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  • 1.
    Beckman, Marie
    et al.
    Södertörn University, School of Life Sciences, Molecular biology.
    Freeman, Craig
    Parish, Christopher R.
    Small, David H.
    Activation of cathepsin D by glycosaminoglycans2009In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, no 24, 7343-7352 p.Article in journal (Refereed)
    Abstract [en]

    We have previously shown that heparin can increase the activity of the proenzyme form of Alzheimer's beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). Cathepsin D (CD) is a member of the aspartic protease family and has sequence similarity to BACE1. Therefore, we examined whether heparin and other glycosaminoglycans (GAGs) can influence the activity of CD. Heparin and other GAGs were found to stimulate the activity of recombinant proCD. Desulfation of heparin almost abolished the stimulation, indicating that sulfate groups were important for the stimulatory effect. In addition, the stimulation was dependent on the length of the GAG chain, as larger GAGs were more potent in their ability to stimulate proCD than shorter fragments. In the presence of heparin, limited autocatalytic proteolysis of the proenzyme was increased, suggesting that heparin increases the activity of proCD by accelerating the conversion of proCD, which has little activity, to pseudoCD, an active form lacking residues 1-26 of the prodomain. Furthermore, the activity of spleen-derived mature CD, which lacks the entire 44 amino acid residue prodomain, was also increased by heparin, indicating that the catalytic domain of CD contains at least one region to which GAGs bind and stimulate enzyme activity. Because heparin also stimulated the activity of pseudoCD, proenzyme activation was probably accelerated by the interaction of heparin with the catalytic domain of pseudoCD. However, it is possible that heparin may also activate the proenzyme directly. On the basis of this study, we propose that GAGs may regulate CD activity in vivo.

  • 2.
    Bertrand, Yann
    et al.
    Göteborg University.
    Töpel, Mats
    Göteborg University.
    Elväng, Annelie
    Södertörn University, School of Life Sciences, Molecular biology.
    Melik, Wessam
    Södertörn University, School of Life Sciences, Chemistry. Södertörn University, School of Life Sciences, Molecular biology.
    Johansson, Magnus
    Södertörn University, School of Life Sciences, Chemistry. Södertörn University, School of Life Sciences, International health.
    First Dating of a Recombination Event in Mammalian Tick-Borne Flaviviruses2012In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 2, e31981- p.Article in journal (Refereed)
    Abstract [en]

    The mammalian tick-borne flavivirus group (MTBFG) contains viruses associated with important human and animal diseases such as encephalitis and hemorrhagic fever. In contrast to mosquito-borne flaviviruses where recombination events are frequent, the evolutionary dynamic within the MTBFG was believed to be essentially clonal. This assumption was challenged with the recent report of several homologous recombinations within the Tick-borne encephalitis virus (TBEV). We performed a thorough analysis of publicly available genomes in this group and found no compelling evidence for the previously identified recombinations. However, our results show for the first time that demonstrable recombination (i.e., with large statistical support and strong phylogenetic evidences) has occurred in the MTBFG, more specifically within the Louping ill virus lineage. Putative parents, recombinant strains and breakpoints were further tested for statistical significance using phylogenetic methods. We investigated the time of divergence between the recombinant and parental strains in a Bayesian framework. The recombination was estimated to have occurred during a window of 282 to 76 years before the present. By unravelling the temporal setting of the event, we adduce hypotheses about the ecological conditions that could account for the observed recombination.

  • 3. Bratic, Ivana
    et al.
    Hench, Jürgen
    Södertörn University, School of Life Sciences.
    Henriksson, Johan
    Södertörn University, School of Life Sciences, Molecular biology.
    Antebi, Adam
    Bürglin, Thomas R.
    Trifunovic, Aleksandra
    Mitochondrial DNA level, but not active replicase, is essential for Caenorhabditis elegans development2009In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 37, no 6, 1817-1828 p.Article in journal (Refereed)
    Abstract [en]

    A number of studies showed that the development and the lifespan of Caenorhabditis elegans is dependent on mitochondrial function. In this study, we addressed the role of mitochondrial DNA levels and mtDNA maintenance in development of C. elegans by analyzing deletion mutants for mitochondrial polymerase gamma (polg-1(ok1548)). Surprisingly, even though previous studies in other model organisms showed necessity of polymerase gamma for embryonic development, homozygous polg-1(ok1548) mutants had normal development and reached adulthood without any morphological defects. However, polg-1 deficient animals have a seriously compromised gonadal function as a result of severe mitochondrial depletion, leading to sterility and shortened lifespan. Our results indicate that the gonad is the primary site of mtDNA replication, whilst the mtDNA of adult somatic tissues mainly stems from the developing embryo. Furthermore, we show that the mtDNA copy number shows great plasticity as it can be almost tripled as a response to the environmental stimuli. Finally, we show that the mtDNA copy number is an essential limiting factor for the worm development and therefore, a number of mechanisms set to maintain mtDNA levels exist, ensuring a normal development of C. elegans even in the absence of the mitochondrial replicase.

  • 4.
    Broniarczyk, Justyna
    et al.
    Department of Molecular Virology, Adam Mickiewicz University.
    Wigerius, Michael
    Södertörn University, School of Life Sciences, Molecular biology. Södertörn University, School of Life Sciences, Chemistry.
    Johansson, Magnus
    Södertörn University, School of Life Sciences, International health. Södertörn University, School of Life Sciences, Chemistry.
    The NS1 protein of Influenza A virus targets human Scribble in asubtype specific mannerManuscript (preprint) (Other academic)
  • 5.
    Bräutigam, Lars
    et al.
    Södertörn University, School of Life Sciences, Molecular biology.
    Hillmer, Janine M.
    Södertörn University, School of Life Sciences, Molecular biology.
    Söll, Iris
    Södertörn University, School of Life Sciences, Molecular biology.
    Hauptmann, Giselbert
    Södertörn University, School of Life Sciences, Molecular biology.
    Localized Expression of Urocortin Genes in the Developing Zebrafish rain2010In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 518, no 15, 2978-2995 p.Article in journal (Refereed)
    Abstract [en]

    The corticotropin-releasing hormone (CRH) family consists of four aralogous genes, CRH and urocortins (UCNs) 1, 2, and 3. In a previous tudy, we analyzed CRH in the teleost model organism zebrafish and its ranscript distribution in the embryonic brain. Here, we describe ull-length cDNAs encoding urotensin 1 (UTS1), the teleost UCN1 rtholog, and UCN3 of zebrafish. Major expression sites of uts1 in adult ebrafish are the caudal neurosecretory system and brain. By using T-PCR analysis, we show that uts1 mRNA is also present in ovary, aternally contributed to the embryo, and expressed throughout embryonic evelopment. Expression of ucn3 mRNA was detected in a range of adult issues and during developmental stages from 24 hours post fertilization nward. Analysis of spatial transcript distributions by whole-mount in itu hybridization revealed limited forebrain expression of uts1 and cn3 during early development. Small numbers of uts1-synthesizing eurons were found in subpallium, hypothalamus, and posterior iencephalon, whereas ucn3-positive cells were restricted to elencephalon and retina. The brainstem was the main site of uts1 and cn3 synthesis in the embryonic brain. uts1 Expression was confined to he midbrain tegmentum; distinct hindbrain cell groups, including locus oeruleus and Mauthner neurons; and the spinal cord. ucn3 Expression was ocalized to the optic tectum, serotonergic raphe, and distinct hombomeric cell clusters. The prominent expression of uts1 and ucn3 in rainstem is consistent with proposed roles of CRH-related peptides in tress-induced modulation of locomotor activity through monoaminergic rainstem neuromodulatory systems. J. Comp. Neurol. 518:2978-2995, 2010.

  • 6.
    Delp, Gabriele
    et al.
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Gradin, Therese
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Ahman, Inger
    Jonsson, Lisbeth M. V.
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Microarray analysis of the interaction between the aphid Rhopalosiphum padi and host plants reveals both differences and similarities between susceptible and partially resistant barley lines2009In: Molecular Genetics and Genomics, ISSN 1617-4615, E-ISSN 1617-4623, Vol. 281, no 3, 233-248 p.Article in journal (Refereed)
    Abstract [en]

    The bird cherry-oat aphid (Rhopalosiphum padi L.) is an important pest on cereals causing plant growth reduction without specific leaf symptoms. Breeding of barley (Hordeum vulgare L.) for R. padi resistance shows that there are several resistance genes, reducing aphid growth. To identify candidate sequences for resistance-related genes, we performed microarray analysis of gene expression after aphid infestation in two susceptible and two partially resistant barley genotypes. One of the four lines is a descendant of two of the other genotypes. There were large differences in gene induction between the four lines, indicating substantial variation in response even between closely related genotypes. Genes induced in aphid-infested tissue were mainly related to defence, primary metabolism and signalling. Only 24 genes were induced in all lines, none of them related to oxidative stress or secondary metabolism. Few genes were down-regulated, with none being common to all four lines. There were differences in aphid-induced gene regulation between resistant and susceptible lines. Results from control plants without aphids also revealed differences in constitutive gene expression between the two types of lines. Candidate sequences for induced and constitutive resistance factors have been identified, among them a proteinase inhibitor, a serine/threonine kinase and several thionins.

  • 7.
    Djupedal, Ingela
    et al.
    Södertörn University, School of Life Sciences.
    Ekwall, Karl
    Södertörn University, School of Life Sciences, Molecular biology.
    Epigenetics: heterochromatin meets RNAi2009In: Cell Research, ISSN 1001-0602, E-ISSN 1748-7838, Vol. 19, no 3, 282-295 p.Article in journal (Refereed)
    Abstract [en]

    The term epigenetics refers to heritable changes not encoded by DNA. The organization of DNA into chromatin fibers affects gene expression in a heritable manner and is therefore one mechanism of epigenetic inheritance. Large parts of eukaryotic genomes consist of constitutively highly condensed heterochromatin, important for maintaining genome integrity but also for silencing of genes within. Small RNA, together with factors typically associated with RNA interference (RNAi) targets homologous DNA sequences and recruits factors that modify the chromatin, commonly resulting in formation of heterochromatin and silencing of target genes. The scope of this review is to provide an overview of the roles of small RNA and the RNAi components, Dicer, Argonaute and RNA dependent polymerases in epigenetic inheritance via heterochromatin formation, exemplified with pathways from unicellular eukaryotes, plants and animals.

