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  • 951.
    Xu, Fu
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Byström, Anders
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Marcus J. O.
    Umeå University, Faculty of Medicine, Department of Odontology.
    SSD1 modifies phenotypes of Elongator mutants2019In: Current Genetics, ISSN 0172-8083, E-ISSN 1432-0983Article in journal (Refereed)
    Abstract [en]

    The translational decoding properties of tRNAs are influenced by post-transcriptional modification of nucleosides in their anticodon region. The Elongator complex promotes the first step in the formation of 5-methoxycarbonylmethyl (mcm(5)), 5-methoxycarbonylhydroxymethyl (mchm(5)), and 5-carbamoylmethyl (ncm(5)) groups on wobble uridine residues in eukaryotic cytosolic tRNAs. Elongator mutants in yeast, worms, plants, mice, and humans not only show a tRNA modification defect, but also a diverse range of additional phenotypes. Even though the phenotypes are almost certainly caused by the reduced functionality of the hypomodified tRNAs in translation, the basis for specific phenotypes is not well understood. Here, we discuss the recent finding that the phenotypes of Saccharomyces cerevisiae Elongator mutants are modulated by the genetic background. This background-effect is largely due to the allelic variation at the SSD1 locus, which encodes an mRNA-binding protein involved in post-transcriptional regulation of gene expression. A nonsense ssd1 allele is found in several wild-type laboratory strains and the presence of this allele aggravates the stress-induced phenotypes of Elongator mutants. Moreover, other phenotypes, such as the histone acetylation and telomeric gene silencing defects, are dependent on the mutant ssd1 allele. Thus, SSD1 is a genetic modifier of the phenotypes of Elongator-deficient yeast cells.

  • 952.
    Xu, Fu
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Zhou, Yang
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Byström, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Marcus J. O.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Identification of factors that promote biogenesis of tRNACGASer2018In: RNA Biology, ISSN 1547-6286, E-ISSN 1555-8584, Vol. 15, no 10, p. 1286-1294Article in journal (Refereed)
    Abstract [en]

    A wide variety of factors are required for the conversion of pre-tRNA molecules into the mature tRNAs that function in translation. To identify factors influencing tRNA biogenesis, we previously performed a screen for strains carrying mutations that induce lethality when combined with a sup61-T47:2C allele, encoding a mutant form of tRNACGASer. Analyzes of two complementation groups led to the identification of Tan1 as a protein involved in formation of the modified nucleoside N4-acetylcytidine (ac4C) in tRNA and Bud13 as a factor controlling the levels of ac4C by promoting TAN1 pre-mRNA splicing. Here, we describe the remaining complementation groups and show that they include strains with mutations in genes for known tRNA biogenesis factors that modify (DUS2, MOD5 and TRM1), transport (LOS1), or aminoacylate (SES1) tRNACGASer. Other strains carried mutations in genes for factors involved in rRNA/mRNA synthesis (RPA49, RRN3 and MOT1) or magnesium uptake (ALR1). We show that mutations in not only DUS2, LOS1 and SES1 but also in RPA49, RRN3 and MOT1 cause a reduction in the levels of the altered tRNACGASer. These results indicate that Rpa49, Rrn3 and Mot1 directly or indirectly influence tRNACGASer biogenesis.

  • 953.
    Xu, Hao
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Functional aspects of modified nucleosides in tRNA2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Transfer ribonucleic acids (tRNAs) are extensively modified, especially their anticodon loops. Modifications at position 34 (wobble base) and 37 in these loops affect the tRNAs’ decoding ability, while modifications outside the anticodon loops, e.g. m1A58 of tRNAMeti, may be crucial for tRNA structure or stability. A number of gene products are required for the formation of modified nucleosides, e.g. at least 26 proteins (including Elongator complex) are needed for U34 modifications in yeast, and methyl transferase activity of the Trm6/61p complex is needed to form m1A58. The aim of the studies which this thesis is based upon was to investigate the functional aspects of tRNA modifications and regulation of the modifying enzymes’ activity.

    First, the hypothesis that ncm5U34, mcm5U34, or mcm5s2U34 modifications may be essential for reading frame maintenance was investigated. The results show that mcm5 and s2 group of mcm5s2U play a vital role in reading frame maintenance. Subsequent experiments showed that the +1 frameshifting event at Lys AAA codon occurs via peptidyl-tRNA slippage due to a slow entry of the hypomodified tRNA-Lys.

    Moreover, the hypothesis that Elp1p N-terminal truncation may regulate Elongator activity was investigated. Cleavage of Elp1p was found to occur between residue 203 (Lys) and 204 (Ala) and to depend on the vacuolar protease Prb1p. However, including trichloroacetic acid (TCA) during protein extraction abolished the appearance of truncated Elp1p, showing that its truncation is a preparation artifact.

    Finally, in glioma cell line C6, PKCα was found to interact with TRM61. RNA silencing of TRM6/61 causes a growth defect that can be partially suppressed by tRNAMeti overexpression. PKCα overexpression reduces the nuclear level of TRM61, likely resulting in reduced level of TRM6/61 complex in the nucleus. Furthermore, lower expression of PKCα in the highly aggressive GBM (relative to its expression in less aggressive Grade II/III glioblastomas) is accompanied by increased expression of TRM6/61 mRNAs and tRNAMeti, highlighting the clinical relevance of the studies.

  • 954.
    Xu, Hao
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Bygdell, Joakim
    Wingsle, Gunnar
    Byström, Anders S.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Yeast Elongator protein Elp1p does not undergo proteolytic processing in exponentially growing cells2015In: MicrobiologyOpen, ISSN 2045-8827, E-ISSN 2045-8827, Vol. 4, no 6, p. 867-878Article in journal (Refereed)
    Abstract [en]

    In eukaryotic organisms, Elongator is a six-subunit protein complex required for the formation of 5-carbamoylmethyl (ncm5) and 5-methylcarboxymethyl (mcm5) side chains on uridines present at the wobble position (U34) of tRNA. The open reading frame encoding the largest Elongator subunit Elp1p has two in-frame 5′ AUG methionine codons separated by 48 nucleotides. Here, we show that the second AUG acts as the start codon of translation. Furthermore, Elp1p was previously shown to exist in two major forms of which one was generated by proteolysis of full-length Elp1p and this proteolytic cleavage was suggested to regulate Elongator complex activity. In this study, we found that the vacuolar protease Prb1p was responsible for the cleavage of Elp1p. The cleavage occurs between residues 203 (Lys) and 204 (Ala) as shown by amine reactive Tandem Mass Tag followed by LC-MS/MS (liquid chromatography mass spectrometry) analysis. However, using a modified protein extraction procedure, including trichloroacetic acid, only full-length Elp1p was observed, showing that truncation of Elp1p is an artifact occurring during protein extraction. Consequently, our results indicate that N-terminal truncation of Elp1p is not likely to regulate Elongator complex activity.

  • 955. Yakushevska, A. E.
    et al.
    Keegstra, W.
    Boekema, E. J.
    Dekker, J. P.
    Andersson, Jenny
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Ruban, A. V.
    Horton, P.
    The structure of photosystem II in Arabidopsis: localization of the CP26 and CP29 antenna complexes2003In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 42, no 3, p. 608-613Article in journal (Refereed)
    Abstract [en]

    A genetic approach has been adopted to investigate the organization of the light-harvesting proteins in the photosystem II (PSII) complex in plants. PSII membrane fragments were prepared from wild-type Arabidopis thaliana and plants expressing antisense constructs to Lhcb4 and Lhcb5 genes, lacking CP29 and CP26, respectively (Andersson et al. (2001) Plant Cell 13, 1193-1204). Ordered PSII arrays and PSII supercomplexes were isolated from the membranes of plants lacking CP26 but could not be prepared from those lacking CP29. Membranes and supercomplexes lacking CP26 were less stable than those prepared from the wild type. Transmission electron microscopy aided by single-particle image analysis was applied to the ordered arrays and the isolated PSII complexes. The difference between the images obtained from wild type and antisense plants showed the location of CP26 to be near CP43 and one of the light-harvesting complex trimers. Therefore, the location of the CP26 within PSII was directly established for the first time, and the location of the CP29 complex was determined by elimination. Alterations in the packing of the PSII complexes in the thylakoid membrane also resulted from the absence of CP26. The minor light-harvesting complexes each have a unique location and important roles in the stabilization of the oligomeric PSII structure.

  • 956. Yang, Aimin
    et al.
    Hacheney, Inken
    Wu, Yao-Wen
    Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany; Max-Planck-Institute of Molecular Physiology, Dortmund, Germany.
    Semisynthesis of autophagy protein LC3 conjugates2017In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 25, no 18, p. 4971-4976Article in journal (Refereed)
    Abstract [en]

    Autophagy is a conserved catabolic process involved in the elimination of proteins, organelles and pathogens. Autophagosome formation is the key process in autophagy. Lipidated Atg8/LC3 proteins that are conjugated to phosphatidylethanolamine (PE) play a key role in autophagosome biogenesis. To understand the function of Atg8/LC3-PE in autophagosome formation and host-pathogen interaction requires preparation and structural manipulation of lipidated Atg8/LC3 proteins. Herein, we report the semisynthesis of LC3 proteins and mutants with modifications of different PE fragments or lipids using native chemical ligation and aminolysis approaches.

