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  • 201.
    Sloma, Marika Salonen
    et al.
    Södertörn University, Avdelning Naturvetenskap. Stockholm University.
    Nygård, Odd
    Södertörn University, Avdelning Naturvetenskap. Stockholm University.
    Possible interaction sites of mRNA, tRNA, translation factors and the nascent peptide in 5S, 5.8S and 28S rRNA in in vivo assembled eukaryotic ribosomal complexes2001In: Biochimica et Biophysica Acta, Gene Structure and Expression, ISSN 0167-4781, E-ISSN 1879-2634, Vol. 1521, no 1-3, p. 30-38Article in journal (Refereed)
    Abstract [en]

    We have investigated possible interaction sites for mRNA, tRNA. translation factors and the nascent peptide on 5S, 5.8S and 28S rRNA in in vivo assembled translational active mouse ribosomes by comparing the chemical footprinting patterns derived from native polysomes, salt-washed polysomes (mainly lacking translational factors) and salt-washed runoff ribosomes (lacking mRNA, tRNA and translational factors). Several ligand-induced footprints were observed in 28S rRNA while no reactivity changes were seen in 5S and 5.8S rRNA. Footprints derived from mRNA, tRNA and/or the nascent peptide chain were observed in domain I of 28S rRNA (hairpin 23), in domain II (helix 37/38 and helices 42 and 43 and in the eukaryotic expansion segment 15), in domain IV (helices 67 and 74) and in domain V (helices 94 and 96 and in the peptidyl transferase ring). Some of the protected sites were homologous to sites previously suggested to be involved in mRNA. tRNA and/or peptide binding in in vitro assembled prokaryotic complexes. Additional footprints were located in regions that have not previously been found involved in ligand binding. Part of these sites could derive from the nascent peptide in the exit channel of the ribosome.

  • 202.
    Slätt, Johnny
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Oxygenation of 2,3-dihydroindoles2002In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 58, no 45, p. 9187-9191Article in journal (Refereed)
    Abstract [en]

    Isatogens (3-oxo-3H-indole 1-oxides) possess interesting biological properties and development of a general method to construct these derivatives has now been developed. Indolines (2,3-dihydroindoles) and isatogens have been prepared in an efficient route starting from indoles substituted in position 2. Reduction of the 2-substituted indoles was performed with tin and hydrochloric acid to give racemic indolines, which were converted to isatogens by 3-chloroperoxybenzoic acid (m-CPBA).

  • 203. Smith, C I E
    et al.
    Islam, T C
    Mattsson, Pekka T
    Södertörn University, Avdelning Naturvetenskap.
    Mohamed, A J
    Nore, B F
    Vihinen, M
    The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species2001In: Bioessays, ISSN 0265-9247, E-ISSN 1521-1878, Vol. 23, no 5, p. 436-446Article in journal (Refereed)
    Abstract [en]

    Cytoplasmic protein-tyrosine kinases (PTKs) are enzymes involved in transducing a vast number of signals in metazoans, The importance of the Tec family of kinases was immediately recognized when, in 1993, mutations in the gene encoding Bruton's tyrosine kinase (Btk) were reported to cause the human disease X-linked agammaglobulinemia (XLA).((1,2)) Since then, additional kinases belonging to this family have been isolated, and the availability of full genome sequences allows identification of all members in selected species enabling phylogenetic considerations. Tec kinases are endowed with Pleckstrin homology (PH) and Tec homology (TH) domains and are involved in diverse biological processes related to the control of survival and differentiation fate, Membrane translocation resulting in the activation of Tec kinases with subsequent Ca2+ release seems to be a general feature, However, nuclear translocation may also be of importance, the purpose of this essay is to characterize members of the Tec family and discuss their involvement in signaling. The three-dimensional structure, expression pattern and evolutionary aspects will also be considered.

  • 204.
    Souter, Petra B.
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Cedhagen, T.
    Souter, D. W.
    Spatial distribution of the large foraminiferan Discobotellina biperforata, off the west shore of Moreton Island, Queensland, Australia2002In: Journal of Foraminiferal Research, ISSN 0096-1191, E-ISSN 1943-264X, Vol. 32, no 4, p. 448-452Article in journal (Refereed)
    Abstract [en]

