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  • 101. Boraschi, Diana
    et al.
    Abebe Alemayehu, Markos
    Aseffa, Abraham
    Chiodi, Francesca
    Chisi, John
    Del Prete, Gianfranco
    Doherty, T Mark
    Elhassan, Ibrahim
    Engers, Howard
    Gyan, Ben
    Harandi, Ali M
    Kariuki, Thomas
    Kironde, Fred
    Kouriba, Bourema
    Langhorne, Jean
    Laskay, Tamás
    Medaglini, Donata
    Olesen, Ole
    Onyebujoh, Philip
    Palma, Carla
    Sauerwein, Robert
    Sibanda, Elopy
    Steinhoff, Ulrich
    Tagliabue, Aldo
    Thiel, Andreas
    Vahedi, Mahnaz
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Immunity against HIV/AIDS, Malaria, and Tuberculosis during Co-Infections with Neglected Infectious Diseases: Recommendations for the European Union Research Priorities.2008In: PLoS Negl Trop Dis, ISSN 1935-2735, Vol. 2, no 6, p. e255-Article in journal (Refereed)
  • 102.
    Boström, Stephanie
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Arama, Charles
    Stockholm University, Faculty of Science, The Wenner-Gren Institute. University of Bamako, Mali.
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Dara, Victor
    Traore, Boubacar
    Dolo, Amagana
    Doumbo, Ogobara
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Changes in the levels of cytokines, chemokines and malaria specific antibodies in response to Plasmodium falciparum infection in children living in sympatry in Mali2012In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, p. 109-Article in journal (Refereed)
    Abstract [en]

    Background: The Fulani are known to be less susceptible to Plasmodium falciparum malaria as reflected by lower parasitaemia and fewer clinical symptoms than other sympatric ethnic groups. So far most studies in these groups have been performed on adults, which is why little is known about these responses in children. This study was designed to provide more information on this gap. Methods: Circulating inflammatory factors and antibody levels in children from the Fulani and Dogon ethnic groups were measured. The inflammatory cytokines; interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12p70, tumor necrosis factor (TNF) and the chemokines; regulated on activation normal T cell expressed and secreted (RANTES), monokine-induced by IFN-gamma (MIG), monocyte chemotactic protein (MCP)-1 and IFN-gamma-inducible protein (IP)-10 were measured by cytometric bead arrays. The levels of interferon (IFN)-alpha, IFN-gamma and malaria-specific antibodies; immunoglobulin (Ig) G, IgM and IgG subclasses (IgG1-IgG4) were measured by ELISA. Results: The results revealed that the Fulani children had higher levels of all tested cytokines compared to the Dogon, in particular IFN-gamma, a cytokine known to be involved in parasite clearance. Out of all the tested chemokines, only MCP-1 was increased in the Fulani compared to the Dogon. When dividing the children into infected and uninfected individuals, infected Dogon had significantly lower levels of RANTES compared to their uninfected peers, and significantly higher levels of MIG and IP-10 as well as MCP-1, although the latter did not reach statistical significance. In contrast, such patterns were not seen in the infected Fulani children and their chemokine levels remained unchanged upon infection compared to uninfected counterparts. Furthermore, the Fulani also had higher titres of malaria-specific IgG and IgM as well as IgG1-3 subclasses compared to the Dogon. Conclusions: Taken together, this study demonstrates, in accordance with previous work, that Fulani children mount a stronger inflammatory and antibody response against P. falciparum parasites compared to the Dogon and that these differences are evident already at an early age. The inflammatory responses in the Fulani were not influenced by an active infection which could explain why less clinical symptoms are seen in this group.