  • 957. Yang, Aimin
    et al.
    Pantoom, Supansa
    Wu, Yao-Wen
    Institute of Chemical Biology and Precision Therapy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany; Max-Planck-Institute of Molecular Physiology, Dortmund, Germany.
    Elucidation of the anti-autophagy mechanism of the Legionella effector RavZ using semisynthetic LC3 proteins2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e23905Article in journal (Refereed)
    Abstract [en]

    Autophagy is a conserved cellular process involved in the elimination of proteins and organelles. It is also used to combat infection with pathogenic microbes. The intracellular pathogen Legionella pneumophila manipulates autophagy by delivering the effector protein RavZ to deconjugate Atg8/LC3 proteins coupled to phosphatidylethanolamine (PE) on autophagosomal membranes. To understand how RavZ recognizes and deconjugates LC3-PE, we prepared semisynthetic LC3 proteins and elucidated the structures of the RavZ:LC3 interaction. Semisynthetic LC3 proteins allowed the analysis of structure-function relationships. RavZ extracts LC3-PE from the membrane before deconjugation. RavZ initially recognizes the LC3 molecule on membranes via its N-terminal LC3-interacting region (LIR) motif. The RavZ α3 helix is involved in extraction of the PE moiety and docking of the acyl chains into the lipid-binding site of RavZ that is related in structure to that of the phospholipid transfer protein Sec14. Thus, Legionella has evolved a novel mechanism to specifically evade host autophagy.

  • 958.
    Yasmin, Lubna
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Veesenmeyer, Jeffrey L
    Diaz, Maureen H
    Francis, Matthew S
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Ottmann, Christian
    Palmer, Ruth H
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hauser, Alan R
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Electrostatic interactions play a minor role in the binding of ExoS to 14-3-3 proteins2010In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 427, no 2, p. 217-224Article in journal (Refereed)
    Abstract [en]

    14-3-3 proteins belong to a family of conserved molecules expressed in all eukaryotic cells that play an important role in a multitude of signalling pathways. 14-3-3 proteins bind either to phosphoserine/phosphothreonine residues or to sequence-specific non-phosphorylated motifs in more than 200 interaction partners [Pozuelo Rubio, Geraghty, Wong, Wood, Campbell, Morrice and Mackintosh (2004) Biochem. J. 379, 395-408]. These interactions result in cell-cycle regulation, apoptosis, stress responses, cell metabolism and malignant transformation. One example of a phosphorylation-independent interaction is the binding of 14-3-3 to ExoS (exoenzyme S), a bacterial ADP-ribosyltransferase toxin of Pseudomonas aeruginosa. In the present study, we have utilized additional biochemical and infection analyses to define further the structural basis of the interaction between ExoS and 14-3-3. An ExoS leucine-substitution mutant dramatically reduced the interaction potential with 14-3-3 suggesting that Leu422, Leu423, Leu426 and Leu428 of ExoS are important for its interaction with 14-3-3, its enzymatic activity and cytotoxicity. However, ExoS substitution mutants of residues that interact with 14-3-3 through an electrostatic interaction, such as Ser416, His418, Asp424 and Asp427, showed no reduction in their interaction potential with 14-3-3. These ExoS substitution mutants were also as aggressive as wild-type ExoS at inducing cell death and to modify endogenous ExoS target within the cell. In conclusion, electrostatic interaction between ExoS and 14-3-3 via polar residues (Ser416, His418, Asp424 and Asp427) appears to be of secondary importance. Thus the interaction between the 'roof' of the groove of 14-3-3 and ExoS relies more on hydrophobic interaction forces, which probably contributes to induce cell death after ExoS infection and activation.

  • 959. Yeh, Johannes T. -H.
    et al.
    Nam, Kwangho
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, 76019-0065, USA.
    Yeh, Joshua T. -H.
    Perrimon, Norbert
    eUnaG: a new ligand-inducible fluorescent reporter to detect drug transporter activity in live cells2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 41619Article in journal (Refereed)
    Abstract [en]

    The absorption, distribution, metabolism and excretion (ADME) of metabolites and toxic organic solutes are orchestrated by the ATP-binding cassette (ABC) transporters and the organic solute carrier family (SLC) proteins. A large number of ABC and SLC transpoters exist; however, only a small number have been well characterized. To facilitate the analysis of these transporters, which is important for drug safety and physiological studies, we developed a sensitive genetically encoded bilirubin (BR)-inducible fluorescence sensor (eUnaG) to detect transporter-coupled influx/efflux of organic compounds. This sensor can be used in live cells to measure transporter activity, as excretion of BR depends on ABC and SLC transporters. Applying eUnaG in functional RNAi screens, we characterize l(2) 03659 as a Drosophila multidrug resistant-associated ABC transporter.

  • 960. Yewdell, Jonathan W.
    et al.
    Dersh, Devin
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Inserm, Paris, France; International Centre for Cancer Vaccine Science (ICCVS), University of Gdansk, Science, Gdansk, Poland; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    Peptide Channeling: The Key to MHC Class I Immunosurveillance?2019In: Trends in Cell Biolology, ISSN 0962-8924, E-ISSN 1879-3088, Vol. 29, no 12, p. 929-939Article, review/survey (Refereed)
    Abstract [en]

    MHC class I presentation of short peptides enables CD8(+) T cell (TCD8+) immunosurveillance of tumors and intracellular pathogens. A key feature of the class I pathway is that the immunopeptidome is highly skewed from the cellular degradome, indicating high selectivity of the access of protease-generated peptides to class I molecules. Similarly, in professional antigen-presenting cells, peptides from minute amounts of proteins introduced into the cytosol outcompete an overwhelming supply of constitutively generated peptides. Here, we propose that antigen processing is based on substrate channeling and review recent studies from the antigen processing and cell biology fields that provide a starting point for testing this hypothesis.

  • 961. Yin, Xiao-Jun
    et al.
    Volk, Sara
    Ljung, Karin
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Mehlmer, Norbert
    Dolezal, Karel
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Laboratory of Growth Regulators, Palacky University and Institute of Experimental Botany, Academy of Sciences of the Czech Republic, CZ-78371 Olomouc, Czech Republic.
    Ditengou, Franck
    Hanano, Shigeru
    Davis, Seth J
    Schmelzer, Elmon
    Sandberg, Göran
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Teige, Markus
    Palme, Klaus
    Pickart, Cecile
    Bachmair, Andreas
    Ubiquitin lysine 63 chain forming ligases regulate apical dominance in Arabidopsis2007In: The Plant Cell, ISSN 1040-4651, E-ISSN 1532-298X, Vol. 19, no 6, p. 1898-1911Article in journal (Refereed)
    Abstract [en]

    Lys-63-linked multiubiquitin chains play important roles in signal transduction in yeast and in mammals, but the functions for this type of chain in plants remain to be defined. The RING domain protein RGLG2 (for RING domain Ligase2) from Arabidopsis thaliana can be N-terminally myristoylated and localizes to the plasma membrane. It can form Lys-63-linked multiubiquitin chains in an in vitro reaction. RGLG2 has overlapping functions with its closest sequelog, RGLG1, and single mutants in either gene are inconspicuous. rglg1 rglg2 double mutant plants exhibit loss of apical dominance and altered phyllotaxy, two traits critically influenced by the plant hormone auxin. Auxin and cytokinin levels are changed, and the plants show a decreased response to exogenously added auxin. Changes in the abundance of PIN family auxin transport proteins and synthetic lethality with a mutation in the auxin transport regulator BIG suggest that the directional flow of auxin is modulated by RGLG activity. Modification of proteins by Lys-63-linked multiubiquitin chains is thus important for hormone-regulated, basic plant architecture.