    A hierarchical sampling study of the distribution of the large foraminiferan Discobotellina biperforata (Collins, 1958) was conducted along the west shore of Moreton Island, at Shark Spit and Tangalooma, in Moreton Bay, Queensland, between March and June 1995. D. biperforata is disc-shaped, with a test made up of organic matter, reinforced with sand grains. The species exhibits different test morphologies, the most abundant type being the biperforate which has two holes, or lunules, through its test. A less common type is the non-lunulate form, and the multiperforate and crescent-shaped types are rare. Possible abundance-substratum correlations were studied and the results indicated that D. biperforata is strongly correlated to a band of siltier and more organic-rich sediment found at the bottom of sand slopes running off Moreton Island. There was a significant difference in abundance between Tangalooma, where the mean abundance was 11.11 individuals per square meter (SD = 3.63) and Shark Spit, where it was found to be 7.73 individuals per square meter (SD = 3.06). No patchiness was apparent within the areas of siltier and organic-rich sediments. There was no significant difference in the ratio between the different forms within the areas sampled, but a size difference was apparent between locations, with larger specimens found at Tangalooma. The mean size of the specimens found was 27.7 mm in diameter. D. biperforata is the most abundant macrofaunal species in the area studied.

  • 205. Strand, Per
    et al.
    Beresford, Nick
    Avila, Rodolfo
    Jones, Steve R.
    Larsson, Carl-Magnus
    Agüero, A.
    Barnett, C.L.
    Brown, Justin
    Gilek, Michael
    Södertörn University College, Avdelning Naturvetenskap.
    Howard, B.J.
    Ilus, E.
    Kautsky, Ulrik
    Kumblad, L.
    Näslund, B.
    Patton, D.
    Robles, B.
    Sanchez, A.L.
    Saxén, R.
    Stenrud, H.
    Suañez, A.
    Wright, S.M.
    Identification of candidate referenceorganisms from a radiation exposurepathways perspective: FASSET deliverable 12001Report (Other academic)
  • 206.
    Strömblad, Staffan
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Fotedar, A
    Brickner, H
    Theesfeld, C
    de Diaz, E A
    Friedlander, M
    Cheresh, D A
    Loss of p53 compensates for alpha(v)-integrin function in retinal neovascularization2002In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 16, p. 13371-13374Article in journal (Refereed)
    Abstract [en]

    alpha(v)-Integrin antagonists block neovascularization in various species, whereas 20% of alpha(v)-integrin null mice are born with many normal looking blood vessels. Given that blockade of alpha(v)-integrins during angiogenesis induces p53 activity, we utilized p53 null mice to elucidate whether loss of p53 can compensate for av-integrin function in neovascularization of the retina. Murine retinal vascularization was inhibited by systemic administration of an alpha(v)-integrin antagonist. In contrast, mice lacking p53 were refractory to this treatment, indicating that neovascularization in normal mice depends on alpha(v)-integrin-mediated suppression of p53. Blockade of alpha(v)-integrins during neovascularization resulted in an induction of p21(CIP1) in wild type and, surprisingly, in p53 null retinas, indicating that alpha(v)-integrin ligation regulates p21(CIP1) levels in a p53-independent manner. In conclusion, we demonstrate for the first time an in vivo intracellular mechanism for compensation of integrin function and that p53 and alpha(v)-integrins act in concert during retinal neovascularization.

  • 207. Syed, M.
    et al.
    Vestrheim, O.
    Mikkelsen, B.
    Lundin, Maria
    Södertörn University, Avdelning Naturvetenskap. Norwegian Sch. of Veterinary Science, Oslo, Norway .
    Isolation of the promoters of Atlantic salmon MHCII genes2003In: Marine Biotechnology, ISSN 1436-2228, E-ISSN 1436-2236, Vol. 5, no 3, p. 253-260Article in journal (Refereed)
    Abstract [en]

    The major histocompatibility complex class II (MHCII) has a central role in the immune response of vertebrates with its function of presenting antigenic peptides to the T-cell receptors. We have isolated the promoters and intron 1 of MHCIIα and MHCIIβ genes of Atlantic salmon. To isolate these promoters, we constructed an Atlantic salmon (Salmo salar) promoter finder kit (analogous to the commercially available "human promoter finder kit"). By nucleotide sequence alignment of known MHCII promoter regions, we identified the 3 conserved regulatory X, X2, and Y boxes in the salmon promoters. The W box was not found. In contrast, a salmon-specific putative W box was identified. Both of the isolated Atlantic salmon MHCIIα and β promoters (included in patent applications by Genomar A/S, Oslo, Norway) were found to be functional since they both gave positive yellow fluorescence protein signal when inserted as promoters in the pEYFP-1 reporter plasmid and transfected into the salmon head kidney cell line (SHK-1).

