyses were inferred to represent pure bred D. alpinum, D. complanatum, D. tristachyum, F1 hybrids, F2 hybrids or backcrosses with one of the parent species. Accessions displaying ambiguous classification were found in both allopatric parent populations as well as in Central European hybrid populations. Presented results indicate the presence of frequently occurring hybrid zones with first and second generation hybrids as well as backcrosses.

    Keyword
    admixture analysis, Bayesian clustering, Diphasiastrum, homoploid hybridization, Lycopodiaceae, Lycopodium, NewHybrids.
    National Category
    Biological Systematics
    Research subject
    Systematic Botany; Population Biology
    Identifiers
    urn:nbn:se:uu:diva-99579 (URN)
    Available from: 2009-03-16 Created: 2009-03-16 Last updated: 2010-01-14
    5. Revised lectotypification of Lycopodium complanatum L. (Lycopodiaceae)
    Open this publication in new window or tab >>Revised lectotypification of Lycopodium complanatum L. (Lycopodiaceae)
    2009 (English)In: Taxon, ISSN 0040-0262, E-ISSN 1996-8175, Vol. 58, no 3, p. 974-976Article in journal (Refereed) Published
    Abstract [en]

    The currently accepted lectotype of the circumboreal species Lycopodium complanatum L., or Diphasiastrum complanatum (L.) Holub, is a specimen of the related species L. tristachyum Pursh, or D. tristachyum (Pursh) Holub, mainly distributed in eastern North America and Europe. This lectotype, in LINN, is here superseded in favour of an alternative original element in the Celsius herbarium in Uppsala, supported by an epitype, on the grounds of conflict with the protologue. Thereby the traditional usage of the well-known name L. complanatum can be maintained.

    Keyword
    Diphasiastrum, nomenclature, Lycopodium, Lycopodiaceae, typification.
    National Category
    Biological Systematics
    Research subject
    Systematic Botany; Biology with specialization in Systematics
    Identifiers
    urn:nbn:se:uu:diva-99572 (URN)000269774900026 ()
    Available from: 2009-03-16 Created: 2009-03-16 Last updated: 2017-12-13Bibliographically approved
  • 3.
    Aagaard, Sunniva M.D.
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics.
    Gyllenstrand, Niclas
    Wikström, Niklas
    Homoploid hybridization in Central European Diphasiastrum (Lycopodiaceae).Manuscript (Other academic)
    Abstract [en]

    Three species of homoploid hybrid origin are commonly recognized among Central European Diphasiastrum, and reticulate evolutionary events have for a long time been acknowledged as an important factor contributing to the species count in the genus. Presented evidence obtained from molecular data has until recently been scarce and inconclusive. Recent studies have, however, documented reticulate phylogenetic patterns involving all putative parental combinations reported from Central Europe. Reciprocal crosses involving the same parental combinations have also been confirmed. In order to further explore these putative reticulate events, admixture analyses using a Bayesian approach as implemented in the program NewHybrids are conducted on an expanded dataset obtained from six Central European populations from where putative hybrid taxa are reported. A majority of the accessions included in the analyses were inferred to represent pure bred D. alpinum, D. complanatum, D. tristachyum, F1 hybrids, F2 hybrids or backcrosses with one of the parent species. Accessions displaying ambiguous classification were found in both allopatric parent populations as well as in Central European hybrid populations. Presented results indicate the presence of frequently occurring hybrid zones with first and second generation hybrids as well as backcrosses.

  • 4.
    Aagaard, Sunniva M.D.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Vogel, Johannes C.
    Wikström, Niklas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Resolving maternal relationships in the clubmoss genus Diphasiastrum (Lycopodiaceae)2009In: Taxon, ISSN 0040-0262, E-ISSN 1996-8175, Vol. 58, no 3, p. 835-848Article in journal (Refereed)
    Abstract [en]

    Diphasiastrum comprises 20-30 species. In addition to a number of species with a circumboreal distribution, several island endemics and putative diploid hybrid species contribute to the diversity of the group. To assess the integrity and relationships of the recognized species, a global phylogeny of Diphasiastrum is constructed using five chloroplast regions comprising ~9000 bp. Six monophyletic groups are identified. Accessions identified as hybrid species cluster in all but one case together with one of its putative parents. Two microsatellite loci are identified, and allelic information combined with sequence information is found diagnostic for the three putative parental taxa in the Central Europe hybrid complexes. Haplotype screening is performed on six Central European populations, from where one or more putative diploid hybrid species have been reported to grow in sympatry with their parent species. The most common parental haplotypes are identified in all populations. Additional intraspecific variation, restricted to single populations, is identified in all sympatric populations at very low frequencies. Taking the low degree of sequence and microsatellite variation into consideration, the acknowledged morphological diversity in Central Europe is probably best explained by phenotypic plasticity, ancestral polymorphisms or relatively recent events of reticulate evolution.

  • 5. Aarrestad, P. A.
    et al.
    Hytteborn, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Masunga, G.
    Skarpe, C.
    Vegetation: Between Soils and Herbivores2014In: Elephants and Savanna Woodland Ecosystems: A Study from Chobe National Park, Botswana / [ed] Christina Skarpe, Johan T. du Toit and Stein R. Moe, Wiley-Blackwell, 2014, p. 61-88Chapter in book (Refereed)
    Abstract [en]

    The vegetation of the study area in Chobe National Park is influenced by a range of factors, including inundation by the Chobe River, soil moisture and fertility, and the impacts of different-size grazers and browsers. This chapter focuses on how the structure and species composition of the present vegetation in northern Chobe National Park is related to recent herbivory by elephants, as agents shaping the vegetation, and by mesoherbivores acting as controllers or responders, along with abiotic controllers such as soil type and distance to the river. In the study, a two-way indicator species analysis classified the vegetation data into four more or less distinct plant community groups (i) Baikiaea plurijuga-Combretum apiculatum woodland, (ii) Combretum mossambicense-Friesodielsia obovata wooded shrubland, (iii) Capparis tomentosa-Flueggea virosa shrubland and (iv) Cynodon dactylon-Heliotropium ovalifolium floodplain, named after the TWINSPAN indicator or preferential species with high cover, and the relative amount of shrubs and trees.

  • 6. Aarrestad, P. A.
    et al.
    Masunga, G. S.
    Hytteborn, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Pitlagano, M. L.
    Marokane, W.
    Skarpe, C.
    Influence of soil, tree cover and large herbivores on field layer vegetation along a savanna landscape gradient in northern Botswana2011In: Journal of Arid Environments, ISSN 0140-1963, E-ISSN 1095-922X, Vol. 75, no 3, p. 290-297Article in journal (Refereed)
    Abstract [en]

    The response of the field layer vegetation to co-varying resource availability (soil nutrients, light) and resource loss (herbivory pressure) was investigated along a landscape gradient highly influenced by elephants and smaller ungulates at the Chobe River front in Botswana. TWINSPAN classification was used to identify plant communities. Detrended Correspondence Analysis (DCA) and Canonical Correspondence Analysis (CCA) were used to explore the vegetation-environment relationships. Four plant communities were described: Panicum maximum woodland, Tribulus terrestris woodland/shrubland, Chloris virgata shrubland and Cynodon dactylon floodplain. Plant height, species richness and diversity decreased with increasing resource availability and resource loss. The species composition was mainly explained by differences in soil resources, followed by variables related to light availability (woody cover) and herbivory, and by interactions between these variables. The vegetation structure and species richness, on the other hand, followed the general theories of vegetation responses to herbivory more closely than resource related theories. The results suggest a strong interaction between resource availability and herbivory in their influence on the composition, species richness and structure of the plant communities.