  • 103.
    Boström, Stéphanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Inflammatory responses due to Plasmodium falciparum infection during pregnancy and childhood2012Licentiate thesis, comprehensive summary (Other academic)
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  • 104.
    Boström, Stéphanie
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Ibitokou, Samad
    Oesterholt, Mayke
    Schmiegelow, Christentze
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Minja, Daniel
    Lusingu, John
    Lemnge, Martha
    Fievet, Nadine
    Deloron, Philippe
    Luty, Adrian J. F.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Biomarkers of Plasmodium falciparum infection during pregnancy in women living in Northeastern Tanzania2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 11, p. e48763-Article in journal (Refereed)
    Abstract [en]

    In pregnant women, Plasmodium falciparum infections are an important cause of maternal morbidity as well as fetal and neonatal mortality. Erythrocytes infected by these malaria-causing parasites accumulate through adhesive interactions in placental intervillous spaces, thus evading detection in peripheral blood smears. Sequestered infected erythrocytes induce inflammation, offering the possibility of detecting inflammatory mediators in peripheral blood that could act as biomarkers of placental infection. In a longitudinal, prospective study in Tanzania, we quantified a range of different cytokines, chemokines and angiogenic factors in peripheral plasma samples, taken on multiple sequential occasions during pregnancy up to and including delivery, from P. falciparum-infected women and matched uninfected controls. The results show that during healthy, uninfected pregnancies the levels of most of the panel of molecules we measured were largely unchanged except at delivery. In women with P. falciparum, however, both comparative and longitudinal assessments consistently showed that the levels of IL-10 and IP-10 increased significantly whilst that of RANTES decreased significantly, regardless of gestational age at the time the infection was detected. ROC curve analysis indicated that a combination of increased IL-10 and IP-10 levels and decreased RANTES levels might be predictive of P. falciparum infections. In conclusion, our data suggest that host biomarkers in peripheral blood may represent useful diagnostic markers of P. falciparum infection during pregnancy, but placental histology results would need to be included to verify these findings.

  • 105. Boukhelifa, Malika
    et al.
    Moza, Monica
    Johansson, Thomas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Rachlin, Andrew
    Parast, Mana
    Huttelmaier, Stefan
    Roy, Partha
    Jockusch, Brigitte, M
    Carpen, Olli
    Karlsson, Roger
    Otey, Carol, A
    The proline-rich protein palladin is a binding partner for profilin2006In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, no 1, p. 26-33Article in journal (Refereed)
    Abstract [en]

    Palladin is an actin-associated protein that has been suggested to play critical roles in establishing cell morphology and maintaining cytoskeletal organization in a wide variety of cell types. Palladin has been shown previously to bind directly to three different actin-binding proteins vasodilator-stimulated phosphoprotein (VASP), α-actinin and ezrin, suggesting that it functions as an organizing unit that recruits actin-regulatory proteins to specific subcellular sites. Palladin contains sequences resembling a motif known to bind profilin. Here, we demonstrate that palladin is a binding partner for profilin, interacting with profilin via a poly proline-containing sequence in the amino-terminal half of palladin. Double-label immunofluorescence staining shows that palladin and profilin partially colocalize in actin-rich structures in cultured astrocytes. Our results suggest that palladin may play an important role in recruiting profilin to sites of actin dynamics.

  • 106. Braun, Bernhard
    et al.
    Pfirrmann, Thorsten
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Menssen, Ruth
    Hofmann, Kay
    Scheel, Hartmut
    Wolf, Dieter H.
    Gid9, a second RING finger protein contributes to the ubiquitin ligase activity of the Gid complex required for catabolite degradation2011In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 585, no 24, p. 3856-3861Article in journal (Refereed)
    Abstract [en]

    The two major antagonistic pathways of carbon metabolism in cells, glycolysis and gluconeogenesis, are tightly regulated. In the eukaryotic model organism Saccharomyces cerevisiae the switch from gluconeogenesis to glycolysis is brought about by proteasomal degradation of the gluconeogenic enzyme fructose-1,6-bisphosphatase. The ubiquitin ligase responsible for polyubiquitylation of fructose-1,6-bisphosphatase is the Gid complex. This complex consists of seven subunits of which subunit Gid2/Rmd5 contains a RING finger domain providing E3 ligase activity. Here we identify an additional subunit containing a degenerated RING finger, Gid9/Fyv10. This subunit binds to Gid2/Rmd5. A mutation in the degenerated RING finger of Gid9/Fyv10 abolishes polyubiquitylation and degradation of three enzymes specific for gluconeogenesis. Structured summary of protein interactions: Gid2 physically interacts with Gid9 by anti tag coimmunoprecipitation (View interaction) (C) 2011 Federation of European Biochemical Societies.

