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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.

    Keywords
    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.

    Keywords
    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

    Keywords
    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.

    Keywords
    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.

    Keywords
    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
    Download full text (pdf)
    FULLTEXT01
  • 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.
    Aase-Remedios, Madeleine E.
    et al.
    Univ Durham, Dept Biosci, Durham DH1 3LE, England..
    Janssen, Ralf
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    Leite, Daniel J.
    Univ Durham, Dept Biosci, Durham DH1 3LE, England..
    Sumner-Rooney, Lauren
    Leibniz Inst Evolut & Biodiversitatsforsch, Museum Nat Kunde, D-10115 Berlin, Germany..
    McGregor, Alistair P.
    Univ Durham, Dept Biosci, Durham DH1 3LE, England..
    Wittkopp, Patricia
    Evolution of the Spider Homeobox Gene Repertoire by Tandem and Whole Genome Duplication2023In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 40, no 12, article id msad239Article in journal (Refereed)
    Abstract [en]

    Gene duplication generates new genetic material that can contribute to the evolution of gene regulatory networks and phenotypes. Duplicated genes can undergo subfunctionalization to partition ancestral functions and/or neofunctionalization to assume a new function. We previously found there had been a whole genome duplication (WGD) in an ancestor of arachnopulmonates, the lineage including spiders and scorpions but excluding other arachnids like mites, ticks, and harvestmen. This WGD was evidenced by many duplicated homeobox genes, including two Hox clusters, in spiders. However, it was unclear which homeobox paralogues originated by WGD versus smaller-scale events such as tandem duplications. Understanding this is a key to determining the contribution of the WGD to arachnopulmonate genome evolution. Here we characterized the distribution of duplicated homeobox genes across eight chromosome-level spider genomes. We found that most duplicated homeobox genes in spiders are consistent with an origin by WGD. We also found two copies of conserved homeobox gene clusters, including the Hox, NK, HRO, Irx, and SINE clusters, in all eight species. Consistently, we observed one copy of each cluster was degenerated in terms of gene content and organization while the other remained more intact. Focussing on the NK cluster, we found evidence for regulatory subfunctionalization between the duplicated NK genes in the spider Parasteatoda tepidariorum compared to their single-copy orthologues in the harvestman Phalangium opilio. Our study provides new insights into the relative contributions of multiple modes of duplication to the homeobox gene repertoire during the evolution of spiders and the function of NK genes.

    Download full text (pdf)
    fulltext
  • 8.
    Abalde, Samuel
    et al.
    Swedish Museum Nat Hist, Dept Zool, Stockholm, Sweden..
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heintz, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Vinnere Pettersson, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jondelius, Ulf
    Swedish Museum Nat Hist, Dept Zool, Stockholm, Sweden.;Stockholm Univ, Dept Zool, Stockholm, Sweden..
    The draft genome of the microscopic Nemertoderma westbladi sheds light on the evolution of Acoelomorpha genomes2023In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 14, article id 1244493Article in journal (Refereed)
    Abstract [en]

    Background: Xenacoelomorpha is a marine clade of microscopic worms that is an important model system for understanding the evolution of key bilaterian novelties, such as the excretory system. Nevertheless, Xenacoelomorpha genomics has been restricted to a few species that either can be cultured in the lab or are centimetres long. Thus far, no genomes are available for Nemertodermatida, one of the group’s main clades and whose origin has been dated more than 400 million years ago.

    Methods: DNA was extracted from a single specimen and sequenced with HiFi following the PacBio Ultra-Low DNA Input protocol. After genome assembly, decontamination, and annotation, the genome quality was benchmarked using two acoel genomes and one Illumina genome as reference. The gene content of three cnidarians, three acoelomorphs, four deuterostomes, and eight protostomes was clustered in orthogroups to make inferences of gene content evolution. Finally, we focused on the genes related to the ultrafiltration excretory system to compare patterns of presence/absence and gene architecture among these clades.