  • 7.
    Abarenkov, Kessy
    et al.
    Univ Tartu, Nat Hist Museum, Tartu, Estonia..
    Adams, Rachel I.
    Univ Calif Berkeley, Plant & Microbial Biol, Berkeley, CA 94720 USA..
    Irinyi, Laszlo
    Westmead Hosp, Ctr Infect Dis & Microbiol, Mol Mycol Res Lab, Sydney Med Sch, Sydney, NSW, Australia.;Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW, Australia.;Westmead Inst Med Res, Westmead, NSW, Australia..
    Agan, Ahto
    Univ Tartu, Inst Ecol & Earth Sci, Tartu, Estonia..
    Ambrosio, Elia
    Univ Tartu, Nat Hist Museum, Tartu, Estonia.;Univ Tartu, Inst Ecol & Earth Sci, Tartu, Estonia.;Via Calamandrei 2, I-53035 Siena, Italy..
    Antonelli, Alexandre
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden.;Gothenburg Bot Garden, Carl Skottsbergs Gata 22A, S-41319 Gothenburg, Sweden..
    Bahram, Mohammad
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology. Univ Tartu, Inst Ecol & Earth Sci, Tartu, Estonia.
    Bengtsson-Palme, Johan
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Guldhedsgatan 10, S-41346 Gothenburg, Sweden..
    Bok, Gunilla
    SP Tech Res Inst Sweden, Box 857, S-50115 Boras, Sweden..
    Cangren, Patrik
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Coimbra, Victor
    Univ Fed Pernambuco UFPE, Dept Micol, CCB, Av Prof Nelson Chaves S-N, BR-50670901 Recife, PE, Brazil..
    Coleine, Claudia
    Univ Tuscia, Dept Ecol & Biol Sci, I-01100 Viterbo, Italy..
    Gustafsson, Claes
    Univ Gothenburg, Herbarium GB, Box 461, S-40530 Gothenburg, Sweden..
    He, Jinhong
    Chinese Acad Sci, South China Bot Garden, 723 Xingke Rd, Guangzhou 510650, Guangdong, Peoples R China..
    Hofmann, Tobias
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Kristiansson, Erik
    Chalmers, Dept Math Sci, S-41296 Gothenburg, Sweden..
    Larsson, Ellen
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Larsson, Tomas
    Univ Gothenburg, Dept Marine Sci, Box 460, S-40530 Gothenburg, Sweden..
    Liu, Yingkui
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Martinsson, Svante
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Meyer, Wieland
    Westmead Hosp, Ctr Infect Dis & Microbiol, Mol Mycol Res Lab, Sydney Med Sch, Sydney, NSW, Australia.;Westmead Inst Med Res, Westmead, NSW, Australia..
    Panova, Marina
    Univ Gothenburg, Dept Marine Sci Tjarno, S-45296 Stromstad, Sweden..
    Pombubpa, Nuttapon
    Univ Calif Riverside, Dept Plant Pathol & Microbiol, Riverside, CA 92521 USA.;Univ Calif Riverside, Inst Integrat Genome Biol, Riverside, CA 92521 USA..
    Ritter, Camila
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Ryberg, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Svantesson, Sten
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Scharn, Ruud
    Univ Gothenburg, Dept Earth Sci, Box 460, S-40530 Gothenburg, Sweden..
    Svensson, Ola
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Töpel, Mats
    Univ Gothenburg, Dept Marine Sci, Box 460, S-40530 Gothenburg, Sweden..
    Unterseher, Martin
    Ernst Moritz Arndt Univ Greifswald, Inst Bot & Landscape Ecol, Soldmannstr 15, D-17487 Greifswald, Germany..
    Visagie, Cobus
    Agr & Agri Food Canada, Biodivers Mycol, 960 Carling Ave, Ottawa, ON K1A 0C6, Canada.;Univ Ottawa, Dept Biol, 30 Marie Curie, Ottawa, ON K1N 6N5, Canada..
    Wurzbacher, Christian
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Taylor, Andy F. S.
    James Hutton Inst, Aberdeen AB15 8QH, Scotland.;Univ Aberdeen, Inst Biol & Environm Sci, Cruickshank Bldg, Aberdeen AB24 3UU, Scotland..
    Köljalg, Urmas
    Univ Tartu, Nat Hist Museum, Tartu, Estonia.;Univ Tartu, Inst Ecol & Earth Sci, Tartu, Estonia..
    Schriml, Lynn
    Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA.;Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA..
    Nilsson, R. Henrik
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Annotating public fungal ITS sequences from the built environment according to the MIxS-Built Environment standard - a report from a May 23-24, 2016 workshop (Gothenburg, Sweden)2016In: MycoKeys, ISSN 1314-4057, E-ISSN 1314-4049, no 16, p. 1-15Article in journal (Refereed)
    Abstract [en]

    Recent molecular studies have identified substantial fungal diversity in indoor environments. Fungi and fungal particles have been linked to a range of potentially unwanted effects in the built environment, including asthma, decay of building materials, and food spoilage. The study of the built mycobiome is hampered by a number of constraints, one of which is the poor state of the metadata annotation of fungal DNA sequences from the built environment in public databases. In order to enable precise interrogation of such data - for example, "retrieve all fungal sequences recovered from bathrooms" - a workshop was organized at the University of Gothenburg (May 23-24, 2016) to annotate public fungal barcode (ITS) sequences according to the MIxS-Built Environment annotation standard (http:// gensc.org/ mixs/). The 36 participants assembled a total of 45,488 data points from the published literature, including the addition of 8,430 instances of countries of collection from a total of 83 countries, 5,801 instances of building types, and 3,876 instances of surface-air contaminants. The results were implemented in the UNITE database for molecular identification of fungi (http://unite.ut.ee) and were shared with other online resources. Data obtained from human/animal pathogenic fungi will furthermore be verified on culture based metadata for subsequent inclusion in the ISHAM-ITS database (http:// its. mycologylab.org).

  • 8.
    Abbassi, Nasrollah
    et al.
    Univ Zanjan, Dept Geol, Fac Sci, Zanjan, Iran..
    Kundrat, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Ataabadi, Majid Mirzaie
    Univ Zanjan, Dept Geol, Fac Sci, Zanjan, Iran..
    Ahlberg, Per E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala Univ, Sub Dept Evolut & Dev, Evolutionary Biol Ctr, Dept Organismal Biol, Uppsala, Sweden..
    Avian ichnia and other vertebrate trace fossils from the Neogene Red Beds of Tarom valley in north-western Iran2016In: Historical Biology, ISSN 0891-2963, E-ISSN 1029-2381, Vol. 28, no 8, p. 1075-1089Article in journal (Refereed)
    Abstract [en]

    The Neogene Red Beds of the Tarom valley (north-western Iran) include conglomerate, sandstone, marl and gypsum. Avian and mammal footprints were discovered in one of the sandstone layers at the base of a third Miocene stratigraphical unit in the Gilankesheh area located in the east Tarom valley. The avian ichnia include Aviadactyla vialovi, Avipeda filiportatis, Charadriipeda disjuncta, Charadriipeda isp. A and B and cf. Ornithotarnocia lambrechti. Bird feeding traces are preserved as bilobate, loop-shaped, sinusoidal and ring-like traces. We have also identified a reticulate texture of sole scale imprints in some of the avian ichnia. Two mammal footprints of camelid-like artiodactyls are also present with the avian ichno-assemblage.

  • 9.
    Abbott, Jessica K.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal Ecology.
    Intra-locus sexual conflict and sexually antagonistic genetic variation in hermaphroditic animals2011In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 278, no 1703, p. 161-169Article, review/survey (Refereed)
    Abstract [en]

    Intra-locus sexual conflict results when sex-specific selection pressures for a given trait act against the intra-sexual genetic correlation for that trait. It has been found in a wide variety of taxa in both laboratory and natural populations, but the importance of intra-locus sexual conflict and sexually antagonistic genetic variation in hermaphroditic organisms has rarely been considered. This is not so surprising given the conceptual and theoretical association of intra-locus sexual conflict with sexual dimorphism, but there is no a priori reason why intra-locus sexual conflict cannot occur in hermaphroditic organisms as well. Here, I discuss the potential for intra-locus sexual conflict in hermaphroditic animals and review the available evidence for such conflict, and for the existence of sexually antagonistic genetic variation in hermaphrodites. I argue that mutations with asymmetric effects are particularly likely to be important in mediating sexual antagonism in hermaphroditic organisms. Moreover, sexually antagonistic genetic variation is likely to play an important role in inter-individual variation in sex allocation and in transitions to and from gonochorism (separate sexes) in simultaneous hermaphrodites. I also describe how sequential hermaphrodites may experience a unique form of intra-locus sexual conflict via antagonistic pleiotropy. Finally, I conclude with some suggestions for further research.

  • 10.
    Abbott, Jessica K.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal Ecology.
    Bedhomme, Stéphanie
    Evolutionary Systems Virology Group, University of Valencia.
    Chippindale, Adam K.
    Biology Department, Queen's University.
    Sexual conflict in wing size and shape in Drosophila melanogaster2010In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 23, no 9, p. 1989-1997Article in journal (Refereed)
    Abstract [en]

    Intralocus sexual conflict occurs when opposing selection pressures operate on loci expressed in both sexes, constraining the evolution of sexual dimorphism and displacing one or both sexes from their optimum. We eliminated intralocus conflict in Drosophila melanogaster by limiting transmission of all major chromosomes to males, thereby allowing them to win the intersexual tug-of-war. Here, we show that this male-limited (ML) evolution treatment led to the evolution (in both sexes) of masculinized wing morphology, body size, growth rate, wing loading, and allometry. In addition to more male-like size and shape, ML evolution resulted in an increase in developmental stability for males. However, females expressing ML chromosomes were less developmentally stable, suggesting that being ontogenetically more male-like was disruptive to development. We suggest that sexual selection over size and shape of the imago may therefore explain the persistence of substantial genetic variation in these characters and the ontogenetic processes underlying them.

  • 11.
    Abbott, Jessica K.
    et al.
    Queen's University.
    Bensch, S.
    Lund University.
    Gosden, Thomas P.
    Lund University.
    Svensson, Erik I.
    Lund University.
    Patterns of differentiation in a colour polymorphism and in neutral markers reveal rapid genetic changes in natural damselfly populations2008In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 17, no 6, p. 1597-1604Article in journal (Refereed)
    Abstract [en]

    The existence and mode of selection operating on heritable adaptive traits can be inferred by comparing population differentiation in neutral genetic variation between populations (often using F(ST) values) with the corresponding estimates for adaptive traits. Such comparisons indicate if selection acts in a diversifying way between populations, in which case differentiation in selected traits is expected to exceed differentiation in neutral markers [F(ST )(selected) > F(ST )(neutral)], or if negative frequency-dependent selection maintains genetic polymorphisms and pulls populations towards a common stable equilibrium [F(ST) (selected) < F(ST) (neutral)]. Here, we compared F(ST) values for putatively neutral data (obtained using amplified fragment length polymorphism) with estimates of differentiation in morph frequencies in the colour-polymorphic damselfly Ischnura elegans. We found that in the first year (2000), population differentiation in morph frequencies was significantly greater than differentiation in neutral loci, while in 2002 (only 2 years and 2 generations later), population differentiation in morph frequencies had decreased to a level significantly lower than differentiation in neutral loci. Genetic drift as an explanation for population differentiation in morph frequencies could thus be rejected in both years. These results indicate that the type and/or strength of selection on morph frequencies in this system can change substantially between years. We suggest that an approach to a common equilibrium morph frequency across all populations, driven by negative frequency-dependent selection, is the cause of these temporal changes. We conclude that inferences about selection obtained by comparing F(ST) values from neutral and adaptive genetic variation are most useful when spatial and temporal data are available from several populations and time points and when such information is combined with other ecological sources of data.