  • 962.
    Yoluk, Özge
    et al.
    KTH, Science for Life Laboratory, SciLifeLab.
    Lindahl, Erik
    KTH, Science for Life Laboratory, SciLifeLab.
    Andersson, Magnus
    Science for Life Laboratory; Theoretical and Computational Biophysics, Department of Theoretical Physics, KTH Royal Institute of Technology, Stockholm, Sweden.
    Conformational Gating Dynamics in the GluCl Anion-Selective Chloride Channel2015In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 6, no 8, p. 1459-1467Article in journal (Refereed)
    Abstract [en]

    Cys-loop receptors are central to propagation of signals in the nervous system. The gating of the membrane-spanning pore is triggered by structural rearrangements in the agonist-binding site, located some so A away from the pore. A sequential conformational change, propagating from the ligand-binding site to the pore, has been proposed to govern gating in all Cys-loop receptors. Here, we identify structural and dynamic components of the conformational gating in the eukaryotic glutamate-gated chloride channel (GluCl) by means of molecular dynamics (MD) simulations with and without the L-glutamate agonist bound. A significant increase in pore opening and accompanying hydration is observed in the presence of glutamate. Potential of mean force calculations reveal that the barrier for ion passage drops from 15 kcal/mol to 5-10 kcal/mol with the agonist bound. This appears to be explained by agonist binding that leads to significant changes in the intersubunit hydrogen-bonding pattern, which induce a slight tilt of the extracellular domain relative to the transmembrane domain in the simulations. This rearrangement is subtle, but correspond to the direction of the quaternary twist observed as a key difference between open and closed X-ray structures. While the full reversible gating is still a much slower process, the observed structural dynamics sheds new light on the early stages of how the agonist influences the extracellular domain, how the extracellular domain interacts with the transmembrane domain, and how changes in the transmembrane domain alter the free energy of ion passage.

  • 963.
    Zafra, Olga
    et al.
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    Ramírez, Sandra
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    Castán, Pablo
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    Moreno, Renata
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    Cava, Felipe
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    Vallés, Cristina
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    Caro, Eddy
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    Berenguer, José
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    A cytochrome c encoded by the nar operon is required for the synthesis of active respiratory nitrate reductase in Thermus thermophilus2002In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 523, no 1-3, p. 99-102Article in journal (Refereed)
    Abstract [en]

    A cytochrome c (NarC) is encoded as the first gene of the operon for nitrate respiration in Thermus thermophilus. NarC is required for anaerobic growth and for the synthesis of active nitrate reductase (NR). The alpha and delta subunits (NarG, NarJ) of the NR were constitutively expressed in narC::kat mutants, but NarG appeared in the soluble fraction instead of associated with the membranes. Our data demonstrate for NarC an essential role in the synthesis of active enzyme and for the attachment to the membrane of the respiratory NR from T. thermophilus.

  • 964. Zannini, Flavien
    et al.
    Roret, Thomas
    Przybyla-Toscano, Jonathan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Université de Lorraine, Inra, IAM, F-54000 Nancy, France; flavien.zannini@univ-lorraine.fr (F.Z.); thomas.roret@sb-roscoff.fr (T.R.); przybylajonathan@orange.fr (J.P.-T.); tiphaine.dhalleine@univ-lorraine.fr (T.D.); nicolas.rouhier@univ-lorraine.fr (N.R.).
    Dhalleine, Tiphaine
    Rouhier, Nicolas
    Couturier, Jeremy
    Mitochondrial arabidopsis thaliana TRXo isoforms bind an iron-sulfur cluster and reduce NFU proteins In Vitro2018In: Antioxidants, ISSN 2076-3921, Vol. 7, no 10, article id 142Article in journal (Refereed)
    Abstract [en]

    In plants, the mitochondrial thioredoxin (TRX) system generally comprises only one or two isoforms belonging to the TRX h or o classes, being less well developed compared to the numerous isoforms found in chloroplasts. Unlike most other plant species, Arabidopsis thaliana possesses two TRXo isoforms whose physiological functions remain unclear. Here, we performed a structure-function analysis to unravel the respective properties of the duplicated TRXo1 and TRXo2 isoforms. Surprisingly, when expressed in Escherichia coli, both recombinant proteins existed in an apo-monomeric form and in a homodimeric iron-sulfur (Fe-S) cluster-bridged form. In TRXo2, the [4Fe-4S] cluster is likely ligated in by the usual catalytic cysteines present in the conserved Trp-Cys-Gly-Pro-Cys signature. Solving the three-dimensional structure of both TRXo apo-forms pointed to marked differences in the surface charge distribution, notably in some area usually participating to protein-protein interactions with partners. However, we could not detect a difference in their capacity to reduce nitrogen-fixation-subunit-U (NFU)-like proteins, NFU4 or NFU5, two proteins participating in the maturation of certain mitochondrial Fe-S proteins and previously isolated as putative TRXo1 partners. Altogether, these results suggest that a novel regulation mechanism may prevail for mitochondrial TRXs o, possibly existing as a redox-inactive Fe-S cluster-bound form that could be rapidly converted in a redox-active form upon cluster degradation in specific physiological conditions.

  • 965.
    Zare, Aman
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Regulation of gene expression in fruit flies: how does it start, and will it be remembered?2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    One of the most distinctive features of eukaryotic chromosomes is the bundling of DNA together with functionally associated RNA and proteins in chromatin. This allows huge amounts of DNA to be packed inside the very tiny space of the nucleus, and alterations in the structure of chromatin enable access to the DNA for transcription (“reading” genes by production of RNA copies). Much of the current knowledge of chromatin structure and regulation comes from studies of Drosophila melanogaster. When the chromatin structure is open the transcription of a gene can start after recruitment of the necessary factors. The main enzyme for gene transcription is Polymerase II (Pol II). For successful gene transcription, Pol II must not only be recruited to the gene’s promoter, but also escape from a pausing state which occurs soon after transcription initiation. CBP/P300 is one of the co-activators involved in transcriptional activation. In the studies this thesis is based upon, my colleagues and I (hereafter we) discovered a new function for CBP in transcription activation. Using high throughput sequencing techniques, we found that CBP directly stimulates recruitment of Pol II to promoters, and facilitates its release from the paused state, enabling progression to the elongation stage of transcription.

    For cells to remember their identity following division during development, the transcriptional state of genes must be transmitted. Intensively studied players involved in this memory are the Polycomb group (PcG) proteins, responsible for maintaining the repressed state of important developmental genes. The core members are Polycomb repressive complex 1 and 2 (PRC1 and PRC2), which are recruited in flies through poorly known mechanisms to target genes by so-called Polycomb response elements (PREs). Using Drosophila mutant cell lines, we showed that (in contrast to previous models) some PREs can recruit PRC1 even when PRC2 is absent. We also observed that at many PREs, PRC1 is needed for recruitment of PRC2 and concluded that targeting PRC complexes to PREs is a much more flexible and variable process than previously thought.

    Some phenotypic effects of environmental changes can be transferred to subsequent generations. Previous efforts to identify the mechanisms involved have focused on material (mainly, but not only, DNA) transferred through germ cells. However, organisms’ microbiomes are also transferred to the next generation. Thus, to investigate possible contributions of microbiomes to such transfer, we used fruit flies as the microbiomes they inherit can be easily controlled. We altered some parents’ environmental conditions by lowering the temperature, then grew offspring that received microbiomes from cold-treated and control parents in control conditions and compared their transcriptional patterns. Our results suggest that most of the crosstalk between the microbiome and the fly happens in the gut, and that further investigation of this previously unsuspected mode of inheritance is warranted.

  • 966. Zegenhagen, Loreen
    et al.
    Weber, Elvira
    Kurade, Chaitanya
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nair, Sharmila
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kroeger, Andrea
    Differential innate immune responses in various brain regions regulate antiviral response in the CNS during Tick-borne encephalitis virus infection2015In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 76, no 1, p. 91-91Article in journal (Other academic)
  • 967. Zelent, B
    et al.
    Yano, T
    Ohlsson, P-I
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Smith, ML
    Paul, J
    Vanderkooi, JM
    Optical spectra of lactoperoxidase as a function of solvent2005In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 44, no 48, p. 15953-15959Article in journal (Refereed)
    Abstract [en]

    The iron of lactoperoxidase is predominantly high-spin at ambient temperature. Optical spectra of lactoperoxidase indicate that the iron changes from high-spin to low-spin in the temperature range from room temperature to 20 K. The transformation is independent of whether the enzyme is in glycerol/water or solid sugar glass. Addition of the inhibitor benzohydroxamic acid increases the amount of the low-spin form, and again the transformation is independent of whether the protein is in an aqueous solution or a nearly anhydrous sugar. In contrast to lactoperoxidase, horseradish peroxidase remains high-spin over the temperature excursion in both solvents and with addition of benzohydroxamic acid. We conclude that details of the heme pocket of lactoperoxidase allow ligation changes with temperature that are dependent upon the apoprotein but independent of solvent fluctuations. At low pH, lactoperoxidase shows a solvent-dependent transition; the high-spin form is predominant in anhydrous sugar glass, but in the presence of water, the low-spin form is also present in abundance. The active site of lactoperoxidase is not as tightly constrained at low pH as at neutrality, though the enzyme is active over a wide pH range.

  • 968.
    Zeng, Qing-Yin
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Development of molecular techniques for fungal diagnostic research2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fungi are present everywhere in indoor and outdoor environments. Many fungi are toxigenic or pathogenic that may cause various public health concerns. Rapid detection, quantification and characterization of fungi in living and working environments are essential for exposure risk assessment to safe guard public health.