    Results: We present the first nemertodermatid genome sequenced from a single specimen of Nemertoderma westbladi. Although genome contiguity remains challenging (N50: 60 kb), it is very complete (BUSCO: 80.2%, Metazoa; 88.6%, Eukaryota) and the quality of the annotation allows fine-detail analyses of genome evolution. Acoelomorph genomes seem to be relatively conserved in terms of the percentage of repeats, number of genes, number of exons per gene and intron size. In addition, a high fraction of genes present in both protostomes and deuterostomes are absent in Acoelomorpha. Interestingly, we show that all genes related to the excretory system are present in Xenacoelomorpha except Osr, a key element in the development of these organs and whose acquisition seems to be interconnected with the origin of the specialised excretory system.

    Conclusion: Overall, these analyses highlight the potential of the Ultra-Low Input DNA protocol and HiFi to generate high-quality genomes from single animals, even for relatively large genomes, making it a feasible option for sequencing challenging taxa, which will be an exciting resource for comparative genomics analyses.

    Download full text (pdf)
    FULLTEXT01
  • 9.
    Abalo, Xesus
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Boije: Zebrafish Neuronal Networks. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lagman, David
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Bergen, Sars Int Ctr Marine Mol Biol, Bergen, Norway.
    Heras, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    del Pozo, Ana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Boije: Zebrafish Neuronal Networks. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eggert, Joel
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Emory Univ, Dept Med, Atlanta, GA 30322 USA.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Circadian regulation of phosphodiesterase 6 genes in zebrafish differs between cones and rods: Implications for photopic and scotopic vision2020In: Vision Research, ISSN 0042-6989, E-ISSN 1878-5646, Vol. 166, p. 43-51Article in journal (Refereed)
    Abstract [en]

    A correlation is known to exist between visual sensitivity and oscillations in red opsin and rhodopsin gene expression in zebrafish, both regulated by the clock gene. This indicates that an endogenous circadian clock regulates behavioural visual sensitivity, apart from the regulation exerted by the pineal organ. However, the specific mechanisms for cones (photopic vision) and rods (scotopic vision) are poorly understood. In this work, we performed gene expression, cosinor and immunohistochemical analyses to investigate other key genes involved in light perception, encoding the different subunits of phosphodiesterase pde6 and transducin G alpha(T), in constant lighting conditions and compared to normal light-dark conditions. We found that cones display prominent circadian oscillations in mRNA levels for the inhibitory subunit gene pde6ha that could contribute to the regulation of photopic sensitivity by preventing overstimulation in photopic conditions. In rods, the mRNA levels of the inhibitory subunit gene pde6ga oscillate under normal conditions and dampen down in constant light but continue oscillating in constant darkness. There is an increase in total relative expression for pde6gb in constant conditions. These observations, together with previous data, suggest a complex regulation of the scotopic sensitivity involving endogenous and non-endogenous components, possibly present also in other teleost species. The G alpha(T) genes do not display mRNA oscillations and therefore may not be essential for the circadian regulation of photosensitivity. In summary, our results support different regulation for the zebrafish photopic and scotopic sensitivities and suggest circadian regulation of pde6ha as a key factor regulating photopic sensitivity, while the regulatory mechanisms in rods appear to be more complex.

  • 10.
    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).