  • 208. Tengö, Maria
    et al.
    Hammer, Monica
    Södertörn University College, Avdelning Naturvetenskap.
    Management practices for building adaptive capacity: a case from northern Tanzania2003In: Navigating social-ecological systems: building resilience for complexity and change / [ed] Fikret Berkes, Johan Colding and Carl Folke, 2003, p. 132-162Conference paper (Other academic)
  • 209.
    Thidholm, Ellinor
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Lindström, V
    Tissier, C
    Robinson, C
    Schröder, Wolfgang P
    Södertörn University, Avdelning Naturvetenskap.
    Funk, C
    Novel approach reveals localisation and assembly pathway of the PsbS and PsbW proteins into the photosystem II dimer2002In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 513, no 2-3, p. 217-222Article in journal (Refereed)
    Abstract [en]

    A blue-native gel electrophoresis system was combined with an in organello import assay to specifically analyse the location and assembly of two nuclear-encoded photosystem 11 (PSII) subunits. With this method we were able to show that initially the low molecular mass PsbW protein is not associated with the monomeric form of PSII. Instead a proportion of newly imported PsbW is directly assembled in dimeric PSH super-complexes with very fast kinetics; its negatively charged N-terminal domain is essential for this process. The chlorophyll-binding PsbS protein, which is involved in energy dissipation, is first detected in the monomeric PSII subcomplexes, and only at later time points in the dimeric form of PSII. It seems to be bound tighter to the PSII core complex than to light harvesting complex II. These data point to radically different assembly pathways for different PSII subunits.

  • 210. Thon, G
    et al.
    Bjerling, Pernilla
    Södertörn University, Avdelning Naturvetenskap.
    Bunner, C M
    Verhein-Hansen, J
    Expression-state boundaries in the mating-type region of fission yeast2002In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 161, no 2, p. 611-622Article in journal (Refereed)
    Abstract [en]

    A transcriptionally silent chromosomal domain is found in the mating-type region of fission yeast. Here we show that this domain is delimited by 2-kb inverted repeats, IR-I, and IR-R, IR-I, and IR-R prevent the expansion of transcription-permissive chromatin into the silenced region and that of silenced chromatin into the expressed region. Their insulator activity is partially orientation dependent. The silencing defects that follow deletion or inversion of IR-R are suppressed by high dosage of the chromodomain protein Swi6. Combining chromosomal deletions and Swi6 overexpression shows that IR-I, and IR-R provide firm borders in a region where competition between silencing and transcriptional competence occurs. IR-R possesses autonomously replicating sequence (ARS) activity, leading to a model where replication factors, or replication itself, participate in boundary formation.

  • 211. Unge, A
    et al.
    Jansson, Janet
    Södertörn University, Avdelning Naturvetenskap.
    Monitoring population size, activity, and distribution of gfp-luxAB-tagged Pseudomonas fluorescens SBW25 during colonization of wheat2001In: Microbial Ecology, ISSN 0095-3628, E-ISSN 1432-184X, Vol. 41, no 4, p. 290-300Article in journal (Refereed)
    Abstract [en]

    Increasingly, focus has been directed towards the use of microorganisms as biological control agents to combat fungal disease, as an alternative to chemical fungicides. Pseudomonas fluorescens SBW25 is one bacterial strain that has been demonstrated to promote plant growth by biocontrol of pathogenic fungi. To understand the mode of action of this bacterium, information regarding its localization and metabolic activity on plants is important. In this study, a gfp/luxAB-tagged derivative of P. fluorescens SBW25, expressing the green fluorescent protein (GFP) and bacterial luciferase, was monitored during colonization of wheat starting from seed inoculation. Since bacterial luciferase is dependent on cellular energy reserves for phenotypic expression, metabolically active cells were detected using this marker. In contrast, the stable GFP fluorescence phenotype was used to detect the cells independently of their metabolic status. The combination of these two markers enabled P. fluorescens SBW25 cells to be monitored on wheat plants to determine their specific location and metabolic activity. Studies on homogenized wheat plant parts demonstrated that the seed was the preferred location of P. fluorescens SBW25 during the 65-day time period studied, but the leaves and roots were also colonized. Interestingly, the bacteria were also found to be metabolically active on all plant parts examined. In situ localization of P. fluorescens SBW25 using a combination of different microscopic techniques confirmed the preference for the cells to colonize specific regions of the seed. We speculate that the colonization pattern of P. fluorescens SBW25 can be linked to the mechanism of protection of plants from fungal infection.