  • 107.
    Brenden, Nina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    MHCI-E mediated protection from IDDM on NOD mice: The role of regulatory T cells1998Doctoral thesis, comprehensive summary (Other academic)
  • 108.
    Brolinson, Annelie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Regulation of Elovl and fatty acid metabolism2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fatty acids are important regulators in the control of mammalian energy homeostasis. They are ingested in the diet but a significant amount are also endogenously produced by de novo lipogenesis. Fatty acid elongation beyond 16 carbons (palmitic acid) can occur to generate very long chain fatty acids (VLCFA), a process that is initiated by the rate-limiting condensation reaction. To date, six mammalian enzymes responsible for this reaction, ELOVL1-6 (Elongation of very long chain fatty acid), have been characterized. All of them exert substrate specificity and tissue-specific gene expression. In this thesis, factors that regulate fatty acid metabolism and, in particular, fatty acid synthesis and elongation will be presented.

    The enclosed papers discuss issues as to how Elovl3 is regulated in liver and in different adipose depots and what effects ablation of this enzyme causes to lipid homeostasis. Hepatic Elovl3 gene expression followed a circadian rhythm, present exclusively in sexually mature male mice. In contrast to the expression of several other lipogenic genes, Elovl3 gene expression was not affected by fasting or refeeding. Instead, the gene expression was influenced by steroid hormones such as glucocorticoids and sex hormones.

    Interestingly, despite reduced levels of leptin, Elovl3-ablated mice were shown to be resistant to diet induced weight gain, which seemed to be due to a decreased ratio between energy intake and energy expenditure. This phenotype was more pronounced in female mice.

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  • 109.
    Brolinson, Annelie
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Fourcade, S
    Jakobsson, A
    Pujol, A
    Jacobsson, A
    Steroid hormones control circadian Elovl3 expression in mouse liver2008In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, no 6, p. 3158-3166Article in journal (Refereed)
    Abstract [en]

    The Elovl3 gene belongs to the Elovl gene family, which encodes for enzymes involved in the elongation of very long chain fatty acids. The recognized role for the enzyme is to control the elongation of saturated and monounsaturated fatty acids up to 24 carbons in length. Elovl3 was originally identified as a highly expressed gene in brown adipose tissue on cold exposure. Here we show that hepatic Elovl3 mRNA expression follows a distinct diurnal rhythm exclusively in mature male mice, with a sharp increase early in the morning Zeitgeber time (ZT) 20, peaks around ZT2, and is back to basal level at the end of the light period at ZT10. In female mice and sexually immature male mice, the Elovl3 expression was constantly low. Fasting and refeeding mice with chow or high-fat diet did not alter the Elovl3 mRNA levels. However, animals that were exclusively fed during the day for 9 d displayed an inverted expression profile. In addition, we show that Elovl3 expression is transcriptionally controlled and significantly induced by the exposure of the synthetic glucocorticoid dexamethasone. Taken together, these data suggest that Elovl3 expression in mouse liver is under strict diurnal control by circulating steroid hormones such as glucocorticoids and androgens. Finally, Elovl3 expression was found to be elevated in peroxisomal transporter ATP-binding cassette, subfamily D(ALD), member 2 ablated mice and suppressed in ATP-binding cassette subfamily D(ALD) member 2 overexpressing mice, implying a tight cross talk between very long chain fatty acid synthesis and peroxisomal fatty acid oxidation

  • 110. Bruton, Joseph D.
    et al.
    Aydin, Jan
    Yamada, Takashi
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Ivarsson, Niklas
    Zhang, Shi-Jin
    Wada, Masanobu
    Tavi, Pasi
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Katz, Abram
    Westerblad, Håkan
    Increased fatigue resistance linked to Ca(2+)-stimulated mitochondrial biogenesis in muscle fibres of cold-acclimated mice2010In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 588, no 21, p. 4275-4288Article in journal (Refereed)
    Abstract [en]