    Rapid and accurate detection and identification of fungi using molecular method require specific markers. In this thesis, partial mt SSU and LSU rDNA were amplified and sequenced from 31 fungal species of 16 genera. Sequence alignments showed that fungal mt SSU and LSU rDNA contained sufficient amount of variation for the development of markers that can discriminate even among closely related species. Forty-eight probes were designed and were verified as highly specific to 25 fungal species commonly detected in living and working environments. These specific probes would have potential applications in clinical diagnosis and public health-related environmental monitoring.

    Nested PCR is a highly sensitive and specific method. Based on the nuclear 18S rDNA sequence variation pattern, three nested PCR systems were developed to detect the conifer tree pathogen Gremmeniella abietina, an ascomycete fungus that causes stem canker and shoot dieback in many conifer species. The three nested PCR systems showed high specificity and sensitivity. These methods could have broad applications in forest protection and disease management programs.

    Quantitative real-time PCR offers the ability of simultaneous detection and quantification of DNA of a specific microbe in one reaction. Based on the 18S rDNA sequence, two real-time PCR assays were developed to detect and quantify Wallemia sebi, a deuteromycete fungus commonly found in agricultural environments and is suspected to be a causative agent of farmer’s lung disease. Both PCR systems proved to be highly specific and sensitive for W. sebi detection even in a high background of other fungal DNAs. Application of the real-time PCR methods in the quantification of W. sebi in the aerosols of a farm revealed a high concentration of W. sebi spores (107/m3). The study indicates that W. sebi is a dominant fungus in agriculture environments.

    Cladosporium spores are important aeroallergens, and prolonged exposure to elevated spore concentrations can provoke chronic allergy and asthma. A TaqMan probe and a SYBR Green I based real-time PCR assay were developed to detect and quantify Cladosporium in aerosols. The two real-time PCR systems proved to be highly specific and sensitive for Cladosporium. These methods were employed to quantify Cladosporium in aerosols of five different indoor environments. High spore concentration of Cladosporium (107/m3) was observed in a cow barn. Cladosporium spore concentration in paper and pulp factory and countryside house also exceeded threshold value for clinical significance. Prolonged exposure in these environments could impose certain health risk. Thus, monitoring Cladosporium spore concentration in indoor environments is important for indoor air quality control.

  • 969.
    Zeng, Qing-Yin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Westermark, Sven-Olof
    Rasmuson-Lestander, Åsa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Wang, Xiao-Ru
    Detection and quantification of Cladosporium in aerosols by real-time PCR2006In: Journal of Environmental Monitoring, ISSN 1464-0325, E-ISSN 1464-0333, Vol. 8, no 1, p. 153-160Article in journal (Refereed)
    Abstract [en]

    Cladosporium is one of the most common airborne molds found in indoor and outdoor environments. Cladosporium spores are important aeroallergens, and prolonged exposure to elevated spore concentrations can provoke chronic allergy and asthma. To accurately quantify the levels of Cladosporium in indoor and outdoor environments, two real-time PCR systems were developed in this study. The two real-time PCR systems are highly specific and sensitive for Cladosporium detection even in a high background of other fungal DNAs. These methods were employed to quantify Cladosporium in aerosols of five different indoor environments. The investigation revealed a high spore concentration of Cladosporium (10(7) m(-3)) in a cow barn that accounted for 28-44% of the airborne fungal propagules. In a countryside house that uses firewood for heating and in a paper and pulp factory, Cladosporium was detected at 10(4) spores m(-3), which accounted for 2-6% of the fungal propagules in the aerosols. The concentrations of Cladosporium in these three indoor environments far exceeded the medical borderline level (3000 spores m(-3)). In a power station and a fruit and vegetable storage, Cladosporium was found to be a minor component in the aerosols, accounted for 0.01-0.1% of the total fungal propagules. These results showed that monitoring Cladosporium in indoor environments is more important than in outdoor environments from the public health point of view. Cladosporium may not be the dominant fungi in some indoor environments, but its concentration could still be exceeding the threshold value for clinical significance. The methods developed in this study could facilitate accurate detection and quantification of Cladosporium for public health related risk assessment.

  • 970.
    Zeng, Qing-Yin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). National Institute for Working Life.
    Westermark, Sven-Olof
    Rasmuson-Lestander, Åsa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Wang, Xiao-Ru
    Detection and quantification of Wallemia sebi in aerosols by real-time PCR, conventional PCR, and cultivation2004In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 70, no 12, p. 7295-7302Article in journal (Refereed)
    Abstract [en]

    Wallemia sebi is a deuteromycete fungus commonly found in agricultural environments in many parts of the world and is suspected to be a causative agent of farmer's lung disease. The fungus grows slowly on commonly used culture media and is often obscured by the fast-growing fungi. Thus, its occurrence in different environments has often been underestimated. In this study, we developed two sets of PCR primers specific to W. sebi that can be applied in either conventional PCR or real-time PCR for rapid detection and quantification of the fungus in environmental samples. Both PCR systems proved to be highly specific and sensitive for W. sebi detection even in a high background of other fungal DNAs. These methods were employed to investigate the presence of W. sebi in the aerosols of a farm. The results revealed a high concentration of W. sebi spores, 10(7) m(-3) by real-time PCR and 10(6) m(-3) by cultivation, which indicates the prevalence of W. sebi in farms handling hay and grain and in cow barns. The methods developed in this study could serve as rapid, specific, and sensitive means of detecting W. sebi in aerosol and surface samples and could thus facilitate investigations of its distribution, ecology, clinical diagnosis, and exposure risk assessment.

  • 971.
    Zetterström, Caroline E.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Uusitalo, Pia
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Hinch, Shannon
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Screening for Inhibitors of Acetaldehyde Dehydrogenase (AdhE) from Enterohemorrhagic Escherichia coli (EHEC)2018In: SLAS Discovery, ISSN 2472-5552, Vol. 23, no 8, p. 815-822Article in journal (Refereed)
    Abstract [en]

    Acetaldehyde dehydrogenase (AdhE) is a bifunctional acetaldehyde-coenzyme A (CoA) dehydrogenase and alcohol dehydrogenase involved in anaerobic metabolism in gram-negative bacteria. This enzyme was recently found to be a key regulator of the type three secretion (T3S) system in Escherichia coli. AdhE inhibitors can be used as tools to study bacterial virulence and a starting point for discovery of novel antibacterial agents. We developed a robust enzymatic assay, based on the acetaldehyde-CoA dehydrogenase activity of AdhE using both absorption and fluorescence detection models (Z' > 0.7). This assay was used to screen similar to 11,000 small molecules in 384-well format that resulted in three hits that were confirmed by resynthesis and validation. All three compounds are noncompetitive with respect to acetaldehyde and display a clear dose-response effect with hill slopes of 1-2. These new inhibitors will be used as chemical tools to study the interplay between metabolism and virulence and the role of AdhE in T3S regulation in gram-negative bacteria, and as starting points for the development of novel antibacterial agents.

  • 972.
    Zhang, Bo
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Sztojka, Bernadette
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Escamez, Sacha
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Vanholme, Ruben
    Hedenström, Mattias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wang, Yin
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Gorzsás, András
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Boerjan, Wout
    Tuominen, Hannele
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    PIRIN2 suppresses S-type lignin accumulation in a noncell-autonomous manner in Arabidopsis xylem elements2019In: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137Article in journal (Refereed)
    Abstract [en]
    • PIRIN (PRN) genes encode cupin domain‐containing proteins that function as transcriptional co‐regulators in humans but that are poorly described in plants. A previous study in xylogenic cell cultures of Zinnia elegans suggested a role for a PRN protein in lignification. This study aimed to identify the function of Arabidopsis (Arabidopsis thaliana) PRN proteins in lignification of xylem tissues.
    • Chemical composition of the secondary cell walls was analysed in Arabidopsis stems and/or hypocotyls by pyrolysis–gas chromatography/mass spectrometry, 2D‐nuclear magnetic resonance and phenolic profiling. Secondary cell walls of individual xylem elements were chemotyped by Fourier transform infrared and Raman microspectroscopy.
    • Arabidopsis PRN2 suppressed accumulation of S‐type lignin in Arabidopsis stems and hypocotyls. PRN2 promoter activity and PRN2:GFP fusion protein were localised specifically in cells next to the vessel elements, suggesting a role for PRN2 in noncell‐autonomous lignification of xylem vessels. Accordingly, PRN2 modulated lignin chemistry in the secondary cell walls of the neighbouring vessel elements.
    • These results indicate that PRN2 suppresses S‐type lignin accumulation in the neighbourhood of xylem vessels to bestow G‐type enriched lignin composition on the secondary cell walls of the vessel elements. Gene expression analyses suggested that PRN2 function is mediated by regulation of the expression of the lignin‐biosynthetic genes.
  • 973.
    Zhang, Bo
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Tremousaygue, Dominique
    Denancé, Nicolas
    van Esse, H. Peter
    Hörger, Anja C.
    Dabos, Patrick
    Goffner, Deborah
    Thomma, Bart P. H. J.
    van der Hoorn, Renier A. L.
    Tuominen, Hannele
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    PIRIN2 stabilizes cysteine protease XCP2 and increases susceptibility to the vascular pathogen Ralstonia solanacearum in Arabidopsis2014In: The Plant Journal, ISSN 0960-7412, E-ISSN 1365-313X, Vol. 79, no 6, p. 1009-1019Article in journal (Refereed)
    Abstract [en]