  • 8.
    Djupedal, Ingela
    et al.
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Kos-Braun, Isabelle C.
    University of Edinburgh, Edinburgh, UK / Universität Heidelberg, Heidelberg, Germany.
    Mosher, Rebecca A.
    University of Cambridge, Cambridge, UK.
    Söderholm, Niklas
    Karolinska Institutet.
    Simmer, Femke
    University of Edinburgh, Edinburgh, UK.
    Hardcastle, Thomas J.
    University of Cambridge, Cambridge, UK.
    Fender, Aurelie
    Uppsala universitet.
    Heidrich, Nadja
    Uppsala universitet.
    Kagansky, Alexander
    University of Edinburgh, Edinburgh, UK.
    Bayne, Elizabeth
    University of Edinburgh, Edinburgh, UK.
    Wagner, E. Gerhart H.
    Uppala universitet.
    Baulcombe, David C.
    University of Cambridge, Cambridge, UK.
    Allshire, Robin C.
    University of Edinburgh, Edinburgh, UK.
    Ekwall, Karl
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Analysis of small RNA in fission yeast; centromeric siRNAs are potentially generated through a structured RNA2009In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 28, no 24, 3832-3844 p.Article in journal (Refereed)
    Abstract [en]

    The formation of heterochromatin at the centromeres in fission yeast depends on transcription of the outer repeats. These transcripts are processed into siRNAs that target homologous loci for heterochromatin formation. Here, high throughput sequencing of small RNA provides a comprehensive analysis of centromere-derived small RNAs. We found that the centromeric small RNAs are Dcr1 dependent, carry 50-monophosphates and are associated with Ago1. The majority of centromeric small RNAs originate from two remarkably well-conserved sequences that are present in all centromeres. The high degree of similarity suggests that this non-coding sequence in itself may be of importance. Consistent with this, secondary structure-probing experiments indicate that this centromeric RNA is partially double-stranded and is processed by Dicer in vitro. We further demonstrate the existence of small centromeric RNA in rdp1D cells. Our data suggest a pathway for siRNA generation that is distinct from the well-documented model involving RITS/RDRC. We propose that primary transcripts fold into hairpin-like structures that may be processed by Dcr1 into siRNAs, and that these siRNAs may initiate heterochromatin formation independent of RDRC activity. The EMBO Journal (2009) 28, 3832-3844. doi: 10.1038/emboj.2009.351; Published online 26 November 2009

  • 9.
    Elväng, Annelie
    et al.
    Södertörn University, School of Life Sciences, Molecular biology.
    Melik, Wessam
    Södertörn University, School of Life Sciences, Chemistry. Södertörn University, School of Life Sciences, Molecular biology.
    Bertrand, Yann
    Södertörn University, School of Life Sciences, Molecular biology.
    Lönn, Mikael
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Environmental science.
    Johansson, Magnus
    Södertörn University, School of Life Sciences, Chemistry. Södertörn University, School of Life Sciences, International health.
    Sequencing of a Tick-Borne Encephalitis Virus from Ixodes ricinus Reveals a Thermosensitive RNA Switch Significant for Virus Propagation in Ectothermic Arthropods.2011In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 11, no 6, 649-658 p.Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) is a flavivirus with major impact on global health. The geographical TBEV distribution is expanding, thus making it pivotal to further characterize the natural virus populations. In this study, we completed the earlier partial sequencing of a TBEV pulled out of a pool of RNA extracted from 115 ticks collected on Torö in the Stockholm archipelago. The total RNA was sufficient for all sequencing of a TBEV genome (Torö-2003), without conventional enrichment procedures such as cell culturing or suckling mice amplification. To our knowledge, this is the first time that the genome of TBEV has been sequenced directly from an arthropod reservoir. The Torö-2003 sequence has been characterized and compared with other TBE viruses. In silico analyses of secondary RNA structures formed by the two untranslated regions revealed a temperature-sensitive structural shift between a closed replicative form and an open AUG accessible form, analogous to a recently described bacterial thermoswitch. Additionally, novel phylogenetic conserved structures were identified in the variable part of the 3'-untranslated region, and their sequence and structure similarity when compared with earlier identified structures suggests an enhancing function on virus replication and translation. We propose that the thermo-switch mechanism may explain the low TBEV prevalence often observed in environmentally sampled ticks. Finally, we were able to detect variations that help in the understanding of virus adaptations to varied environmental temperatures and mammalian hosts through a comparative approach that compares RNA folding dynamics between strains with different mammalian cell passage histories.

  • 10.
    Ferreira, Monica E.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska institutet.
    Studies of transcription factor domains and their interactions with other transcription factors2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The studies in this thesis deal with different questions concerning interactions of functional domains of factors involved in transcriptional regulation. The first study of this thesis is focused on the target factor binding mechanism of transcriptional activators. Many activators in evolutionary distant species are classified as acidic based on a high content of acidic residues in the activation domain and intrinsically unstructured in solution. Our results indicate that such activation domains interact with target factors through coupled binding and folding of the activation domain after an initial ionic interaction, and demonstrate the generality of this binding mechanism. We propose that target interaction through coupled binding and folding of the recruiting domain is important for the role of activators as regulators of transcription. In the following study we show that deletion of two regions that mediate interaction with activators in vitro prevents promoter recruitment of the SWI/SNF chromatinremodeling complex in vivo, and causes strongly reduced transcriptional activity of the corresponding genes. This study validates direct interaction between the Swi1- and Snf5 activator binding domains of the S. cerevisiae SWI/SNF complex and activators previously demonstrated in vitro, and importantly indicates that the activator binding domains are essential for the ability of SWI/SNF to function as co-activator. In the last study we investigate which domains are involved in distinct in vivo function of the paralogous co-repressors Tup11 and Tup12 of the Ssn6/Tup complex in S. pombe. Tup11 and Tup12 have been shown to differ in importance in context of a common complex for subsets of Ssn6/Tup target genes, and it was proposed that this might depend on divergence in the histone-interaction domain. Here we show that distinct in vivo roles of Tup12 do not depend on differences in the highly diverged histoneinteraction domain, but mainly on differences in the overall highly conserved WD40 repeat domain, which putatively mediates interaction with repressors and target factors such as histone modifying complexes and components of the transcriptional machinery. We propose that clusters of amino acids, putatively located in blade 3 of the WD40 repeat domain, could be important for interaction with distinct target factors of Tup11 and Tup12. Furthermore, we show that the stoichiometry of the Ssn6/Tup complex is likely to change under CaCl2 stress, by a mechanism involving changes in the relative cellular levels of the complex components.

  • 11.
    Ferreira, Monica E.
    et al.
    Södertörn University, School of Life Sciences, Molecular biology.
    Berndt, Kurt D.
    Södertörn University, School of Life Sciences, Chemistry.
    Nilsson, Johan
    Södertörn University, School of Life Sciences, Molecular biology.
    Wright, Anthony P. H.
    Södertörn University, School of Life Sciences, Molecular biology.
    WD40 Domain Divergence Is Important for Functional Differences between he Fission Yeast Tup11 and Tup12 Co-Repressor Proteins2010In: PLoS ONE, ISSN 1932-6203, Vol. 5, no 6, e11009- p.Article in journal (Refereed)
    Abstract [en]

    We have previously demonstrated that subsets of Ssn6/Tup target genes ave distinct requirements for the Schizosaccharomyces pombe homologs of he Tup1/Groucho/TLE co-repressor proteins, Tup11 and Tup12. The very igh level of divergence in the histone interacting repression domains f the two proteins suggested that determinants distinguishing Tup11 and up12 might be located in this domain. Here we have combined hylogenetic and structural analysis as well as phenotypic haracterization, under stress conditions that specifically require up12, to identify and characterize the domains involved in up12-specific action. The results indicate that divergence in the epression domain is not generally relevant for Tup12-specific function. nstead, we show that the more highly conserved C-terminal WD40 repeat omain of Tup12 is important for Tup12-specific function. Surface amino cid residues specific for the WD40 repeat domain of Tup12 proteins in ifferent fission yeasts are clustered in blade 3 of the propeller-like tructure that is characteristic of WD40 repeat domains. The Tup11 and up12 proteins in fission yeasts thus provide an excellent model system or studying the functional divergence of WD40 repeat domains.

  • 12.
    Ferreira, Monica E.
    et al.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Nilsson, Johan
    Södertörn University, School of Life Sciences, Molecular biology.
    Berndt, Kurt D.
    Södertörn University, School of Life Sciences, Chemistry. Karolinska Institutet.
    Wright, Anthony P. H.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Protein domains underlying functional divergence between the Tup11 and Tup12 co-repressor proteins in fission yeastManuscript (preprint) (Other academic)
  • 13.
    Ferreira, Monica E.
    et al.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska instiutet.
    Prochasson, Philippe
     Stowers Institute for Medical Research, Kansas City, MO, USA.
    Berndt, Kurt D.
    Södertörn University, School of Life Sciences, Chemistry. Karolinska institutet.
    Workman, Jerry L.
    Stowers Institute for Medical Research, Kansas City, MO, USA.
    Wright, Anthony P. H.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska institutet.
    Activator-binding domains of the SWI/SNF chromatin remodeling complex characterized in vitro are required for its recruitment to promoters in vivo2009In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, no 9, 2557-2565 p.Article in journal (Refereed)
    Abstract [en]

    Interaction between acidic activation domains and the activator-binding domains of Swi1 and Snf5 of the yeast SWI/SNF chromatin remodeling complex has previously been characterized in vitro. Although deletion of both activator-binding domains leads to phenotypes that differ from the wild-type, their relative importance for SWI/SNF recruitment to target genes has not been investigated. In the present study, we used chromatin immunoprecipitation assays to investigate the individual and collective importance of the activator-binding domains for SWI/SNF recruitment to genes within the GAL regulon in vivo. We also investigated the consequences of defective SWI/SNF recruitment for target gene activation. We demonstrate that deletion of both activator-binding domains essentially abolishes galactose-induced SWI/SNF recruitment and causes a reduction in transcriptional activation similar in magnitude to that associated with a complete loss of SWI/SNF activity. The activator-binding domains in Swi1 and Snf5 make approximately equal contributions to the recruitment of SWI/SNF to each of the genes studied. The requirement for SWI/SNF recruitment correlates with GAL genes that are highly and rapidly induced by galactose.

  • 14.
    Figueroa, Ricardo
    et al.
    Södertörn University, School of Life Sciences, Molecular biology. Karloinska institutet.
    Gudise, Santhosh
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska institutet.
    Larsson, Veronica
    Karloinska institutet.
    Hallberg, Einar
    Södertörn University, School of Life Sciences, Molecular biology.
    A transmembrane inner nuclear membrane protein in the mitotic spindle2010In: Nucleus, ISSN 1949-1042, Vol. 1, no 3, 249-253 p.Article in journal (Refereed)
    Abstract [en]

    We have recently characterized a novel transmembrane protein of the inner nuclear membrane of mammalian cells. The protein has two very interesting features. First, despite being an integral membrane protein it is able to concentrate in the membranes colocalizing with the mitotic spindle in metaphase and anaphase. Hence, the protein was named Samp1, Spindle associated membrane protein 1. Secondly, it displays a functional connection to centrosomes. This article discusses various aspects of Samp1 in relation to possible cellular function(s).

