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  • 1. Adamsson, I
    et al.
    Edlund, Charlotta
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Nord, C E
    Microbial ecology and treatment of Helicobacter pylori infections: Review2000In: Journal of chemotherapy, ISSN 1120-009X, E-ISSN 1973-9478, Vol. 12, no 1, 5-16 p.Article, review/survey (Refereed)
    Abstract [en]

    The aims of the present study were to investigate the ecological disturbances caused by four different anti-H. pylori regimens, to compare different methods for diagnosing H. pylori, and to study the genetic variability of H. pylori. The patients included in the study were all treated at the Center of Gastroenterology, Huddinge University Hospital, Karolinska Institute. All patients were H. pylori-positive before entering the study, confirmed by rapid urease test, histology, culture and urea breath test or PCR. Treatment regimens included in the study were omeprazole alone (OP), in combination with amoxicillin (OA), in combination with amoxicillin and metronidazole (OAM) and in combination with clarithromycin and metronidazole (OCM). Samples from the mouth (saliva and dental plaque), stomach (biopsies from the gastric mucosa in the corpus and in the antrum) and the intestine (feces) were collected before, during and after treatment. The oral microflora was challenged by the three treatment regimens including antimicrobial agents, with the emergence of resistant streptococci and staphylococci in the OCM group. Bacterial strains in the gastric mucosa increased in numbers during treatment in all treatment groups, probably due to the pH rise, which provides a better environment for the commensal microflora. This overgrowth was especially pronounced during treatment with omeprazole alone (OP), possibly due to the fact that a concomitant suppression exerted by the antimicrobial agents occurred in the other treatment groups. H. pylori was, on the other hand, suppressed during treatment in all treatment groups, possibly due to a direct effect of omeprazole and to the colonization resistance expressed by the normal microflora, An emergence of resistant commensal strains in the gastric mucosa was seen in the OCM and the OAM groups. The intestinal microflora was most altered in the OAM and the OCM groups, with persistent disturbances in the OCM group 4 weeks after treatment. The frequency of resistant Enterococcus spp, (OCM), Enterobacteriaceae spp, (OA and OAM) and Bacteroides spp, (OCM) was increased during and after treatment. Different detection methods for H. pylori were compared and PCR was shown to have higher sensitivity than other routine diagnostic tests. The patients in the present study seemed to be colonized with a single strain of H. pylori. Treatment failures in patients treated with OAM were caused by recrudescence. These four patients with relapsing H. pylori infection, were shown to be reinfected with the original H. pylori strain, indicating that H. pylori escapes treatment by a thus far unknown mechanism.

  • 2. Adamsson, I
    et al.
    Edlund, Charlotta
    Södertörn University, Avdelning Naturvetenskap.
    Seensalu, R
    Engstrand, L
    The use of AP-PCR and flaA-RFLP typing to investigate treatment failure in Helicobacter pylori infection2000In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 6, no 5, 265-267 p.Article in journal (Refereed)
  • 3. Agvald-Öhman, C
    et al.
    Wernerman, J
    Nord, C E
    Edlund, Charlotta
    Södertörn University, Avdelning Naturvetenskap.
    Anaerobic bacteria commonly colonize the lower airways of intubated ICU patients2003In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 9, no 5, 397-405 p.Article in journal (Refereed)
    Abstract [en]

    Objectives To investigate respiratory tract colonization by aerobic and anaerobic bacteria in mechanically ventilated patients. Methods Bacterial colonization of the stomach and the respiratory tract was qualitatively and quantitatively analyzed over time in 41 consecutive mechanically ventilated patients in a Swedish intensive care unit (ICU), with special emphasis on elucidation of the role of anaerobic bacteria in the lower respiratory tract. Samples were taken from the oropharynx, gastric juice, subglottic space and trachea within 24 h (median 14 h) of intubation, and then every third day until day 18 and every fifth day until day 33. Results The patients were often heavily colonized with microorganisms not considered to belong to a healthy normal oropharyngeal and gastric flora on admission to the ICU. A majority harbored enterococci, coagulase-negative staphylococci and Candida spp. in at least one site on day 1. Anaerobic bacteria, mainly peptostreptococci and Prevotella spp., were isolated from subglottic and/or tracheal secretions in 59% of the patients. Different routes of tracheal colonization for different groups of microorganisms were found. Primary or concomitant colonization of the oropharynx with staphylococci, enterococci, enterobacteria and Candida was often seen, while Pseudomonas spp., other non-fermenting Gram-negative rods and several anaerobic species often primarily colonized the trachea, indicating exogenous or direct gastrointestinal routes of colonization. Conclusions Mechanically ventilated patients were heavily colonized in their lower airways by potential pathogenic microorganisms, including a high load of anaerobic bacteria. Different routes of colonization were shown for different species.

  • 4. Ahnström, G.
    et al.
    Nygren, Jonas
    Södertörn University, Avdelning Naturvetenskap. Karlinska Instiutet.
    Eriksson, S.
    The effect of dimethyl sulphoxide on the induction and repair of double-strand breaks in human cells after irradiation with γ-rays and accelerated ions: Rapid or slow repair may depend on accessibility of breaks in chromatin of different compactness2000In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 76, no 4, 533-538 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: The repair of double-strand breaks (dsb) in mammalian cells is characterized by a rapid phase with a half-life of less than half an hour and a slower phase that lasts for many hours. The proportion of slow repair increase with LET and it has been suggested that the slow repair component consists of more complex damage and is more deleterious to the cells. To see if removal of OH radicals could remove part of the damage in complex dsb and make them easier to repair, human cells were irradiated in the presence of dimethyl sulphoxide (DMSO). Methods: Induction and repair of dsb were studied by neutral elution in human VH10 cells exposed to γ-rays, helium ions (mean LET 40 keV/μm) and 80 and 125 keV/μm monoenergetic nitrogen ions in the presence and absence of 2 M DMSO. Results: Incubation of cells exposed to γ-rays, 40 keV/μm helium and 80 keV/μm N ions demonstrated that scavenging of OH radicals by DMSO removed most of the rapid repair component. The response to DMSO was less marked after 125 keV/μm nitrogen ions, where about half of the repair was resistant to DMSO. Conclusions: It is unlikely that the complexity of dsb is responsible for the slow repair because the removal of OH radicals did not make the breaks easier to repair. Instead, it is suggested that rapid and slow repair can be explained on the basis of how different parts of the chromatin are accessible to repair enzymes.

  • 5.
    Alheim, Katarina
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Corness, J
    Samuelsson, M K R
    Bladh, L G
    Murata, T
    Nilsson, T
    Okret, S
    Identification of a functional glucocorticoid response element in the promoter of the cylcin-dependant kinase inhibitor p57(Kip2)2003In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 30, no 3, 359-368 p.Article in journal (Refereed)
    Abstract [en]

    Glucocorticoids are known regulators of the cell cycle, normally exerting an anti-proliferative effect. We have previously shown that glucocorticoids stimulate expression of p57(Kip2), a member of the Cip/Kip family of cyclin-dependent kinase inhibitors which, in some cell types, may account for the anti-proliferative responses seen after glucocorticoid treatment. The induction of p57(Kip2) involves primary transcriptional effects where no de novo protein synthesis is necessary, suggesting a direct interaction of the glucocorticoid receptor with the p57(Kip2) gene. In this study we have identified a functional glucocorticoid response element (GRE), located 5 kilo bases (kb) upstream of the transcription start site in the human P57(Kip2) promoter. This GRE was functional also when isolated, suggesting a direct transcriptional effect of the glucocorticoid receptor. Furthermore, mutation of this GRE abolished glucocorticoid induction of the reporter gene, whereas mutation of a nearby Sp1 site did not. Using electrophoretic mobility shift assays, we have shown that the -5 kb p57(Kip2) promoter GRE was able to compete with a well-known GRE for glucocorticoid receptor binding. Sequence comparisons with the mouse genome showed that this GRE is highly conserved, further strengthening the biological importance of this site. All these data emphasize the involvement of this GRE in the glucocorticoid-mediated induction of p57(Kip2) expression.