  • 12.
    Abbott, Jessica K.
    et al.
    Queen's University.
    Gosden, Thomas P.
    Lund University.
    Correlated morphological and colour differences among females of the damselfly Ischnura elegans2009In: Ecological Entomology, ISSN 0307-6946, E-ISSN 1365-2311, Vol. 34, no 3, p. 378-386Article in journal (Refereed)
    Abstract [en]

    1. The female-limited colour polymorphic damselfly Ischnura elegans has proven to be an interesting study organism both as an example of female sexual polymorphism, and in the context of the evolution of colour polymorphism. The study of colour polymorphism can also have broader applications as a model of speciation processes.

    2. Previous research suggests that there exist correlations between colour morph and other phenotypic traits, and that the different female morphs in I. elegans may be pursuing alternative phenotypically integrated strategies. However, previous research on morphological differences in southern Swedish individuals of this species was only carried out on laboratory-raised offspring from a single population, leaving open the question of how widespread such differences are.

    3. We therefore analysed multi-generational data from 12 populations, investigating morphological differences between the female morphs in the field, differences in the pattern of phenotypic integration between morphs, and quantified selection on morphological traits.

    4. We found that consistent morphological differences did indeed exist between the morphs across all study populations, confirming that the previously observed differences were not simply a laboratory artefact.  We also found, somewhat surprisingly, that despite the existence of sexual dimorphism in body size and shape, patterns of phenotypic integration differed most between the morphs and not between the sexes. Finally, linear selection gradients showed that female morphology affected fecundity differently between the morphs.

    5. We discuss the relevance of these results to the male mimicry hypothesis and to the existence of potential ecological differences between the morphs.

  • 13.
    Abbott, Jessica K.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal Ecology.
    Morrow, Edward H.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal Ecology.
    Obtaining snapshots of genetic variation using hemiclonal analysis2011In: Trends in Ecology & Evolution, ISSN 0169-5347, E-ISSN 1872-8383, Vol. 26, no 7, p. 359-368Article, review/survey (Refereed)
    Abstract [en]

    Hemiclones are naturally occurring or artificially produced individuals that share a single specific genetic haplotype. Natural hemiclones are produced via hybridization between two closely related species, whereas hemiclonal analysis in Drosophila is carried out in the laboratory via crosses with artificially created 'clone-generator' females with a specific genetic make-up. Hemiclonal analysis in Drosophila has been applied successfully to date to obtain measures of standing genetic variation for numerous traits. Here, we review the current hemiclonal literature and suggest future directions for hemiclonal research, including its application in molecular and genomic studies, and the adaptation of natural hemiclonal systems to carry out Drosophila-type studies of standing genetic variation.

  • 14.
    Abbott, Jessica K.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Animal Ecology.
    Svensson, Erik I.
    Lund University.
    Morph-specific variation in intersexual genetic correlations in an intra-specific mimicry system2010In: Evolutionary Ecology Research, ISSN 1522-0613, E-ISSN 1937-3791, Vol. 12, no 1, p. 105-118Article in journal (Refereed)
    Abstract [en]

    Background: Positive intersexual genetic correlations are typically viewed as constraining the evolution of sexual dimorphism, when traits are subject to sexually antagonistic selection. Our study species, the damselfly Ischnura elegans, has a female-limited colour polymorphism with three female colour morphs (males are monomorphic), one of which is considered a male mimic.

    Question: Are there morph-specific differences in the magnitude of intersexual genetic correlations in I. elegans? Specifically, do male-mimic (Androchrome) females have higher intersexual genetic correlations for morphological traits than non-mimic (Infuscans) females?

    Methods: We collected copulating pairs in the field and raised offspring from these pairs in the laboratory. We measured five morphological traits in both parent and offspring generations and investigated their heritabilities and genetic correlations.

    Results: We found a negative overall relationship between the degree of sexual dimorphism for a trait and its intersexual genetic correlation. But the magnitude and direction of intersexual genetic correlations depended on the female morph. As expected, male mimic (Androchrome) females had higher intersexual genetic correlations. In addition, the genetic correlations between the morphs were in all cases significantly lower than unity. Male mimic (Androchrome) females had higher mother-son covariances than the non-mimic (Infuscans) morph, and this difference is the proximate explanation for the difference in intersexual genetic correlations between the morphs.

  • 15.
    Abbott, Jessica K.
    et al.
    Lund University.
    Svensson, Erik I.
    Lund University.
    Ontogeny of sexual dimorphism and phenotypic integration in heritable morphs2008In: Evolutionary Ecology, ISSN 0269-7653, E-ISSN 1573-8477, Vol. 22, no 1, p. 103-121Article in journal (Refereed)
    Abstract [en]

    In this study we investigated the developmental basis of adult phenotypes in a non-model organism, a polymorphic damselfly (Ischnura elegans) with three female colour morphs. This polymorphic species presents an ideal opportunity to study intraspecific variation in growth trajectories, morphological variation in size and shape during the course of ontogeny, and to relate these juvenile differences to the phenotypic differences of the discrete adult phenotypes; the two sexes and the three female morphs. We raised larvae of different families in individual enclosures in the laboratory, and traced morphological changes during the course of ontogeny. We used principal components analysis to examine the effects of Sex, Maternal morph, and Own morph on body size and body shape. We also investigated the larval fitness consequences of variation in size and shape by relating these factors to emergence success. Females grew faster than males and were larger as adults, and there was sexual dimorphism in body shape in both larval and adult stages. There were also significant effects of both maternal morph and own morph on growth rate and body shape in the larval stage. There were significant differences in body shape, but not body size, between the adult female morphs, indicating phenotypic integration between colour, melanin patterning, and body shape. Individuals that emerged successfully grew faster and had different body shape in the larval stage, indicating internal (non-ecological) selection on larval morphology. Overall, morphological differences between individuals at the larval stage carried over to the adult stage. Thus, selection in the larval stage can potentially result in correlated responses in adult phenotypes and vice versa.

  • 16.
    Abbott, Jessica K.
    et al.
    Lund University.
    Svensson, Erik I.
    Lund University.
    Phenotypic and genetic variation in emergence and development time of a trimorphic damselfly2005In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 18, no 6, p. 1464-1470Article in journal (Refereed)
    Abstract [en]

    Although colour polymorphisms in adult organisms of many taxa are often adaptive in the context of sexual selection or predation, genetic correlations between colour and other phenotypic traits expressed early in ontogeny could also play an important role in polymorphic systems. We studied phenotypic and genetic variation in development time among female colour morphs in the polymorphic damselfly Ischnura elegans in the field and by raising larvae in a common laboratory environment. In the field, the three different female morphs emerged at different times. Among laboratory-raised families, we found evidence of a significant correlation between maternal morph and larval development time in both sexes. This suggests that the phenotypic correlation between morph and emergence time in the field has a parallel in a genetic correlation between maternal colour and offspring development time. Maternal colour morph frequencies could thus potentially change as correlated responses to selection on larval emergence dates. The similar genetic correlation in male offspring suggests that sex-limitation in this system is incomplete, which may lead to an ontogenetic sexual conflict between selection for early male emergence (protandry) and emergence times associated with maternal morph.

  • 17. Abdurahman, Samir
    et al.
    Vegvari, Akos
    Levi, Michael
    Höglund, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Högberg, Marita
    Tong, Weimin
    Romero, Ivan
    Balzarini, Jan
    Vahlne, Anders
    Isolation and characterization of a small antiretroviral molecule affecting HIV-1 capsid morphology2009In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 6, p. 34-Article in journal (Refereed)
    Abstract [en]

    Background: Formation of an HIV-1 particle with a conical core structure is a prerequisite for the subsequent infectivity of the virus particle. We have previously described that glycineamide (G-NH2) when added to the culture medium of infected cells induces non-infectious HIV-1 particles with aberrant core structures. Results: Here we demonstrate that it is not G-NH2 itself but a metabolite thereof that displays antiviral activity. We show that conversion of G-NH2 to its antiviral metabolite is catalyzed by an enzyme present in bovine and porcine but surprisingly not in human serum. Structure determination by NMR suggested that the active G-NH2 metabolite was alpha-hydroxy-glycineamide (alpha-HGA). Chemically synthesized alpha-HGA inhibited HIV-1 replication to the same degree as G-NH2, unlike a number of other synthesized analogues of G-NH2 which had no effect on HIV-1 replication. Comparisons by capillary electrophoresis and HPLC of the metabolite with the chemically synthesized alpha-HGA further confirmed that the antiviral G-NH2-metabolite indeed was alpha-HGA. Conclusion: alpha-HGA has an unusually simple structure and a novel mechanism of antiviral action. Thus, alpha-HGA could be a lead for new antiviral substances belonging to a new class of anti-HIV drugs, i.e. capsid assembly inhibitors.

  • 18.
    Abdurakhmanov, Eldar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Discovery and evaluation of direct acting antivirals against hepatitis C virus2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Until recently, the standard therapy for hepatitis C treatment has been interferon and ribavirin. Such treatment has only 50% efficacy and is not well tolerated. The emergence of new drugs has increased the treatment efficacy to 90%. Despite such an achievement, the success is limited since the virus mutates rapidly, causing the emergence of drug resistant forms. In addition, most new drugs were developed to treat genotype 1 infections. Thus, development of new potent antivirals is needed and drug discovery against hepatitis C is continued.