  • 15. Gabriel, Jens Peter
    et al.
    Mahmood, Riyadh
    Kyriakatos, Alexandros
    Söll, Iris
    Södertörn University, School of Life Sciences, Molecular biology.
    Hauptmann, Giselbert
    Södertörn University, School of Life Sciences, Molecular biology.
    Calabrese, Ronald L.
    El Manira, Abdeljabbar
    Serotonergic Modulation of Locomotion in Zebrafish-Endogenous Release and Synaptic Mechanisms2009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 33, 10387-10395 p.Article in journal (Refereed)
    Abstract [en]

    Serotonin (5-HT) plays an important role in shaping the activity of the spinal networks underlying locomotion in many vertebrate preparations. At larval stages in zebrafish, 5-HT does not change the frequency of spontaneous swimming; and it only decreases the quiescent period between consecutive swimming episodes. However, it is not known whether 5-HT exerts similar actions on the locomotor network at later developmental stages. For this, the effect of 5-HT on the fictive locomotor pattern of juvenile and adult zebrafish was analyzed. Bath-application of 5-HT (1-20 mu M) reduced the frequency of the NMDA-induced locomotor rhythm. Blocking removal from the synaptic cleft with the reuptake inhibitor citalopram had similar effects, suggesting that endogenous serotonin is modulating the locomotor pattern. One target for this modulation was the mid-cycle inhibition during locomotion because the IPSPs recorded in spinal neurons during the hyperpolarized phase were increased both in amplitude and occurrence by 5-HT. Similar results were obtained for IPSCs recorded in spinal neurons clamped at the reversal potential of excitatory currents (0 mV). 5-HT also slows down the rising phase of the excitatory drive recorded in spinal cord neurons when glycinergic inhibition is blocked. These results suggest that the decrease in the locomotor burst frequency induced by 5-HT is mediated by a potentiation of mid-cycle inhibition combined with a delayed onset of the subsequent depolarization.

  • 16. Granhall, Ulf
    et al.
    Welsh, Allana
    Throbäck, Ingela Noredal
    Hjort, Karin
    Södertörn University, School of Life Sciences, Molecular biology.
    Hansson, Mikael
    Hallin, Sara
    Bacterial community diversity in paper mills processing recycled paper2010In: Journal of Industrial Microbiology & Biotechnology, ISSN 1367-5435, E-ISSN 1476-5535, Vol. 37, no 10, 1061-1069 p.Article in journal (Refereed)
    Abstract [en]

    Paper mills processing recycled paper suffer from biofouling causing roblems both in the mill and final product. The total bacterial ommunity composition and identification of specific taxa in the process ater and biofilms at the stock preparation and paper machine areas in a ill with recycled paper pulp was described by using a DNA-based pproach. Process water in a similar mill was also analyzed to nvestigate if general trends can be found between mills and over time. acterial community profiles, analyzed by terminal-restriction fragment ength polymorphism (T-RFLP), in process water showed that the dominant eaks in the profiles were similar between the two mills, although the verall composition was unique for each mill. When comparing process ater and biofilm at different locations within one of the mills, we bserved a separation according to location and sample type, with the iofilm from the paper machine being most different. 16S rRNA gene clone ibraries were generated and 404 clones were screened by RFLP analysis. rouping of RFLP patterns confirmed that the biofilm from the paper achine was most different. A total of 99 clones representing all RFLP atterns were analyzed, resulting in sequences recovered from nine acterial phyla, including two candidate phyla. Bacteroidetes epresented 45% and Actinobacteria 23% of all the clones. Sequences with imilarity to organisms implicated in biofouling, like Chryseobacterium pp. and Brevundimonas spp., were recovered from all samples even though he mill had no process problems during sampling, suggesting that they re part of the natural paper mill community. Moreover, many sequences howed little homology to as yet uncultivated bacteria implying that aper mills are interesting for isolation of new organisms, as well as or bioprospecting.

  • 17.
    Hench, Jürgen
    et al.
    Södertörn University, School of Life Sciences.
    Henriksson, Johan
    Södertörn University, School of Life Sciences, Molecular biology.
    Lüppert, Martin
    Södertörn University, School of Life Sciences.
    Bürglin, Thomas R.
    Södertörn University, School of Life Sciences, Molecular biology.
    Spatio-temporal reference model of Caenorhabditis elegans embryogenesis with cell contact maps2009In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 333, no 1, 1-13 p.Article in journal (Refereed)
    Abstract [en]

    The nematode Caenorhabditis elegans has been used as a model for developmental biology for decades. Still, the few publicly available spatio-temporal (4D) data sets have conflicting information regarding variability of cell positions and are not well-suited for a standard 4D embryonic model, due to compression. We have recorded six uncompressed embryos, and determined their lineage and 4D coordinates, including nuclear radii, until the end of gastrulation. We find a remarkable degree of stability in the cell positions, as well as little rotational movement, which allowed us to combine the data into a single reference model of C. elegans embryogenesis. Using Voronoi decomposition we generated the list of all predicted cell contacts during early embryogenesis and calculated these contacts up to the similar to 150 cell stage, and find that about 1500 contacts last 2.5 min or longer. The cell contact map allows for comparison of multiple 4D data sets, e. g., mutants or related species, at the cellular level. A comparison of our uncompressed 4D model with a compressed embryo shows that up to 40% of the cell contacts can be different. To visualize the 4D model interactively we developed a software utility. Our model provides an anatomical resource and can serve as foundation to display 4D expression data, a basis for developmental systems biology.

  • 18.
    Hjort, Karin
    et al.
    Södertörn University, School of Life Sciences, Molecular biology.
    Bergström, Maria
    Adesina, Modupe F.
    Jansson, Janet K.
    Smalla, Kornelia
    Sjöling, Sara
    Södertörn University, School of Life Sciences, Environmental science. Södertörn University, School of Life Sciences, Molecular biology.
    Chitinase genes revealed and compared in bacterial isolates, DNA extracts and a metagenomic library from a phytopathogen-suppressive soil2010In: FEMS Microbiology Ecology, ISSN 0168-6496, E-ISSN 1574-6941, Vol. 71, no 2, 197-207 p.Article in journal (Refereed)
    Abstract [en]

    Soil that is suppressive to disease caused by fungal pathogens is an interesting source to target for novel chitinases that might be contributing towards disease suppression. In this study, we screened for chitinase genes, in a phytopathogen-suppressive soil in three ways: (1) from a metagenomic library constructed from microbial cells extracted from soil, (2) from directly extracted DNA and (3) from bacterial isolates with antifungal and chitinase activities. Terminal restriction fragment length polymorphism (T-RFLP) of chitinase genes revealed differences in amplified chitinase genes from the metagenomic library and the directly extracted DNA, but approximately 40% of the identified chitinase terminal restriction fragments (TRFs) were found in both sources. All of the chitinase TRFs from the isolates were matched to TRFs in the directly extracted DNA and the metagenomic library. The most abundant chitinase TRF in the soil DNA and the metagenomic library corresponded to the TRF103 of the isolate Streptomyces mutomycini and/or Streptomyces clavifer. There were good matches between T-RFLP profiles of chitinase gene fragments obtained from different sources of DNA. However, there were also differences in both the chitinase and the 16S rRNA gene T-RFLP patterns depending on the source of DNA, emphasizing the lack of complete coverage of the gene diversity by any of the approaches used.

  • 19.
    Hjort, Karin
    et al.
    Södertörn University, School of Life Sciences, Molecular biology.
    Goldberg, Alina V.
    Tsaousis, Anastasios D.
    Hirt, Robert P.
    Embley, T. Martin
    Diversity and reductive evolution of mitochondria among microbial eukaryotes2010In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, Vol. 365, no 1541, 713-727 p.Article, review/survey (Refereed)
    Abstract [en]

    All extant eukaryotes are now considered to possess mitochondria in one form or another. Many parasites or anaerobic protists have highly reduced versions of mitochondria, which have generally lost their genome and the capacity to generate ATP through oxidative phosphorylation. These organelles have been called hydrogenosomes, when they make hydrogen, or remnant mitochondria or mitosomes when their functions were cryptic. More recently, organelles with features blurring the distinction between mitochondria, hydrogenosomes and mitosomes have been identified. These organelles have retained a mitochondrial genome and include the mitochondrial-like organelle of Blastocystis and the hydrogenosome of the anaerobic ciliate Nyctotherus. Studying eukaryotic diversity from the perspective of their mitochondrial variants has yielded important insights into eukaryote molecular cell biology and evolution. These investigations are contributing to understanding the essential functions of mitochondria, defined in the broadest sense, and the limits to which reductive evolution can proceed while maintaining a viable organelle.

  • 20. Hogan, C. J.
    et al.
    Aligianni, S.
    Durand-Dubief, M.
    Persson, J.
    Will, W. R.
    Webster, J.
    Wheeler, L.
    Mathews, C. K.
    Elderkin, S.
    Oxley, D.
    Ekwall, Karl
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Varga-Weisz, P. D.
    Fission yeast Iec1-Ino80-mediated nucleosome eviction regulates nucleotide and phosphate metabolism2010In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 30, no 3, 657-674 p.Article in journal (Refereed)
    Abstract [en]

    Ino80 is an ATP-dependent nucleosome-remodeling enzyme involved in transcription, replication, and the DNA damage response. Here, we characterize the fission yeast Ino80 and find that it is essential for cell viability. We show that the Ino80 complex from fission yeast mediates ATP-dependent nucleosome remodeling in vitro. The purification of the Ino80-associated complex identified a highly conserved complex and the presence of a novel zinc finger protein with similarities to the mammalian transcriptional regulator Yin Yang 1 (YY1) and other members of the GLI-Krüppel family of proteins. Deletion of this Iec1 protein or the Ino80 complex subunit arp8, ies6, or ies2 causes defects in DNA damage repair, the response to replication stress, and nucleotide metabolism. We show that Iec1 is important for the correct expression of genes involved in nucleotide metabolism, including the ribonucleotide reductase subunit cdc22 and phosphate- and adenineresponsive genes. We find that Ino80 is recruited to a large number of promoter regions on phosphate starvation, including those of phosphate- and adenine-responsive genes that depend on Iec1 for correct expression. Iec1 is required for the binding of Ino80 to target genes and subsequent histone loss at the promoter and throughout the body of these genes on phosphate starvation. This suggests that the Iec1-Ino80 complex promotes transcription through nucleosome eviction.

  • 21.
    Jaensson, Alia
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Pheromonal Mediated Behaviour and Endocrine Responses in Salmonids: The impact of Cypermethrin, Copper, and Glyphosate2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The effects of cypermethrin, copper and glyphosate on the endocrine system and subsequent response to female pheromones were investigated in mature male brown trout (Salmo trutta) parr.  Responses measured were the amount of strippable milt, blood plasma levels of both an androgen (11-ketotestosterone (11-KT)) and a progestin (17α,20β-dihydroxy-4-pregnen-3-one (17,20b-P)), and behavioural changes. This was done in a two phased investigation where parr were exposed to one of the following via ambient water: 1) 0.1 or 1.0 μg L-1 cypermethrin, 2) 10 or 100 μg L-1 copper (Cu2+), or 3) 150 μg L-1 glyphosate for a 96 hour period.  Phase one was a priming experiment exposing parr to a treatment followed by priming with PGF or ovarian fluid (OVF). Atlantic salmon (Salmo salar) parr were, also exposed to glyphosate during phase I. The second phase was centered on behavioural observations.  Exposed parr were placed in a 35,000 L stream aquarium together with two ovulated females and four anadromous males. After the experiments a blood sample was taken, milt volumes measured and testes weighed.  The plasma was analyzed for 11-KT and 17,20b-P concentrations using radioimmunoassay (RIA).