  • 6.
    Alkemar, Gunnar
    et al.
    Södertörn University, Avdelning Naturvetenskap. Stockholm Universtiy.
    Nygård, Odd
    Södertörn University, Avdelning Naturvetenskap.
    A possible tertiary rRNA interaction between expansion segments ES3 and ES6 in eukaryotic 40S ribosomal subunits2003In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 9, no 1, 20-24 p.Article in journal (Refereed)
    Abstract [en]

    Eukaryotic 16S-like ribosomal RNAs contain 12 so-called expansion segments, i.e., sequences not included in the RNA secondary structure core common to eubacteria, archaea, and eukarya. Two of these expansion segments, ES3 and ES6, are juxtaposed in the recent three-dimensional model of the eukaryotic 40S ribosomal subunit. We have analyzed ES3 and ES6 sequences from more than 2900 discrete eukaryotic species, for possible sequence complementarity between the two expansion segments. The data show that ES3 and ES6 could interact by forming a helix consisting of seven to nine contiguous base pairs in almost all analyzed species. We, therefore, suggest that ES3 and ES6 form a direct RNA-RNA contact in the ribosome.

  • 7.
    Appelgren, Henrik
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Kniola, Barbara
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Ekwall, Karl
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Distinct centromere domain structures with separate functions demonstrated in live fission yeast cells2003In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 116, no 19, 4035-4042 p.Article in journal (Refereed)
    Abstract [en]

    Fission yeast (Saccharomyces pombe) centromere DNA is organized in a central core region flanked on either side by a region of outer repeat (otr) sequences. The otr region is known to be heterochromatic and bound by the Swi6 protein whereas the central core region contains an unusual chromatin structure involving the histone H3 variant Cnp1 (S. pombe CENP-A). The central core is the base for formation of the kinetochore structure whereas the flanking region is important for sister centromere cohesion. We have previously shown that the ultrastructural domain structure of S. pombe centromeres in interphase is similar to that of human centromeres. Here we demonstrate that S. pombe centromeres are organized in cytologically distinct domains even in mitosis. Fluorescence in situ hybridization of fixed metaphase cells revealed that the otr regions of the centromere were still held together by cohesion even after the sister kinetochores had separated. In live cells, the central cores and kinetochores of sister chromosomes could be distinguished from one Another when they were subjected to mitotic tension. The function of the different centromeric domains was addressed. Transacting mutations affecting the kinetochore (nuf2) central core domain (mis6) and the heterochromatin domain (rik1) were analyzed in live cells. In interphase, both nuf2 and mis6 caused declustering of centromeres from the spindle pole body whereas centromere clustering was normal in rik1 despite an apparent decondensation defect. The declustering of centromeres in mis6 cells correlated with loss the Ndc80 kinetochore marker protein from the centromeres. Interestingly the declustered centromeres were still restricted to the nuclear periphery thus revealing a kinetochore-independent peripheral localization mechanism for heterochromatin. Time-lapse microscopy of live mis6 and nuf2-1 mutant cells in mitosis showed similar severe misaggregation phenotypes whereas the rik1 mutants showed a mild cohesion defect. Thus, S. pombe centromeres have two distinguishable domains even during mitosis, and our functional analyses support the previous observations that the kinetochore/central core and the heterochromatin domains have distinct functions both in interphase and mitosis.

  • 8.
    Arabi, Azadeh
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Rustum, Cecilia
    Södertörn University, Avdelning Naturvetenskap. Stockholm University.
    Hallberg, Einar
    Södertörn University, Avdelning Naturvetenskap.
    Wright, Anthony P H
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Accumulation of c-Myc and proteasomes at the nucleoli of cells containing elevated c-Myc protein levels2003In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 116, no 9, 1707-1717 p.Article in journal (Refereed)
    Abstract [en]

    c-Myc is a predominately nuclear transcription factor that is a substrate for rapid turnover by the proteasome system. Cancer-related mutations in c-Myc lead to defects in its degradation and thereby contribute to the increase in its cellular level that is associated with the disease. Little is known about the mechanisms that target c-Myc to the proteasomes. By using a GFP fusion protein and live analysis we show that c-Myc shuttles between the nucleus and cytoplasm and thus it could be degraded in either compartment. Strikingly, at elevated levels of expression c-Myc accumulates at nucleoli in some cells, consistent with saturation of a nucleolus-associated degradation system in these cells. This idea is further supported by the observation that proteasome inhibitor treatment causes accumulation of c-Myc at the nucleoli of essentially all cells. Under these conditions c-Myc is relatively stably associated with the nucleolus, as would be expected if the nucleolus functions as a sequestration/degradation site for excess c-Myc. Furthermore, during elevated c-Myc expression or proteasome inhibition, nucleoli that are associated with c-Myc also accumulate proteasomes. c-Myc and proteasomes co-localise in intranucleolar regions distinct from the dense fibrillar component of the nucleolus. Based on these results we propose a model for c-Myc downregulation where c-Myc is sequestered at the nucleoli. Sequestration of c-Myc is accompanied by recruitment of proteasomes and may lead to subsequent degradation.

  • 9. Arnqvist, L
    et al.
    Dutta, P C
    Jonsson, Lisbeth
    Södertörn University, Avdelning Naturvetenskap.
    Sitbon, F
    Reduction of cholesterol and glycoalkaloid levels in transgenic potato plants by overexpression of a type 1 sterol methyltransferase cDNA2003In: Plant Physiology, ISSN 0032-0889, E-ISSN 1532-2548, Vol. 131, no 4, 1792-1799 p.Article in journal (Refereed)
    Abstract [en]

    Transgenic potato (Solanum tuberosum cv Desiree) plants overexpressing a soybean (Glycine max) type 1 sterol methyltransferase (GmSMT1) cDNA were generated and used to study sterol biosynthesis in relation to the production of toxic glycoalkaloids. Transgenic plants displayed an increased total sterol level in both leaves and tubers, mainly due to increased levels of the 24-ethyl sterols isofucosterol and sitosterol. The higher total sterol level was due to increases in both free and esterified sterols. However, the level of free cholesterol, a nonalkylated sterol, was decreased. Associated with this was a decreased glycoalkaloid level in leaves and tubers, down to 41% and 63% of wild-type levels, respectively. The results show that glycoalkaloid biosynthesis can be down-regulated in transgenic potato plants by reducing the content of free nonalkylated sterols, and they support the view of cholesterol as a precursor in glycoalkaloid biosynthesis.

  • 10.
    Articus, Kristina
    et al.
    Belgian Biodiversity Platform, Université Libre de Bruxelles.
    Wedin, Mats
    Naturhistoriska riksmuseet, Stockholm.
    Mattsson, Jan-Eric
    Södertörn University, Avdelning Naturvetenskap, Biology.
    Tibell, Leif
    Uppsala universitet.
    Grube, Martin
    Institute of plan sciences, University of Graz, Austria.
    Phylogenetic studies in Usnea.2000In: The Fourth IAL Symposium Progress and Problems in Lichenology at the Turn of the Millenium, Abstracts: 100. Barcelona., 2000Conference paper (Other academic)
  • 11. Backhed, F
    et al.
    Normark, S
    Schweda, Elke K H
    Södertörn University, Avdelning Naturvetenskap.
    Oscarson, S
    Richter-Dahlfors, A
    Structural requirements for TLR4-mediated LPS signalling: a biological role for LPS modifications2003In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 5, no 12, 1057-1063 p.Article in journal (Refereed)
    Abstract [en]

    Cells of the mucosal lining are the first to encounter invading bacteria during infection, and as such, they have developed numerous ways of detecting microbial intruders. Recently, we showed that epithelial cells recognize lipopolysaccharide (LPS) through the CD14-Toll-like receptor (TLR)-4 complex. Here, we identify the substructures of LPS that are recognized by the TLR4 receptor complex. In contrast to lipid A, the O-antigen does not mediate an inflammatory response; rather it interferes with the lipid A recognition. An Escherichia coli strain genetically modified to express penta-acylated lipid A not only showed reduced immunogenicity, but was also found to inhibit proinflammatory signalling induced by wild-type E. coli (hexa-acylated lipid A) as well as LPS from other bacteria of the Enterobacteriaceae family. Furthermore, penta-acylated LPS from Pseudomonas aeruginosa acted as an antagonist to hexa-acylated E. coli LPS, as did E. coli, as shown by its inhibitory effect on IL-8 production in stimulated cells. Hypo-acylated lipidA, such as that of P. aeruginosa, is found in several species within the gut microflora as well as in several bacteria causing chronic infections. Thus, our results suggest that the composition of the microflora may be important in modulating pro-inflammatory signalling in epithelial cells under normal as well as pathologic conditions.