  • 212.
    Van Gijssel, Hilde E.
    et al.
    Leiden University, Leiden, The Netherlands.
    Ohlson, Lena C. E.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Torndal, Ulla-Britta
    Huddinge University Hospital, Karolinska Institute.
    Mulder, Gerard J.
    Leiden University, Leiden, The Netherlands.
    Eriksson, Lennart C.
    Huddinge University Hospital, Karolinska Institute.
    Porsch Hällström, Inger
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Meerman, John H N
    Huddinge University Hospital, Karolinska Institute.
    Loss of nuclear p53 protein in preneoplastic rat hepatocytes is accompanied by Mdm2 and Bcl-2 overexpression and by defective response to DNA damage in vivo2000In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 32, no 4, p. 701-710Article in journal (Refereed)
  • 213. Vargas, L
    et al.
    Nore, B F
    Berglöf, A
    Heinonen, J E
    Mattsson, P T
    Smith, C I E
    Mohamed, Abdalla J
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Functional interaction of caveolin-1 with Bruton's tyrosine kinase and Bmx2002In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 11, p. 9351-9357Article in journal (Refereed)
    Abstract [en]

    Bruton's tyrosine kinase (Btk), a member of the Tec family of protein-tyrosine kinases, has been shown to be crucial for B cell development, differentiation, and signaling. Mutations in the Btk gene lead to X-linked agammaglobulinemia in humans and X-linked immunodeficiency in mice. Using a co-transfection approach, we present evidence here that Btk interacts physically with caveolin-1, a 22-kDa integral membrane protein, which is the principal structural and regulatory component of caveolae membranes. In addition, we found that native Bmx, another member of the Tec family kinases, is associated with endogenous caveolin-1 in primary human umbilical vein endothelial cells. Second, in transient transfection assays, expression of caveolin-1 leads to a substantial reduction in the in vivo tyrosine phosphorylation of both Btk and its constitutively active form, E41K. Furthermore, a caveolin-1 scaffolding peptide (amino acids 82-101) functionally suppressed the autokinase activity of purified recombinant Btk protein. Third, we demonstrate that mouse splenic B-lymphocytes express substantial amounts of caveolin-1. Interestingly, caveolin-1 was found to be constitutively phosphorylated on tyrosine 14 in these cells. The expression of caveolin-1 in B-lymphocytes and its interaction with Btk may have implications not only for B cell activation and signaling, but also for antigen presentation.

  • 214. von Schantz, Torbjörn
    et al.
    Bensch, Staffan
    Grahn, Mats
    Södertörn University, Avdelning Naturvetenskap.
    Hasselquist, Dennis
    Wittzell, Håkan
    Good genes, oxidative stress and condition-dependent sexual signals1999In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 266, no 1414, p. 1-12Article in journal (Refereed)
    Abstract [en]

    The immune and the detoxication systems of animals are characterized by allelic polymorphisms, which underlie individual differences in ability to combat assaults from pathogens and toxic compounds. Previous studies have shown that females may improve offspring survival by selecting mates on the basis of sexual ornaments and signals that honestly reveal health. In many cases the expression of these ornaments appears to be particularly sensitive to oxidative stress. Activated immune and detoxication systems often generate oxidative stress by an extensive production of reactive metabolites and free radicals. Given that tolerance or resistance to toxic compounds and pathogens can be inherited, female choice should promote the evolution of male ornaments that reliably reveal the status of the bearers' level of oxidative stress. Hence, oxidative stress may be one important agent linking the expression of sexual ornaments to genetic variation in fitness-related traits, thus promoting the evolution of female mate choice and male sexual ornamentation, a controversial issue in evolutionary biology ever since Darwin.

  • 215. Wallberg, A E
    et al.
    Neely, K E
    Hassan, A H
    Gustafsson, J A
    Workman, J L
    Wright, Anthony P H
    Södertörn University, Avdelning Naturvetenskap.
    Recruitment of the SWI-SNF chromatin remodeling complex as a mechanism of gene activation by the glucocorticoid receptor tau 1 activation domain2000In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 20, no 6, p. 2004-2013Article in journal (Refereed)
    Abstract [en]

    The SWI-SNF complex has been shown to alter nucleosome conformation in an ATP-dependent manner, leading to increased accessibility of nucleosomal DNA to transcription factors. In this study, we show that the SWI-SNF complex can potentiate the activity of the glucocorticoid receptor (GR) through the N-terminal transactivation domain, tau 1, in both yeast and mammalian cells. GR-sl can directly interact with purified SWI-SNF complex, and mutations in tau 1 that affect the transactivation activity in vivo also directly affect tau 1 interaction with SWI-SNF. Furthermore, the SWI-SNF complex can stimulate tau 1-driven transcription from chromatin templates in vitro, Taken together, these results support a model in which the GR can directly recruit the SWI-SNF complex to target promoters during glucocorticoid-dependent gene activation. We also provide evidence that the SWI-SNF and SAGA complexes represent independent pathways of tau 1-mediated activation but play overlapping roles that are able to compensate for one another under some conditions.