    Results from phase I-priming: 1.0 μg L-1 cypermethrin exposure lowered 17,20b-P and 11-KT; Copper exposure lowered milt volumes; glyphosate exposure lowered 11-KT in salmon and raised 17,20b-P in trout.  Results from phase II-behaviour: 1.0 μg L-1 cypermethrin exposure lowered 11-KT, milt and spawning behaviour; copper exposure lowered spawning behaviour and raised 11-KT; Glyphosate exposure lowered 11KT; continuous cypermethrin exposure raised 17,20b-P, 11-KT and gave a tendency towards increased aggression. It is concluded that low concentration exposure to the compounds examined can induce negative effects on male salmonid endocrine systems, either through a disruption in the olfactory system or through a direct effect.

  • 22. Jensen, Lasse Dahl Ejby
    et al.
    Cao, Renhai
    Hedlund, Eva-Maria
    Söll, Iris
    Södertörn University, School of Life Sciences, Molecular biology.
    Lundberg, Jon O.
    Hauptmann, Giselbert
    Södertörn University, School of Life Sciences, Molecular biology.
    Steffensen, John Fleng
    Cao, Yihai
    Nitric oxide permits hypoxia-induced lymphatic perfusion by controlling arterial-lymphatic conduits in zebrafish and glass catfish2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 43, 18408-18413 p.Article in journal (Refereed)
    Abstract [en]

    The blood and lymphatic vasculatures are structurally and functionally coupled in controlling tissue perfusion, extracellular interstitial fluids, and immune surveillance. Little is known, however, about the molecular mechanisms that underlie the regulation of bloodlymphatic vessel connections and lymphatic perfusion. Here we show in the adult zebrafish and glass catfish (Kryptopterus bicirrhis) that blood-lymphatic conduits directly connect arterial vessels to the lymphatic system. Under hypoxic conditions, arterial-lymphatic conduits (ALCs) became highly dilated and linearized by NO-induced vascular relaxation, which led to blood perfusion into the lymphatic system. NO blockage almost completely abrogated hypoxia-induced ALC relaxation and lymphatic perfusion. These findings uncover mechanisms underlying hypoxia-induced oxygen compensation by perfusion of existing lymphatics in fish. Our results might also imply that the hypoxia-induced NO pathway contributes to development of progression of pathologies, including promotion of lymphatic metastasis by modulating arterial-lymphatic conduits, in the mammalian system.

  • 23.
    Johnsson, Anna
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Characterization of Gcn5 histone acetyltransferase in Schizosaccharomyces pombe2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The organisation of eukaryotic DNA into chromatin provides a natural barrier that prevents full access to the DNA thereby inhibiting events such as transcription, replication and repair. In order for these DNA-related events to occur, the chromatin needs to be modified by chromatin remodelling or, by reversible post-translational modifications. Histone acetylation is such a modification and is essential of numerous DNA related events. The enzymes involved in this event are conserved throughout evolution, underscoring their importance. This thesis describes the role of the conserved histone acetyltransferase (HAT) Gcn5 in transcriptional regulation in Schizosaccharomyces pombe. Here we show that Gcn5 plays an important role in stress response. We map genome-wide Gcn5 occupancy and show that Gcn5 is predominantly localized to coding regions of highly transcribed genes. We also map H3K14 acetylation during salt stress and show that Gcn5 collaborates antagonistically with the class-II histone deacetylase, Clr3, to modulate H3K14ac levels and transcriptional elongation. The interplay between Gcn5 and Clr3 is crucial for the regulation of many stress-response genes. Our findings suggest a new role for Gcn5 during transcriptional elongation, in addition to its known role in transcriptional initiation. We also investigate the interactions between Gcn5 and other histone deacetylases and acetyltransferases and show overlapping functionality between Gcn5 and another histone acetyltransferase, Mst2, in stress response, regulation of subtelomeric genes and DNA damage repair. Finally, we show that the role of Gcn5 in stress response is mediated by its catalytic activity and that its function in stress response is conserved among yeast species.

  • 24.
    Johnsson, Anna
    et al.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Durand-Dubief, Mickael
    Karolinska Intitutet.
    Xue-Franzen, Yongtao
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Rönnerblad, Michelle
    Karolinska Institutet.
    Ekwall, Karl
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Wright, Anthony P. H.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    HAT-HDAC interplay modulates global histone H3K14 acetylation in gene-coding regions during stress2009In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 10, no 9, 1009-1014 p.Article in journal (Refereed)
    Abstract [en]

    Histone acetylation and deacetylation are important for gene regulation. The histone acetyltransferase, Gcn5, is an activator of transcriptional initiation that is recruited to gene promoters. Here, we map genome-wide Gcn5 occupancy and histone H3K14ac at high resolution. Gcn5 is predominantly localized to coding regions of highly transcribed genes, where it collaborates antagonistically with the class-II histone deacetylase, Clr3, to modulate H3K14ac levels and transcriptional elongation. An interplay between Gcn5 and Clr3 is crucial for the regulation of many stress-response genes. Our findings suggest a new role for Gcn5 during transcriptional elongation, in addition to its known role in transcriptional initiation.

  • 25.
    Johnsson, Anna E.
    et al.
    Södertörn University, School of Life Sciences, Molecular biology.
    Wright, Anthony P. H.
    Södertörn University, School of Life Sciences, Molecular biology.
    The role of specific HAT-HDAC interactions in transcriptional elongation2010In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 9, no 3, 467-471 p.Article in journal (Refereed)
    Abstract [en]

    We previously reported genome-wide evidence that the Gcn5 histone cetyltransferase (HAT) is located in the transcribed region of highly xpressed genes and that it plays an important role in transcriptional longation in the fission yeast, Schizosaccharomyces pombe (EMBO Reports 009; 10: 1009-14). Furthermore, the specific interplay between Gcn5 and he Clr3 histone deacetylase (HDAC) controls the acetylation levels of ysine-14 in histone H3 in the same class of highly expressed genes. utants of histone H3 that cannot be acetylated at residue 14 show imilar stress phenotypes to those observed for mutants lacking Gcn5. In his Extra View article we review these findings in relation to related iterature and extend important aspects of the original study. Notably, cn5 and Gcn5-dependent acetylation of histone H3K14 tend to be more nriched in the upstream regions of genes that require Gcn5 for correct xpression compared to genes that are independent of Gcn5. This suggests critical role of Gcn5 in the transcriptional initiation of these enes. Gcn5 is however most highly enriched in the transcribed regions f these gene sets but there is no difference between Gcn5-dependent and cn5-independent gene sets. Thus we suggest that Gcn5 plays an important ut redundant role in the transcriptional elongation of these genes. The ir2 HDAC has a similar genomic localization and enzymatic activity to lr3. We studied gcn5 Delta sir2 Delta double mutants that do not show a uppressed phenotype in relation to gcn5 Delta single mutants, compared o gcn5 Delta clr3 Delta mutants that do, in order to better understand he specificity of the interplay between Gcn5 and Clr3. In some classes f non-highly expressed genes the clr3 Delta mutant tends to restore evels of histone H3K14 acetylation in the double mutant strain more ffectively than sir2 Delta.

  • 26.
    Johnsson, Anna
    et al.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Xue-Franzen, Yongtao
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Intitutet.
    Lundin, Maria
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Wright, Anthony P. H.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Stress-specific role of fission yeast Gcn5 histone acetyltransferase in programming a subset of stress response genes2006In: Eukaryotic Cell, ISSN 1535-9778, E-ISSN 1535-9786, Vol. 5, no 8, 1337-1346 p.Article in journal (Refereed)
    Abstract [en]

    Gcn5 is a coactivator protein that contributes to gene activation by acetylating specific lysine residues within the N termini of histone proteins. Gcn5 has been intensively studied in the budding yeast, Saccharomyces cerevisiae, but the features of genes that determine whether they require Gcn5 during activation have not been conclusively clarified. To allow comparison with S. cerevisiae, we have studied the genome-wide role of Gcn5 in the distantly related fission yeast, Schizosaccharomyces pombe. We show that Gcn5 is specifically required for adaptation to KCl- and CaCl2-mediated stress in S. pombe. We have characterized the genome-wide gene expression responses to KCl stress and show that Gcn5 is involved in the regulation of a subset of stress response genes. Gcn5 is most clearly associated with KCl-induced genes, but there is no correlation between Gcn5 dependence and the extent of their induction. Instead, Gen5-dependent KCl-induced genes are specifically enriched in four different DNA motifs. The Gcn5-dependent KCl-induced genes are also associated with biological process gene ontology terms such as carbohydrate metabolism, glycolysis, and nicotinamide metabolism that together constitute a subset of the ontology parameters associated with KCl-induced genes.

  • 27. Khorosjutina, Olga
    et al.
    Wanrooij, Paulina H.
    Walfridsson, Julian
    Södertörn University, School of Life Sciences, Molecular biology.
    Szilagyi, Zsolt
    Zhu, Xuefeng
    Baraznenok, Vera
    Ekwall, Karl
    Södertörn University, School of Life Sciences, Molecular biology.
    Gustafsson, Claes M.
    A Chromatin-remodeling Protein Is a Component of Fission Yeast Mediator2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 39, 29729-29737 p.Article in journal (Refereed)
    Abstract [en]

    The multiprotein Mediator complex is an important regulator of RNA polymerase II-dependent genes in eukaryotic cells. In contrast to the situation in many other eukaryotes, the conserved Med15 protein is not a stable component of Mediator isolated from fission yeast. We here demonstrate that Med15 exists in a protein complex together with Hrp1, a CHD1 ATP-dependent chromatin-remodeling protein. The Med15-Hrp1 subcomplex is not a component of the core Mediator complex but can interact with the L-Mediator conformation. Deletion of med15(+) and hrp1(+) causes very similar effects on global steady-state levels of mRNA, and genome-wide analyses demonstrate that Med15 associates with a distinct subset of Hrp1-bound gene promoters. Our findings therefore indicate that Mediator may directly influence histone density at regulated promoters.