  • 12. Bakhiet, M
    et al.
    Tjernlund, A
    Mousa, A
    Gad, Annica
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Strömblad, Staffan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Kuziel, W A
    Seiger, A
    Andersson, J
    RANTES promotes growth and survival of human first-trimester forebrain astrocytes2001In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 3, no 2, 150-157 p.Article in journal (Refereed)
    Abstract [en]

    We have examined the role of alpha and beta chemokines in the promotion of the ontogenetic development of the brain. RANTES was expressed preferentially in human fetal astrocytes in an age-dependent manner. Astrocytes from 5-week-old brains showed high proliferation and reduced survival, whereas 10-week-old astrocytes exhibited opposite effects. These effects were suppressed by anti-RANTES or anti-RANTES receptor antibodies and were enhanced by recombinant RANTES. RANTES induced tyrosine phosphorylation of several cellular proteins and nuclear translocation of STAT-1 in astrocytes. Interferons (IFN-gamma) was required for RANTES effects because RANTES induced IFN-gamma, and only 10-week-old astrocytes expressed the IFN-gamma receptor. Blocking of IFN-gamma with antibody reversed the effects of RANTES, indicating that cytokine/chemokine networks are critically involved in brain development.

  • 13. Bao, W J
    et al.
    Thullberg, M
    Zhang, H Q
    Onischenko, A
    Strömblad, Staffan
    Södertörn University, Avdelning Naturvetenskap.
    Cell attachment to the extracellular matrix induces proteasomal degradation of p21(CIP1) via Cdc42/Rac1 signaling2002In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 22, no 13, 4587-4597 p.Article in journal (Refereed)
    Abstract [en]

    The cyclin-dependent kinase 2 (Cdk2) inhibitors p21(CIP1) and p27(KIP1) are negatively regulated by anchorage during cell proliferation, but it is unclear how integrin signaling may affect these Cdk2 inhibitors. Here, we demonstrate that integrin ligation led to rapid reduction of p21(CIp1) and p27(KIP1) protein levels in three distinct cell types upon attachment to various extracellular matrix (ECM) proteins, including fibronectin (FN), or to immobilized agonistic anti-integrin monoclonal antibodies. Cell attachment to FN did not rapidly influence p21(CIp1) mRNA levels, while the protein stability of p21(CIp1) was decreased. Importantly, the down-regulation of p21(CIP1) and p27(KIP1) was completely blocked by three distinct proteasome inhibitors, demonstrating that integrin ligation induced proteasomal degradation of these Cdk2 inhibitors. Interestingly, ECM-induced proteasomal proteolysis of a ubiquitination-deficient p21(CIP1) mutant (p21K6R) also occurred, showing that the proteasomal degradation of p21(CIP1) was ubiquitin independent. Concomitant with our finding that the small GTPases Cdc42 and Rac1 were activated by attachment to FN, constitutively active (ca) Cdc42 and ca Rac1 promoted down-regulation of p21(CIP1). However, dominant negative (dn) Cdc42 and do Rac1 mutants blocked the anchorage-induced degradation of p21(CIP1), suggesting that an integrin-induced Cdc42/Rac1 signaling pathway activates proteasomal degradation of p21(CIP1). Our results indicate that integrin-regulated proteasomal proteolysis might contribute to anchorage-dependent cell cycle control.

  • 14.
    Bartish, Galyna I
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Jeppsson, N
    Bartish, I V
    Nybom, H
    Assessment of genetic diversity using RAPD analysis in a germplasm collection of sea buckthorn2000In: AGRICULTURAL AND FOOD SCIENCE IN FINLAND, ISSN 1239-0992, Vol. 9, no 4, 279-289 p.Article in journal (Refereed)
    Abstract [en]

    Random amplified polymorphic DNA (RAPD) markers were used to characterize a part of a sea buckthorn gene bank collected for plant breeding purposes. Molecular markers were generated in 55 cultivars and accessions, representing five subspecies of Hippophae rhamnoides L. and intraspecific hybrids between different subspecies. Sixty-three markers were used to generate a Dice's similarity coefficient matrix of pairwise comparisons between individual RAPD profiles. Cluster (UPGMA) and principal co-ordinate analyses, based on this matrix, revealed clustering of plants into groups which generally correspond to their taxonomic classification or geographic origin. The analysis of molecular variance (AMOVA) was found useful for estimating components of genetic variation between and within taxonomic and geographic groups of accessions and cultivars. Whereas both alternatives for grouping the material (taxonomic or geographic origin) resulted in significant between-group variation, the major part of molecular variance (approximately 75%) was still attributed to variation within groups. We conclude that the RAPD analysis is useful for clarification of taxonomic and geographic origin of accessions and cultivars of sea buckthorn.

  • 15. Bauer, S H J
    et al.
    Månsson, Martin
    Södertörn University, Avdelning Naturvetenskap.
    Hood, D W
    Richards, J C
    Moxon, E R
    Schweda, Elke K H
    Södertörn University, Avdelning Naturvetenskap.
    A rapid and sensitive procedure for determination of 5-N-acetyl neuraminic acid in lipopolysaccharides of Haemophilus influenzae: a survey of 24 non-typeable H-influenzae strains2001In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 335, no 4, 251-260 p.Article in journal (Refereed)
    Abstract [en]

    In view of the importance of 5-N-acetyl neuraminic acid in bacterial pathogenesis, a sensitive, reproducible and reliable method for the determination of 5-N-acetyl neuraminic acid levels in lipopolysaccharide (LPS) is described and applied to 24 different non-typeable Haemophilus influenzae (NTHi) strains. The method involves analysis by high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) of terminal 5-N-acetyl neuraminic acid residues released by neuraminidase treatment of O-deacylated LPS. The procedure is relatively fast and the instrumental effort is moderate. The results of the procedure were compared with data obtained by H-1 NMR and electrospray ionisation-mass spectrometry (ESI-MS). The analysis of LPS from 24 NTHi strains showed that 5-N-acetyl neuraminic acid was found to be a common constituent of LPS in NTHi. Only one strain (NTHi 432) did not show any sialylation. Molar ratios (LPS /5-N-acetyl neuraminic acid) ranged between 5/1 and 500/1. Several strains in which no 5-N-acetyl neuraminic acid could be determined by other methods including 1H NMR and ESI-MS were shown to contain 5-N-acetyl neuraminic acid by this HPAEC-PAD procedure. The method was applied to determine levels of terminal 5-N-acetyl neuraminic acid in LPS from NTHi strains grown under different conditions and mutant strains containing inactive LPS biosynthetic genes.