    Mammals exposed to a cold environment initially generate heat by repetitive muscle activity (shivering). Shivering is successively replaced by the recruitment of uncoupling protein-1 (UCP1)-dependent heat production in brown adipose tissue. Interestingly, adaptations observed in skeletal muscles of cold-exposed animals are similar to those observed with endurance training. We hypothesized that increased myoplasmic free [Ca2+] ([Ca2+]i) is important for these adaptations. To test this hypothesis, experiments were performed on flexor digitorum brevis (FDB) muscles, which do not participate in the shivering response, of adult wild-type (WT) and UCP1-ablated (UCP1-KO) mice kept either at room temperature (24 ºC) or cold-acclimated (4 ºC) for 4-5 weeks. [Ca2+]i (measured with indo-1) and force were measured under control conditions and during fatigue induced by repeated tetanic stimulation in intact single fibres. The results show no differences between fibres from WT and UCP1-KO mice. However, muscle fibres from cold-acclimated mice showed significant increases in basal [Ca2+]i (~50%), tetanic [Ca2+]i (~40%), and sarcoplasmic reticulum (SR) Ca2+ leak (~four-fold) as compared to fibres from room-temperature mice. Muscles of cold-acclimated mice showed increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and increased citrate synthase activity (reflecting increased mitochondrial content). Fibres of cold-acclimated mice were more fatigue resistant with higher tetanic [Ca2+]i and less force loss during fatiguing stimulation. In conclusion, cold exposure induces changes in FDB muscles similar to those observed with endurance training and we propose that increased [Ca2+]i is a key factor underlying these adaptations.

  • 111. Bryan-Sisneros, A
    et al.
    Sabanov, V
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Thoroed, S
    Doroshenko, P
    Dual role of ATP in supporting volume-regulated chloride channels in mouse fibroblasts2000In: Biochim. Biophys. Acta Biomembranes, ISSN 0005-2736, Vol. 1468, no 1-2, p. 63-72Article in journal (Refereed)
  • 112. Busayavalasa, Kiran
    et al.
    Chen, Xin
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Cell Biology.
    Wagner, Nicole
    Sabri, Nafiseh
    The nup155 mediated organisation of inner nuclear membrane proteins is independent of nup155 anchoring to the metazoan nuclear pore complex2012In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 125, no 18, p. 4214-4218Article in journal (Refereed)
    Abstract [en]

    The nuclear envelope (NE), an important barrier between the nucleus and the cytoplasm, is composed of three structures: the outer nuclear membrane, which is continuous with the ER, the inner nuclear membrane (INM), which interfaces with chromatin, and nuclear pore complexes (NPCs), which are essential for the exchange of macromolecules between the two compartments. The NPC protein Nup155 has an evolutionarily conserved role in the metazoan NE formation; but the in vivo analysis of Nup155 has been severely hampered by the essential function of this protein in cell viability. Here, we take advantage of the hypomorphicity of RNAi systems and use a combination of protein binding and rescue assays to map the interaction sites of two neighbouring NPC proteins Nup93 and Nup53 on Nup155, and to define the requirements of these interactions in INM protein organization. We show that different parts of Drosophila Nup155 have distinct functions: the Nup155 beta-propeller anchors the protein to the NPC, whereas the alpha-solenoid part of Nup155 is essential for the correct localisation of INM proteins lamin-B receptor (LBR) and otefin. Using chromatin extracts from semisynchronized cells, we also provide evidence that the Nup155 alpha-solenoid has a chromatin-binding activity that is stronger at the end of mitosis. Our results argue that the role of Nup155 in INM protein localisation is not mediated through the NPC anchoring activity of the protein and suggest that regions other than Nup155 beta-propeller are necessary for the targeting of proteins to the INM.

  • 113.
    Calado Botelho, Salomé
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Tyagi, A.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Hessle, Viktoria
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Visa, Neus
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    The association of Brahma with the Balbiani ring 1 gene of Chironomus tentans studied by immunoelectron microscopy and chromatin immunoprecipitation2008In: Insect molecular biology (Print), ISSN 0962-1075, E-ISSN 1365-2583, Vol. 17, no 5, p. 505-13Article in journal (Refereed)
    Abstract [en]