  • 216. Wallberg, A E
    et al.
    Wright, Anthony P H
    Södertörn University, Avdelning Naturvetenskap.
    Gustafsson, J A
    Chromatin-remodeling complexes involved in gene activation by the glucocorticoid receptor2001In: Vitamines and Hormones, ISSN 0083-6729, Vol. 60, p. 75-122Article in journal (Refereed)
  • 217.
    Westerberg, Karolina
    et al.
    Stockholm University.
    Elväng, Annelie M
    Stockholm Unversity.
    Stackebrandt, E
    DSMZ–Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Germany.
    Jansson, Janet K
    Södertörn University, Avdelning Naturvetenskap.
    Arthrobacter chlorophenolicus sp nov., a new species capable of degrading high concentrations of 4-chlorophenol2000In: International Journal of Systematic and Evolutionary Microbiology, ISSN 1466-5026, E-ISSN 1466-5034, Vol. 50, p. 2083-2092Article in journal (Refereed)
    Abstract [en]

    A micro-organism was isolated from soil which could grow on high concentrations [up to 350 p.p.m. (2.7 mM)] of 4-chlorophenol (4-CP). The isolate, designated strain A6(T), was obtained from a soil suspension that had been selectively enriched with gradually increasing concentrations of 4-CP. Strain A6T could also grow on several other para-substituted phenols. Characterization of strain A6T with respect to chemical, biochemical and morphological properties, 16S rDNA sequencing and DNA-DNA hybridization indicated that the isolate is a novel species within the genus Arthrobacter for which the name Arthrobacter chlorophenolicus sp. nov. is proposed. The type strain is DSM 12829(T).

  • 218.
    Wiklund, Per
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Ring forming reactions of imines of 2-aminobenzaldehyde and related compounds2003In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 1, no 2, p. 367-372Article in journal (Refereed)
  • 219.
    Wiklund, Per
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Romero, Ivan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Products from dehydration of dicarboxylic acids derived from anthranilic acid2003In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 1, no 19, p. 3396-3403Article in journal (Refereed)
  • 220. Witt, A
    et al.
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Recent developments in the field of quinazoline chemistry2003In: Current organic chemistry, ISSN 1385-2728, E-ISSN 1875-5348, Vol. 7, no 7, p. 659-677Article in journal (Refereed)
    Abstract [en]

    Recent developments in the chemistry of quinazolines and quinazolinones are discussed. The chemistry of quinazoline alkaloids is reviewed featuring chrysogine, luotonin A, tryptanthrin, febrifugine. and rutaecarpine.

  • 221. Witt, A
    et al.
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap.
    Synthesis and reactions of some 2-vinyl-3H-quinazolin-4-ones2000In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 56, no 37, p. 7245-7253Article in journal (Refereed)
    Abstract [en]

    A simple, high-yielding synthesis of 2-vinyl-3H-quinazolin-4-one, 2-(1-chlorovinyl)-3H-quinazolin-4-one and 2-(1-bromovinyl)-3H-quinazolin-4-one. The 2-vinylquinazolinones 11a and 14 participate readily in nucleophilic addition reactions. Treatment with both carbon and nitrogen nucleophiles results in a clean conversion into a variety of 2-substituted 3H-quinazolin-4-one derivatives. The 2-(1-halovinyl)-3H-quinazolin-4-ones 11b and Ile reacted with carbon nucleophiles to give several derivatives of 2-substituted 3H-quinazolin-4-one, such as dihydrofurancarboxylic ethyl ester 23.

  • 222. Witt, A
    et al.
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Total syntheses of the benzodiazepine alkaloids circumdatin F and circumdatin C2001In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 66, no 8, p. 2784-2788Article in journal (Refereed)
    Abstract [en]

    Total syntheses of circumdatin F and circumdatin C, which both possess a 3H-quinazolin-4-one as well as a 1,4-benzodiazepin-5-one moiety, are described. A tripeptide derivative was synthesized as a key intermediate and dehydrated to a benzoxazine by reaction with triphenylphosphine, iodine, and a tertiary amine. The natural products were attained via rearrangements to an amidine intermediate, deprotection with 45% HBr in acetic acid, and cyclization on silica gel.