  • 16. Belyaev, I Y
    et al.
    Eriksson, S
    Nygren, Jonas
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute / Stockholm University.
    Torudd, J
    Harms-Ringdahl, M
    Effects of ethidium bromide on DNA loop organisation in human lymphocytes measured by anomalous viscosity time dependence and single cell gel electrophoresis1999In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1428, no 2-3, 348-356 p.Article in journal (Refereed)
    Abstract [en]

    The effects of ethidium bromide (EtBr) on human lymphocytes were studied by the method of anomalous viscosity time dependence (AVTD) and by the comet assay. EtBr at low concentrations increased the maximum viscosity and time of radial migration as measured with AVTD at neutral conditions of lysis. A pronounced relaxation of DNA loops was observed with the neutral comet assay. The maximal comet length corresponded to 2 Mb DNA loops. At high concentrations of EtBr, 2. mg/ml, significant reduction in AVTD below control level was seen that suggested hypercondensation of chromatin. The hypercondensation was directly observed with the neutral comet assay. EtBr did not induce DNA strand breaks as measured by the alkaline comet assay. The hypercondensed nuclei could be decondensed by irradiation with gamma-rays or exposure to light. The data provide evidence that EtBr at high concentrations resulted in hypercondensation of chromatin below control level. The comet assay confirmed that the increase in AVTD peaks deals with relaxation of loops and AVTD decrease is caused by chromatin condensation. The prediction of the AVTD theory for a correlation between time of radial migration and condensation of chromatin was verified. Further, the data show that the comet assay at neutral conditions of lysis is rather sensitive to DNA loop relaxation in the absence of DNA damage. Finally, donor specificity was found for the hypercondensation.

  • 17. Benach, J
    et al.
    Filling, C
    Oppermann, U C T
    Roversi, P
    Bricogne, G
    Berndt, Kurt D
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Jörnvall, H
    Ladenstein, R
    Structure of bacterial 3 beta/17 beta-hydroxysteroid dehydrogenase at 1.2 angstrom resolution: A model for multiple steroid recognition2002In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 41, no 50, 14659-14668 p.Article in journal (Refereed)
    Abstract [en]

    The enzyme 3beta/17beta-hydroxysteroid dehydrogenase (3beta/17beta-HSD) is a steroid-inducible component of the Gram-negative bacterium Conramonas testosteroni. It catalyzes the reversible reduction/ dehydrogenation of the oxo/beta-hydroxy groups at positions 3 and 17 of steroid compounds, including hormones and isobile acids. Crystallographic analysis at 1.2 Angstrom resolution reveals the enzyme to have nearly identical subunits that form a tetramer with 222 symmetry. This is one of the largest oligomeric structures refined at this resolution. The subunit consists of a monomer with a single-domain structure built around a seven-stranded beta-sheet flanked by six alpha-helices. The active site contains a Ser-Tyr-Lys triad, typical for short-chain dehydrogenases/reductases (SDR). Despite their highly diverse substrate specificities, SDR members show a close to identical folding pattern architectures and a common catalytic mechanism. In contrast to other SDR apostructures determined, the substrate binding loop is well-defined. Analysis of structure-activity relationships of catalytic cleft residues, docking analysis of substrates and inhibitors, and accessible surface analysis explains how 3beta/17beta-HSD accommodates steroid substrates of different conformations.

  • 18. Berg, H
    et al.
    Francis, J
    Souter, Petra
    Södertörn University, Avdelning Naturvetenskap.
    Support to marine research for sustainable management of marine and coastal resources in the Western Indian Ocean2002In: Ambio, ISSN 0044-7447, E-ISSN 1654-7209, Vol. 31, no 7-8, 597-601 p.Article in journal (Refereed)
  • 19. Bergander, L
    et al.
    Wahlström, Niklas
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Alsberg, T
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Rannug, A
    Rannug, U
    Characterization of in vitro metabolites of the aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b] carbazole by liquid chromatography-mass spectrometry and NMR.2003In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 31, no 2, 233-241 p.Article in journal (Refereed)
    Abstract [en]

    The tryptophan photoproduct 6-formylindolo[3,2-b] carbazole (FICZ) exhibits the highest aryl hydrocarbon receptor (AhR) binding affinity reported so far. In different cells, in vitro, both extracts of UV-irradiated tryptophan and the synthesized pure compound FICZ induce a rapid and transient expression of AhR-regulated genes. The transient induction suggests that the biotransformation gene battery induced by AhR activation takes part in a metabolic degradation of the ligand, whereby a low steady-state level is regained. The down-regulation of AhR-regulated gene expression was previously shown to be dependent on cytochrome P450 1A1 (CYP1A1). Metabolism of FICZ generates five major metabolites, which appeared as three peaks (M1-M3) in the high performance liquid chromatography. The aim of the present study was to use rat liver S9 from Aroclor-pretreated rats to produce large enough quantities of FICZ metabolites for structure characterization and to determine their product precursor relationship. NMR analysis of large combined fractions of the metabolites indicated that M3 and M2 contained 2 isomers, respectively. By means of liquid chromatography-mass spectrometry (negative ion electrospray mode) and NMR spectroscopy (by H-1-NMR, correlation spectroscopy, and nuclear Overhauser effect spectroscopy techniques) five metabolites of FICZ were identified, and their structures were elucidated. The molecular weights of the two M3 isomers were 300 and both M2 and M1 compounds demonstrated molecular weights of 316, corresponding to addition of one (M3) and of two oxygen (M2 and M1), respectively. The structures were assigned as 2- and 8-hydroxy (M3), 2,10- and 4,8-dihydroxy (M2) and 2,8-dihydroxy derivatives of indolo[3,2-b] carbazole-6-carboxaldehyde (6-formylindolo[ 3,2-b] carbazole).

  • 20. Bergh, F T
    et al.
    Flinn, Elisabeth M
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Svaren, J
    Wright, Anthony P
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Horz, W
    Comparison of nucleosome remodeling by the yeast transcription factor Pho4 and the glucocorticoid receptor2000In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 275, no 12, 9035-9042 p.Article in journal (Refereed)
    Abstract [en]

    Chromatin reorganization of the PHO5 and murine mammary tumor virus (MMTV) promoters is triggered by binding of either Pho4 or the glucocorticoid receptor (GR), respectively. In order to compare the ability of Pho4 and GR to remodel chromatin and activate transcription, hybrid promoter constructs were created by insertion of the MMTV B nucleosome sequence into the PHO5 promoter and then transformed into a yeast strain expressing GR, Activation of either Pho4 (by phosphate depletion) or GR (by hormone addition) resulted in only slight induction of hybrid promoter activity. However, simultaneous activation of both Pho4 and GR resulted in synergistic activation to levels exceeding that of the wild type PHO5 promoter. Under these conditions, Pho4 completely disrupted the nucleosome containing its binding site. In contrast, GR had little effect on the stability of the MMTV B nucleosome. A minimal transactivation domain of the GR fused to the Pho4 DNA-binding domain is capable of efficiently disrupting the nucleosome with a Pho4-binding site, whereas the complementary hybrid protein (Pho4 activation domain, GR DNA-binding domain) does not labilize the B nucleosome. Therefore, we conclude that significant activation by Pho4 requires nucleosome disruption, whereas equivalent transcriptional activation by GR is not accompanied by overt perturbation of nucleosome structure. Our results show that the DNA-binding domains of the two factors play critical roles in determining how chromatin structure is modified during promoter activation.

  • 21.
    Bergman, Jan
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Engqvist, Robert
    Karolinska Institute.
    Stålhandske, C
    Chemical Centre, Lund.
    Wallberg, H
    KTH.
    Studies of the reactions between indole-2,3-diones (isatins) and 2-aminobenzylamine2003In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 59, no 7, 1033-1048 p.Article in journal (Refereed)
  • 22.
    Bergman, Jan
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Janosik, T
    Koch, E
    Pelcman, B
    Acid-induced dimerization of 3-(1H-indol-3-yl)maleimides. Formation of cyclopentindole derivatives2000In: JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, ISSN 1470-4358, no 16, 2615-2621 p.Article in journal (Refereed)
    Abstract [en]

    Acid-induced dimerizations of 3-substituted maleimides have been investigated, leading to e.g. the cyclopentindole 9 and the deeply coloured spiro compounds 24 and 25 in good yields. 3-(1H-Indol-3-yl)maleimide 6b readily gave the cycloaddition products 13-15 on treatment with appropriate dienophiles. In addition, several related 3,3-di-(1H-indol-3-yl)succinimides have been prepared and studied.