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  • 11.
    Abarenkov, Kessy
    et al.
    Univ Tartu, Nat Hist Museum, Vanemuise 46, EE-51014 Tartu, Estonia..
    Kristiansson, Erik
    Chalmers Univ Technol, Dept Math Sci, Gothenburg, Sweden.;Univ Gothenburg, Gothenburg, Sweden..
    Ryberg, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Nogal-Prata, Sandra
    Real Jardin Bot CSIC, Dept Mycol, Madrid, Spain..
    Gomez-Martinez, Daniela
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Stueer-Patowsky, Katrin
    Tech Univ Munich, Chair Urban Water Syst Engn, Coulombwall 3, D-85748 Garching, Germany..
    Jansson, Tobias
    Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Polme, Sergei
    Univ Tartu, Nat Hist Museum, Vanemuise 46, EE-51014 Tartu, Estonia..
    Ghobad-Nejhad, Masoomeh
    Iranian Res Org Sci & Technol, Dept Biotechnol, POB 3353-5111, Tehran 3353136846, Iran..
    Corcoll, Natalia
    Univ Gothenburg, Gothenburg Global Biodivers Ctr, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    Scharn, Ruud
    Univ Gothenburg, Dept Earth Sci, Box 460, S-40530 Gothenburg, Sweden..
    Sanchez-Garcia, Marisol
    Swedish Univ Agr Sci, Dept Forest Mycol & Plant Pathol, Uppsala, Sweden..
    Khomich, Maryia
    Univ Bergen, Dept Clin Sci, Box 7804, N-5020 Bergen, Norway..
    Wurzbacher, Christian
    Tech Univ Munich, Chair Urban Water Syst Engn, Coulombwall 3, D-85748 Garching, Germany..
    Nilsson, R. Henrik
    Univ Gothenburg, Gothenburg Global Biodivers Ctr, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden..
    The curse of the uncultured fungus2022In: MycoKeys, ISSN 1314-4057, E-ISSN 1314-4049, no 86, p. 177-194Article in journal (Refereed)
    Abstract [en]

    The international DNA sequence databases abound in fungal sequences not annotated beyond the kingdom level, typically bearing names such as "uncultured fungus". These sequences beget lowresolution mycological results and invite further deposition of similarly poorly annotated entries. What do these sequences represent? This study uses a 767,918-sequence corpus of public full-length that represent truly unidentifiable fungal taxa - and what proportion of them that would have deposition. Our results suggest that more than 70% of these sequences would have been trivial to identify to at least the order/family level at the time of sequence deposition, hinting that factors other than poor availability of relevant reference sequences explain the low-resolution names. We speculate that researchers' perceived lack of time and lack of insight into the ramifications of this problem are the main explanations for the low-resolution names. We were surprised to find that more than a fifth of these sequences seem to have been deposited by mycologists rather than researchers unfamiliar with the consequences of poorly annotated fungal sequences in molecular repositories. The proportion of these needlessly poorly annotated sequences does not decline over time, suggesting that this problem must not be left unchecked.

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  • 12.
    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.

  • 13.
    Abbey-Lee, Robin N.
    et al.
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Uhrig, Emily J.
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Zidar, Josefina
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Favati, Anna
    Stockholm Univ, Dept Zool, Stockholm, Sweden.
    Almberg, Johan
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Dahlbom, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lövlie, Hanne
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    The Influence of Rearing on Behavior, Brain Monoamines, and Gene Expression in Three-Spined Sticklebacks2018In: Brain, behavior, and evolution, ISSN 0006-8977, E-ISSN 1421-9743, Vol. 91, no 4, p. 201-213Article in journal (Refereed)
    Abstract [en]

    The causes of individual variation in behavior are often not well understood, and potential underlying mechanisms include both intrinsic and extrinsic factors, such as early environmental, physiological, and genetic differences. In an exploratory laboratory study, we raised three-spined sticklebacks (Gasterosteus aculeatus) under 4 different environmental conditions (simulated predator environment, complex environment, variable social environment, and control). We investigated how these manipulations related to behavior, brain physiology, and gene expression later in life, with focus on brain dopamine and serotonin levels, turnover rates, and gene expression. The different rearing environments influenced behavior and gene expression, but did not alter monoamine levels or metabolites. Specifically, compared to control fish, fish exposed to a simulated predator environment tended to be less aggressive, more exploratory, and more neophobic; and fish raised in both complex and variable social environments tended to be less neophobic. Exposure to a simulated predator environment tended to lower expression of dopamine receptor DRD4A, a complex environment increased expression of dopamine receptor DRD1B, while a variable social environment tended to increase serotonin receptor 5-HTR2B and serotonin transporter SLC6A4A expression. Despite both behavior and gene expression varying with early environment, there was no evidence that gene expression mediated the relationship between early environment and behavior. Our results confirm that environmental conditions early in life can affect phenotypic variation. However, the mechanistic pathway of the monoaminergic systems translating early environmental variation into observed behavioral responses was not detected.