    PIRIN (PRN) is a member of the functionally diverse cupin protein superfamily. There are four members of the Arabidopsis thaliana PRN family, but the roles of these proteins are largely unknown. Here we describe a function of the Arabidopsis PIRIN2 (PRN2) that is related to susceptibility to the bacterial plant pathogen Ralstonia solanacearum. Two prn2 mutant alleles displayed decreased disease development and bacterial growth in response to R. solanacearum infection. We elucidated the underlying molecular mechanism by analyzing PRN2 interactions with the papain-like cysteine proteases (PLCPs) XCP2, RD21A, and RD21B, all of which bound to PRN2 in yeast two-hybrid assays and in Arabidopsis protoplast co-immunoprecipitation assays. We show that XCP2 is stabilized by PRN2 through inhibition of its autolysis on the basis of PLCP activity profiling assays and enzymatic assays with recombinant protein. The stabilization of XCP2 by PRN2 was also confirmed in planta. Like prn2 mutants, an xcp2 single knockout mutant and xcp2 prn2 double knockout mutant displayed decreased susceptibility to R.solanacearum, suggesting that stabilization of XCP2 by PRN2 underlies susceptibility to R.solanacearum in Arabidopsis.

  • 974.
    Zhang, Jin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Iakovleva, Irina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindberg, Mikael J.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Andersson, Patrik L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sauer-Eriksson, A. Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Interspecies variation between fish and human transthyretins in their binding of thyroid-disrupting chemicals2018In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 52, no 20, p. 11865-11874Article in journal (Refereed)
    Abstract [en]

    Thyroid-disrupting chemicals (TDCs) are xenobiotics that can interfere with the endocrine system and cause adverse effects in organisms and their offspring. TDCs affect both the thyroid gland and regulatory enzymes associated with thyroid hormone homeostasis. Transthyretin (TTR) is found in the serum and cerebrospinal fluid of vertebrates, where it transports thyroid hormones. Here, we explored the interspecies variation in TDC binding to human and fish TTR (exemplified by Gilthead seabream (Sparus aurata)). The in vitro binding experiments showed that TDCs bind with equal or weaker affinity to seabream TTR than to the human TTR, in particular, the polar TDCs (>500-fold lower affinity). Crystal structures of the seabream TTR TDC complexes revealed that all TDCs bound at the thyroid binding sites. However, amino acid substitution of Ser117 in human TTR to Thr117 in seabream prevented polar TDCs from binding deep in the hormone binding cavity, which explains their low affinity to seabream TTR Molecular dynamics and in silico alanine scanning simulation also suggested that the protein backbone of seabream TTR is more rigid than the human one and that Thr117 provides fewer electrostatic contributions than Ser117 to ligand binding. This provides an explanation for the weaker affinities of the ligands that rely on electrostatic interactions with Thr117. The lower affinities of TDCs to fish TTR, in particular the polar ones, could potentially lead to milder thyroid-related effects in fish.

  • 975. Zhang, Peng
    et al.
    Chen, Lin
    Zhang, Qingsong
    Jönsson, Leif J.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hong, Feng F.
    Using in situ nanocellulose-coating technology based on dynamic bacterial cultures for upgrading conventional biomedical materials and reinforcing nanocellulose hydrogels2016In: Biotechnology progress (Print), ISSN 8756-7938, E-ISSN 1520-6033, Vol. 32, no 4, p. 1077-1084Article in journal (Refereed)
    Abstract [en]

    Bacterial nanocellulose (BNC) is a microbial nanofibrillar hydrogel with many potential applications. Its use is largely restricted by insufficient strength when in a highly swollen state and by inefficient production using static cultivation. In this study, an in situ nanocellulose-coating technology created a fabric-frame reinforced nanocomposite of BNC hydrogel with superior strength but retained BNC native attributes. By using the proposed technology, production time could be reduced from 10 to 3 days to obtain a desirable hydrogel sheet with approximately the same thickness. This novel technology is easier to scale up and is more suitable for industrial-scale manufacture. The mechanical properties (tensile strength, suture retention strength) and gel characteristics (water holding, absorption and wicking ability) of the fabric-reinforced BNC hydrogel were investigated and compared with those of ordinary BNC hydrogel sheets. The results reveal that the fabric-reinforced BNC hydrogel was equivalent with regard to gel characteristics, and exhibited a qualitative improvement with regard to its mechanical properties. For more advanced applications, coating technology via dynamic bacterial cultures could be used to upgrade conventional biomedical fabrics, i.e. medical cotton gauze or other mesh materials, with nanocellulose.

  • 976. Zhang, Qi
    et al.
    Wang, Guangji
    Du, Yu
    Zhu, Lingling
    Jiye, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    GC/MS analysis of the rat urine for metabonomic research2007In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 854, no 1-2, p. 20-25Article in journal (Refereed)
    Abstract [en]

    In this paper, an optimized protocol was established and validated for the metabonomic profiling in rat urine using GC/MS. The urine samples were extracted by methanol after treatment with urease to remove excessive urea, then the resulted supernatant was dried, methoximated, trimethylsilylated, and analyzed by GC/MS. Forty-nine endogenous metabolites were separated and identified in GC/MS chromatogram, of which 26 identified compounds were selected for quantitative analysis to evaluate the linearity, precision, and sensitivity of the method. It showed good linearity between mass spectrometry responses and relative concentrations of the 26 endogenous compounds over the range from 0.063 to 1.000(v/v, urine/urine+ water) and satisfactory reproducibility with intra-day and inter-days precision values all below 15%. The metabonomic profiling method based on GC/MS was successfully applied to urine samples from hyperlipidemia model rats. Obviously, separated clustering of model rats and the control rats were shown by principal components analysis (PCA); time-dependent metabonomic modification was detected as well. It was suggested that metabonomic profiling based on GC/MS be a robust method for urine samples.

  • 977. Zhang, Shuo
    et al.
    Winestrand, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Guo, Xiang
    Chen, Lin
    Hong, Feng
    Jönsson, Leif
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Effects of aromatic compounds on the production of bacterial nanocellulose by Gluconacetobacter xylinus2014In: Microbial Cell Factories, ISSN 1475-2859, E-ISSN 1475-2859, Vol. 13, p. 62-Article in journal (Refereed)
    Abstract [en]

    Background:

    Bacterial cellulose (BC) is a polymeric nanostructured fibrillar network produced by certain microorganisms, principally Gluconacetobacter xylinus. BC has a great potential of application in many fields. Lignocellulosic biomass has been investigated as a cost-effective feedstock for BC production through pretreatment and hydrolysis. It is well known that detoxification of lignocellulosic hydrolysates may be required to achieve efficient production of BC. Recent results suggest that phenolic compounds contribute to the inhibition of G. xylinus. However, very little is known about the effect on G. xylinus of specific lignocellulose-derived inhibitors. In this study, the inhibitory effects of four phenolic model compounds (coniferyl aldehyde, ferulic acid, vanillin and 4-hydroxybenzoic acid) on the growth of G. xylinus, the pH of the culture medium, and the production of BC were investigated in detail. The stability of the phenolics in the bacterial cultures was investigated and the main bioconversion products were identified and quantified.

    Results:

    Coniferyl aldehyde was the most potent inhibitor, followed by vanillin, ferulic acid, and 4-hydroxybenzoic acid. There was no BC produced even with coniferyl aldehyde concentrations as low as 2 mM. Vanillin displayed a negative effect on the bacteria and when the vanillin concentration was raised to 2.5 mM the volumetric yield of BC decreased to similar to 40% of that obtained in control medium without inhibitors. The phenolic acids, ferulic acid and 4-hydroxybenzoic acid, showed almost no toxic effects when less than 2.5 mM. The bacterial cultures oxidized coniferyl aldehyde to ferulic acid with a yield of up to 81%. Vanillin was reduced to vanillyl alcohol with a yield of up to 80%.

    Conclusions:

    This is the first investigation of the effect of specific phenolics on the production of BC by G. xylinus, and is also the first demonstration of the ability of G. xylinus to convert phenolic compounds. This study gives a better understanding of how phenolic compounds and G. xylinus cultures are affected by each other. Investigations in this area are useful for elucidating the mechanism behind inhibition of G. xylinus in lignocellulosic hydrolysates and for understanding how production of BC using lignocellulosic feedstocks can be performed in an efficient way.