  • 23.
    Bergman, Jan
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Janosik, T
    Yudina, L
    Desarbre, E
    Lidgren, G
    Venemalm, L
    Reactions of 1,2-bis(1H-indol-2-yl)ethane: Formation of indolo[2,3-c]carbazole and cyclohept[1,2-b : 5,4-b ']bisindole derivatives2000In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 56, no 13, 1911-1916 p.Article in journal (Refereed)
    Abstract [en]

    1,2-Bis(1H-indol-2-yl)ethane (9) has been prepared and converted into indolo[2,3-c]carbazole (8) using palladium acetate in refluxing acetic acid. Reaction of 9 with CoF3 in hot TFA led to isolation of cyclohept[1,2-b:5,4-b']bisindole derivatives 11 and 12, which could be elaborated into further derivatives. Treatment of 9 with orthoesters, aldehydes and ketones under acidic conditions afforded additional bisindoles containing a seven-membered ring.

  • 24.
    Bergman, Jan
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Janosik, Tomasz
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Recent progress in the chemistry of sulfur-containing indoles2002In: Progress in Heterocyclic Chemistry, ISSN 0959-6380, Vol. 14, no C, 1-18 p.Article in journal (Refereed)
  • 25.
    Bergman, Jan
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Koch, E
    Pelcman, B
    Coupling reactions of indole-3-acetic acid derivatives. Synthesis of arcyriaflavin A2000In: JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, ISSN 1470-4358, no 16, 2609-2614 p.Article in journal (Refereed)
    Abstract [en]

    The bisindolesuccinic acid methyl ester 10 was obtained by an iodine-promoted coupling of the dianion 9. The diester was converted to the N-benzylimide 12, which was oxidatively cyclized to the indolo[2,3-a]pyrrolo[3,4-c]carbazole 15. The diester 10 could be directly transformed to the known indolocarbazole diester 27 via acid-induced intramolecular cyclization in TFA. The same methodology gave arcyriaflavin A 4 from the succinimide 18b.

  • 26.
    Bergman, Jan
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Rehn, S
    Synthesis of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester and its isomer 1-oxo-2,9-dihydro-1H-beta-carboline-4-carboxylic acid ethyl ester2002In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 58, no 45, 9179-9185 p.Article in journal (Refereed)
    Abstract [en]

    4-Oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester was obtained when TosMIC was reacted with 3-methylene-oxindole acetic acid ethyl ester. An alternative synthesis to this pyrroloquinolone was performed via a reduction of a 2,3,4-trisubstituted pyrrole obtained in turn by treatment of a vinyl sulfone with ethyl isocyanoacetate under basic conditions. A beta-carboline, isomeric with the pyrroloquinolone, was synthesised utilizing a tosylimine.

  • 27.
    Bergman, Jan
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Wahlström, Niklas
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Yudina, L N
    Tholander, J
    Lidgren, G
    Synthesis of indolocarbazole quinones; potent aryl hydrocarbon receptor ligands2002In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 58, no 7, 1443-1452 p.Article in journal (Refereed)
    Abstract [en]

    Syntheses of indolo[2,3-b]carbazole-6,12-dione and the isomeric indolo[3,2-b]carbazole-6,12-dione, an extremely efficient inducer of the aryl hydrocarbon (Ah) receptor are described. Initial oxidation of the parent indolo[3,2-b]carbazole followed by several different ring-closing strategies produced the latter compound. Entries into syntheses of unsymmetrical 6,12-disubstituted indolo[2,3-b]carbazoles are also described.

  • 28.
    Bjerling, Pernilla
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Ekwall, Karl
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Centromere domain organization and histone modifications2002In: Brazilian journal of medical and biological research, ISSN 0100-879X, E-ISSN 1414-431X, Vol. 35, no 5, 499-507 p.Article in journal (Refereed)
    Abstract [en]

    Centromere function requires the proper coordination of several subfunctions, such as kinetochore assembly, sister chromatid cohesion, binding of kinetochore microtubules, orientation of sister kinetochores to opposite spindle poles, and their movement towards the spindle poles. Centromere structure appears to be organized in different, separable domains in order to accomplish these functions. Despite the conserved nature of centromere functions, the molecular genetic definition of the DNA sequences that form a centromere in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, in the fruit fly Drosophila melanogaster, and in humans has revealed little conservation at the level of centromere DNA sequences. Also at the protein level few centromere proteins are conserved in all of these four organisms and many are unique to the different organisms. The recent analysis of the centromere structure in the yeast S. pombe by electron microscopy and detailed immunofluorescence microscopy of Drosophila centromeres have brought to light striking similarities at the overall structural level between these centromeres and the human centromere. The structural organization of the centromere is generally multilayered with a heterochromaun domain and a central core/inner plate region, which harbors the outer plate structures of the kinetochore. It is becoming increasingly clear that the key factors for assembly and function of the centromere structure are the specialized histories and modified histones which are present in the centromeric heterochromatin and in the chromatin of the central core. Thus, despite the differences in the DNA sequences and the proteins that define a centromere, there is an overall structural similarity between centromeres in evolutionarily diverse eukaryotes.

  • 29.
    Bjerling, Pernilla
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Silverstein, Rebecca A
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Thon, G
    Caudy, A
    Grewal, S
    Ekwall, Karl
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Functional divergence between histone deacetylases in fission yeast by distinct cellular localization and in vivo specificity2002In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 22, no 7, 2170-2181 p.Article in journal (Refereed)
    Abstract [en]

    Histone deacetylases (HDACs) are important for gene regulation and the maintenance of heterochromatin in eukaryotes. Schizosaccharomyces pombe was used as a model system to investigate the functional divergence within this conserved enzyme family. S. pombe has three HDACs encoded by the hda1(+), clr(3+), and clr6(+) genes. Strains mutated in these genes have previously been shown to display strikingly different phenotypes when assayed for viability, chromosome loss, and silencing. Here, conserved differences in the substrate binding pocket identify Clr6 and Hda1 as class I HDACs, while Clr3 belongs in the class II family. Furthermore, these HDACs were shown to have strikingly different subcellular localization patterns. Hda1 was localized to the cytoplasm, while most of Clr3 resided throughout the nucleus. Finally, Clr6 was localized exclusively on the chromosomes in a spotted pattern. Interestingly, Clr3, the only HDAC present in the nucleolus, was required for ribosomal DNA (rDNA) silencing. Clr3 presumably acts directly on heterochromatin, since it colocalized with the centromere, mating-type region, and rDNA as visualized by in situ hybridization. In addition, Clr3 could be cross-linked to mat3 in chromatin immunoprecipitation experiments. Western analysis of bulk histone preparations indicated that Hda1 (class I) had a generally low level of activity in vivo and Clr6 (class 1) had a high level of activity and broad in vivo substrate specificity, whereas Clr3 (class II) displayed its main activity on acetylated lysine 14 of histone H3. Thus, the distinct functions of the S. pombe HDACs are likely explained by their distinct cellular localization and their different in vivo specificities.

  • 30.
    Bredenberg, Johan
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Nilsson, L
    Karolinska Institutet.
    Conformational states of the glucocorticoid receptor DNA-binding domain from molecular dynamics simulations2002In: Proteins: Structure, Function, and Genetics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 49, no 1, 24-36 p.Article in journal (Refereed)
    Abstract [en]

    Molecular dynamics simulations (MD) have been performed on variant crystal and NMR-derived structures of the glucocorticoid receptor DNA-binding domain (GR DBD). A loop region five residues long, the so-called D-box, exhibits significant flexibility, and transient perturbations of the tetrahedral geometry of two structurally important Cys4 zinc finger are seen, coupled to conformational changes in the D-box. In some cases, one of the Cys ligands to zinc exchanges with water, although no global distortion of the protein structure is observed. Thus, from MD simulation, dynamics of the D-box could partly be explained by solvent effects in conjunction with structural reformation of the zinc finger.