    In this thesis, a FRET-based protease assay was used to evaluate new pyrazinone based NS3 protease inhibitors that are structurally different to the newly approved and currently developing drugs. Several compounds in this series showed good potencies in the nanomolar range against NS3 proteases from genotype 1, 3, and the drug resistance variant R155K. We assume that these compounds can be further developed into drug candidates that possess activity against above mentioned enzyme variants.

    By using SPR technology, we analyzed interaction mechanisms and characteristics of allosteric inhibitors targeting NS5B polymerases from genotypes 1 and 3. The compounds exhibited different binding mechanisms and displayed a low affinity against NS5B from genotype 3.

    In order to evaluate the activity and inhibitors of the NS5B polymerase, we established an SPR based assay, which enables the monitoring of polymerization and its inhibition in real time. This assay can readily be implemented for the discovery of inhibitors targeting HCV.

    An SPR based fragment screening approach has also been established. A screen of a fragment library has been performed in order to identify novel scaffolds that can be used as a starting point for development of new allosteric inhibitors against NS5B polymerase. Selected fragments will be further elaborated to generate a new potent allosteric drug candidate.

    Alternative approaches have successfully been developed and implemented to the discovery of potential lead compounds targeting two important HCV drug targets.

    List of papers
    1. Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
    Open this publication in new window or tab >>Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
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    2016 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, no 12, p. 2603-2620Article in journal (Refereed) Published
    Abstract [en]

    Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

    Keyword
    Hepatitis C virus; Drug resistance; Pyrazinone; NS3 protease inhibitors; R155K
    National Category
    Organic Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-243315 (URN)10.1016/j.bmc.2016.03.066 (DOI)000376727800002 ()27160057 (PubMedID)
    Funder
    Swedish Research Council, D0571301
    Available from: 2015-02-08 Created: 2015-02-08 Last updated: 2017-12-04Bibliographically approved
    2. Pyrazinone based hepatitis C virus NS3 protease inhibitors targeting genotype 1a, 3a and the drug-resistant enzyme variant R155K
    Open this publication in new window or tab >>Pyrazinone based hepatitis C virus NS3 protease inhibitors targeting genotype 1a, 3a and the drug-resistant enzyme variant R155K
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265295 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
    3. Resolution of the Interaction Mechanisms and Characteristics of Non-nucleoside Inhibitors of Hepatitis C Virus Polymerase - Laying the Foundation for Discovery of Allosteric HCV Drugs
    Open this publication in new window or tab >>Resolution of the Interaction Mechanisms and Characteristics of Non-nucleoside Inhibitors of Hepatitis C Virus Polymerase - Laying the Foundation for Discovery of Allosteric HCV Drugs
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    2013 (English)In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 97, no 3, p. 356-368Article in journal (Other academic) Published
    Abstract [en]

    Development of allosteric inhibitors into efficient drugs is hampered by their indirect mode-of-action and complex structure-kinetic relationships. To enablethe design of efficient allosteric drugs targeting the polymerase of hepatitis C virus(NS5B), the interaction characteristics of three non-nucleoside compounds (filibuvir, VX-222, and tegobuvir) inhibiting HCV replication via NS5B have been analyzed. Since there was no logical correlation between the anti-HCV replicative and enzyme inhibitory effects of the compounds, surface plasmon resonance biosensor technology was used to resolve the mechanistic, kinetic, thermodynamic and chemodynamic features of their interactions with their target and their effect on itsinteraction with RNA. Tegobuvir could not be seen to interact with NS5B at all while filibuvir interacted in a single reversible step (except at low temperatures) and VX-222 in two serial steps, interpreted as an induced fit mechanism. Both filibuvir and VX-222 interfered with the interaction between NS5B and RNA. They competed for binding to the enzyme, suggesting that they had a common inhibition mechanism and identical or overlapping binding sites. The greater anti-HCV replicative activityof VX-222 over filibuvir is hypothesized to be due to a greater allosteric conformational effect, resulting in the formation of a less catalytically competent complex. In addition, the induced fit mechanism of VX-222 gives it a kinetic advantage over filibuvir, exhibited as a longer residence time. These insights have important consequences for the selection and optimization of new allosteric NS5Binhibitors.

    Keyword
    HCV, NS5B, filibuvir, VX-222, tegobuvir, allosteric inhibitor, induced fit, kinetics, chemodynamics, thermodynamics
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biochemistry; Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-171996 (URN)10.1016/j.antiviral.2012.12.027 (DOI)000317709400018 ()
    Available from: 2012-04-03 Created: 2012-03-31 Last updated: 2017-12-07Bibliographically approved
    4. Characterization of allosteric inhibitors of hepatitis C virus polymerase – a genotype comparative study
    Open this publication in new window or tab >>Characterization of allosteric inhibitors of hepatitis C virus polymerase – a genotype comparative study
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265287 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
    5. A time-resolved surface plasmon resonance based hepatitis C virus NS5B polymerase assay and its application for drug discovery
    Open this publication in new window or tab >>A time-resolved surface plasmon resonance based hepatitis C virus NS5B polymerase assay and its application for drug discovery
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265290 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
    6. Fragment library screening addressing Hepatitis C protein NS5B from genotypes 1 and 3 using an SPR-based approach
    Open this publication in new window or tab >>Fragment library screening addressing Hepatitis C protein NS5B from genotypes 1 and 3 using an SPR-based approach
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265292 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
  • 19. Abdurakhmanov, Eldar
    et al.
    Danielson, Helena
    A time-resolved surface plasmon resonance based hepatitis C virus NS5B polymerase assay and its application for drug discoveryManuscript (preprint) (Other academic)
  • 20.
    Abdurakhmanov, Eldar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Solbak, Sara
    Danielson, Helena
    Characterization of allosteric inhibitors of hepatitis C virus polymerase – a genotype comparative studyManuscript (preprint) (Other academic)
  • 21.
    Abdurakhmanov, Eldar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Solbak, Sara Oie
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase2017In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 9, no 6, article id 151Article in journal (Refereed)
    Abstract [en]

    Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment of genotype 1, although their mode of action and potential to inhibit other isolates and genotypes are not well established. We have used biophysical techniques and a novel biosensor-based real-time polymerase assay to investigate the mode-of-action and selectivity of four inhibitors against enzyme from genotypes 1b (BK and Con1) and 3a. Two thumb inhibitors (lomibuvir and filibuvir) interacted with all three NS5B variants, although the affinities for the 3a enzyme were low. Of the two tested palm inhibitors (dasabuvir and nesbuvir), only dasabuvir interacted with the 1b variant, and nesbuvir interacted with NS5B 3a. Lomibuvir, filibuvir and dasabuvir stabilized the structure of the two 1b variants, but not the 3a enzyme. The thumb compounds interfered with the interaction between the enzyme and RNA and blocked the transition from initiation to elongation. The two allosteric inhibitor types have different inhibition mechanisms. Sequence and structure analysis revealed differences in the binding sites for 1b and 3a variants, explaining the poor effect against genotype 3a NS5B. The indirect mode-of-action needs to be considered when designing allosteric compounds. The current approach provides an efficient strategy for identifying and optimizing allosteric inhibitors targeting HCV genotype 3a.

  • 22. Abel, John H.
    et al.
    Drawert, Brian
    Hellander, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Petzold, Linda R.
    GillesPy: A Python package for stochastic model building and simulation2016In: IEEE Life Sciences Letters, E-ISSN 2332-7685, Vol. 2, p. 35-38Article in journal (Refereed)
  • 23.
    Abeysinghe, Kasun S.
    et al.
    Chinese Acad Sci, Xishuangbanna Trop Bot Garden, Key Lab Trop Forest Ecol, Mengla, Yunnan, Peoples R China.;Univ Chinese Acad Sci, Beijing, Peoples R China..
    Yang, Xiao-Dong
    Chinese Acad Sci, Xishuangbanna Trop Bot Garden, Key Lab Trop Forest Ecol, Mengla, Yunnan, Peoples R China..
    Goodale, Eben
    Guangxi Univ, Coll Forestry, Nanning, Guangxi, Peoples R China..
    Anderson, Christopher W. N.
    Massey Univ, Inst Agr & Environm, Soil & Earth Sci, Palmerston North, New Zealand..
    Bishop, Kevin
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL. Swedish Univ Agr Sci, Dept Aquat Sci & Assessment, Uppsala, Sweden..
    Cao, Axiang
    Chinese Acad Sci, Inst Geochem, State Key Lab Environm Geochem, Guiyang, Peoples R China.;Guizhou Normal Univ, Sch Chem & Mat Sci, Guiyang, Peoples R China..
    Feng, Xinbin
    Chinese Acad Sci, Inst Geochem, State Key Lab Environm Geochem, Guiyang, Peoples R China..
    Liu, Shengjie
    Chinese Acad Sci, Xishuangbanna Trop Bot Garden, Key Lab Trop Forest Ecol, Mengla, Yunnan, Peoples R China.;Univ Chinese Acad Sci, Beijing, Peoples R China..
    Mammides, Christos
    Chinese Acad Sci, Xishuangbanna Trop Bot Garden, Key Lab Trop Forest Ecol, Mengla, Yunnan, Peoples R China..
    Meng, Bo
    Chinese Acad Sci, Inst Geochem, State Key Lab Environm Geochem, Guiyang, Peoples R China..
    Quan, Rui-Chang
    Chinese Acad Sci, Xishuangbanna Trop Bot Garden, Key Lab Trop Forest Ecol, Mengla, Yunnan, Peoples R China..
    Sun, Jing
    Nanjing Agr Univ, Coll Resources & Environm Sci, Nanjing, Jiangsu, Peoples R China..
    Qiu, Guangle
    Chinese Acad Sci, Inst Geochem, State Key Lab Environm Geochem, Guiyang, Peoples R China..
    Total mercury and methylmercury concentrations over a gradient of contamination in earthworms living in rice paddy soil2017In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 36, no 5, p. 1202-1210Article in journal (Refereed)
    Abstract [en]