  • 978. Zhang, Sicai
    et al.
    Berntsson, Ronnie P. A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden.
    Tepp, William H.
    Tao, Liang
    Johnson, Eric A.
    Stenmark, Pal
    Dong, Min
    Structural basis for the unique ganglioside and cell membrane recognition mechanism of botulinum neurotoxin DC2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 1637Article in journal (Refereed)
    Abstract [en]

    Botulinum neurotoxins (BoNTs), the most potent toxins known, are potential bioterrorism agents. It is well established that all seven serotypes of BoNTs (BoNT/A-G) require complex gangliosides as co-receptors. Here, we report that BoNT/DC, a presumed mosaic toxin between BoNT/D and BoNT/C1, binds and enters efficiently into neurons lacking complex gangliosides and shows no reduction in toxicity in mice deficient in complex gangliosides. The co-crystal structure of BoNT/DC with sialyl-Thomsen-Friedenreich antigen (Sialyl-T) suggests that BoNT/DC recognizes only the sialic acid, but not other moieties in gangliosides. Using liposome flotation assays, we demonstrate that an extended loop in BoNT/DC directly interacts with lipid membranes, and the co-occurring sialic acid binding and loop-membrane interactions mediate the recognition of gangliosides in membranes by BoNT/DC. These findings reveal a unique mechanism for cell membrane recognition and demonstrate that BoNT/DC can use a broad range of sialic acid-containing moieties as co-receptors.

  • 979.
    Zhang, Zhen
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Aung, Kyaw Min
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Reversible senescence of human colon cancer cells after blockage of mitosis/cytokinesis caused by the CNF1 cyclomodulin from Escherichia coli2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 17780Article in journal (Refereed)
    Abstract [en]

    Cytotoxic necrotizing factor 1 (CNF1), a protein toxin produced by extraintestinal pathogenic Escherichia coli, activates the Rho-family small GTPases in eukaryotic cell, thereby perturbing multiple cellular functions. Increasing epidemiological evidence suggests a link between CNF1 and human inflammatory bowel disease and colorectal cancer. At the cellular level, CNF1 has been hypothesized to reprogram cell fate towards survival due to the role in perturbing cell cycle and apoptosis. However, it remains undetermined how cells survive from CNF1 intoxication. In this work, we show that CNF1 treatment blocks mitosis/cytokinesis, elicits endoreplication and polyploidisation in cultured human colon cancer cells, and drives them into reversible senescence, which provides a survival route for cells via depolyploidisation. Senescence in CNF1-treated cells is demonstrated with upregulation of several senescence markers including senescence-associated β-galactosidase activity, p53, p21 and p16, and concomitant inhibition of the retinoblastoma protein phosphorylation. Importantly, progeny derived from CNF1 treatment exhibit genomic instability exemplified by increased aneuploidy and become more resistant to CNF1, but not to 5-fluorouracil and oxaliplatin, the two agents commonly used in chemotherapeutic treatment for colorectal cancer. These observations display survival features of the cell after CNF1 treatment that may have implications for the potential role of CNF1 in carcinogenesis.

  • 980. Zhao, Chengsong
    et al.
    Lasses, Theres
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Bako, Laszlo
    Kong, Danyu
    Zhao, Bingyu
    Chanda, Bidisha
    Bombarely, Aureliano
    Cruz-Ramírez, Alfredo
    Scheres, Ben
    Brunner, Amy M.
    Beers, Eric P.
    XYLEM NAC DOMAIN1, an angiosperm NAC transcription factor, inhibits xylem differentiation through conserved motifs that interact with RETINOBLASTOMA-RELATED2017In: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137, Vol. 216, no 1, p. 76-89Article in journal (Refereed)
    Abstract [en]

    The Arabidopsis thaliana gene XYLEM NAC DOMAIN1 (XND1) is upregulated in xylem tracheary elements. Yet overexpression of XND1 blocks differentiation of tracheary elements. The molecular mechanism of XND1 action was investigated. Phylogenetic and motif analyses indicated that XND1 and its homologs are present only in angiosperms and possess a highly conserved C-terminal region containing linear motifs (CKII-acidic, LXCXE, E2F(TD)-like and LXCXE-mimic) predicted to interact with the cell cycle and differentiation regulator RETINOBLASTOMA-RELATED (RBR). Protein-protein interaction and functional analyses of XND1 deletion mutants were used to test the importance of RBR-interaction motifs. Deletion of either the LXCXE or the LXCXE-mimic motif reduced both the XND1-RBR interaction and XND1 efficacy as a repressor of differentiation, with loss of the LXCXE motif having the strongest negative impacts. The function of the XND1 C-terminal domain could be partially replaced by RBR fused to the N-terminal domain of XND1. XND1 also transactivated gene expression in yeast and plants. The properties of XND1, a transactivator that depends on multiple linear RBR-interaction motifs to inhibit differentiation, have not previously been described for a plant protein. XND1 harbors an apparently angiosperm-specific combination of interaction motifs potentially linking the general differentiation regulator RBR with a xylem-specific pathway for inhibition of differentiation.

  • 981.
    Zhao, Guang-Hui
    et al.
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China.
    Yang, Lei
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China; School of Nursing, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China; School of Nursing, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China.
    Guo, Xiong
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China.
    A preliminary analysis of microRNA profiles in the subchondral bone between Kashin-Beck disease and primary knee osteoarthritis2019In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 38, no 9, p. 2637-2645, article id 31062252Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Kashin-Beck disease (KBD) is a chronic osteochondral disorder primarily associated with cartilage degeneration. The bone texture structure in KBD was also changed but it was not identical to primary knee osteoarthritis (OA). This study investigates the differences in microRNA (miRNA) profiles of subchondral bone collected from patients suffering from KBD in comparison with those with primary knee osteoarthritis (OA).

    METHODS: Subchondral bone tissues were taken from four patients with KBD and four patients with primary knee OA undergoing total knee replacement. The miRNA array profiling was performed using an Affymetrix miRNA 4.0 Array, and then the target gene predictions and function annotations of the predicted targets were performed.

    RESULTS: Our results showed that 124 miRNAs had lower expression levels in the subchondral bone sampled from KBD patients in comparison with OA patients. Gene ontology (GO) and KEGG pathway analyses of the predicted targets demonstrated numerous significantly enriched GO terms and signal pathways essential for bone development and integrity, such as metabolic processes, PI3K-Akt, and MAPK signaling pathways.

    CONCLUSIONS: Our study confirms that a large set of miRNAs are differentially expressed in the subchondral bone of patients with KBD and OA and contributes new insights into potential pathological changes in the subchondral bone of KBD patients.

  • 982.
    Zhou, Xiangzhi
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Westlund, Per-Olof
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    1H NMRD profiles and ESR lineshapes of Gd(III) complexes: a comparison between the generalized SBM and the stochastic Liouville approach2005In: Journal of magnetic resonance, ISSN 1090-7807, E-ISSN 1096-0856, Vol. 173, no 1, p. 75-83Article in journal (Refereed)
    Abstract [en]

    A complete description of the T1-NMRD profiles and the ESR lineshape of Gd(III) complexes (S = 7/2) was presented using second-order perturbation theory (GSBM) by Zhou et al. [J. Magn. Reson. 167 (2004) 147]. This report compares the GSBM with the stochastic Liouville approach (SLA) to determine the validity of the closed analytical expressions of NMRD and the ESR lineshape functions. Both approaches give the same results at high fields while a very small divergence is observed for X- and W-band ESR lineshapes when the magnitude of the perturbation term times the correlation time approaches the limit of the perturbation regime, ΔZFSτf ≈ 0.1. There was a clear discrepancy between the theoretical GSBM X-band spectrum and the recorded ESR spectrum of the Gd(III) MS-325 + HSA complex. This is probably due to a slow-motion effect caused by a slow modulation of the ZFS interaction. The characteristic correlation time of this slow modulation is in the range of 150 ps, which therefore cannot be due to the reorientational motion of the whole MS-325 + HSA complex.

  • 983.
    Zhou, Yang
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Regulation of pre-mRNA splicing and mRNA degradation in Saccharomyces cerevisiae2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Messenger RNAs are transcribed and co-transcriptionally processed in the nucleus, and transported to the cytoplasm. In the cytoplasm, mRNAs serve as the template for protein synthesis and are eventually degraded. The removal of intron sequences from a precursor mRNA is termed splicing and is carried out by the dynamic spliceosome. In this thesis, I describe the regulated splicing of two transcripts in Saccharomyces cerevisiae. I also describe a study where the mechanisms that control the expression of magnesium transporters are elucidated.