  • 14.
    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.

  • 15.
    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.

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  • 16.
    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.

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  • 17.
    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.

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  • 18.
    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.

  • 19.
    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.

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  • 20.
    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.

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  • 21.
    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.

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  • 22.
    Abd El-Gaber, Amira S.
    et al.
    Menoufia Univ, Fac Sci, Dept Chem, Shibin Al Kawm, Egypt.
    El Gendy, Abdel Nasser G.
    Natl Res Ctr, Med & Aromat Plants Res Dept, 33 El Bohouth St,PO 12622, Giza, Egypt.
    Elkhateeb, Ahmed
    Natl Res Ctr, Phytochem & Plant Systemat Dept, 33 El Bohouth St,PO 12622, Giza, Egypt.
    Saleh, Ibrahim A.
    Natl Res Ctr, Phytochem Dept, 33 El Bohouth St,PO 12622, Giza, Egypt.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Menoufia Univ, Fac Sci, Dept Chem, Shibin Al Kawm, Egypt;Univ Karachi, ICCBS, Karachi 75270, Pakistan.
    Microwave Extraction of Essential Oil from Anastatica hierochuntica (L): Comparison with Conventional Hydro-Distillation and Steam Distillation2018In: Journal of Essential Oil-Bearing Plants (JEOBP), ISSN 0972-060X, E-ISSN 0976-5026, Vol. 21, no 4, p. 1003-1010Article in journal (Refereed)
    Abstract [en]

    This article stands to introduce microwave assisted extraction (MAE) as a more effective method for extraction of Anastatica hierochuntica (L) essential oils (EOs) compared to traditional hydrodistillation (HD) and steam distillation (SD) methods. Analysis of EOs by gas chromatography-mass spectrometry (GC/MS) showed significant differences in the constituents and percentages of the obtained oils. Using MAE and HD obtained oxygenated monoterpenes 50.79 % whereas SD obtained sesquiterpene hydrocarbons 79.84 % as major contents of the extracted oils. This is the first report of EO composition of the aerials parts of A. heirochunatica. It offered several advantages of MAE technique as a green method with shorter extraction time (60 min) and better yield.

  • 23.
    Abdalaal, Hind
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala.
    Deciphering molecular mechanisms in the evolution of new functions2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

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

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

    The two first authors contributed equally to this work.

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

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

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

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

     

     

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

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

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

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

     

    National Category
    Biological Sciences
    Research subject
    Biology with specialization in Microbiology
    Identifiers
    urn:nbn:se:uu:diva-423416 (URN)
    Available from: 2020-10-25 Created: 2020-10-25 Last updated: 2020-10-25
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  • 24.
    Abdalaal, Hind
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University.
    Näsvall, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evolvability of orthologous genesManuscript (preprint) (Other academic)
    Abstract [en]

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

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

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

     

  • 25.
    Abdalaal, Hind
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala university.
    Näsvall, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Intermittent selection directs evolution of a specialist enzyme to become a generalistManuscript (preprint) (Other academic)
    Abstract [en]

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

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

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

     

     

  • 26.
    Abdalaal, Hind
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pundir, Shreya
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Ge, Xueliang
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Sanyal, Suparna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Näsvall, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Collateral toxicity limits the evolution of bacterial Release Factor 2 towards total omnipotence2020In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 37, no 10, p. 2918-2930Article in journal (Refereed)
    Abstract [en]

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

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    fulltext
  • 27.
    Abdelaziz, Nouha
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    The role of RNA-binding protein FUBL-1 in epigenetic inheritance in C. elegans2022Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
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  • 28. 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, 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.

  • 29.
    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
    Show others...
    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.

    Keywords
    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: 2022-01-28Bibliographically 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)
    Abstract
    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: 2022-01-25
    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.

    Keywords
    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
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    (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
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  • 30. 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)
  • 31.
    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)
  • 32.
    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, 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.