    Mercury (Hg) deposited from emissions or from local contamination, can have serious health effects on humans and wildlife. Traditionally, Hg has been seen as a threat to aquatic wildlife, because of its conversion in suboxic conditions into bioavailable methylmercury (MeHg), but it can also threaten contaminated terrestrial ecosystems. In Asia, rice paddies in particular may be sensitive ecosystems. Earthworms are soil-dwelling organisms that have been used as indicators of Hg bioavailability; however, the MeHg concentrations they accumulate in rice paddy environments are not well known. Earthworm and soil samples were collected from rice paddies at progressive distances from abandoned mercury mines in Guizhou, China, and at control sites without a history of Hg mining. Total Hg (THg) and MeHg concentrations declined in soil and earthworms as distance increased from the mines, but the percentage of THg that was MeHg, and the bioaccumulation factors in earthworms, increased over this gradient. This escalation in methylation and the incursion of MeHg into earthworms may be influenced by more acidic soil conditions and higher organic content further from the mines. In areas where the source of Hg is deposition, especially in water-logged and acidic rice paddy soil, earthworms may biomagnify MeHg more than was previously reported. It is emphasized that rice paddy environments affected by acidifying deposition may be widely dispersed throughout Asia.

  • 24.
    Aboye, Teshome L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bruhn, Jan G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, K. Johan
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    A Cactus-Derived Toxin-Like Cystine Knot Peptide with Selective Antimicrobial Activity2015In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 16, no 7, p. 1068-1077Article in journal (Refereed)
    Abstract [en]

    Naturally occurring cystine knot peptides show a wide range of biological activity, and as they have inherent stability they represent potential scaffolds for peptide-based drug design and biomolecular engineering. Here we report the discovery, sequencing, chemical synthesis, three-dimensional solution structure determination and bioactivity of the first cystine knot peptide from Cactaceae (cactus) family: Ep-AMP1 from Echinopsis pachanoi. The structure of Ep-AMP1 (35 amino acids) conforms to that of the inhibitor cystine knot (or knottin) family but represents a novel diverse sequence; its activity was more than 500 times higher against bacterial than against eukaryotic cells. Rapid bactericidal action and liposome leakage implicate membrane permeabilisation as the mechanism of action. Sequence homology places Ec-AMP1 in the plant C6-type of antimicrobial peptides, but the three dimensional structure is highly similar to that of a spider neurotoxin.

  • 25. Abrahamson, Alexandra
    et al.
    Andersson, Carin
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fogelberg, Oscar
    Orberg, Jan
    Brunstrom, Bjorn
    Brandt, Ingvar
    Gill EROD in monitoring of CYP1A inducers in fish - A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters2007In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 85, no 1, p. 1-8Article in journal (Refereed)
  • 26.
    Abrahamson, Alexandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Andersson, Carin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Fogelberg, Oscar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters2007In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 85, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    The gill filament 7-ethoxyresorufin O-deethylase (EROD) assay was evaluated as a monitoring tool for waterborne cytochrome P4501 A (CYP1A) inducers using rainbow trout (Oncorhynchus mykiss) caged in urban area waters in Sweden. To compare the CYP1A induction response in different tissues, EROD activity was also analyzed in liver and kidney microsomes. Immunohistochemistry was used to localize CYP1A protein in gill and kidney. In two separate experiments fish were caged at sites with fairly high expected polyaromatic hydrocarbon (PAH) contamination. In the first experiment, gill EROD activities were analyzed in fish exposed for 1-21 days in a river running through Uppsala. The reference site was upstream of Uppsala. In the second, gill, liver and kidney EROD activities were analyzed in fish exposed for 1-5 days in fresh or brackish waters of Stockholm and in a reference lake 60 km north of Stockholm. Fish exposed for 5 days followed by 2 days of recovery in tap water in the laboratory were also examined. The gill consistently showed a higher EROD induction compared with the liver and the kidney. After I day of caging, gill EROD activity was markedly induced (6-17-fold) at all sites examined. Induction in gill was pronounced (5-7-fold) also in fish caged at the reference sites. In the 21-day exposure study gill EROD activity remained highly induced throughout the experiment (26-fold at most) and the induced CYP1A protein was exclusively confined to the gill secondary lamellae. In the 5-day exposure experiment, EROD activity peaked after I day and then declined in both gill and liver, while CYP1A immunostaining in the gill remained intense over the 5-day period. In the kidney, CYP1A staining was weak or absent. We conclude that gill EROD activity is a more sensitive biomarker of exposure to waterborne CYP1A inducers than EROD activity in liver and kidney.

  • 27.
    Abrahamson, Alexandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Sundt, Rolf
    Jørgensen, Even
    Monitoring contaminants from oil production at sea by measuring gill EROD activity in Atlantic cod (Gadus morhua)2008In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 153, no 1, p. 169-175Article in journal (Refereed)
    Abstract [en]

    An ex vivo gill EROD assay was applied in Atlantic cod (Gadus morhua) as a biomarker for waterborne CYP1A-inducing compounds derived from oil production at sea. Exposure to nominal concentrations of 1 ppm or 10 ppm North Sea crude oil in a static water system for 24 h caused a concentration-dependent gill EROD induction. Further, exposure of cod for 14 days to environmentally relevant concentrations of produced water (PW, diluted 1:200 or 1:1000) from a platform in the North Sea using a flow-through system resulted in a concentration-dependent induction of gill EROD. Crude oil (0.2 ppm) from the same oil field also proved to induce EROD. Finally, gill EROD activity in cod caged for 6 weeks at 500-10 000 m from two platforms outside Norway was measured. The activities in these fish were very low and did not differ from those in fish caged at reference sites.

  • 28.
    Abramenkovs, Andris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity2017In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 188, no 6, p. 597-604Article in journal (Refereed)
    Abstract [en]

    Uncontrolled generation of DNA double-strand breaks (DSBs) in cells is regarded as a highly toxic event that threatens cell survival. Radiation-induced DNA DSBs are commonly measured by pulsed-field gel electrophoresis, microscopic evaluation of accumulating DNA damage response proteins (e.g., 53BP1 or gamma-H2AX) or flow cytometric analysis of gamma-H2AX. The advantage of flow cytometric analysis is that DSB formation and repair can be studied in relationship to cell cycle phase or expression of other proteins. However, gamma-H2AX is not able to monitor repair kinetics within the first 60 min postirradiation, a period when most DSBs undergo repair. A key protein in non-homologous end joining repair is the catalytic subunit of DNA-dependent protein kinase. Among several phosphorylation sites of DNA-dependent protein kinase, the threonine at position 2609 (T2609), which is phosphorylated by ataxia telangiectasia mutated (ATM) or DNA-dependent protein kinase catalytic subunit itself, activates the end processing of DSB. Using flow cytometry, we show here that phosphorylation at T2609 is faster in response to DSBs than gamma-H2AX. Furthermore, flow cytometric analysis of T2609 resulted in a better representation of fast repair kinetics than analysis of gamma-H2AX. In cells with reduced ligase IV activity, and wild-type cells where DNA-dependent protein kinase activity was inhibited, the reduced DSB repair capacity was observed by T2609 evaluation using flow cytometry. In conclusion, flow cytometric evaluation of DNA-dependent protein kinase T2609 can be used as a marker for early DSB repair and gives a better representation of early repair events than analysis of gamma-H2AX.

  • 29.
    Abramson, Jeff
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Structural studies on the integral membrane protein, ubiquinol oxidase from Escherichia coli2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Heme-copper oxidases are redox-driven proton pumps that couple the reduction of molecular oxygen to water with the vectorial translocation of protons across the membrane. The proton gradient generated by heme-copper oxidases and the other members of the aerobic respiratory chain is ultimately used to drive the synthesis of ATP. There are two main branches of the heme-copper oxidases that are characterized by the electron donating substrate; the cytochrome c oxidases, which use cytochrome c as the electron donor, and the ubiquinol oxidases, which use a lipid-soluble molecule, ubiquinol, as their electron donor. These enzymes share important structural and functional features.

    This thesis presents the procedures that have led to the first crystal structure of a ubiquinol oxidase, cytochrome bo, oxidase from Escherichia coli, at a resolution of 3.5 Å. The overall structure of the enzyme is similar to those of cytochrome c oxidases; however the membrane spanning region of subunit I contains a cluster of polar residues exposed to the interior of the lipid bilayer. No such structural feature is present in cytochrome c oxidases. Mutagenesis studies on residues in this region strongly suggest that this area forms a ubiquinone binding site. A comparison of this region with known ubiquinone binding sites shows remarkable similarities. In light of these findings specific roles for these polar residues is proposed in electron and proton transfer in ubiquinol oxidase.

    A fusion protein of cytochrome bo3-Protein Z was generated in an attempt to increase the hydrophilic surface of the protein, thus extending protein-protein contacts within the crystal lattice structure. Such an approach can be used to facilitate crystallization.