    Many steps of gene expression take place during transcription, and important functional information can thus be obtained by determining the distribution of specific factors along a transcribed gene. The Balbiani ring (BR) genes of the dipteran Chironomus tentans constitute a unique system for mapping the association of specific factors along a eukaryotic gene using immuno-electron microscopy (immuno-EM). The chromatin immunoprecipitation (ChIP) technique has provided an alternative, more general method for studying the association of proteins with specific genomic sequences. The immuno-EM and the ChIP methods suffer from different limitations, and thus a combination of both is advantageous. We have established optimal conditions for ChIP on chromatin extracted from the salivary glands of C. tentans, and we have analyzed the association of the SWI/SNF chromatin remodelling factor Brahma (Brm) with the BR1 gene by combined immuno-EM and ChIP. We show that Brm is not restricted to the promoter of the BR1 gene but is also associated with sequences in the middle and distal portions of the gene, which suggests that Brm has additional roles apart from regulating transcription initiation.

  • 114.
    Calla-Magarinos, Jacqueline
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology. National University Hospital of Iceland.
    Fernandez, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Freysdottir, Jona
    Alkaloids from Galipea longiflora Krause modify the maturation of human dendritic cells and their ability to stimulate allogeneic CD4(+) T cells2013In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 16, no 1, p. 79-84Article in journal (Refereed)
    Abstract [en]

    Alkaloids obtained from the plant Evanta have been shown to have dual effects in Leishmania infection; a direct leishmanicidal effect on the parasite and more importantly, the alkaloids affect both polyclonal and Leishmania-specific stimulation of T-cells. Dendritic cells (DCs) play a pivotal role in stimulation and polarization of naive T cells towards a Th1, Th2, Th17 or regulatory phenotype. In leishmaniasis, the interactions between the parasites and DCs are complex and involve contradictory functions that can stimulate or suppress T cell responses, leading to the control of infection or progression of disease. In this study the effect of an alkaloid extract of Evanta (AEE) or the purified alkaloid 2-phenilquinoline (2Ph) on the activation of human DCs and their ability to stimulate allogeneic CD4(+) T cells was analyzed. The expression of surface activation molecules was not affected on DCs stimulated in the presence of AEE or 2Ph nor did AEE-DCs or 2Ph-CDs affect the expression of activation surface molecules on allogeneic CD4(+) T cells. In contrast, as compared with control, the secretion of IL-12p40, IL-23 and IL-6 was lower from AEE-DCs and 2Ph-CDs and allogeneic CD4(+) T cells co-cultured with these DCs secreted lower levels of IFN-gamma and IL-10 but the same levels of IL-17. These results demonstrate that AEE and 2Ph affect the stimulation of DCs and their ability to stimulate allogeneic CD4(+) T cells by reducing the production of IFN-gamma, IL-12 p40, IL-6 and IL-23. This suggests that AEE and 2Ph may take part in regulation of inflammation.

  • 115.
    Calla-Magariños, Jacqueline
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Bioactive leishmanicidal alkaloid molecules from Galipea longiflora Krause with immunomodulatory activity2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    According to WHO, leishmaniasis is endemic in 98 countries, and has been placed ninth in a global analysis of infectious diseases. Treatment of leishmaniasis is based on pentavalent antimonials but toxicity and developing resistance have been reported. Traditional medicine and scientific studies have shown that the extract of Galipea longiflora Krause (Evanta) exhibits antileishmanial activity. We hypothesized that the healing observed when using this plant might not only be due to the direct action on the parasite, but possibly to a parallel effect on the host immune response. We found that an alkaloid extract of Evanta (AEE) inhibited the growth of Leishmania braziliensis promastigotes while viability of eukaryotic cells was practically not affected. We also found that AEE interfered with polyclonal activation or Leishmania-specific re-stimulation of lymphocytes, as revealed by a reduction of in vitro cellular proliferation and IFN-g production. More important, AEE treatment of mice hosting L. braziliensis showed that AEE is able to control both inflammation and parasite load. Additionally, the healing process was improved when AEE and meglumine antimoniate were administered simultaneously. Dendritic cells (DCs) play a pivotal role in T-cell stimulation and polarization of naïve T cells. Therefore, we investigated if AEE could alter the activation of DCs and if allostimulatory DCs properties were altered if activated in the presence of AEE. DCs activated in the presence of AEE reduced the production of IL-12p40 and IL-23. When we analyzed the allostimulatory capacity of AEE-treated DCs, we found that allogeneic CD4+ T-cells secreted lower levels of IFN-γ.