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  • 33. 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)
  • 34.
    Abel, Pascal
    et al.
    Eberhani Karls Univ Tubingen, Senckenberg Ctr Human Evolut & Palaeoenvironm, Sigwartstr 28, D-72076 Tubingen, Germany..
    Hornung, Jahn
    Niedersachs Landesmuseum Hannover, Willy Brandt Allee 5, D-30169 Hannover, Germany..
    Kear, Benjamin P.
    Uppsala University, Music and Museums, Museum of Evolution.
    Sachs, Sven
    Nat Kunde Museum Bielefeld, Abt Geowissensch, Adenauerpl 2, D-33602 Bielefeld, Germany..
    An anhanguerian pterodactyloid mandible from the lower Valanginian of Northern Germany, and the German record of Cretaceous pterosaurs2021In: Acta Palaeontologica Polonica, ISSN 0567-7920, E-ISSN 1732-2421, Vol. 66, no 3, p. S5-S12Article in journal (Refereed)
    Abstract [en]

    The record of Cretaceous pterosaur remains from Germany is sparse. The material recovered to date includes the fragmentary holotypes of Targaryendraco wiedenrothi and Ctenochasma roemeri, as well as a few isolated pterodactyloid teeth and some indeterminate skeletal elements, together with a plaster cast of a large Purbeckopus manus imprint. Here, we report the discovery of a pterodactyloid pterosaur mandible from lower Valanginian strata of the Stadthagen Formation in the Lower Saxony Basin of Northern Germany. Based on the size and spacing of its alveoli, this fossil is attributable to the cosmopolitan Early Cretaceous pteranodontoid clade Anhangueria. Moreover, it represents the first and only known pterosaur from the Valanginian of Germany and is one of only a handful Valanganian pterosaur occurrences presently recognized worldwide. In addition to the approximately coeval Coloborhynchus clavirostris from the Hastings Bed Group of southern England, the Stadthagen Formation pterosaur mandible is among the stratigraphically oldest identifiable anhanguerians.

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  • 35.
    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.

  • 36.
    Abosedera, Dalia A.
    et al.
    Univ Sadat City, Environm Studies & Res Inst, Dept Nat Resources, Sadat City, Egypt..
    Emara, S. A.
    Univ Sadat City, Fac Vet Med, Dept Cytol & Histol, Sadat City, Egypt..
    Tamam, Omar A. S.
    Univ Sadat City, Environm Studies & Res Inst, Dept Nat Resources, Sadat City, Egypt..
    Badr, Osama M.
    Univ Sadat City, Anim Biotechnol Dept, Genet Engn & Biotechnol Inst GEBRI, Sadat City, Egypt..
    Khalifa, Shaden A. M.
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, S-10691 Stockholm, Sweden..
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. BJiangsu Univ, Int Res Ctr Food Nutr & Safety, Zhenjiang 212013, Jiangsu, Peoples R China.;Jiangsu Univ, Jiangsu Educ Dept, Int Joint Res Lab Intelligent Agr & Agriprod Proc, Zhenjiang, Jiangsu, Peoples R China.;Menoufia Univ, Fac Sci, Dept Chem, Menoufia 32511, Egypt..
    Refaey, Mohamed S.
    Univ Sadat City, Fac Pharm, Dept Pharmacognosy, Menoufia 32897, Egypt..
    Metabolomic profile and in vitro evaluation of the cytotoxic activity of Asphodelus microcarpus against human malignant melanoma cells A3752022In: Arabian Journal of Chemistry, ISSN 1878-5352, E-ISSN 1878-5379 , Vol. 15, no 10, article id 104174Article in journal (Refereed)
    Abstract [en]