  • 30.
    Abrikossov, Alexei
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Computer simulations: Orientation of Lysozyme in vacuum under the influence of an electric field2011Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The possibility to orient a protein in space using an external electrical field was studied bymeans of molecular dynamics simulations. To model the possible conditions of an electrospray ionization (ESI) the protein Lysozyme in vacuum was considered under the influence ofdifferent field strengths. The simulations showed three distinct patterns: (1) the protein wasdenaturated when exposed to too strong electrical fields, above 1.5 V/nm; (2) the proteinoriented without being denaturated at field strengths between 0.5 V/nm and 1.5 V/nm (3) theprotein did not orient and did not denaturate if the strength of the field became to low, below0.5 V/nm. Our simulations show that the orientation of the protein in the fields correspondingto the second pattern takes place within time intervals from about 100 ps at 1.5 V/nm to about1 ns at 0.5 V/nm. We therefore predict, that there exists a window of field strengths, which issuitable for orientation of proteins in experimental studies without affecting their structure.The orientation of proteins potentially increases the amount of information that can beobtained from experiments such as single particle imaging. This study will therefore bebeneficial for the development of such modern techniques.

  • 31.
    Abu-Siniyeh, Ahmed
    et al.
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    Owen, Dylan M.
    Kings Coll London, Dept Phys, London WC2R 2LS, England.;Kings Coll London, Randall Div Cell & Mol Biophys, London WC2R 2LS, England..
    Benzing, Carola
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    Rinkwitz, Silke
    Becker, Thomas S.
    Univ Sydney, Brain & Mind Res Inst, Sydney Med Sch, Sydney, NSW 2006, Australia.;Univ Sydney, Dept Hlth Sci, Sydney, NSW 2006, Australia..
    Majumdar, Arindam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gaus, Katharina
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    The aPKC/Par3/Par6 Polarity Complex and Membrane Order Are Functionally Interdependent in Epithelia During Vertebrate Organogenesis2016In: Traffic: the International Journal of Intracellular Transport, ISSN 1398-9219, E-ISSN 1600-0854, Vol. 17, no 1, p. 66-79Article in journal (Refereed)
    Abstract [en]

    The differential distribution of lipids between apical and basolateral membranes is necessary for many epithelial cell functions, but how this characteristic membrane organization is integrated within the polarity network during ductal organ development is poorly understood. Here we quantified membrane order in the gut, kidney and liver ductal epithelia in zebrafish larvae at 3-11 days post fertilization (dpf) with Laurdan 2-photon microscopy. We then applied a combination of Laurdan imaging, antisense knock-down and analysis of polarity markers to understand the relationship between membrane order and apical-basal polarity. We found a reciprocal relationship between membrane order and the cell polarity network. Reducing membrane condensation by exogenously added oxysterol or depletion of cholesterol reduced apical targeting of the polarity protein, aPKC. Conversely, using morpholino knock down in zebrafish, we found that membrane order was dependent upon the Crb3 and Par3 polarity protein expression in ductal epithelia. Hence our data suggest that the biophysical property of membrane lipid packing is a regulatory element in apical basal polarity.

  • 32. Achatz, Johannes Georg
    et al.
    Hooge, Matthew
    Wallberg, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Systematic Biology.
    Jondelius, Ulf
    Tyler, Seth
    Systematic revision of acoels with 9+0 sperm ultrastructure (Convolutida) and the influence of sexual conflict on morphology2010In: Journal of Zoological Systematics and Evolutionary Research, ISSN 0947-5745, E-ISSN 1439-0469, Vol. 48, no 1, p. 9-32Article, review/survey (Refereed)
    Abstract [en]

    We have used newly discerned morphological characters as well as molecular-sequence data from 18S and 28S rDNA to revise the families recently designated as the '9+0' acoels - what we call Convolutida. Characters from the ultrastructure of sperm, with their '9+0' axonemes, are useful in delineating the Convolutida, but are either species-specific or too conserved within the group to be used to infer relationships within it. Male genital organs, prostatoid organs, and sagittocysts, on the other hand, give a good phylogenetic signal for reconstructing relationships of such genera as Conaperta, Anaperus, and Achoerus; some features of the reproductive organs correlate with habitat and show how the Convolutida probably originated as epiphytic predators and radiated into the mesopsammon, pelagic, and coral-associated realms. In this revision of the Convolutida we provide revised synopses of its families - which we restrict to the Anaperidae, Convolutidae, and Sagittiferidae - and describe a new species, Polychoerus gordoni, from New Zealand. We transfer the genus Adenopea from the Antroposthiidae to the Convolutidae; Conaperta, Neochildia, and Oxyposthia from the Convolutidae to the Anaperidae; Paranaperus and Praeanaperus from the Anaperidae to the Haploposthiidae. Convoluta aegyptica is synonymized with Convoluta boehmigi, Convoluta lacazii with Convoluta sordida, and the genus Picola (Convolutidae) with Deuterogonaria (Haploposthiidae). Amphiscolops blumi, A. carvalhoi, and A. langerhansi, all of which possess a cellular seminal bursa, are transferred to the genus Heterochaerus. Convoluta elegans and Pseudanaperus tinctus are classified as nomina nuda. We use our findings on the ultrastructure of female genital organs and spermatozoa to show that sexual conflict plays a major role in the evolution of diversity of these structures and that the phylogeny of the Acoela would comprise early forms without female genital organs and hyper- or hypodermal transfer of sperm through advanced forms with ever longer and narrower bursal nozzles and sperm with axial microtubules. Moreover, our results show that the acquisition of endosymbiotic algae happened at least twice within the Acoela.

  • 33.
    Adler, J
    et al.
    Stockholms universitet, Wenner-Grens institut för experimentell biologi.
    Pagakis, S N
    Parmryd, I
    Stockholms universitet, Wenner-Grens institut för experimentell biologi.
    Replicate-based noise corrected correlation for accurate measurements of colocalization.2008In: Journal of Microscopy, ISSN 0022-2720, E-ISSN 1365-2818, Vol. 230, no Pt 1, p. 121-33Article in journal (Refereed)
  • 34.
    Adler, Jeremy
    et al.
    Stockholms universitet, Wenner-Grens institut för experimentell biologi.
    Parmryd, Ingela
    Stockholms universitet, Wenner-Grens institut för experimentell biologi.
    In support of the Pearson correlation coefficient.2007In: Journal of Microscopy, Vol. 227, no Pt 1, p. 83; author reply 84-5Article in journal (Other academic)
  • 35.
    Adler, Jeremy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quantification of Colocalisation; Co-Occurrence, Correlation, Empty Voxels, Regions of Interest and Thresholding2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 602A-602AArticle in journal (Other academic)
    Abstract [en]

    Measuring colocalisation is not straightforward with a plethora of coefficients that encapsulate different definitions. Measurements may also be implemented differently. Not only do measurements differ; interconversion is impossible making comparisons challenging. There is a need to cull coefficients and for clear definitions of what precisely is meant by colocalisation in individual studies. Colocalisation can be considered to have two components; co-occurrence which reports whether the fluorophores are found together and correlation which reports on the similarity in their patterns of intensity.

  • 36.
    Adler, Jeremy
    et al.
    Stockholms universitet, Wenner-Grens institut.
    Parmryd, Ingela
    Stockholms universitet, Wenner-Grens institut.
    Quantifying Colocalization by Correlation: The Pearson Correlation Coefficient is Superior to the Mander's Overlap Coefficient2010In: CYTOMETRY PART A, ISSN 1552-4922, Vol. 77A, no 8, p. 733-742Article in journal (Refereed)
    Abstract [en]

    The Pearson correlation coefficient (PCC) and the Mander's overlap coefficient (MOC) are used to quantify the degree of colocalization between fluorophores. The MOC was introduced to overcome perceived problems with the PCC. The two coefficients are mathematically similar, differing in the use of either the absolute intensities (MOC) or of the deviation from the mean (PCC). A range of correlated datasets, which extend to the limits of the PCC, only evoked a limited response from the MOC. The PCC is unaffected by changes to the offset while the MOC increases when the offset is positive. Both coefficients are independent of gain. The MOC is a confusing hybrid measurement, that combines correlation with a heavily weighted form of co-occurrence, favors high intensity combinations, downplays combinations in which either or both intensities are low and ignores blank pixels. The PCC only measures correlation. A surprising finding was that the addition of a second uncorrelated population can substantially increase the measured correlation, demonstrating the importance of excluding background pixels. Overall, since the MOC is unresponsive to substantial changes in the data and is hard to interpret, it is neither an alternative to nor a useful substitute for the PCC. The MOC is not suitable for making measurements of colocalization either by correlation or co-occurrence.

  • 37.
    Adler, Jeremy
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Quantifying colocalization: thresholding, void voxels and the H-coef2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e111983-Article in journal (Refereed)
    Abstract [en]

    A critical step in the analysis of images is identifying the area of interest e.g. nuclei. When the nuclei are brighter than the remainder of the image an intensity can be chosen to identify the nuclei. Intensity thresholding is complicated by variations in the intensity of individual nuclei and their intensity relative to their surroundings. To compensate thresholds can be based on local rather than global intensities. By testing local thresholding methods we found that the local mean performed poorly while the Phansalkar method and a new method based on identifying the local background were superior. A new colocalization coefficient, the Hcoef, highlights a number of controversial issues. (i) Are molecular interactions measurable (ii) whether to include voxels without fluorophores in calculations, and (iii) the meaning of negative correlations. Negative correlations can arise biologically (a) because the two fluorophores are in different places or (b) when high intensities of one fluorophore coincide with low intensities of a second. The cases are distinct and we argue that it is only relevant to measure correlation using pixels that contain both fluorophores and, when the fluorophores are in different places, to just report the lack of co-occurrence and omit these uninformative negative correlation. The Hcoef could report molecular interactions in a homogenous medium. But biology is not homogenous and distributions also reflect physico-chemical properties, targeted delivery and retention. The Hcoef actually measures a mix of correlation and co-occurrence, which makes its interpretation problematic and in the absence of a convincing demonstration we advise caution, favouring separate measurements of correlation and of co-occurrence.