    The pre-mRNA retention and splicing (RES) complex is a spliceosome-associated protein complex that promotes the splicing and nuclear retention of a subset of pre-mRNAs. The RES complex consists of three subunits, Bud13p, Snu17p and Pml1p. We show that the lack of RES factors causes a decrease in the formation of N4-acetylcytidine (ac4C) in tRNAs. This phenotype is caused by inefficient splicing of the pre-mRNA of the TAN1 gene, which is required for the formation of ac4C in tRNAs. The RES mutants also show growth defects that are exacerbated at elevated temperatures. We show that the temperature sensitive phenotype of the bud13Δ and snu17Δ cells is caused by the inefficient splicing of the MED20 pre-mRNA. The MED20 gene encodes a subunit of the Mediator complex. Unspliced pre-mRNAs that enter the cytoplasm are usually degraded by the nonsense-mediated mRNA decay (NMD) pathway, which targets transcripts that contain premature translation termination codons. Consistent with the nuclear retention function of the RES complex, we find that NMD inactivation in the RES mutants leads to the accumulation of both TAN1 and MED20 pre-mRNAs. We also show that the cis-acting elements that promote RES-dependent splicing are different between the TAN1 and MED20 pre-mRNAs.

    The NMD pathway also targets transcripts with upstream ORFs (uORFs) for degradation. The ALR1 gene encodes the major magnesium importer in yeast, and its expression is controlled by the NMD pathway via a uORF in the 5’ untranslated region. We show that the ribosome reaches the downstream main ORF by a translation reinitiation mechanism. The NMD pathway was shown to control cellular Mg2+ levels by regulating the expression of the ALR1 gene. We further show that the NMD pathway targets the transcripts of the vacuolar Mg2+ exporter Mnr2p and the mitochondrial Mg2+ exporter Mme1p for degradation.

    In summary, we conclude that the RES complex has a role in the splicing regulation of a subset of transcripts. We also suggest a regulatory role for the NMD pathway in maintaining the cellular Mg2+ concentration by controlling the expression of Mg2+ transporters.

  • 984.
    Zhou, Yang
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Marcus
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The nonsense-mediated mRNA decay pathway controls the expression of magnesium transporters in Saccharomyces cerevisiaeManuscript (preprint) (Other academic)
  • 985.
    Zhou, Yang
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Marcus J O
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). BRF Krutet, Norra Majorsgatan, Umea, Sweden; University of Tartu, Institute ofTechnology, Nooruse, Tartu, Estonia.
    The pre-mRNA retention and splicing complex controls expression of the Mediator subunit Med202017In: RNA Biology, ISSN 1547-6286, E-ISSN 1555-8584, Vol. 14, no 10, p. 1411-1417Article in journal (Refereed)
    Abstract [en]

    The heterotrimeric pre-mRNA retention and splicing (RES) complex, consisting of Bud13p, Snu17p and Pml1p, promotes splicing and nuclear retention of a subset of intron-containing pre-mRNAs. Yeast cells deleted for individual RES genes show growth defects that are exacerbated at elevated temperatures. Although the growth phenotypes correlate to the splicing defects in the individual mutants, the underlying mechanism is unknown. Here, we show that the temperature sensitive (Ts) growth phenotype of bud13Δ and snu17Δ cells is a consequence of inefficient splicing of MED20 pre-mRNA, which codes for a subunit of the Mediator complex; a co-regulator of RNA polymerase II transcription. The MED20 pre-mRNA splicing defect is less pronounced in pml1Δ cells, explaining why they grow better than the other 2 RES mutants at elevated temperatures. Inactivation of the cytoplasmic nonsense-mediated mRNA decay (NMD) pathway in the RES mutants leads to accumulation of MED20 pre-mRNA, indicating that inefficient nuclear retention contributes to the growth defect. Further, the Ts phenotype of bud13Δ and snu17Δ cells is partially suppressed by the inactivation of NMD, showing that the growth defects are augmented by the presence of a functional NMD pathway. Collectively, our results demonstrate an important role of the RES complex in maintaining the Med20p levels.

  • 986. Zhou, Yizhou
    et al.
    Smith, Daniel
    Leong, Bryan J
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Chapman, Matthew R
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Promiscuous cross-seeding between bacterial amyloids promotes interspecies biofilms2012In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 42, p. 35092-35103Article in journal (Refereed)
    Abstract [en]

    Amyloids are highly aggregated proteinaceous fibers historically associated with neurodegenerative conditions including Alzheimer's, Parkinson's and prion-based encephalopathies. Polymerization of amyloidogenic proteins into ordered fibers can be accelerated by preformed amyloid aggregates derived from the same protein in a process called seeding. Seeding of disease-associated amyloids and prions is highly specific and cross-seeding is usually limited or prevented. Here we describe the first study on the cross-seeding potential of bacterial functional amyloids. Curli are produced on the surface of many Gram-negative bacteria where they facilitate surface attachment and biofilm development. Curli fibers are composed of the major subunit CsgA and the nucleator CsgB, which templates CsgA into fibers. Our results showed that curli subunit homologs from Escherichia coli, Salmonella typhimurium LT2 and Citrobacter koseri were able to cross-seed in vitro. The polymerization of E. coli CsgA was also accelerated by fibers derived from a distant homolog in Shewanella oneidensis that shares less than 30% identity in primary sequence. Cross-seeding of curli proteins was also observed in mixed colony biofilms with E. coli and S. typhimurium. CsgA secreted from E. coli csgB- mutants assembled into fibers on adjacent S. typhimurium that presented CsgB on its surfaces. Similarly, CsgA secreted by S. typhimurium csgB- mutants formed curli on CsgB-presenting E. coli. This interspecies curli assembly enhanced bacterial attachment to agar surfaces and supported pellicle biofilm formation. Collectively, this work suggests that the seeding specificity among curli homologs is relaxed and that heterogeneous curli fibers can facilitate multispecies biofilm development.

  • 987.
    Zou, Xiaozhou
    et al.
    State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Donghua University, Shanghai, China; China-Sweden Associated Research Laboratory in Industrial Biotechnology, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, China; Group of Microbiological Engineering and Industrial Biotechnology, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, China.
    Wu, Guochao
    Umeå University, Faculty of Science and Technology, Department of Chemistry. China-Sweden Associated Research Laboratory in Industrial Biotechnology, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, China.
    Stagge, Stefan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. China-Sweden Associated Research Laboratory in Industrial Biotechnology, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, China.
    Chen, Lin
    Jönsson, Leif J.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. China-Sweden Associated Research Laboratory in Industrial Biotechnology, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, China.
    Hong, Feng F.
    Comparison of tolerance of four bacterial nanocellulose-producing strains to lignocellulose-derived inhibitors2017In: Microbial Cell Factories, ISSN 1475-2859, E-ISSN 1475-2859, Vol. 16, article id 229Article in journal (Refereed)
    Abstract [en]

    Background: Through pretreatment and enzymatic saccharification lignocellulosic biomass has great potential as a low-cost feedstock for production of bacterial nanocellulose (BNC), a high value-added microbial product, but inhibitors formed during pretreatment remain challenging. In this study, the tolerance to lignocellulose-derived inhibitors of three new BNC-producing strains were compared to that of Komagataeibacter xylinus ATCC 23770. Inhibitors studied included furan aldehydes (furfural and 5-hydroxymethylfurfural) and phenolic compounds (coniferyl aldehyde and vanillin). The performance of the four strains in the presence and absence of the inhibitors was assessed using static cultures, and their capability to convert inhibitors by oxidation and reduction was analyzed.

    Results: Although two of the new strains were more sensitive than ATCC 23770 to furan aldehydes, one of the new strains showed superior resistance to both furan aldehydes and phenols, and also displayed high volumetric BNC yield (up to 14.78 ± 0.43 g/L) and high BNC yield on consumed sugar (0.59 ± 0.02 g/g). The inhibitors were oxidized and/or reduced by the strains to be less toxic. The four strains exhibited strong similarities with regard to predominant bioconversion products from the inhibitors, but displayed different capacity to convert the inhibitors, which may be related to the differences in inhibitor tolerance.

    Conclusions: This investigation provides information on different performance of four BNC-producing strains in the presence of lignocellulose-derived inhibitors. The results will be of benefit to the selection of more suitable strains for utilization of lignocellulosics in the process of BNC-production.

  • 988. Zou, Zhen
    et al.
    Evans, Jay
    Lu, Zhiqiang
    Zhao, Picheng
    Williams, Michael
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Sumathipala, Niranji
    Hetru, Charles
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Jiang, Haobo
    Comparative genomic analysis of the Tribolium immune system.2007In: Genome Biol, ISSN 1465-6914, Vol. 8, no 8, p. R177.1-16Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Tribolium castaneum is a species of Coleoptera, the largest and most diverse order of all eukaryotes. Components of the innate immune system are hardly known in this insect, which is in a key phylogenetic position to inform us about genetic innovations accompanying the evolution of holometabolous insects. We have annotated immunity-related genes and compared them with homologous molecules from other species. RESULTS: Around 300 candidate defense proteins are identified based on sequence similarity to homologs known to participate in immune responses. In most cases, paralog counts are lower than those of Drosophila melanogaster or Anopheles gambiae but are substantially higher than Apis mellifera. The genome contains probable orthologs for nearly all members of the Toll, IMD, and JAK/STAT pathways. While total numbers of the clip-domain serine proteinases are approximately equal in the fly (29), mosquito (32) and beetle (30), lineage-specific expansion of the family is discovered in all three species. Sixteen of the thirty-one serpin genes form a large cluster in a 50 kb region resulted from extensive gene duplications. Among the nine Toll-like proteins, four are orthologous to Drosophila Toll. The presence of scavenger receptors and other related proteins indicates a role of cellular responses in the entire system. The structures of some antimicrobial peptides drastically differ from those in other orders of insects. CONCLUSIONS: A framework of information on Tribolium immunity is established, which may serve as a stepping stone for future genetic analyses of defense responses in a nondrosophiline genetic model insect.