    Melanoma is a huge worldwide health problem that must be handled more effectively with better therapeutic options. As a result, new treatment drugs are required to treat this condition. The goal of this study was to investigate the cytotoxic activity of the anthraquinone-rich fractions obtained from Asphodelus microcarpus against human melanoma cell A375. On these melanoma cell lines; the cytotoxicity of these fractions had never been studied before. Liquid chromatography linked to mass spectrometry (LC-MS-MS) and Nuclear Magnetic Resonance was used to determine the chemical profiles of these fractions. The cytotoxicity of the fractions studied was determined by measuring cell viability and calculating IC50 values. Both ethyl acetate (EtOAC) and the precipitate fractions (PPT) exhibited selective cytotoxicity on human melanoma A 375 cell line with IC50 values of 83 and 65 mu g/mL, respectively. The antiproliferative properties of EtOAc fraction and PPT were supported by a noticeable decrease in cell numbers during the G2/M cell cycle arrest. Our findings suggest that the anthraquinone content of A. microcarpus tubers is responsible for its anti-proliferative and apoptotic properties and that further in vivo investigations should be conducted to establish the viability of using them to treat human melanomas.

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  • 37.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Tano, Hanna
    KTH Royal Inst Technol, AlbaNova Univ Ctr, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden..
    Nagy, Abel
    KTH Royal Inst Technol, AlbaNova Univ Ctr, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden..
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Wadeea, Fadya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Kumar, Sharmishtaa
    KTH Royal Inst Technol, AlbaNova Univ Ctr, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden..
    Westerlund, Kristina
    KTH Royal Inst Technol, AlbaNova Univ Ctr, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk 634050, Russia.
    Eriksson Karlström, Amelie
    KTH Royal Inst Technol, AlbaNova Univ Ctr, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden..
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab. Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Centrum Oncotheranost, Tomsk 634050, Russia..
    Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer2020In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 12, no 10, article id 977Article in journal (Refereed)
    Abstract [en]

    The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) to an ABD (albumin-binding domain), we aimed to extend the blood circulation of peptides. The synthesized conjugate DOTA-ABD-RM26 was labelled with indium-111 and evaluated in vitro and in vivo. The labelled conjugate was stable in PBS and retained specificity and its antagonistic function against GRPR. The half-maximal inhibitory concentration (IC50) of In-nat-DOTA-ABD-RM26 in the presence of human serum albumin was 49 +/- 5 nM. [In-111]In-DOTA-ABD-RM26 had a significantly longer residence time in blood and in tumors (without a significant decrease of up to 144 h pi) than the parental RM26 peptide. We conclude that the ABD-RM26 conjugate can be used for GRPR-targeted therapy and delivery of cytotoxic drugs. However, the undesirable elevated activity uptake in kidneys abolishes its use for radionuclide therapy. This proof-of-principle study justified further optimization of the molecular design of the ABD-RM26 conjugate.

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  • 38.
    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.

  • 39.
    Abozeid, Hassanein H.
    et al.
    Cairo Univ, Fac Vet Med, Dept Poultry Dis, Giza 12211, Egypt..
    Naguib, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Infectious Bronchitis Virus in Egypt: Genetic Diversity and Vaccination Strategies2020In: Veterinary Sciences, E-ISSN 2306-7381, Vol. 7, no 4, article id 204Article, review/survey (Refereed)
    Abstract [en]

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

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  • 40. 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)
  • 41.
    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.

  • 42.
    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.

  • 43.
    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.

  • 44.
    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.

  • 45. Abramsson, Mia L
    et al.
    Sahin, Cagla
    Hopper, Jonathan T S
    Branca, Rui M M
    Danielsson, Jens
    Xu, Mingming
    Chandler, Shane A
    Österlund, Nicklas
    Ilag, Leopold L
    Leppert, Axel
    Costeira-Paulo, Joana
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Lang, Lisa
    Teilum, Kaare
    Robinson, Carol V
    Laganowsky, Arthur
    Benesch, Justin L P
    Oliveberg, Mikael
    Marklund, Erik G
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Allison, Timothy M
    Winther, Jakob R
    Landreh, Michael
    Charge engineering reveals the roles of ionizable side chains in electrospray ionization mass spectrometryManuscript (preprint) (Other academic)
    Abstract [en]

    The role of ionizable side chains in the electrospray ionization mass spectrometry of intact proteins remains hotly debated but has not been conclusively addressed because multiple chargeable sites are present in virtually all proteins. Using engineered soluble proteins, we show that ionizable side chains are completely dispensable for charging under native conditions, but if present, they are preferential protonation sites. The absence of ionizable side chains results in identical charge state distributions under native-like and denaturing conditions, whilst co-existing conformers can be distinguished using ion mobility separation. An excess of ionizable side chains, on the other hand, effectively modulates protein ion stability. We conclude that the sum of charges is governed solely by Coulombic terms, while their locations affect the stability of the protein in the gas phase.