  • 31.
    Bredenberg, Johan
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Nilsson, L
    Modeling zinc sulfhydryl bonds in zinc fingers2001In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 83, no 3-4, 230-244 p.Article in journal (Refereed)
    Abstract [en]

    Molecular dynamics simulations have been carried out employing three different model descriptions of the zinc sulfhydryl interactions in class II fingers. One bonded and two nonbonded models were studied. Two variant structures of the glucocorticoid receptor DNA-binding; domain and a NMR structure from a fragment of methionyl-tRNA synthetase were subjected to long-time MD simulations with these models. Our analysis is focused on comparison with experimental and quantum mechanical data, concerning the local Zn-finger and overall structural and dynamic properties for these models. All models performed M ell, but the nonbonded models appeared to reproduce the protein dynamics in better agreement with experimental data than does the bonded description.

  • 32. Brenden, N.
    et al.
    Böhme, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Differential MHC expression requirements for positive selection of separate TCR Vb families1999In: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 49, no 1, 1-6 p.Article in journal (Refereed)
    Abstract [en]

    Positive selection has been proposed to be involved in protection from diabetes. We examined positive selection by fluorescence-activated cell sorter analyses in thymocytes of protected and susceptible E-transgenic and non-transgenic NOD mice. Three Vb families showed positive selection in E-transgenic mice. Vb6+CD4+ and Vb10+CD4+ thymocytes were found at higher frequencies in both protected NOD-Ea and susceptible NOD-DY mice. The increased frequencies of Vb13+CD8+ thymocytes were found in protected NOD-Ea mice only, and not in susceptible NOD-DY transgenic mice. These three Vb families were further examined in bone-marrow chimeras between NOD-Ea and non-transgenic NOD mice, where we could examine the contribution of E-expressing bone-marrow-derived cells in positive selection. We find that NOD-Ea→NOD-Ea chimeras have an increased positive selection of Vb13+CD8+ cells and that positive selection is more efficient when both thymic epithelium and bone-marrow-derived cells express the E molecule. This was also seen for Vb6+CD4+ cells. However, for Vb6, bone-marrow-derived cells alone were also capable of positive selection. Positive selection of Vb10+CD4+ cells was restricted to E-expressing thymic epithelium only. For Vb13+CD8+ cells, we found that positive selection is most efficient with E-expression on both thymic epithelium and bone-marrow-derived cells, although positive selection also occurs with E-positive epithelium only. For Vb6+CD4+ cells, the dominating selecting cells are bone-marrow-derived cells, and Vb10+CD4+ cells seem to be selected exclusively by the thymic epithelium. Thus, the conditions for positive selection seem to vary considerably between different Vb families.

  • 33. Brenden, N.
    et al.
    Böhme, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Disease-protected major histocompatibility complex Ea-transgenic non- obese diabetic (NOD) mice show interleukin-4 production not seen in susceptible Ea-transgenic and non-transgenic NOD mice1998In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 95, no 1, 1-7 p.Article in journal (Refereed)
    Abstract [en]

    The non-obese diabetic (NOD) mouse is an animal model for insulin- dependent diabetes that has many similarities to the human disease. NOD mice transgenic for the Ea gene, allowing expression of the E molecule, are protected from diabetes and rarely develop insulitis. An Ea transgene mutated in the promoter region, (ΔY) lacks E expression on most B cells, thymic medullary epithelium and primary antigen-presenting cells, and confers no protection whatsoever. We have used these transgenic NOD mice, together with non-transgenic NOD mice, to study the correlation of E expression and production of interleukin-4 (IL-4) and interferon-γ (IFN-γ). We show that protected E-transgenic NOD mice have elevated levels of IL-4 compared with non-transgenic mice, both in the thymus and in the periphery. However, susceptible ΔY-transgenic mice have elevated thymic IL-4 levels, but express almost as little IL-4 as non-transgenic NOD mice in the periphery. This drop in peripheral IL-4 production seen in ΔY-transgenic mice thus correlates with the decreased E expression in the periphery of ΔY-transgenic NOD mice. In contrast, there were no differences in IFN-γ production between the three NOD lines. We suggest that Ea-transgenic NOD mice have E-selected regulatory T cells producing IL-4, which are subsequently activated by E-expressing primary antigen-presenting cells in the periphery. This activation would then be instrumental for the E-mediated protection from disease in NOD mice. Such a process would explain the total absence of protection in ΔY-transgenic NOD mice, despite their widespread E expression.

  • 34. Brenden, N.
    et al.
    Rietz, C.
    Böhme, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    E expression is needed on both bone marrow derived cells and thymic epithelium to increase IL-4 production and achieve protection in NOD bone marrow chimeras1999In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 11, no 10, 766-772 p.Article in journal (Refereed)
    Abstract [en]

    The NOD mouse is an animal model for insulin-dependent diabetes with many similarities to the human disease. NOD mice which are transgenic for the Ea gene, allowing expression of the E molecule, are protected from diabetes and rarely develop insulitis. We have constructed bone marrow chimeras between transgenic and non-transgenic NOD mice to study the correlation of E expression on bone marrow derived cells and thymic epithelium vs the production of IL-4 and IFN-γ. We show that NOD-E→NOD-E and NOD-E→NOD chimeras have elevated levels of IL-4 compared to NOD→NOD and NOD→NOD-E chimeras in the thymus. However, in the periphery the protected NOD-E→NOD-E show much higher IL-4 levels than any of the other chimeras. This drop in peripheral IL-4 production seen in NOD-E→NOD, NOD→NOD-E and NOD→NOD chimeras correlates with the increased insulitis seen in these mice compared to NOD-E→NOD-E. In contrast, there were no differences in IFN-γ production between the chimeras. We suggest that the precommitted, regulatory T cells, selected in an E-expressing thymic environment, need continuous interaction with E-expressing primary antigen presenting cells in the periphery for optimal IL-4 production. Decrease in IL-4 production correlates with increased insulitis.

  • 35. Brooks, Andrew J
    et al.
    Johansson, Magnus
    Södertörn University College, Avdelning Naturvetenskap.
    Criswell, Erin
    Jans, David A
    Vasudevan, Subhash G
    The Interdomain Region of Dengue NS5 ProteinInteracts with NS3 and Host Proteins2002In: Dengue Bulletin, ISSN 1020-895X, Vol. 26, 155-161 p.Article in journal (Other academic)
    Abstract [en]

    Although dengue virus genome replication occurs in the cytoplasm of infected cells, it has been shown that the NS5 protein (RNA-dependent RNA polymerase) is hyperphosphorylated at a late stage in infection and localized to the cell nucleus. A 37 amino acid sequence of NS5 (residues 369-405) was shown to contain a functional nuclear localization signal (NLS) that interacted with the cellular nuclear transport factor, importin α/β heterodimer. Further studies using the yeast two-hybrid system revealed that the NS5 region (residues 320-368) immediately adjacent to the NLS contained an importin β-binding site that abuts or overlaps the binding site for the NS3 protein (protease/helicase). The importin β-binding site has also been shown to be a functional NLS (bNLS). Intriguingly, when both bNLS and NLS (residues 320-405) were present, the fused β -galactosidase protein did not accumulate in the nucleus. Here we provide a review of our studies on the NS5 interdomain region and compare it to other members of the Flavivirus genus in order to highlight the importance of this region as a possible target for developing broad-acting antiviral agent against dengue and other mechanistically-related viruses.