  • 223. Witt, A
    et al.
    Gustavsson, A
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Studies towards the synthesis of the benzodiazepine alkaloid auranthine. Synthesis of an acetylated derivative2003In: Journal of Heterocyclic Chemistry, ISSN 0022-152X, E-ISSN 1943-5193, Vol. 40, no 1, p. 29-35Article in journal (Refereed)
  • 224.
    Wramner, Per
    Södertörn University College, Avdelning Naturvetenskap, Coastal Management Research Center (COMREC).
    Levande kulturlandskap - en halvtidsutvärdering av Miljö- och landsbygdsprogrammet: betänkande av Landsbygdsutvärderingen2003Report (Other academic)
  • 225.
    Wramner, Per
    Södertörn University College, Avdelning Naturvetenskap, Coastal Management Research Center (COMREC).
    Tavvavuoma: tundra och fågelparadis2003In: Natur i nord: naturskydd i Norden under 1900-talet / [ed] Jon Suul, Kjell Samuelsson, Köpenhamn: Nordiska ministerrådet , 2003, p. 148-151Chapter in book (Other (popular science, discussion, etc.))
  • 226. Wärnmark, A
    et al.
    Treuter, E
    Wright, Anthony P H
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Gustafsson, J A
    Activation functions 1 and 2 of nuclear receptors: Molecular strategies for transcriptional activation2003In: Molecular Endocrinology, ISSN 0888-8809, E-ISSN 1944-9917, Vol. 17, no 10, p. 1901-1909Article in journal (Refereed)
    Abstract [en]

    Nuclear receptors (NRs) comprise a family of ligand inducible transcription factors. To achieve transcriptional activation of target genes, DNA-bound NRs directly recruit general transcription factors (GTFs) to the preinitiation complex or bind intermediary factors, so-called coactivators. These coactivators often constitute subunits of larger multiprotein complexes that act at several functional levels, such as chromatin remodeling, enzymatic modification of histone tails, or modulation of the preinitiation complex via interactions with RNA polymerase II and GTFs. The binding of NR to coactivators is often mediated through one of its activation domains. Many NRs have at least two activation domains, the ligand-independent activation function (AF)-1, which resides in the N-terminal domain, and the ligand-dependent AF-2, which is localized in the C-terminal domain. In this review, we summarize and discuss current knowledge regarding the molecular mechanisms of AF-1- and AF-2-mediated gene activation, focusing on AF-1 and AF-2 conformation and coactivator binding.

  • 227. Wärnmark, A
    et al.
    Wikström, Anja
    KTH.
    Wright, Anthony P H
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Gustafsson, J A
    Härd, T
    The N-terminal regions of estrogen receptor alpha and beta are unstructured in vitro and show different TBP binding properties2001In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, no 49, p. 45939-45944Article in journal (Refereed)
    Abstract [en]

    The N-terminal regions of the estrogen receptor ve (ER alpha -N) and beta (ER beta -N) were expressed and purified to homogeneity. Using NAM and circular dichroism spectroscopy, we conclude that both ER alpha -N and ER beta -N are unstructured in solution. The TATA box-binding protein (TBP) has been shown previously to interact with ERa-N in vitro and to potentiate ER-activated transcription. We used surface plasmon resonance and circular dichroism spectroscopy to confirm and further characterize the ER-N-TBP interaction. Our results show that the intrinsically unstructured ERa-N interacts with TBP, and suggest that structural changes are induced in ERa-N upon TBP interaction. Conformational changes upon target factor interaction have not previously been demonstrated for any N-terminal region of nuclear receptors. In addition, no binding of ER beta -N to TBP was detected. This difference in TBP binding could imply differential recruitment of target proteins by ERa-N and ER beta -N. The affinity of the ER alpha -N-TBP interaction was determined to be in the micromolar range (K-D = 10(-6) to 10(-5) m). Our results support models of TBP as a target protein for the N-terminal activation domain of ER alpha. Further, our results suggest that target proteins can induce and/or stabilize ordered structure in N-terminal regions of nuclear receptors upon interaction.

  • 228.
    Wärnmark, Anette
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Intsitute.
    Gustafsson, J A
    Karolinska Institute.
    Wright, Anthony P H
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Architectural principles for the structure and function of the glucocorticoid receptor tau 1 core activation domain2000In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 275, no 20, p. 15014-15018Article in journal (Refereed)
    Abstract [en]

    A 58-amino acid region mediates the core transactivation activity of the glucocorticoid receptor tau 1 activation domain. This tau 1 core domain is unstructured in aqueous buffers, but in the presence of trifluoroethanol three Alpha-helical segments are induced. Two of these putative structural modules have been tested in different combinations with regard to transactivation potential in vivo and binding capacity to the coactivators in vitro, The results show that whereas single modules are not transcriptionally active, any combination of two or three modules is sufficient, with trimodular constructs having the highest activity. However, proteins containing one, two, or three segments bind Ada2 and cAMP-response element-binding protein with similar affinity. A single segment is thus able to bind a target factor but cannot transactivate target genes significantly. The results are consistent with models in which activation domains are comprised of short activation modules that allow multiple interactions with coactivators. Our results also suggest that an increased number of modules may not result in correspondingly higher affinity but instead that the concentration of binding sites is increased, which gives rise to a higher association rate. This is consistent with a model where the association rate for activator-target factor interactions rather than the equilibrium constant is the most relevant measure of activator potency.