  • 28.
    Larsson, Kristina A. E.
    et al.
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Saheed, Sefiu A.
    Gradin, Therese
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Delp, Gabriele
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Karpinska, Barbara
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Botha, Christiaan E. J.
    Jonsson, Lisbeth M. V.
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Differential regulation of 3-aminomethylindole/N-methyl-3-aminomethylindole N-methyltransferase and gramine in barley by both biotic and abiotic stress conditions2011In: Plant physiology and biochemistry (Paris), ISSN 0981-9428, Vol. 49, no 1, 96-102 p.Article in journal (Refereed)
    Abstract [en]

    The expression of NMT (3-aminomethylindole/N-methyl-3-aminomethylindole N-methyltransferase; EC 2.1.1.), involved in the biosynthesis of the indole alkaloid gramine, was investigated in aphid-infested barley (Hordeum vulgare L). NMT is induced by methyl jasmonate and it was hypothesized that the gene would be more strongly upregulated in aphid-resistant barley. We examined the effects of feeding by three aphid species; Russian wheat aphid (Diuraphis noxia Mordvilko), rose-grain aphid (Metopolophium dirhodum Walker) and bird cherry-oat aphid (Rhopalosiphum padi L.) on barley genotypes with varying resistance characteristics. The barley genotypes selected included the cultivar Libra, known to upregulate gramine after feeding by Schizaphis graminum. Infestation by R. padi and M. dirhodum resulted in higher NMT expression in the doubled haploid line 5172-28:4 (DH28:4), which has moderate resistance against R. padi, but not in other aphid barley combinations. None of the aphid plant combinations had however increased gramine, suggesting that aphid-induction of gramine is specific to S. graminum. The increased abundance of NMT transcript in aphid-infested DH28:4 did not lead to higher amounts of NMT protein or NMT enzyme activity, neither did 200 times upregulation of NMT transcript in cotyledons incubated with methyl jasmonate, illustrating that even large differences measured at transcript level may have no metabolic consequences. Drought stress or treatments with abscisic acid did lead to higher gramine concentrations in several barley cultivars, but without any concomitant increase of NMT transcripts. Thus, the regulation of the biosynthetic pathway to gramine at transcript and metabolite level diverges during two different stress conditions.

  • 29. Lee, Samantha Lin Chiou
    et al.
    Rouhi, Pegah
    Jensen, Lasse Dahl
    Zhang, Danfang
    Ji, Hong
    Hauptmann, Giselbert
    Södertörn University, School of Life Sciences, Molecular biology.
    Ingham, Philip
    Cao, Yihai
    Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 46, 19485-19490 p.Article in journal (Refereed)
    Abstract [en]

    Mechanisms underlying pathological angiogenesis in relation to hypoxia in tumor invasion and metastasis remain elusive. Here, we have developed a zebrafish tumor model that allows us to study the role of pathological angiogenesis under normoxia and hypoxia in arbitrating early events of the metastatic cascade at the single cell level. Under normoxia, implantation of a murine T241 fibrosarcoma into the perivitelline cavity of developing embryos of transgenic fli1:EGFP zebrafish did not result in significant dissemination, invasion, and metastasis. In marked contrast, under hypoxia substantial tumor cells disseminated from primary sites, invaded into neighboring tissues, and metastasized to distal parts of the fish body. Similarly, expression of the hypoxia-regulated angiogenic factor, vascular endothelial growth factor (VEGF) to a high level resulted in tumor cell dissemination and metastasis, which correlated with increased tumor neovascularization. Inhibition of VEGF receptor signaling pathways by sunitinib or VEGFR2 morpholinos virtually completely ablated VEGF-induced tumor cell dissemination and metastasis. To the best of our knowledge, hypoxia- and VEGF-induced pathological angiogenesis in promoting tumor dissemination, invasion, and metastasis has not been described perviously at the single cell level. Our findings also shed light on molecular mechanisms of beneficial effects of clinically available anti-VEGF drugs for cancer therapy.

  • 30.
    Lind, Emma E
    et al.
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Grahn, Mats
    Södertörn University, School of Life Sciences, Environmental science. Södertörn University, School of Life Sciences, Biology.
    Directional genetic selection by pulp mill effluent on multiple natural populations of three-spined stickleback (Gasterosteus aculeatus)2011In: Ecotoxicology, ISSN 0963-9292, E-ISSN 1573-3017, Vol. 20, 503-512 p.Article in journal (Refereed)
    Abstract [en]

    Contamination can cause a rapid environmental change which may require populations to respond with evolutionary changes. To evaluate the effects of pulp mill effluents on population genetics, we sampled three-spined sticklebacks (Gasterosteus aculeatus) near four pulp mills and four adjacent reference sites and analyzed Amplified Fragment Length Polymorphism (AFLP) to compare genetic variability. A fine scale genetic structure was detected and samples from polluted sites separated from reference sites in multidimensional scaling plots (P < 0.005, 1000 permutations) and locus-by-locus Analysis of Molecular Variance (AMOVA) further confirmed that habitats are significantly separated (F(ST) = 0.021, P < 0.01, 1023 permutations). The amount of genetic variation between populations did not differ between habitats, and populations from both habitats had similar levels of heterozygosity (polluted sites Nei's Hs = 0.11, reference sites Nei's Hs = 0.11). Still, pairwise F(ST): s between three, out of four, pairs of polluted-reference sites were significant. A F(ST)-outlier analysis showed that 21 (8.4%) loci were statistically different from a neutral distribution at the P < 0.05 level and therefore indicated to be under divergent selection. When removing 13 F(ST)-outlier loci, significant at the P < 0.01 level, differentiation between habitats disappeared in a multidimensional scaling plot. In conclusion, pulp mill effluence has acted as a selective agent on natural populations of G. aculeatus, causing a convergence in genotype composition change at multiple sites in an open environment.

  • 31.
    Markovic, Maja Pavlovic
    et al.
    Södertörn University, School of Life Sciences.
    Kylsten, Per
    Södertörn University, School of Life Sciences, Molecular biology.
    Dushay, Mitchell S.
    Södertörn University, School of Life Sciences.
    Drosophila lamin mutations cause melanotic mass formation and lamellocyte differentiation2009In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 46, no 16, 3245-3250 p.Article in journal (Refereed)
    Abstract [en]

    The fruit fly immune system is a valuable model for invertebrate and innate immunity. Cellular immune reactions in Drosophila are of great interest, especially the molecular genetic mechanisms of hemocyte differentiation and the encapsulation of foreign bodies. Here we report that changes in the lamin gene cause melanotic masses. These darkened clusters of cells result from autoimmune-like encapsulation of self-tissue, as shown by the presence in lam larvae of lamellocytes, effector hemocytes that appear in larvae following wounding or parasitization. Lamins thus affect immunity in Drosophila, and lam mutations can serve as genetic tools to dissect cellular immune signaling and effector pathways.

  • 32. Massinen, Satu
    et al.
    Hokkanen, Marie-Estelle
    Matsson, Hans
    Tammimies, Kristiina
    Tapia-Paez, Isabel
    Dahlstrom-Heuser, Vanina
    Kuja-Panula, Juha
    Burghoorn, Jan
    Södertörn University, School of Life Sciences, Molecular biology.
    Jeppsson, Kristian E.
    Södertörn University, School of Life Sciences, Molecular biology.
    Swoboda, Peter
    Södertörn University, School of Life Sciences, Molecular biology.
    Peyrard-Janvid, Myriam
    Toftgard, Rune
    Castren, Eero
    Kere, Juha
    Increased Expression of the Dyslexia Candidate Gene DCDC2 Affects Length and Signaling of Primary Cilia in Neurons2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, e20580- p.Article in journal (Refereed)
    Abstract [en]

    DCDC2 is one of the candidate susceptibility genes for dyslexia. It belongs to the superfamily of doublecortin domain containing proteins that bind to microtubules, and it has been shown to be involved in neuronal migration. We show that the Dcdc2 protein localizes to the primary cilium in primary rat hippocampal neurons and that it can be found within close proximity to the ciliary kinesin-2 subunit Kif3a. Overexpression of DCDC2 increases ciliary length and activates Shh signaling, whereas downregulation of Dcdc2 expression enhances Wnt signaling, consistent with a functional role in ciliary signaling. Moreover, DCDC2 overexpression in C. elegans causes an abnormal neuronal phenotype that can only be seen in ciliated neurons. Together our results suggest a potential role for DCDC2 in the structure and function of primary cilia.

  • 33.
    Melik, Wessam
    Södertörn University, School of Life Sciences, Chemistry. Södertörn University, School of Life Sciences, Molecular biology.
    Molecular characterization of the Tick-borne encephalitis virus: Environments and replication2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The flavivirus genus is of major concern for world morbidity and mortality and includes viruses causing both encephalitic as well as hemorrhagic diseases. The incidence of Tick-borne encephalitis is increasing in many European countries and several reports have emphasized the expansion of the main vector, Ixodes ricinus. The pattern of vector distribution is also changing in Sweden, which makes it important to set up solid and successful strategies for detection and genetic characterization of novel Swedish TBEV strains.

    In this study we have generated strategies for detection of broad types of tick-borne flaviviruses in pools of I. ricinus sampled in Sweden.

    The positive collection on the island of Torö was used to generate a sequence of a complete TBEV genome straight from the arthropod reservoir. This cloned virus was used to construct a self-replicating DNA based sub-genomic TBEV replicon capable of expressing reporter genes. The replicon was used to study the effect of TBEV on neurite outgrowth, which revealed that the MTase domain of NS5 block the formation of the Scribble/Rac1/βPIX protein complex, impairing neurite outgrowth in neuronal growth factor induced PC12 cells.

    We also demonstrate that TBEV replication is affected by two PDZ binding motifs within NS5 and reveal putative PDZ binding proteins. These interactions might affect cellular pathways and might have a role in flavivirus replication.

    We also characterize the variable 3´ non-coding region (V3’-NCR) by in silico studies on TBEV. Analysis brings new evidence that V3’-NCR region carries an enhancer element important for different replication/translation dynamics during the viral lifecycle in mammalian and tick cells. We also propose a temperature-sensitive trans-acting riboswitch mechanism; altering the secondary RNA structures of a closed form at lower temperatures and a form open for translation at higher temperatures. This mechanism may explain the low TBEV level observed in sampled ticks.

  • 34.
    Melik, Wessam
    et al.
    Södertörn University, School of Life Sciences, Molecular biology. Södertörn University, School of Life Sciences, Chemistry.
    Ellencrona, Karin
    Södertörn University, School of Life Sciences.
    Wigerius, Michael
    Södertörn University, School of Life Sciences, Molecular biology. Södertörn University, School of Life Sciences, Chemistry.
    Elväng, Annelie
    Södertörn University, School of Life Sciences, Molecular biology.
    Hedström, Chister
    Södertörn University, School of Life Sciences, Molecular biology.
    Johansson, Magnus
    Södertörn University, School of Life Sciences, International health. Södertörn University, School of Life Sciences, Chemistry.
    Two PDZ binding motifs within NS5 have roles in Tick-borne encephalitis virus replication2012In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 169, no 1, 54-62 p.Article in journal (Refereed)
    Abstract [en]

    The flavivirus genus includes important human pathogens like Tick-borne encephalitis virus (TBEV), Dengue virus (DV) and West-Nile virus (WNV), that can cause severe disease e.g. encephalitis or hemorrhagic fever. The NS5 protein is a multifunctional RNA dependent RNA polymerase indispensable for the flavivirus replication. We have previously shown that TBEVNS5 contains a unique internal PDZ binding motif (YS223) for specific targeting of the PDZ protein Scribble. This interaction has impact on both viral down regulation of host cellular defense systems and neurite outgrowth. Putative C-terminal PDZ binding motifs present in TBEVNS5 (-SII903) and WNVNS5 (-TVL905) have also previously been highlighted.