  • 36.
    Burglin, Thomas R
    Södertörn University, Avdelning Naturvetenskap.
    The homeobox genes of Encephalitozoon cuniculi (Microsporidia) reveal a putative mating-type locus2003In: Development, Genes and Evolution, ISSN 0949-944X, E-ISSN 1432-041X, Vol. 213, no 1, 50-52 p.Article in journal (Refereed)
  • 37.
    Carlson, Tomas
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Skorupinska-Tudek, K
    Hertel, J
    Chojnacki, T
    Olsson, J M
    Swiezewska, E
    Single polyprenol and dolichol isolation by semipreparative high-performance liquid chromatography technique2000In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 41, no 7, 1177-1180 p.Article in journal (Refereed)
    Abstract [en]

    A new method of separation of single polyprenols (or dolichols) from a mixture of isoprenoid alcohols is described. Application of a high-performance liquid chromatography (HPLC) apparatus equipped with a semipreparative ODS column resulted in preparation of long-chain (dihydro)polyprenols of high purity (>95%). This approach substantially decreases the time scale of the conventional chromatographical preparative procedure. The method can be widely used in chemical and biochemical projects, where single polyprenols or dolichols are required.

  • 38.
    Choe, Yonhyok
    et al.
    Södertörn University, Avdelning 1, Political science.
    Hassler, BjörnSödertörn University, Avdelning Naturvetenskap.Zyborowicz, Stanislaw
    Sweden and Poland from a European perspective: some aspects on the integration process2003Collection (editor) (Other academic)
  • 39. Cunnea, P M
    et al.
    Miranda-Vizuete, A
    Bertoli, G
    Simmen, T
    Damdimopoulos, A E
    Hermann, Stefan
    Södertörn University, Avdelning Naturvetenskap.
    Leinonen, S
    Huikko, M P
    Gustafsson, J A
    Sitia, R
    Spyrou, G
    ERdJ5, an endoplasmic reticulum (ER)-resident protein containing DnaJ and thioredoxin domains, is expressed in secretory cells or following ER stress2003In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 2, 1059-1066 p.Article in journal (Refereed)
  • 40. Czene, S
    et al.
    Testa, E
    Nygren, Jonas
    Södertörn University, Avdelning Naturvetenskap.
    Belyaev, I
    Harms-Ringdahl, M
    DNA fragmentation and morphological changes in apoptotic human lymphocytes2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 294, no 4, 872-878 p.Article in journal (Refereed)
    Abstract [en]

    Cell suspensions enriched in cells at various stages of apoptosis were obtained by separation of irradiated human peripheral blood lymphocytes on density gradients at different post-irradiation times. The state of DNA fragmentation in the cells was determined by comet assay and pulsed field gel electrophoresis. The morphologically distinguishable features of apoptosis such as chromatin condensation and cell shrinkage correlated with discrete stages of DNA fragmentation. It was found that greater than or equal to50kbp fragmentation of DNA occurs already in cells of normal density whereas the subsequent DNA fragmentation onto fragments <50 kbp occurs in parallel with cell shrinkage and simultaneous increase in cell density. The observed stages of DNA fragmentation seem to be separated in time that could allow in case of abortive apoptosis formation of chromosomal aberrations.

  • 41.
    Daigle, N
    et al.
    European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
    Beaudouin, J
    European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
    Hartnell, L
    NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH) - USA.
    Imreh, Gabriela
    Södertörn University, Avdelning Naturvetenskap.
    Hallberg, Einar
    Södertörn University, Avdelning Naturvetenskap.
    Lippincott-Schwartz, J
    NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH) - USA.
    Ellenberg, J
    European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
    Nuclear pore complexes form immobile networks and have a very low turnover in live mammalian cells2001In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 154, no 1, 71-84 p.Article in journal (Refereed)
    Abstract [en]

    The nuclear pore complex (NPC) and its relationship to the nuclear envelope (NE) was characterized in living cells using POM121-green fluorescent protein (GFP) and GFP-Nup153, and GFP-lamin B1. No independent movement of single pore complexes was found within the plane of the NE in interphase. Only large arrays of NPCs moved slowly and synchronously during global changes in nuclear shape, strongly suggesting mechanical connections which form an NPC network. The nuclear lamina exhibited identical movements. NPC turnover measured by fluorescence recovery after photobleaching of POM121 was less than once per cell cycle. Nup153 association with NPCs was dynamic and turnover of this nucleoporin was three orders of magnitude faster. Overexpression of both nucleoporins induced the formation of annulate lamellae (AL) in the endoplasmic reticulum (ER). Turnover of AL pore complexes was much higher than in the NE (once every 2.5 min). During mitosis, POM121 and Nup153 were completely dispersed and mobile in the ER (POM121) or cytosol (Nup153) in metaphase, and rapidly redistributed to an immobilized pool around chromatin in late anaphase. Assembly and immobilization of both nucleoporins occurred before detectable recruitment of lamin B1, which is thus unlikely to mediate initiation of NPC assembly at the end of mitosis.

  • 42. Dubruille, R
    et al.
    Laurencon, A
    Vandaele, C
    Shishido, E
    Coulon-Bublex, M
    Swoboda, Peter
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Couble, P
    Kernan, M
    Durand, B
    Drosophila regulatory factor X is necessary for ciliated sensory neuron differentiation2002In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 129, no 23, 5487-5498 p.Article in journal (Refereed)
    Abstract [en]

    Ciliated neurons play an important role in sensory perception in many animals. Modified cilia at dendrite endings serve as sites of sensory signal capture and transduction. We describe Drosophila mutations that affect the transcription factor RFX and genetic rescue experiments that demonstrate its central role in sensory cilium differentiation. Rfx mutant flies show defects in chemosensory and mechanosensory behaviors but have normal phototaxis, consistent with Rfx expression in ciliated sensory neurons and neuronal precursors but not in photoreceptors. The mutant behavioral phenotypes are correlated with abnormal function and structure of neuronal cilia, as shown by the loss of sensory transduction and by defects in ciliary morphology and ultrastructure. These results identify Rfx as an essential regulator of ciliated sensory neuron differentiation in Drosophild.

  • 43.
    Edin, Michaela
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Grivas, Spiros
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    First synthesis of 6,7-diaminoindole and 1,2,5-selenadiazolo[3,4-g]indole2000In: ARKIVOC, ISSN 1424-6376, no 1, 1-5 p.Article in journal (Refereed)
    Abstract [en]

    5-Methyl-4-nitro-2,1,3-benzoselenadiazole (1) was converted into 1,2,5-selenadiazolo[3,4-g]indole (3) by the Batcho-Leimgruber indole synthesis. Subsequent deselenation afforded 6,7-diaminoindole (4) which on treatment with biacetyl afforded 2,3-dimethylpyrrolo[2,3-f]quinoxaline (5) in 80% yield from 3.

  • 44.
    Edin, Michaela
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Grivas, Spiros
    Södertörn University, Avdelning Naturvetenskap.
    On the preparation of 1,2,5-selenadiazolo [3,4-e]indole and its [3,4-f] and [3,4-g] isomers through the Batcho-Leimgruber indole synthesis2001In: ARKIVOC, ISSN 1551-7004, E-ISSN 1551-7012, Vol. 2, no 1, 136-142 p.Article in journal (Refereed)
    Abstract [en]

    1,2,5-Selenadiazolo[3,4-e]indole 6 was prepared by applying the Batcho-Leimgruber indole synthesis on 4-methyl-5-nitro-2,1,3-benzoselenadiazole 9. This methodology was unsuccessful when applied to 5-methyl-6-nitro-2,1,3-benzoselenadiazole 14 for the synthesis of 1,2,5-selenadiazolo[3,4-f]indole 5. An improvement on the preparation of 1,2,5-selenadiazolo[3,4-g]indole 3 is reported. An initial study on the bromination of 3 and the Se-77-NMR chemical shifts of 3 and 6, and of their precursors are presented.