  • 38. Adler, Jeremy
    et al.
    Shevchuk, Andrew I
    Novak, Pavel
    Korchev, Yuri E
    Parmryd, Ingela
    Plasma membrane topography and interpretation of single-particle tracks.2010In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 7, no 3, p. 170-1Article in journal (Refereed)
  • 39.
    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.

    Keyword
    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
  • 40.
    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.

  • 41.
    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.

  • 42. Adomas, Aleksandra
    et al.
    Eklund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Martin
    Asiegbu, Frederick O.
    Identification and analysis of differentially expressed cDNAs during nonself-competitive interaction between Phlebiopsis gigantea and Heterobasidion parviporum2006In: FEMS Microbiology Ecology, ISSN 0168-6496, E-ISSN 1574-6941, Vol. 57, no 1, p. 26-39Article in journal (Refereed)
    Abstract [en]

    The molecular factors regulating interspecific interaction between the saprotrophic biocontrol fungus Phlebiopsis gigantea and the conifer pathogen Heterobasidion parviporum were investigated. We constructed cDNA libraries and used expressed sequence tag analysis for the identification and characterization of genes expressed during the self and nonself-hyphal interaction. cDNA clones from either the pathogen or biocontrol agent were arrayed on nylon membrane filters and differentially screened with cDNA probes made from mycelia forming the barrage zone during nonself-interactions, mycelia growing outside the barrage zones or monocultures. BlastX analysis of the differentially expressed clones led to the identification of genes with diverse functions, including those with potential as virulence factors, such as hydrophobins. Because of the high sequence conservation (r2 = 0.81) between P. gigantea and H. parviporum, a selected number of genes from either fungus were used to monitor the expression profile under varying interaction conditions by virtual northern blot. The results are discussed with respect to the potential role of the induced genes during the nonself-competitive interaction for space and nutrients between P. gigantea and H. parviporum.

  • 43. Adrian, Rita
    et al.
    O`Reilly, Catherine M.
    Zagarese, Horacio
    Baines, Stephen B.
    Hessen, Dag O.
    Keller, Wendel
    Livingstone, David M.
    Sommaruga, Ruben
    Straile, Dietmar
    Van Donk, Ellen
    Weyhenmeyer, Gesa A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Limnology.
    Winder, Monika
    Lakes as sentinels of climate change2009In: Limnology and Oceanography, ISSN 0024-3590, E-ISSN 1939-5590, Vol. 54, no 6(2), p. 2283-2297Article in journal (Refereed)
    Abstract [en]

    While there is a general sense that lakes can act as sentinels of climate change, their efficacy has not been thoroughly analyzed. We identified the key response variables within a lake that act as indicators of the effects of climate change on both the lake and the catchment. These variables reflect a wide range of physical, chemical, and biological responses to climate. However, the efficacy of the different indicators is affected by regional response to climate change, characteristics of the catchment, and lake mixing regimes. Thus, particular indicators or combinations of indicators are more effective for different lake types and geographic regions. The extraction of climate signals can be further complicated by the influence of other environmental changes, such as eutrophication or acidification, and the equivalent reverse phenomena, in addition to other land-use influences. In many cases, however, confounding factors can be addressed through analytical tools such as detrending or filtering. Lakes are effective sentinels for climate change because they are sensitive to climate, respond rapidly to change, and integrate information about changes in the catchment.

  • 44.
    Afewerki, Isaias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Genflödet från genetiskt modifierade grödor till vilda populationer2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Tillämpningen av genetiskt modifierade (GM) grödor har varit utbredd över hela världen och har ökat markant sedan den första GM-grödan blev tillgänglig för kommersiellt bruk 1996. Sedan starten har det tillkommit mycket forskning kring risken för spridning av transgener från grödor till vilda populationer. För att en transgen ska kunna etableras i en vild population så måste tidiga generationer av hybrider överleva för att kunna återkorsas upprepade gånger med den vilda arten, det gör att det genetiska materialet från grödan succesivt reduceras i varje generation tills det att transgenen är det enda DNA från grödan kvar hos avkomman. För att denna process ska vara stabil krävs det en stark selektion för transgenen. Det här sättet för en gen att etableras i en population kallas för introgression och tros ha spelat en stor roll i växternas evolution. Hos vete så har man observerat introgression i ett tidigt skede med det besläktade ogräset bockvete där man även observerade en ökande fertilitet i efterföljande generationer. Hos odlad majs har man lyckats visa att majs kunnat anpassa sig till kallare klimat i nya habitat genom introgression från inhemska besläktade arter. Tecken på hybridisering och introgression har observerats hos flera grödor där selektionen har visat sig vara en av de viktigaste faktorerna för en nyintroducerad transgens fortlevnad inom en population. Migration mellan två populationer av besläktade arter, i form av pollen och fröspridning, påverkar kraftigt utsträckningen av hybridisering medan migration mellan subpopulationer inom en metapopulation påverkar effektiviteten av introgression. Om en transgen ger en förhöjd fitness till en sådan grad att hybrider framgångsrikt kan konkurrera med andra individer och reproducera sig så leder det till en spridning av genen. Trangenens interaktion med miljön påverkar också plantans fitness. En gen för insektresistens kommer att ge en ökad fitness när insektspopulationerna är stora, om insektspopulationen reduceras kraftigt så kommer genen stå för en onödig kostnad och utsättas för en negativ selektion. Den selektion som råder på åkern är anpassad för att möta våra behov av hög kvalitativ produktion av livsmedel och råvaror medan den naturliga selektionen väljer de individer som är bäst anpassade att överleva i den miljön. Sannolikheten för fixering av en transgen, skapad för att möta våra behov, in en vild population är låg, men den risken kräver ändå en noggrann utvärdering där man ser till de olika faktorerna i varje enskilt fall. 

  • 45.
    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.

  • 46. Agalou, Adamantia
    et al.
    Purwantomo, Sigit
    Övernäs, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Physiological Botany.
    Johannesson, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Physiological Botany.
    Zhu, Xiaoyi
    Estiati, Amy
    de Kam, Rolf J.
    Engström, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Physiological Botany.
    Slamet-Loedin, Inez H.
    Zhu, Zhen
    Wang, Mei
    Xiong, Lizhong
    Meijer, Annemarie H.
    Ouwerkerk, Pieter B. F.
    A genome-wide survey of HD-Zip genes in rice and analysis of drought-responsive family members2008In: Plant Molecular Biology, ISSN 0167-4412, E-ISSN 1573-5028, Vol. 66, no 1-2, p. 87-103Article in journal (Refereed)
    Abstract [en]

    The homeodomain leucine zipper (HD-Zip) genes encode transcription factors that have diverse functions in plant development and have often been implicated in stress adaptation. The HD-Zip genes are the most abundant group of homeobox (HB) genes in plants and do not occur in other eukaryotes. This paper describes the complete annotation of the HD-Zip families I, II and III from rice and compares these gene families with Arabidopsis in a phylogeny reconstruction. Orthologous pairs of rice and Arabidopsis HD-Zip genes were predicted based on neighbour joining and maximum parsimony (MP) trees with support of conserved intron-exon organization. Additionally, a number of HD-Zip genes appeared to be unique to rice. Searching of EST and cDNA databases and expression analysis using RT-PCR showed that 30 out of 31 predicted rice HD-Zip genes are expressed. Most HD-Zip genes were broadly expressed in mature plants and seedlings, but others showed more organ specific patterns. Like in Arabidopsis and other dicots, a subset of the rice HD-Zip I and II genes was found to be regulated by drought stress. We identified both drought-induced and drought-repressed HD-Zip genes and demonstrate that these genes are differentially regulated in drought-sensitive versus drought-tolerant rice cultivars. The drought-repressed HD-Zip family I gene, Oshox4, was selected for promoter-GUS analysis, showing that drought-responsiveness of Oshox4 is controlled by the promoter and that Oshox4 expression is predominantly vascular-specific. Loss-of-function analysis of Oshox4 revealed no specific phenotype, but overexpression analysis suggested a role for Oshox4 in elongation and maturation processes.

  • 47.
    Agarwal, Prasoon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Regulation of Gene Expression in Multiple Myeloma Cells and Normal Fibroblasts: Integrative Bioinformatic and Experimental Approaches2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work presented in this thesis applies integrative genomic and experimental approaches to investigate mechanisms involved in regulation of gene expression in the context of disease and normal cell biology.

    In papers I and II, we have explored the role of epigenetic regulation of gene expression in multiple myeloma (MM). By using a bioinformatic approach we identified the Polycomb repressive complex 2 (PRC2) to be a common denominator for the underexpressed gene signature in MM. By using inhibitors of the PRC2 we showed an activation of the genes silenced by H3K27me3 and a reduction in the tumor load and increased overall survival in the in vivo 5TMM model. Using ChIP-sequencing we defined the distribution of H3K27me3 and H3K4me3 marks in MM patients cells. In an integrated bioinformatic approach, the H3K27me3-associated genes significantly correlated to under-expression in patients with less favorable survival. Thus, our data indicates the presence of a common under-expressed gene profile and provides a rationale for implementing new therapies focusing on epigenetic alterations in MM.

    In paper III we address the existence of a small cell population in MM presenting with differential tumorigenic properties in the 5T33MM murine model. We report that the predominant population of CD138+ cells had higher engraftment potential, higher clonogenic growth, whereas the CD138- MM cells presented with less mature phenotype and higher drug resistance. Our findings suggest that while designing treatment regimes for MM, both the cellpopulations must be targeted.