    To determine whether the PDZ binding motifs of TBEVNS5 has an effect on virus replication we constructed a DNA based sub-genomic TBEV replicon expressing firefly luciferase. The motifs within NS5 were mutated individually and in concert and the replicons were assayed in cell culture. Our results show that the replication rate was impaired in all mutants, which indicates that PDZ dependent host interactions influence flavivirus replication.We also find that the C-terminal PDZ binding motif present in TBEVNS5 and WNVNS5 are targeting various human PDZ domain proteins. TBEVNS5 has high affinity to Zonulaoccludens-2 (ZO-2),GIAP C-terminus interacting protein (GIPC), Calcium/calmodulin-dependent serine protein kinase (CASK) and Interleukin 16 (IL-16).A different pattern was observed for WNVNS5 as it associated with IL-16, and several other putative interaction partners.

  • 35. Muhlenbock, Per
    et al.
    Szechynska-Hebda, Magdalena
    Plaszczyca, Marian
    Baudo, Marcela
    Mullineaux, Philip M.
    Parker, Jane E.
    Karpinska, Barbara
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Karpinski, Stanislaw
    Chloroplast Signaling and LESION SIMULATING DISEASE1 Regulate Crosstalk between Light Acclimation and Immunity in Arabidopsis2008In: The Plant Cell, ISSN 1040-4651, E-ISSN 1532-298X, Vol. 20, no 9, 2339-2356 p.Article in journal (Refereed)
    Abstract [en]

    Plants are simultaneously exposed to abiotic and biotic hazards. Here, we show that local and systemic acclimation in Arabidopsis thaliana leaves in response to excess excitation energy (EEE) is associated with cell death and is regulated by specific redox changes of the plastoquinone (PQ) pool. These redox changes cause a rapid decrease of stomatal conductance, global induction of ASCORBATE PEROXIDASE2 and PATHOGEN RESISTANCE1, and increased production of reactive oxygen species (ROS) and ethylene that signals through ETHYLENE INSENSITIVE2 (EIN2). We provide evidence that multiple hormonal/ROS signaling pathways regulate the plant's response to EEE and that EEE stimulates systemic acquired resistance and basal defenses to virulent biotrophic bacteria. In the Arabidopsis LESION SIMULATING DISEASE1 (lsd1) null mutant that is deregulated for EEE acclimation responses, propagation of EEE-induced programmed cell death depends on the plant defense regulators ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1) and PHYTOALEXIN DEFICIENT4 (PAD4). We find that EDS1 and PAD4 operate upstream of ethylene and ROS production in the EEE response. The data suggest that the balanced activities of LSD1, EDS1, PAD4, and EIN2 regulate signaling of programmed cell death, light acclimation, and holistic defense responses that are initiated, at least in part, by redox changes of the PQ pool.

  • 36. Mukherjee, K.
    et al.
    Brocchieri, L.
    Bürglin, Tomas R.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska institutet.
    A comprehensive classification and evolutionary analysis of plant homeobox genes2009In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 26, no 12, 2775-2794 p.Article in journal (Refereed)
    Abstract [en]

    The full complement of homeobox transcription factor sequences, including genes and pseudogenes, was determined from the analysis of 10 complete genomes from flowering plants, moss, Selaginella, unicellular green algae, and red algae. Our exhaustive genome-wide searches resulted in the discovery in each class of a greater number of homeobox genes than previously reported. All homeobox genes can be unambiguously classified by sequence evolutionary analysis into 14 distinct classes also characterized by conserved intron-exon structure and by unique codomain architectures. We identified many new genes belonging to previously defined classes (HD-ZIP I to IV, BEL, KNOX, PLINC, WOX). Other newly identified genes allowed us to characterize PHD, DDT, NDX, and LD genes as members of four new evolutionary classes and to define two additional classes, which we named SAWADEE and PINTOX. Our comprehensive analysis allowed us to identify several newly characterized conserved motifs, including novel zinc finger motifs in SAWADEE and DDT. Members of the BEL and KNOX classes were found in Chlorobionta (green plants) and in Rhodophyta. We found representatives of the DDT, WOX, and PINTOX classes only in green plants, including unicellular green algae, moss, and vascular plants. All 14 homeobox gene classes were represented in flowering plants, Selaginella, and moss, suggesting that they had already differentiated in the last common ancestor of moss and vascular plants.

  • 37. Muleta, Diriba
    et al.
    Assefa, Fassil
    Hjort, Karin
    Södertörn University, School of Life Sciences, Molecular biology.
    Roos, Stefan
    Granhall, Ulf
    Characterization of Rhizobacteria isolated from Wild Coffea arabica L.2009In: Engineering in Life Sciences, ISSN 1618-0240, E-ISSN 1618-2863, Vol. 9, no 2, 100-108 p.Article in journal (Refereed)
    Abstract [en]

    Rhizobacteria from wild Arabica coffee Populations (Coffea arabica L.) in southwestern Ethiopia were isolated and characterized. The main purpose was to identify coffee-associated rhizobacteria and evaluate their potential in synthesizing the phytohormone indole acetic acid (IAA) and in degrading the ethylene precursor 1-aminocyclopropane-1-carboxylate (ACC). A total of 878 bacterial isolates were screened, of which 395 (45%) isolates were preliminarily characterized using metabolic identification kits (API). Both Gram-negative and Gram-positive bacteria were isolated, with the former group predominating (63% of cases). Based on pre-screening results of the biochemical tests, 51 of the isolates were subjected to PCR-RFLP (Restriction Fragment Length Polymorphism) analysis that yielded ten groups, of which 24 isolates were identified by 16S rRNA gene sequencing. The major genera identified were Pseudomonas (six species) and Bacillus (four species). Single species of Erwinia, Ochrobactrum and Serratia were also identified. The Erwinia sp., Serratia marcescens and many Pseudomonas spp. produced IAA, and some isolates (all Pseudomonas spp.) were also able to degrade ACC. Several of the microbes found in association with wild Arabica coffee bushes have potential agronomic importance, like e.g. Bacillus thuringiensis, which deserve further testing. According to these in vitro Studies, Isolates of Erwinia, Serratia and Pseudomonas are of particular interest in inoculant development due to their plant growth promoting traits.

  • 38.
    Nilsson, Johan
    et al.
    Södertörn University, School of Life Sciences, Molecular biology.
    Grahn, Mats
    Södertörn University, School of Life Sciences, Environmental science. Södertörn University, School of Life Sciences, Biology.
    Wright, Anthony Ph
    Södertörn University, School of Life Sciences, Molecular biology.
    Proteome-wide evidence for enhanced positive Darwinian selection within intrinsically disordered regions in proteins2011In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, no 7, R65- p.Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: BACKGROUND: Understanding the adaptive changes that alter the function of proteins during evolution is an important question for biology and medicine. The increasing number of completely sequenced genomes from closely related organisms, as well as individuals within species, facilitates systematic detection of recent selection events by means of comparative genomics. RESULTS: We have used genome-wide strain-specific single nucleotide polymorphism data from 64 strains of budding yeast (Saccharomyces cerevisiae or Saccharomyces paradoxus) to determine whether adaptive positive selection is correlated with protein regions showing propensity for different classes of structure conformation. Data from phylogenetic and population genetic analysis of 3746 gene alignments consistently shows a significantly higher degree of positive Darwinian selection in intrinsically disordered regions of proteins compared to regions of alpha helix, beta sheet or tertiary structure. Evidence of positive selection is significantly enriched in classes of proteins whose functions and molecular mechanisms can be coupled to adaptive processes and these classes tend to have a higher average content of intrinsically unstructured protein regions. CONCLUSIONS: We suggest that intrinsically disordered protein regions may be important for the production and maintenance of genetic variation with adaptive potential and that they may thus be of central significance for the evolvability of the organism or cell in which they occur.

  • 39.
    Nugent, Rebecca L.
    et al.
    University of Southern California.
    Johnsson, Anna
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Intitutet.
    Fleharty, Brian
    Stowers Institute for Medical Research.
    Gogol, Madelaine
    Stowers Institute for Medical Research.
    Xue-Franzen, Yongtao
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Seidel, Chris
    Stowers Institute for Medical Research.
    Wright, Anthony P. H.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Forsburg, Susan L.
    University of Southern California.
    Expression profiling of S. pombe acetyltransferase mutants identifies redundant pathways of gene regulation2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, 59Article in journal (Refereed)
    Abstract [en]

    Background: Histone acetyltransferase enzymes (HATs) are implicated in egulation of transcription. HATs from different families may overlap in arget and substrate specificity. esults: We isolated the elp3(+) gene encoding the histone cetyltransferase subunit of the Elongator complex in fission yeast and haracterized the phenotype of an Delta elp3 mutant. We examined genetic nteractions between Delta elp3 and two other HAT mutants, Delta mst2 nd Delta gcn5 and used whole genome microarray analysis to analyze heir effects on gene expression. onclusions: Comparison of phenotypes and expression profiles in single, ouble and triple mutants indicate that these HAT enzymes have verlapping functions. Consistent with this, overlapping specificity in istone H3 acetylation is observed. However, there is no evidence for verlap with another HAT enzyme, encoded by the essential mst1(+) gene.

  • 40.
    Persson, Jenna
    et al.
    Karolinska Institutet.
    Ekwall, Karl
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Chd1 remodelers maintain open chromatin and regulate the epigenetics of differentiation2010In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 316, no 8, 1316-1323 p.Article in journal (Refereed)
    Abstract [en]

    Eukaryotic DNA is packaged around octamers of histone proteins into nucleosomes, the basic unit of chromatin. In addition to enabling meters of DNA to fit within the confines of a nucleus, the structure of chromatin has functional implications for cell identity. Covalent chemical modifications to the DNA and to histones, histone variants, ATP-dependent chromatin remodelers, small noncoding RNAs and the level of chromatin compaction all contribute to chromosomal structure and to the activity or silencing of genes. These chromatin-level alterations are defined as epigenetic when they are heritable from mother to daughter cell. The great diversity of epigenomes that can arise from a single genome permits a single, totipotent cell to generate the hundreds of distinct cell types found in humans. Two recent studies in mouse and in fly have highlighted the importance of Chd1 chromatin remodelers for maintaining an open, active chromatin state. Based on evidence from fission yeast as a model system, we speculate that Chd1 remodelers are involved in the disassembly of nucleosomes at promoter regions, thus promoting active transcription and open chromatin. It is likely that these nucleosomes are specifically marked for disassembly by the histone variant H2A.Z.