  • 46.
    Abreu, Murilo S.
    et al.
    Fed Univ Santa Maria UFSM, Grad Program Pharmacol, BR-97105900 Santa Maria, RS, Brazil.
    Messias, Joao P. M.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal.
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Soares, Marta C.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal.
    Monoaminergic levels at the forebrain and diencephalon signal for the occurrence of mutualistic and conspecific engagement in client reef fish2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 7346Article in journal (Refereed)
    Abstract [en]

    Social interactions are commonly found among fish as in mammals and birds. While most animals interact socially with conspecifics some however are also frequently and repeatedly observed to interact with other species (i.e. mutualistic interactions). This is the case of the (so-called) fish clients that seek to be cleaned by other fish (the cleaners). Clients face an interesting challenge: they raise enough motivation to suspend their daily activities as to selectively visit and engage in interactions with cleaners. Here we aimed, for the first time, to investigate the region-specific brain monoaminergic level differences arising from individual client fish when facing a cleaner (interspecific context) compared to those introduced to another conspecific (socio-conspecific context). We show that monoaminergic activity differences occurring at two main brain regions, the diencephalon and the forebrain, are associated with fish clients' social and mutualistic activities. Our results are the first demonstration that monoaminergic mechanisms underlie client fish mutualistic engagement with cleanerfish. These pathways should function as a pre-requisite for cleaning to occur, providing to clients the cognitive and physiological tools to seek to be cleaned.

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  • 47.
    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.

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  • 48.
    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.

  • 49. Achatz, Johannes Georg
    et al.
    Hooge, Matthew
    Wallberg, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, 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.

  • 50.
    Adams, Susan B.
    et al.
    US Forest Serv, USDA, Southern Res Stn, Ctr Bottomland Hardwoods Res, 1000 Front St, Oxford, MS 38655 USA..
    Hereford, Scott G.
    US Fish & Wildlife Serv, Mississippi Sandhill Crane Natl Wildlife Refuge, 7200 Crane Lane, Gautier, MS 39553 USA..
    Hyseni, Chaz
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Burrow Densities of Primary Burrowing Crayfishes in Relation to Prescribed Fire and Mechanical Vegetation Treatments2021In: Water, E-ISSN 2073-4441, Vol. 13, no 13, article id 1854Article in journal (Refereed)
    Abstract [en]

    Fire suppression and other factors have drastically reduced wet prairie and pine savanna ecosystems on the Coastal Plain of the southeastern United States. Restoration of these open-canopy environments often targets one or several charismatic species, and semi-aquatic species such as burrowing crayfishes are often overlooked in these essentially terrestrial environments. We examined the relationship between primary burrowing crayfishes and three vegetation treatments implemented over at least the past two decades in the Mississippi Sandhill Crane National Wildlife Refuge. Vegetation in the 12 study sites had been frequently burned, frequently mechanically treated, or infrequently managed. Creaserinus spp., primarily C. oryktes, dominated the crayfish assemblage in every site. We counted crayfish burrow openings and coarsely categorized vegetation characteristics in 90, 0.56-m(2) quadrats evenly distributed among six transects per site. The number of active burrow openings was negatively, exponentially related to both the percent cover of woody vegetation and the maximum height of woody vegetation in quadrats, and to the number of trees taller than 1.2 m per transect, indicating that woody plant encroachment was detrimental to the crayfishes. Results were consistent with several other studies from the eastern US, indicating that some primary burrowing crayfishes are habitat specialists adapted to open-canopy ecosystems.

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