  • 229.
    Xia, Ling
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Björnstedt, M.
    Nordman, Tomas
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Eriksson, L. C.
    Olsson, J. M.
    Reduction of ubiquinone by lipoamide dehydrogenase: An antioxidant regenerating pathway2001In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 268, no 5, p. 1486-1490Article in journal (Refereed)
    Abstract [en]

    Lipoamide dehydrogenase belongs to a family of pyridine nucleotide disulfide oxidoreductases and is ubiquitous in aerobic organisms. This enzyme also reduces ubiquinone (the only endogenously synthesized lipid-soluble antioxidant) to ubiquinol, the form in which it functions as an antioxidant. The reduction of ubiquinone was linear with time and exhibited turnover numbers of 5 and 1.2 min-1 in the presence and absence of zinc, respectively. The reaction was stimulated by zinc and cadmium but not by the other divalent ions tested. The zinc/cadmium-dependent stimulation of the reaction increased rapidly and linearly up to a concentration of 0.1 mM and was even further increased at 0.5 mM. At pH 6, the activity was three times higher than at physiological pH. Alteration of the NADPH : NADP+ ratio revealed that the reaction is inhibited by higher concentrations of the oxidized cofactors. FAD reduced ubiquinone in a dose-dependent manner at a considerably lower rate, suggesting that the reduction of ubiquinone by lipoamide dehydrogenase involves the FAD moiety of the enzyme.

  • 230.
    Xia, Ling
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Nordman, Tomas
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Olsson, J M
    Damdimopoulos, A
    Björkhem-Bergman, L
    Nalvarte, I
    Eriksson, L C
    Arner, E S J
    Spyrou, Giannis
    Södertörn University, Avdelning Naturvetenskap. Karolinska Instiutet.
    Björnstedt, Mikael
    Karolinska Institutet.
    The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone - A novel mechanism for defense against oxidative stress2003In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 4, p. 2141-2146Article in journal (Refereed)
  • 231. Yang, Y
    et al.
    Griffiths, W J
    Nordling, M
    Nygren, Jonas
    Södertörn University, Avdelning Naturvetenskap. Karoliska Institute.
    Möller, L
    Bergman, Jan
    Liepinsh, E
    Otting, G
    Gustafsson, J A
    Rafter, J
    Sjövall, J
    Ring opening of benzo[a]pyrene in the germ-free rat is a novel pathway for formation of potentially genotoxic metabolites2000In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 39, no 50, p. 15585-15591Article in journal (Refereed)
    Abstract [en]

    The metabolism of benzo[a]pyrene (BP) is known to lead to a large number of oxygenated compounds, some of which can bind covalently to DNA. We have studied the integrated metabolism of BP in vivo in germ-free rats given C-14-labeled BP. Urinary metabolites were separated into groups according to acidity using lipophilic ion exchangers. The groups were analyzed by mass spectrometry and were further fractionated by high-performance liquid chromatography. The fraction of urinary metabolites previously shown to contain N-acetylcysteine and glucuronic acid conjugates was found to contain derivatives of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid as major components. These compounds, which were identified by mass spectrometry and NMR, accounted for about 30% of the total metabolites in urine, demonstrating that, surprisingly, ring opening is a major pathway for metabolism of BP in the germ-free rat. The dicarboxylic acid may be excreted in urine as an ester glucuronide. By using the single cell gel electrophoresis or COMET assay, we were able to demonstrate that the anhydride of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid was an efficient inducer of DNA damage. Taken together, these results indicate that the novel ring opening metabolic pathway may provide alternative mechanisms for the toxicity of BP.

  • 232. Yudina, Larisa N
    et al.
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Synthesis and alkylation of indolo[3,2-b]carbazoles2003In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 59, no 8, p. 1265-1275Article in journal (Refereed)
  • 233. Zhang, H Q
    et al.
    Li, Z L
    Viklund, E K
    Strömblad, Staffan
    Södertörn University, Avdelning Naturvetenskap.
    P21-activated kinase 4 interacts with integrin alpha v beta 5 and regulates alpha v beta 5-mediated cell migration2002In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 158, no 7, p. 1287-1297Article in journal (Refereed)
    Abstract [en]