  • 41.
    Rahman, Mokhlasur
    et al.
    Södertörn University, School of Life Sciences, Molecular biology.
    Kylsten, Per
    Södertörn University, School of Life Sciences, Molecular biology.
    Rhomboid-7 over-expression results in Opa1-like processing and malfunctioning mitochondria2011In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 414, no 2, 315-320 p.Article in journal (Refereed)
    Abstract [en]

    Rhomboid-7 (rho-7) is a mitochondrial-specific intramembranous protease. The loss-of-function mutation rho-7 results in semi-lethality, while escapers have a reduced lifespan with several neurological disorders [1]. Here we show that general, or CNS-specific expression of rho-7 can rescue the lethality of rho-7. General, or CNS-specific over-expression of rho-7 in otherwise wild-type animals caused semi-lethality, with approximately 50% of the animals escaping this lethality, developing into adults displaying a shortened life span with larval locomotory problem. On a cellular level, over-expression resulted in severe depression of ATP levels and cytochrome c oxidase subunit II mRNA levels, a lowered number of mitochondria in neurons and aggregation of mitochondria in the brain indicating mitochondrial malfunction. Over-expression of rho-7 in developing eye discs resulted in an elevated apoptotic index. In the CNS, elevated levels of rho-7 were accompanied by both isoforms of Opal-like, a dynamin-like GTPase, a mitochondrial component involved in regulating mitochondrial dynamics and function, including apoptosis. Most, but not all, of rho-7 over-expression phenotypes were suppressed by introducing a heterozygous mutation for Opal-like. Our results suggest that rho-7 and Opal-like function in a common molecular pathway affecting mitochondrial function and apoptosis in Drosophila melanogaster.

  • 42.
    Reyhanian, Nasim
    et al.
    Södertörn University, School of Life Sciences, Environmental science. Södertörn University, School of Life Sciences, Molecular biology.
    Volkova, Kristina
    Södertörn University, School of Life Sciences, Environmental science.
    Hallgren, Stefan
    Södertörn University, School of Life Sciences, Environmental science. Södertörn University, School of Life Sciences, Biology.
    Bollner, Tomas
    Södertörn University, School of Life Sciences, Biology.
    Olsson, Per-Erik
    Olsén, K Håkan
    Södertörn University, School of Life Sciences, Environmental science. Södertörn University, School of Life Sciences, Biology.
    Porsch Hällström, Inger
    Södertörn University, School of Life Sciences, Environmental science. Södertörn University, School of Life Sciences, Molecular biology.
    17α-Ethinyl estradiol affects anxiety and shoaling behavior in adult male zebra fish (Danio rerio)2011In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 105, 41-48 p.Article in journal (Refereed)
  • 43. Rhind, Nicholas
    et al.
    Chen, Zehua
    Yassour, Moran
    Thompson, Dawn A.
    Haas, Brian J.
    Habib, Naomi
    Wapinski, Ilan
    Roy, Sushmita
    Lin, Michael F.
    Heiman, David I.
    Young, Sarah K.
    Furuya, Kanji
    Guo, Yabin
    Pidoux, Alison
    Chen, Huei Mei
    Robbertse, Barbara
    Goldberg, Jonathan M.
    Aoki, Keita
    Bayne, Elizabeth H.
    Berlin, Aaron M.
    Desjardins, Christopher A.
    Dobbs, Edward
    Dukaj, Livio
    Fan, Lin
    FitzGerald, Michael G.
    French, Courtney
    Gujja, Sharvari
    Hansen, Klavs
    Keifenheim, Dan
    Levin, Joshua Z.
    Mosher, Rebecca A.
    Mueller, Carolin A.
    Pfiffner, Jenna
    Priest, Margaret
    Russ, Carsten
    Smialowska, Agata
    Södertörn University, School of Life Sciences, Molecular biology.
    Swoboda, Peter
    Sykes, Sean M.
    Vaughn, Matthew
    Vengrova, Sonya
    Yoder, Ryan
    Zeng, Qiandong
    Allshire, Robin
    Baulcombe, David
    Birren, Bruce W.
    Brown, William
    Ekwall, Karl
    Södertörn University, School of Life Sciences, Molecular biology.
    Kellis, Manolis
    Leatherwood, Janet
    Levin, Henry
    Margalit, Hanah
    Martienssen, Rob
    Nieduszynski, Conrad A.
    Spatafora, Joseph W.
    Friedman, Nir
    Dalgaard, Jacob Z.
    Baumann, Peter
    Niki, Hironori
    Regev, Aviv
    Nusbaum, Chad
    Comparative Functional Genomics of the Fission Yeasts2011In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 332, no 6032, 930-936 p.Article in journal (Refereed)
    Abstract [en]

    The fission yeast clade-comprising Schizosaccharomyces pombe, S. octosporus, S. cryophilus, and S. japonicus-occupies the basal branch of Ascomycete fungi and is an important model of eukaryote biology. A comparative annotation of these genomes identified a near extinction of transposons and the associated innovation of transposon-free centromeres. Expression analysis established that meiotic genes are subject to antisense transcription during vegetative growth, which suggests a mechanism for their tight regulation. In addition, trans-acting regulators control new genes within the context of expanded functional modules for meiosis and stress response. Differences in gene content and regulation also explain why, unlike the budding yeast of Saccharomycotina, fission yeasts cannot use ethanol as a primary carbon source. These analyses elucidate the genome structure and gene regulation of fission yeast and provide tools for investigation across the Schizosaccharomyces clade.

  • 44. Rich, Rebecca L.
    et al.
    Papalia, Giuseppe A.
    Flynn, Peter J.
    Furneisen, Jamie
    Quinn, John
    Klein, Joshua S.
    Katsamba, Phini S.
    Waddell, M. Brent
    Scott, Michael
    Thompson, Joshua
    Berlier, Judie
    Corry, Schuyler
    Baltzinger, Mireille
    Zeder-Lutzi, Gabrielle
    Schoenemann, Andreas
    Clabbers, Anca
    Wieckowski, Sebastien
    Murphy, Mary M.
    Page, Phillip
    Ryan, Thomas E.
    Duffner, Jay
    Ganguly, Tanmoy
    Corbin, John
    Gautam, Satyen
    Anderluh, Gregor
    Bavdek, Andrej
    Reichmann, Dana
    Yadav, Satya P.
    Hommema, Eric
    Pol, Ewa
    Drake, Andrew
    Klakamp, Scott
    Chapman, Trevor
    Kernaghan, Dawn
    Miller, Ken
    Schuman, Jason
    Lindquist, Kevin
    Herlihy, Kara
    Murphy, Michael B.
    Bohnsack, Richard
    Andrien, Bruce
    Brandani, Pietro
    Terwey, Danny
    Millican, Rohn
    Darling, Ryan J.
    Wang, Liann
    Carter, Quincy
    Dotzlaf, Joe
    Lopez-Sagaseta, Jacinto
    Campbell, Islay
    Torreri, Paola
    Hoos, Sylviane
    England, Patrick
    Liu, Yang
    Abdiche, Yasmina
    Malashock, Daniel
    Pinkerton, Alanna
    Wong, Melanie
    Lafer, Eileen
    Hinck, Cynthia
    Thompson, Kevin
    Di Primo, Carmelo
    Joyce, Alison
    Brooks, Jonathan
    Torta, Federico
    Hagel, Anne Birgitte Bagge
    Krarup, Janus
    Pass, Jesper
    Ferreira, Monica
    Södertörn University, School of Life Sciences, Molecular biology.
    Shikov, Sergei
    Mikolajczyk, Malgorzata
    Abe, Yuki
    Barbato, Gaetano
    Giannetti, Anthony M.
    Krishnamoorthy, Ganeshram
    Beusink, Bianca
    Satpaev, Daulet
    Tsang, Tiffany
    Fang, Eric
    Partridge, James
    Brohawn, Stephen
    Horn, James
    Pritsch, Otto
    Obal, Gonzalo
    Nilapwar, Sanjay
    Busby, Ben
    Gutierrez-Sanchez, Gerardo
    Das Gupta, Ruchira
    Canepa, Sylvie
    Witte, Krista
    Nikolovska-Coleska, Zaneta
    Cho, Yun Hee
    D'Agata, Roberta
    Schlick, Kristian
    Calvert, Rosy
    Munoz, Eva M.
    Hernaiz, Maria Jose
    Bravman, Tsafir
    Dines, Monica
    Yang, Min-Hsiang
    Puskas, Agnes
    Boni, Erica
    Li, Jiejin
    Wear, Martin
    Grinberg, Asya
    Baardsnes, Jason
    Dolezal, Olan
    Gainey, Melicia
    Anderson, Henrik
    Peng, Jinlin
    Lewis, Mark
    Spies, Peter
    Trinh, Quyhn
    Bibikov, Sergei
    Raymond, Jill
    Yousef, Mohammed
    Chandrasekaran, Vidya
    Feng, Yuguo
    Emerick, Anne
    Mundodo, Suparna
    Guimaraes, Rejane
    McGirr, Katy
    Li, Yue-Ji
    Hughes, Heather
    Mantz, Hubert
    Skrabana, Rostislav
    Witmer, Mark
    Ballard, Joshua
    Martin, Loic
    Skladal, Petr
    Korza, George
    Laird-Offringa, Ite
    Lee, Charlene S.
    Khadir, Abdelkrim
    Podlaski, Frank
    Neuner, Phillippe
    Rothacker, Julie
    Rafique, Ashique
    Dankbar, Nico
    Kainz, Peter
    Gedig, Erk
    Vuyisich, Momchilo
    Boozer, Christina
    Ly, Nguyen
    Toews, Mark
    Uren, Aykut
    Kalyuzhniy, Oleksandr
    Lewis, Kenneth
    Chomey, Eugene
    Pak, Brian J.
    Myszka, David G.
    A global benchmark study using affinity-based biosensors2009In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 386, no 2, 194-216 p.Article in journal (Refereed)
    Abstract [en]

    To explore the variability in biosensor studies, 150 participants from 20 countries were given the same protein samples and asked to determine kinetic rate constants for the interaction. We chose a protein system that was amenable to analysis using different biosensor platforms as well as by users of different expertise levels. The two proteins (a 50-kDa Fab and a 60-kDa glutathione S-transferase [GST] antigen) form a relatively high-affinity complex, so participants needed to optimize several experimental parameters, including ligand immobilization and regeneration conditions as well as analyte concentrations and injection/dissociation times. Although most participants collected binding responses that could be fit to yield kinetic parameters, the quality of a few data sets could have been improved by optimizing the assay design. Once these outliers were removed, the average reported affinity across the remaining panel of participants was 620 pM with a standard deviation of 980 pM. These results demonstrate that when this biosensor assay was designed and executed appropriately, the reported rate constants were consistent, and independent of which protein was immobilized and which biosensor was used.