    In paper IV we have studied the general mechanism of differential gene expression regulation by CGGBP1 in response to growth signals in normal human fibroblasts. We found that CGGBP1 binding affects global gene expression by RNA Polymerase II. This is mediated by Alu RNAdependentinhibition of RNA Polymerase II. In presence of growth signals CGGBP1 is retained in the nuclei and exhibits enhanced Alu binding thus inhibiting RNA Polymerase III binding on Alus. Hence we suggest a mechanism by which CGGBP1 orchestrates Alu RNA-mediated regulation of RNA Polymerase II. This thesis provides new insights for using integrative bioinformatic approaches to decipher gene expression regulation mechanisms in MM and in normal cells.

    List of papers
    1. Polycomb target genes are silenced in multiple myeloma
    Open this publication in new window or tab >>Polycomb target genes are silenced in multiple myeloma
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    2010 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 7, p. e11483-Article in journal (Refereed) Published
    Abstract [en]

    Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.

    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-133207 (URN)10.1371/journal.pone.0011483 (DOI)000279715300003 ()20634887 (PubMedID)
    Available from: 2010-11-03 Created: 2010-11-03 Last updated: 2017-12-12Bibliographically approved
    2. The epigenomic map of multiple myeloma reveals the importance of Polycomb gene silencing for the malignancy
    Open this publication in new window or tab >>The epigenomic map of multiple myeloma reveals the importance of Polycomb gene silencing for the malignancy
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Multiple myeloma (MM) is characterized by accumulation of post-germinal center, isotype switched, long-living plasma cells with retained proliferation capacity within the bone marrow. MM is highly heterogeneous and remains fatal. This heterogeneity has hampered identification of a common underlying mechanism for disease establishment and the development of targeted therapy. We recently provided proof-of-principle that gene silencing associated with H3K27me3 contributes to the malignancy of MM. Here we present the first epigenomic map of MM for H3K27me3 and H3K4me3 derived by ChIP- and RNA sequencing from freshly-isolated bone marrow plasma cells from four patients. We compile lists of targets common among the patients as well as unique to MM when compared with PBMCs. Indicating the clinical relevance of our findings, we find increased silencing of H3K27me3 targets with disease progression and in patients presenting with a poor prognosis. Bivalent genes further significantly correlated to under-expressed genes in MM and were unique to MM when compared to PBMCs. Furthermore, bivalent genes, unlike H3K27me3 targets, significantly associated with transcriptional activation upon Polycomb inhibition indicating a potential for drug targeting. Thus, we suggest that gene silencing by Polycomb plays an important role in the development of the malignant phenotype of the MM cell during tumor progression.

    National Category
    Cell and Molecular Biology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-199492 (URN)
    Available from: 2013-05-06 Created: 2013-05-06 Last updated: 2018-01-11Bibliographically approved
    3. Tumor-initiating capacity of CD138- and CD138+ tumor cells in the 5T33 multiple myeloma model
    Open this publication in new window or tab >>Tumor-initiating capacity of CD138- and CD138+ tumor cells in the 5T33 multiple myeloma model
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    2012 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, no 6, p. 1436-1439Article in journal, Letter (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-177948 (URN)10.1038/leu.2011.373 (DOI)000305081000040 ()22289925 (PubMedID)
    Available from: 2012-07-25 Created: 2012-07-20 Last updated: 2017-12-07Bibliographically approved
    4. Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs
    Open this publication in new window or tab >>Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs
    Show others...
    2016 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 15, no 12, p. 1558-1571Article in journal (Refereed) Published
    Abstract [en]

    CGGBP1 (CGG triplet repeat-binding protein 1) regulates cell proliferation, stress response,cytokinesis, telomeric integrity and transcription. It could affect these processes by modulatingtarget gene expression under different conditions. Identification of CGGBP1-target genes andtheir regulation could reveal how a transcription regulator affects such diverse cellular processes.Here we describe the mechanisms of differential gene expression regulation by CGGBP1 inquiescent or growing cells. By studying global gene expression patterns and genome-wide DNAbindingpatterns of CGGBP1, we show that a possible mechanism through which it affects theexpression of RNA Pol II-transcribed genes in trans depends on Alu RNA. We also show that itregulates Alu transcription in cis by binding to Alu promoter. Our results also indicate thatpotential phosphorylation of CGGBP1 upon growth stimulation facilitates its nuclear retention,Alu-binding and dislodging of RNA Pol III therefrom. These findings provide insights into howAlu transcription is regulated in response to growth signals.

    Keyword
    Alu-SINEs; CGGBP1; ChIP-seq; growth signals; RNA Pol III; transcription; tyrosine phosphorylation
    National Category
    Cell Biology
    Research subject
    Bioinformatics; Biology
    Identifiers
    urn:nbn:se:uu:diva-230959 (URN)10.4161/15384101.2014.967094 (DOI)000379743800011 ()25483050 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
  • 48.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Teichmann, Martin
    Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux 2, rue , Robert Escarpit, 33607 Pessac, France..
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Smit, Arian
    Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Singh, Umashankar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs2016In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 15, no 12, p. 1558-1571Article in journal (Refereed)
    Abstract [en]

    CGGBP1 (CGG triplet repeat-binding protein 1) regulates cell proliferation, stress response,cytokinesis, telomeric integrity and transcription. It could affect these processes by modulatingtarget gene expression under different conditions. Identification of CGGBP1-target genes andtheir regulation could reveal how a transcription regulator affects such diverse cellular processes.Here we describe the mechanisms of differential gene expression regulation by CGGBP1 inquiescent or growing cells. By studying global gene expression patterns and genome-wide DNAbindingpatterns of CGGBP1, we show that a possible mechanism through which it affects theexpression of RNA Pol II-transcribed genes in trans depends on Alu RNA. We also show that itregulates Alu transcription in cis by binding to Alu promoter. Our results also indicate thatpotential phosphorylation of CGGBP1 upon growth stimulation facilitates its nuclear retention,Alu-binding and dislodging of RNA Pol III therefrom. These findings provide insights into howAlu transcription is regulated in response to growth signals.

  • 49.
    Agervald, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Photochemistry and Molecular Science, Microbial Chemistry.
    Baebprasert, Wipawee
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Photochemistry and Molecular Science, Microbial Chemistry.
    Zhang, Xiaohui
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Photochemistry and Molecular Science, Microbial Chemistry.
    Incharoensakdi, Aran
    Lindblad, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Photochemistry and Molecular Science, Microbial Chemistry.
    Stensjö, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Photochemistry and Molecular Science, Microbial Chemistry.
    The CyAbrB transcription factor CalA regulates the iron superoxide dismutase in Nostoc sp. strain PCC 71202010In: Environmental Microbiology, ISSN 1462-2912, E-ISSN 1462-2920, Vol. 12, no 10, p. 2826-2837Article in journal (Refereed)
    Abstract [en]

    P>In the present investigation the results of induced over-production of the CyAbrB transcription factor CalA (Cyanobacterial AbrB-like, annotated as Alr0946) in the cyanobacterium Nostoc sp. PCC 7120 were analysed. The CalA overexpression strain showed a bleaching phenotype with lower growth rate and truncated filaments 2 days after induction of overexpression. The phenotype was even more pronounced when illumination was increased from 35 to 125 mu mol m-2 s-1. Using gel-based quantitative proteomics, the induced overexpression of CalA was shown to downregulate the abundance of FeSOD, one of two types of superoxide dismutases in Nostoc sp. PCC 7120. The change in protein abundance was also accompanied by lower transcript as well as activity levels. Purified recombinant CalA from Nostoc sp. PCC 7120 was shown to interact with the promoter region of alr2938, encoding FeSOD, indicating a transcriptional regulation of FeSOD by CalA. The bleaching phenotype is in line with a decreased tolerance against oxidative stress and indicates that CalA is involved in regulation of cellular responses in which FeSOD has an important and specific function in the filamentous cyanobacterium Nostoc sp. PCC 7120.

  • 50.
    Agervald, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Photochemistry and Molecular Science, Microbial Chemistry.
    Zhang, Xiaohui
    Department of Biological Sciences, Purdue University.
    Stensjö, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Photochemistry and Molecular Science, Microbial Chemistry.
    Devine, Ellenor
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Photochemistry and Molecular Science, Microbial Chemistry.
    Lindblad, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Photochemistry and Molecular Science, Microbial Chemistry.
    CalA, a cyanobacterial AbrB protein, interacts with the upstream region of hypC and acts as a repressor of its transcription in the cyanobacterium Nostoc sp. strain PCC 71202010In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 76, no 3, p. 880-890Article in journal (Refereed)
    Abstract [en]

    The filamentous, heterocystous, nitrogen-fixing cyanobacterium Nostoc sp. strain PCC 7120 may contain, depending on growth condition, up to two hydrogenases directly involved in hydrogen metabolism. HypC is one out of at least seven auxiliary gene products required for synthesis of a functional hydrogenase, specifically involved in the maturation of the large subunit. In this study we present a protein, Alr0946, belonging to the transcription regulator family AbrB, which in protein-DNA assays was found to interact with the upstream region of hypC. Transcriptional investigations showed that alr0946 is co-transcribed with the downstream gene alr0947, which encodes a putative protease from the abortive infection superfamily, Abi. Alr0946 was shown to interact specifically not only with the upstream region of hypC but also with its own upstream region, acting as a repressor on both. The bidirectional hydrogenase activity was significant down-regulated when Alr0946 was over-expressed demonstrating a correlation to the transcription factor, either direct or indirect. In silico studies showed that homologues to both Alr0946 and Alr0947 are highly conserved proteins within cyanobacteria with a very similar physical organisation of the corresponding structural genes. Possible functions of the co-transcribed downstream protein Alr0947 are presented. In addition, we present a 3D model of the CyAbrB domain of Alr0946 and putative DNA-binding mechanisms are discussed.

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