  • 45.
    Edlund, Charlotta
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Alvan, G
    Barkholt, L
    Vacheron, F
    Nord, C E
    Pharmacokinetics and comparative effects of telithromycin (HMR 3647) and clarithromycin on the oropharyngeal and intestinal microflora2000In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 46, no 5, 741-749 p.Article in journal (Refereed)
    Abstract [en]

    The pharmacokinetics in plasma and saliva of a new ketolide, telithromycin (HMR 3647), and the effect on the normal oropharyngeal and intestinal microflora were studied in healthy volunteers and compared with those of clarithromycin. Ten subjects received 800 mg telithromycin perorally once daily and 10 other subjects received 500 mg clarithromycin bid for 10 days. Blood, saliva and faecal specimens were collected at defined intervals before, during and after administration for pharmacokinetic and microbiological analyses. In subjects receiving telithromycin, the mean C(max), AUC and C(24) (24 h) in saliva exceeded the values obtained from plasma, while saliva and serum pharmacokinetic parameters were in the same range for the clarithromycin group. The quantitative ecological disturbances in the normal microflora during administration of telithromycin were moderate and comparable to those associated with clarithromycin administration. No overgrowth of yeasts or Clostridium difficile occurred. Emergence of resistant strains was seen in both treatment groups. Administration of both telithromycin and clarithromycin was associated with significant increases in MICs for intestinal Bacteroides isolates, which persisted 2 weeks after discontinuation of treatment. In addition, a significant emergence of highly clarithromycin-resistant a-haemolytic streptococci, intestinal enterococci and Enterobacteriaceae was detected at day 10 in the clarithromycin group. In conclusion, administration of telithromycin resulted in high drug levels in saliva, which indicates a good therapeutic profile for throat infections. Telithromycin seems to have a more favourable ecological profile compared with clarithromycin in terms of resistance development in the normal microflora.

  • 46.
    Edlund, Charlotta
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Nord, C E
    Effect on the human normal microflora of oral antibiotics for treatment of urinary tract infections2000In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 46, 41-48 p.Article in journal (Refereed)
    Abstract [en]

    Oral administration of antibiotics for treatment of urinary tract infections (UTIs) can cause ecological disturbances in the normal intestinal microflora. Poorly absorbed drugs can reach the colon in active form, suppress susceptible microorganisms and disturb the ecological balance. Suppression of the normal microflora may lead to reduced colonization resistance with subsequent overgrowth of pre-existing, naturally resistant microorganisms, such as yeasts and Clostridium difficile. New colonization by resistant potential pathogens may also occur and may spread within the body or to other patients and cause severe infections. It is therefore important to learn more about the ecological effects of antibacterial agents on the human microflora. The impact on intestinal microorganisms of oral antibiotics used for the treatment of UTIs is reviewed here. Ampicillin, amoxycillin and co-amoxiclav suppress both the aerobic and anaerobic intestinal microflora with overgrowth of ampicillin-resistant Enterobacteriaceae. Pivmecillinam also affects the intestinal microflora, suppressing Escherichia coli, but does not have a major effect on the anaerobic microflora. Several orally administered cephalosporins, such as cefixime, cefpodoxime, cefprozil and ceftibuten, reduce the number of Enterobacteriaceae and increase the number of enterococci. Colonization with C. difficile has also been observed. Fluoroquinolones eliminate or strongly suppress intestinal Enterobacteriaceae, but affect enterococci and anaerobic bacteria only slightly. When antimicrobial agents are prescribed for the treatment of UTIs, not only the antimicrobial spectrum of the agent but also the potential ecological disturbances, including the risk of emergence of resistant strains, should be considered.

  • 47.
    Edlund, Charlotta
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Nord, C E
    The evaluation and prediction of the ecologic impact of antibiotics in human phase I and II trials2001In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 7, 37-41 p.Article in journal (Refereed)
  • 48.
    Edlund, Charlotte
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Beyer, G.
    Hiemer-Bau, M.
    Ziege, S.
    Lode, H.
    Nord, C. E.
    Comparative effects of moxifloxacin and clarithromycin on the normal intestinal microflora2000In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 32, no 1, 81-85 p.Article in journal (Refereed)
    Abstract [en]

    Twelve healthy male subjects age range 24-40 y participated in the investigation. The trial was divided into 2 35-d periods. The 2 treatment regimens were: (i) 1 x 400 mg moxifloxacin tablet in the morning and 1 placebo tablet in the evening for 7 d; and (ii) 1 x 500 mg clarithromycin tablet in the morning and 1 x 500 mg clarithromycin tablet in the evening for 7 d. Each subject received firstly 1 treatment regimen and secondly the other treatment regimen. The wash-out period was 6 weeks between the two treatment regimens. Moxifloxacin caused significant decreases of enterococci and enterobacteria during the administration period while the numbers of staphylococci, streptococci, Bacillus and Candida were not affected. No impact on peptostreptococci, lactobacilli, Veillonella, Bacteroides or fusobacteria was observed, while bifidobacteria and clostridia decreased during moxifloxacin administration. The microflora was normalized after 35 d. Clarithromycin caused significant reduction of Escherichia coli while the numbers of enterococci, Enterobacter, Citrobacter, Klebsiella and Pseudomonas increased markedly. No significant changes in the numbers of staphylococci, streptococci, Bacillus and Candida were noticed. In the anaerobic microflora bifidobacteria, lactobacilli and clostridia were suppressed, while no changes in peptostreptococci, Veillonella, Bacteroides and fusobacteria were found. The microflora was normalized in all volunteers after 35 d.

  • 49. Ehrlén, Johan
    et al.
    Lehtilä, Kari
    Södertörn University, Avdelning Naturvetenskap. Stockholm University.
    How perennial are perennial plants?2002In: Oikos, ISSN 0030-1299, E-ISSN 1600-0706, Vol. 98, no 2, 308-322 p.Article in journal (Refereed)
    Abstract [en]

    Trade-offs involving life span are important in the molding of plant life histories. However, the empirical examination of such patterns has so far been limited by the fact that information on life span is mainly available in terms of discrete categories; annuals, semelparous perennials and iteroparous perennials. We used transition matrix models to project continuous estimates of conditional life spans from published information on size- or stage-structured demography for 71 perennial plant species. The projected life span ranged from 4.3 to 988.6 years and more than half of the species had a life span of more than 35 years. Woody plants had on average a projected life span more than four times as long as non-woody plants. Life spans were higher in forests than in open habitats and individuals of non-clonal species tended to have a longer life span than ramets of clonal species. Self-incompatible plants on average lived longer than self-compatible plants. There were no clear relations between life span and geographical region, dispersal syndrome, pollination mode, seed size or the presence of a seed bank. We conclude that accurate estimates of life span are central to understand how longevity is correlated to other traits within the group of perennial plants.

  • 50. Ekblom, Robert
    et al.
    Grahn, Mats
    Södertörn University, Avdelning Naturvetenskap.
    Höglund, Jacob
    Patterns of polymorphism in the MHC class II of a non-passerine bird, the great snipe (Gallinago media)2003In: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 54, no 10, 734-741 p.Article in journal (Refereed)
    Abstract [en]

    The genomic organisation of the major histocompatibility complex (MHC) seems to vary considerably between different bird species. In order to understand this variation it is important to gather information from different species. We have, for the first time, investigated MHC class 11 polymorphism in a wader species, the great snipe (Gallinago media). Eleven alleles were found in five sequenced individuals; these come from at least three different loci, but RFLP data suggest that a larger number of genes may be present. For MHC genes, amino acid substitutions followed the, for MHC genes, general pattern of high non-synonymous substitution rates in peptide-binding regions, suggesting that the sequenced alleles may be expressed. The number of genes, lengths of introns and exon sequences of the great snipe MHC seem to be intermediate between those of chicken and passerine birds.

12345 1 - 50 of 235
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