  • 989.
    Ådén, Jörgen
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Folding of an unfolded protein by macromolecular crowding in vitro2014In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 53, no 14, p. 2271-2277Article in journal (Refereed)
    Abstract [en]

    Protein folding in vivo takes place in a highly crowded environment. The resulting excluded volume forces are thought to stabilize folded forms of proteins. In agreement, many in vitro studies have shown that the presence of macromolecular crowding agents increases the stability of folded proteins but often by only a few kJ per mol. Although it should not matter at what position in the transition between folded and unfolded forms the effect of crowding is employed, there have been no studies assessing whether excluded volume forces alone can correctly fold polypeptides that are mostly unfolded. However, some studies have indicated that the effect of crowding becomes larger the more destabilized the protein is (but still being folded), suggesting that the crowding effect may be exaggerated for unfolded proteins. To address this question directly, we turned to a destabilized mutant of protein L that is mostly unfolded in water but can be folded upon addition of salt. We find that the effect of 200 mg/mL Dextran 20 on the folding equilibrium constant for unfolded protein L (ΔΔGU ≈ 2 kJ mol(-1)) matches the crowding effects found on the folded wild type protein and the mutant when prefolded by salt. This result indicates that the excluded volume effect is independent of starting protein stability and that crowding can shift the reaction toward the folded form when the polypeptide is in the transition region between folded and unfolded states.

  • 990.
    Åström, Stefan U
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Byström, Anders S
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rit1, a tRNA backbone-modifying enzyme that mediates initiator and elongator tRNA discrimination1994In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 79, no 3, p. 535-546Article in journal (Refereed)
    Abstract [en]

    Using a genetic screen in yeast aimed at identifying cellular factors involved in initiator and elongator methionine tRNA discrimination in the translational process, we have identified a mutation that abolish the requirement for elongator methionine tRNA. The gene affected, which we call the ribosylation of the initiator tRNA gene or RIT1, encodes a 2'-O-ribosyl phosphate transferase. This enzyme modifies exclusively the initiator tRNA in position 64 using 5'-phosphoribosyl-1'-pyrophosphate as the modification donor. As the initiator tRNA participates both in the initiation and elongation of translation in a rit1 strain, we conclude that the 2'-O-ribosyl phosphate modification discriminates the initiator tRNAs from the elongator tRNAs during protein synthesis. The modification enzyme was shown to recognize the stem-loop IV region that is unique in eukaryotic cytoplasmic initiator tRNAs.

  • 991. Ögren, Erling
    et al.
    Öquist, Gunnar
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Photoinhibition of photosynthesis in Lemna gibba as induced by the interaction between light and temperature. II. Photosynthetic electron transport1984In: Physiologia Plantarum: An International Journal for Plant Biology, ISSN 0031-9317, E-ISSN 1399-3054, Vol. 62, no 2, p. 187-192Article in journal (Refereed)
    Abstract [en]

    Photoinhibition of photosynthesis in Lemna gibba L. was induced by exposing intact plants to a high photosynthetic photon flux density of 1 750 μmol m−2 s−1 at a low temperature of 3°C. Subsequently isolated chloroplasts showed pronounced reductions in the capacity of whole chain electron transport, measured as Hill activity, and in the efficiency of electron transport to the primary electron acceptor Q of photosystem II, measured as variable chlorophyll fluorescence at 20°C. These changes proceeded with similar kinetics (probably of the first-order reaction), suggesting that the site of photoinhibition is in the electron transfer to Q. A partial uncoupling of the whole chain electron transport also occured. The capacity of electron transport mediated by photosystem I was unaffected. The extent of photoinhibition of photosynthetic electron transport, as produced by a 2 h exposure of L. gibba to three different combinations of photon flux density and temperature was studied. It was shown that intrinsically similar states of photoinhibition, on the evidence of their time courses of recovery, were induced by either a high photon flux density and 25°C or by a moderate photon flux density and 3°C.

  • 992. Ögren, Erling
    et al.
    Öquist, Gunnar
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Photoinhibition of photosynthesis in lemna-gibba as induced by the interaction between light and temperature .3. Chlorophyll fluorescence at 77-K1984In: Physiologia Plantarum: An International Journal for Plant Biology, ISSN 0031-9317, E-ISSN 1399-3054, Vol. 62, no 2, p. 193-200Article in journal (Refereed)
    Abstract [en]

    Photoinhibition in Lemna gibba L. was studied by interpreting chlorophyll fluorescence characteristics at 77 K on the basis of the bipartite model of Butler and co-workers (Butler 1978). Application of this analysis to chloroplasts (isolated from plants before and after exposure to a photosynthetic photon flux density of 1 750 μmol m−2 s−1 at 3°C for 2 h) revealed that photoinhibition had the following effect on primary events in photosynthesis. Firstly, the fluorescence of PS II increased (44%) in the state of open traps (Fo) and decreased (32%) in the state of closed traps (Fm). It is suggested, that the Fo-decrease reflects increased quenching by radiationless decay, both effects occurring at PS II reaction centers. Secondly, the rate constant for transfer of excitation energy from PS II to PS I (kT(μ→J)) increased by 34%. However, in the state of closed traps, the flux of excitation energy via this transfer process decreased, most likely because of increased quenching by radiationless decay at PS II reaction centers. Thirdly, the probability for fluorescence from PS I decreased (19%). This indicates increased quenching by radiationless decay.

  • 993.
    Önskog, Jenny
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Freyhult, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Landfors, Mattias
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Hvidsten, Torgeir R
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Classification of microarrays: synergistic effects between normalization, gene selection and machine learning2011In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 12, no 1, article id 390Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Machine learning is a powerful approach for describing and predicting classes in microarray data. Although several comparative studies have investigated the relative performance of various machine learning methods, these often do not account for the fact that performance (e.g. error rate) is a result of a series of analysis steps of which the most important are data normalization, gene selection and machine learning.

    RESULTS: In this study, we used seven previously published cancer-related microarray data sets to compare the effects on classification performance of five normalization methods, three gene selection methods with 21 different numbers of selected genes and eight machine learning methods. Performance in term of error rate was rigorously estimated by repeatedly employing a double cross validation approach. Since performance varies greatly between data sets, we devised an analysis method that first compares methods within individual data sets and then visualizes the comparisons across data sets. We discovered both well performing individual methods and synergies between different methods.

    CONCLUSION: Support Vector Machines with a radial basis kernel, linear kernel or polynomial kernel of degree 2 all performed consistently well across data sets. We show that there is a synergistic relationship between these methods and gene selection based on the T-test and the selection of a relatively high number of genes. Also, we find that these methods benefit significantly from using normalized data, although it is hard to draw general conclusions about the relative performance of different normalization procedures.

  • 994.
    Öquist, Gunnar
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Effects of low temperature on photosynthesis1983In: Plant, Cell and Environment, ISSN 0140-7791, E-ISSN 1365-3040, Vol. 6, no 4, p. 281-300Article, review/survey (Refereed)
  • 995.
    Österberg, Sofia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    del Peso-Santos, Teresa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Shingler, Victoria
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Regulation of alternative sigma factor use2011In: Annual Review of Microbiology, ISSN 0066-4227, E-ISSN 1545-3251, Vol. 65, p. 37-55Article in journal (Refereed)
    Abstract [en]

    Alternative bacterial sigma factors bind the catalytic core RNA polymerase to confer promoter selectivity on the holoenzyme. The different holoenzymes are thus programmed to recognize the distinct promoter classes in the genome to allow coordinated activation of discrete sets of genes needed for adaptive responses. To form the holoenzymes, the different sigma factors must be available to compete for their common substrate (core RNA polymerase). This review highlights (a) the roles of antisigma factors in controlling the availability of alternative sigma factors and (b) the involvement of diverse regulatory molecules that promote the use of alternative sigma factors through subversion of the domineering housekeeping σ(70). The latter include the nucleotide alarmone ppGpp and small proteins (DksA, Rsd, and Crl), which directly target the transcriptional machinery to mediate their effects.

  • 996.
    Östman, J.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundgren, E.
    Caspase independent cytotoxicity induced by oligomeric TTR- mutants in neuroblastoma cellsManuscript (Other academic)
  • 997.
    Överby Wernstedt, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Weber, Friedemann
    Hiding from intracellular pattern recognition receptors, a passive strategy of flavivirus immune evasion2011Conference paper (Refereed)
17181920 951 - 997 of 997
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