    In conclusion, this thesis provides valuable insight into the effects of Evanta derived extract. The dual effect found for AEE, on Leishmania parasite and on the immune response, suggests that AEE may be useful in controlling the parasite burden and preventing over-production of inflammatory mediators and subsequently avoiding tissue damage.

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  • 116.
    Calla-Magariños, Jacqueline
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Fernádez, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Freysdottir, Jona
    Alkaloids from Galipea longiflora Krause modify the maturation of human dendritic cells and their ability to stimulate allogeneic CD4+ T cellsArticle in journal (Refereed)
    Abstract [en]

    Alkaloids obtained from the plant Evanta have been shown to have dual effects in Leishmania infection; a direct leishmanicidal effect on the parasite and more importantly, the alkaloids affect both polyclonal and Leishmania-specific stimulation of T-cells.  

    Dendritic cells (DCs) play a pivotal role in stimulation and polarization of naïve T cells towards a Th1, Th2, Th17 or regulatory phenotype. In leishmaniasis, the interactions between the parasites and DCs are complex and involve contradictory functions that can stimulate or suppress T cell responses, leading to the control of infection or progression of disease.

     In this study the effect of an alkaloid extract of Evanta (AEE) or the purified alkaloid 2-phenilquinoline (2Ph) on the activation of human DCs and their ability to stimulate allogeneic CD4+ T cells was analyzed. The expression of surface activation molecules was not affected on DCs stimulated in the presence of AEE or 2Ph nor did AEE-DCs or 2Ph-CDs affect the expression of activation surface molecules on allogeneic CD4+ T cells. In contrast, as compared with control, the secretion of IL-12p40, IL-23 and IL-6 was lower from AEE-DCs and 2Ph-CDs and allogeneic CD4+ T cells co-cultured with these DCs secreted lower levels of IFN-γ and IL-10 but the same levels of IL-17.

    These results demonstrate that AEE and 2Ph affect the stimulation of DCs and their ability to stimulate allogeneic CD4+ T cells by reducing the production of IFN-g, IL-12 p40, IL-6 and IL-23. This suggests that AEE and 2Ph may take part in regulation of inflammation.

  • 117.
    Calla-Magariños, Jacqueline
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Gimenez, A.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Fernandez, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    An alkaloid extract of Evanta, traditionally used as anti-Leishmania agent in Bolivia, inhibits cellular proliferation and interferon-g production in polyclonally activated cells2009In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 69, no 3, p. 251-258Article in journal (Refereed)
    Abstract [en]

    Traditional medicine and scientific studies have shown that the raw extract ofEvanta [Galipea longiflora, Angostura longiflora (Krause) Kallunki] exhibits antileishmanialactivity. We hypothesized that the healing observed when usingthis plant might not only be due to the direct action on the parasite, but possiblyto a parallel effect on the host immune response to the parasite involvedin the healing process. We show here that an alkaloid extract of Evanta (AEE)directly killed the parasite already at a dose of 10 lg ⁄ ml, but at this low concentration,AEE did not have a major effect on viability and proliferation ofeukaryotic cells. The whole extract was also found to be stronger than 2-phenylquinoline,the most prominent alkaloid in AEE. AEE was not directlystimulating B or T cells or J774 macrophages. However, it interfered with theactivation of both mouse and human T cells, as revealed by a reduction of invitro cellular proliferation and interferon-gamma (IFN-c) production. The effectwas more evident when the cells were pretreated with AEE and subsequentlystimulated with the polyclonal T-cell activators Concanavalin A and anti-CD3.Taken together, our results suggest that Evanta have a direct leishmanicidaleffect and due to the effect on IFN-c production it might contribute to controlthe chronic inflammatory reaction that characterize Leishmania infectionpathology, but in vivo studies are necessary to corroborate this finding.