  • 45. Saheed, Sefiu A.
    et al.
    Jonsson, Lisbeth M. V.
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Botha, Christaan E. J.
    Russian wheat aphid causes greater reduction in phloem transport apacity of barley leaves than bird cherry-oat aphid.2010In: Acta Botanica Croatica, ISSN 0365-0588, Vol. 69, no 1, 7-18 p.Article in journal (Refereed)
    Abstract [en]

    The effects of feeding by the Russian wheat aphid (RWA). Dutraplu.s nom! ordvilko and the Bird cherry-oat aphid (BC A). Rhopaloppluan pad, L on he transport capacity of barley Holdeum vulgare L leaves were nvestigated and compated with a view to i-elan ng these effects to the isible symptoms shown by the respective infested plants RWA causes xtensive chlorosis and neciosis on an infested plant whereas I3CA auses no obseivable symptoms Our results using the xenobiotic. phloem obile Bum ophole. 5, 6 carboxyBurn escei n chacetate (5. 6-CFDA) evealed striking ch fletences in damage to the transpol t of ssimilates thiough the phloem by these two aphids The result clearly uggests that short-term feeding by RWA causes a reduction in tiansport f assimikites and a mole severe reduction oi pei haps even permanent essation of transport during long-term feed111,2. In contrast. feechntz y BCA does not lead to a !milked dect ease in transport do ring hort-term feeding period. howevei, a !eduction in the uanspoit was ecorded donne long-term feeding activities These iesults perhaps uggest that damage to ti ansport capacities of the barley leaves ppeals lobe partly responsible for the observed symptoms in WIA-infested plants and the lack of them during BCA in symptoms such as eduction ol cessation in transport of assionlates to growing tissues ay lead to such observable symptoms

  • 46. Saheed, Sefiu Adekilekun
    et al.
    Botha, Christiaan Edward Johannes
    Liu, Lin
    Jonsson, Lisbeth
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Comparison of structural damage caused by Russian wheat aphid (Diuraphis noxia) and Bird cherry-oat aphid (Rhopalosiphum padi) in a susceptible barley cultivar, Hordeum vulgare cv. Clipper2007In: Physiologia Plantarum: An International Journal for Plant Biology, ISSN 0031-9317, E-ISSN 1399-3054, Vol. 129, no 2, 429-435 p.Article in journal (Refereed)
    Abstract [en]

    The Russian wheat aphid (RWA, (Diuraphis noxia) and the Bird cherry-oat aphid (BCA, (Rhopalosiphum padi L.) cause severe damage to grain crops, including barley. An investigation of the effects of these aphids on a susceptible cultivar revealed that BCA-infested barley plants remained healthy looking for 2 weeks after feeding commenced. In contrast, signs of stress and damage, including chlorosis and leaf necrosis were evident in RWA-infested plants. Our study suggests that damage to the vascular tissue because of sustained feeding by BCA was not as extensive as that caused by RWA. In addition, there is a marked difference in the salivary secretion pattern within xylem elements punctured by aphids tapping the xylem for water. RWA deposit electron-dense, amorphous to smooth saliva, which completely encases the inner walls of affected elements, and saliva encases pit membranes between xylem elements, and between xylem vessels and xylem parenchyma. Xylem tapped by BCA contained more granular saliva, which apparently does not occlude vessel wall apertures or the pit membranes to the same extent, as was observed with RWA. Damage to phloem tissue, including phloem parenchyma elements, sieve tube-companion cell (CC-ST) complexes as well as thick-walled ST, was extensive. Plasmodesmata between phloem parenchyma elements as well as pore plasmodesmata between the CC and ST were occluded by callose. We conclude that severe, perhaps permanent damage to conducting elements in RWA-infested leaves may be responsible for the detrimental chlorosis and necrosis symptoms. These symptoms are absent in BCA-infested plants.

  • 47. Saheed, Sefiu
    et al.
    Cierlik, Izabela
    Södertörn University, School of Life Sciences.
    Larsson, Kristina A. E.
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Delp, Gabriele
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Bradley, Graeme
    Jonsson, Lisbeth M. V.
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Botha, Christiaan E. J.
    Stronger induction of callose deposition in barley by Russian wheat aphid than bird cherry-oat aphid is not associated with differences in callose synthase or beta-1,3-glucanase transcript abundance2009In: Physiologia Plantarum: An International Journal for Plant Biology, ISSN 0031-9317, E-ISSN 1399-3054, Vol. 135, no 2, 150-161 p.Article in journal (Refereed)
    Abstract [en]

    The effects of infestation by the bird cherry-oat aphid (BCA), (Rhopalosiphum padi L) and the Russian wheat aphid (RWA) (Diuraphis noxia Mordvilko) on callose deposition and transcription of genes related to callose accumulation were investigated in barley (Hordeum vulgare L. cv. Clipper). The BCA, which gives no visible symptoms, induced very limited callose deposition, even after 14 days of infestation. In contrast, RWA, which causes chlorosis, white and yellow streaking and leaf rolling, induced callose accumulation already after 24 h in longitudinal leaf veins. The deposition was pronounced after 72 h, progressing during 7 and 14 days of infestation. In RWA-infested source leaves, callose was also induced in longitudinal veins basipetal to the aphid-infested tissue, whereas in sink leaves, more callose deposition was found above the feeding sites. Eight putative callose synthase genes were identified in a database search, of which seven were expressed in the leaves, but with similar transcript accumulation in control and aphid-infested tissue. Five out of 12 examined beta-1,3-glucanases were expressed in the leaves. All five were upregulated in RWA-infested tissue, but only two in BCA-infested tissue, and to a lesser extent than by RWA. The results suggest that callose accumulation may be partly responsible for the symptoms resulting from RWA infestation and that a callose-inducing signal may be transported in the phloem. Furthermore, it is concluded that the absence of callose deposition in BCA-infested leaves is not because of a stronger upregulation of callose-degrading beta-1,3-glucanases in this tissue, as compared to RWA-infested leaves.

  • 48.
    Senti, Gabriele
    et al.
    Södertörn University, School of Life Sciences.
    Ezcurra, Marina
    Löbner, Jana
    Södertörn University, School of Life Sciences.
    Schafer, William R.
    Swoboda, Peter
    Södertörn University, School of Life Sciences, Molecular biology.
    Worms With a Single Functional Sensory Cilium Generate Proper Neuron-Specific Behavioral Output2009In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 183, no 2, 595-605 p.Article in journal (Refereed)
    Abstract [en]

    Studying the development and mechanisms of sensory perception is challenging in organisms with complex neuronal networks. The worm Caenorhabditis elegans possesses a simple neuronal network of 302 neurons that includes 60 ciliated sensory neurons (CSNs) for detecting external sensory input. C. elegans is thus an excellent model in which to study sensory neuron development., function, and behavior. We have generated a genetic rescue system that allows in vivo analyses of isolated CSNs at both cellular and systemic levels. We used the RFX transcription factor DAF-19, a key regulator of ciliogenesis. Mutations in daf-19 result in the complete absence of all sensory cilia and thus of external sensory input. In daf-19 mutants, we used cell-specific rescue of DAF-19 function in selected neurons, thereby generating animals with single, fully functional CSNs. Otherwise and elsewhere these animals are completely devoid of any environmental input through cilia. We demonstrated the rescue of fully functional, single cilia using fluorescent markers, sensory behavioral assays, and calcium imaging. Our technique, functional rescue in single sensory cilia (FRISSC), can thus cell-autonomously and cell-specifically restore the function of single sensory neurons and their ability to respond to sensory input. FRISSC can be adapted to many different CSNs and thus constitutes an excellent tool for studying sensory behaviors, both in single animals and in populations of worms. FRISSC will be Very useful for the molecular dissection of sensory perception in CSNs and for the analysis of the developmental aspects of ciliogenesis.

  • 49.
    Shiue, Chiounan N
    et al.
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Berkson, Rachel G.
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Wright, Anthony P H
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    c-Myc induces changes in higher order rDNA structure on stimulation of quiescent cells2009In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 28, no 16, 1833-1842 p.Article in journal (Refereed)
    Abstract [en]

    c-Myc is an oncogenic transcription factor capable of activating transcription by all three nuclear RNA polymerases, thus acting as a high-level coordinator of protein synthesis capacity and cell growth rate. c-Myc recruits RNA polymerase I-related transcription factors to the rDNA when quiescent cells are stimulated to re-enter the cell cycle. Using a model system of cell lines with variable c-Myc status, we show that on stimulation c-Myc rapidly induces gene loop structures in rDNA chromatin that juxtapose upstream and downstream rDNA sequences. c-Myc activation is both necessary and sufficient for this change in rDNA chromatin conformation. c-Myc activation induces association of TTF-1 with the rDNA, and c-Myc is physically associated with induced rDNA gene loops. The origins of two or more rDNA gene loops are closely juxtaposed, suggesting the possibility that c-Myc induces nucleolar chromatin hubs. Induction of rDNA gene loops may be an early step in the reprogramming of quiescent cells as they re-enter the growth cycle.

  • 50.
    Sinha, Indranil
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Intstitutet.
    Genome-wide patterns of histone modifications in fission yeast2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    DNA is wrapped almost two times around a group of proteins called histones to form a chromosomal structure known as the nucleosome. Both DNA and histones can be modified with different chemical tags by several enzymes to activate or suppress a particular gene or group of genes. Histones can be covalently modified at several places. Among many different types of post-translational histone modifications, histone acetylation and methylation are two important modification types that are associated with transcriptional activation and repression. Histone acetylation and methylation can be added by histone acetyltransferases (HATs) and histone methyletransferases (HMTs), whereas these modifications can be removed by histone deacetylases (HDACs) and histone demethylases (HDMs). Histone modifications are not only involved in the regulation of gene expression, but also in DNA-based processes, such as replication, repair, and the formation and maintenance of heterochromatin. Combinations of modified and unmodified states of histones can form distinct histone modification patterns. In many different genome-wide studies, it was observed that a distinctive pattern of histone modification in various organisms is important for gene regulation, DNA replication, chromosome segregation and heterochromatin-mediated silencing. In this thesis, we have conducted several genome-wide investigations to uncover different histone modification patterns and their roles in transcriptional control in fission yeast. Our analysis of six different HDACs in fission yeast showed that Clr6 and Clr3 are mainly involved in keeping repressed genes silent; Sir2 and Hst2 repress non-expressed genes, and Hst4 acts globally to reduce gene expression, whereas Hos2 is required for the activation of gene expression. By investigating the influence of each HDAC on nucleosome density, we found that all sirtuins and Hos2 enzymes are required to maintain normal nucleosome density and distribution in the S. pombe genome. We have reported that histone acetylation patterns show a 5` to 3` polarity, i.e., the modification levels peak near the ATG and gradually decrease in the coding regions. We also found that histone acetylation patterns depend on gene expression but are independent of gene length. Comparing our data with other published datasets, we observed that different HDAC mutants affect acetylation in different parts of open reading frames (ORFs). We have demonstrated that histone H4 acetylation proceeds in the direction from K16 to K5, consistent with a `zip` model that may be involved in transcriptional control. Our analysis revealed antagonistic crosstalk between H3K36me2/me3 and H3K27ac at promoter regions. We observed that histone H3 K18, K27 and K9 acetylation positively correlate with gene expression, and a conserved pattern was also reported in other organisms. Finally, we report that histone H4K20me1 is strongly linked to active genes, whereas H4K20me3 is associated with weakly expressed genes. Our analysis further shows that H4K20me1 modification levels peak at 3‟UTR regions in active genes. Thus, our analysis revealed many different aspects of histone modification patterns and their roles in transcriptional control in fission yeast.

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