    P21-activated kinase 1 (PAK1) can affect cell migration (Price et al., 1998; del Pozo et al., 2000) and modulate myosin light chain kinase and LIM kinase, which are components of the cellular motility machinery (Edwards, D.C., L.C. Sanders, G.M. Bokoch, and G.N. Gill. 1999. Nature Cell Biol. 1:253-259; Sanders, L.C., F. Matsumura, G.M. Bokoch, and P. de Lanerolle. 1999. Science. 283: 2083-2085). We here present a novel cell motility pathway by demonstrating that PAK4 directly interacts with an integrin intracellular domain and regulates carcinoma cell motility in an integrin-specific manner. Yeast two-hybrid screening identified PAK4 binding to the cytoplasmic domain of the integrin beta5 subunit, an association that was also found in mammalian cells between endogenous PAK4 and integrin alphavbeta5. Furthermore, we mapped the PAK4 binding to the membrane-proximal region of integrin beta5, and identified an integrin-binding domain at aa 505-530 in the COOH terminus of PAK4. Importantly, engagement of integrin alphavbeta5 by cell attachment to vitronectin led to a redistribution of PAK4 from the cytosol to dynamic lamellipodial structures where PAK4 colocalized with integrin alphavbeta5. Functionally, PAK4 induced integrin alphavbeta5-mediated, but not beta1-mediated, human breast carcinoma cell migration, while no changes in integrin cell surface expression levels were observed. In conclusion, our results demonstrate that PAK4 interacts with integrin alphavbeta5 and selectively promotes integrin alphavbeta5-mediated cell migration.

  • 234. Zhang, X F
    et al.
    Meining, Winfried
    Södertörn University, Avdelning Naturvetenskap.
    Cushman, M
    Haase, I
    Fischer, M
    Bacher, A
    Ladenstein, R
    A structure-based model of the reaction catalyzed by lumazine synthase from Aquifex aeolicus2003In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 328, no 1, p. 167-182Article in journal (Refereed)
    Abstract [en]

    6,7-Dimethyl-8-ribityllumazine is the biosynthetic precursor of riboflavin, which, as a coenzyme, plays a vital role in the electron transfer process for energy production in all cellular organisms. The enzymes involved in lumazine biosynthesis have been studied in considerable detail. However, the conclusive mechanism of the reaction catalyzed by lumazine synthase has remained unclear. Here, we report four crystal structures of the enzyme from the hyperthermophilic bacterium Aquifex aeolicus in complex with different inhibitor compounds. The structures were refined at resolutions of 1.72 Angstrom, 1.85 Angstrom, 2.05 Angstrom and 2.2 Angstrom, respectively. The inhibitors have been designed in order to mimic the substrate, the putative reaction intermediates and the final product. Structural comparisons of the native enzyme and the inhibitor complexes as well as the kinetic data of singlesite mutants of lumazine synthase from Bacillus subtilis showed that several highly conserved residues at the active site, namely Phe22, His88, Arg127, Lys135 and Glu138 are most likely involved in catalysis. A structural model of the catalytic process, which illustrates binding of substrates, enantiomer specificity, proton abstraction/donation, inorganic phosphate elimination, formation of the Schiff base and cyclization is proposed.

  • 235. Zhang, X F
    et al.
    Meining, Winfried
    Södertörn University, Avdelning Naturvetenskap.
    Fischer, M
    Bacher, A
    Ladenstein, R
    X-ray structure analysis and crystallographic refinement of lumazine synthase from the hyperthermophile Aquifex aeolicus at 1.6 angstrom resolution: Determinants of thermostability revealed from structural comparisons2001In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 306, no 5, p. 1099-1114Article in journal (Refereed)
    Abstract [en]

    An open reading frame optimized for expression of 6,7-dimethyl-8-ribityllumazine synthase of the hyperthermophilic bacterium Aquifex aeolicus in Escherichia coli was synthesized and expressed in a recombinant E. coli strain to a level of around 15%. The recombinant protein was purified by heat-treatment and gel-filtration. The protein was crystallized in the cubic space group 123 with the cell dimensions a = b = c = 180.8 Angstrom, and diffraction data were collected to 1.6 Angstrom resolution. The structure was solved by molecular replacement using lumazine synthase from Bacillus subtilis as search model. The structure of the A. aeolicus enzyme was refined to a resolution of 1.6 Angstrom. The spherical protein consists of 60 identical subunits with strict icosahedral 532 symmetry. The subunit fold is closely related to that of the B. subtilis enzyme (rmsd 0.80 Angstrom). The extremely thermostable lumazine synthase from A. aeolicus has a melting temperature of 119.9 degreesC. Compared to other icosahedral and pentameric lumazine synthases, the A. aeolicus enzyme has the largest accessible surface presented by charged residues and the smallest surface presented by hydrophobic residues. It also has the largest number of ion-pairs per subunit. Two ion-pair networks involving two, respectively three, stacking arginine residues assume a distinct role in linking adjacent subunits. The findings indicate the influence of the optimization of hydrophobic and ionic contacts in gaining thermostability.

2345 201 - 235 of 235
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