  • 118.
    Calla-Magariños, Jacqueline
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Quispe, T.
    Giménez, A.
    Freysdottir, J.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Quinolinic Alkaloids from Galipea longiflora Krause Suppress Production of Proinflammatory Cytokines in vitro and Control Inflammation in vivo upon Leishmania Infection in Mice2013In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 77, no 1, p. 30-38Article in journal (Refereed)
    Abstract [en]

    An antileishmanial activity of quinolinic alkaloids from Galipea longiflora Krause, known as Evanta, has been demonstrated. We have previously shown that, apart from its leishmanicidal effect, in vitro pretreatment of spleen cells with an alkaloid extract of Evanta (AEE) interfered with the proliferation and interferon-γ production in lymphocytes polyclonally activated either with concanavalin A or anti-CD3. In the present study, we investigated if AEE could interfere with antigen-specific lymphocyte activation. We found that in vitro and in vivo treatment reduced recall lymphocyte responses, as measured by IFN-γ production (55% and 63% reduction compared to untreated cells, respectively). Apart from IFN-γ, the production of IL-12 and TNF was also suppressed. No effects were observed for meglumine antimoniate (SbV), the conventional drug used to treat leishmaniasis. When mice infected with Leishmania braziliensis promastigotes in the hind footpad were treated with AEE, the dynamics of the infection changed and the footpath thickness was efficiently controlled. The parasite load was also reduced but to a lesser extent than upon treatment with SbV. Combined treatment efficiently controlled both the thickness and parasite load as smaller lesions during the entire course of the infection were seen in the mice treated with AEE plus SbV compared with AEE or SbV alone. We discuss the benefits of combined administration of AEE plus SbV.

  • 119.
    Calla-Magariños, Jacqueline
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Quispe, Teddy
    Giménez, Alberto
    Freysdottir, Jona
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Quinolinic alkaloids from Galipea longiflora suppress inflammatory cytokine production in vitro and control inflammatory reaction in vivo upon Leishmania infectionIn: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083Article in journal (Refereed)
    Abstract [en]

    An antileishmanial activity of quinolinic alkaloids from Galipea longiflora Krause, known as Evanta, has been demonstrated. We have previously shown that, apart from its leishmanicidal effect, in vitro pretreatment of spleen cells with an alkaloid extract of Evanta (AEE) interfered with the proliferation and interferon-g production in lymphocytes polyclonally activated either with concanavalin A or anti-CD3. In the present study, we investigated if AEE could interfere with antigen-specific lymphocyte activation. We found that in vitro and in vivo treatment reduced recall lymphocyte responses, as measured by IFN-g production (55 % and 63 % reduction compared to untreated cells, respectively). Apart from IFN-g, the production of IL-12 and TNF were also suppressed. No effects were observed for meglumine antimoniate (SbV), the conventional drug used to treat leishmaniasis. When mice infected with Leishmania braziliensis promastigotes in the hind footpad were treated with AEE, the dynamics of the infection changed and the footpath thickness was efficiently controlled. The parasite load was also reduced but to a lesser extent than upon treatment with SbV. Combined treatment efficiently controlled both the thickness and parasite load since smaller lesions during the entire course of the infection were seen in the mice treated with AEE plus SbV compared with AEE or SbV alone. We discuss the benefits of combined administration of AEE plus SbV.

  • 120.
    Cannon, Barbara
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Developmental biology: Neither fat nor flesh.2008In: Nature, ISSN 1476-4687, Vol. 454, no 7207, p. 947-8Article in journal (Refereed)
  • 121.
    Cannon, Barbara
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Metabolic and angiogenic consequences of the presence or absence of UCP12010In: Research and Perspectives in Endocrine Interactions, p. 111-120Article in journal (Refereed)
    Abstract [en]

    Adaptive adrenergic thermogenesis – both the form that develops subsequent to cold acclimation and the form that develops subsequent to a palatable diet challenge – is entirely dependent on the presence and activity of the brown fat uncoupling protein, UCP1. In a cold environment, the absence of UCP1 can be compensated by alternative means, such as shivering or exercise. Upon a challenge with a palatable diet, similar alternatives are not available, and mice become obese in the absence of UCP1. The recent identification of active brown fat in adult humans raises questions as to its role in protection from obesity and in a potential therapeutic context.

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  • 122.
    Cannon, Barbara
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue in mice (and probably in humans)2010In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 34, no 1, p. S7-S16Article in journal (Refereed)
    Abstract [en]

    Only with the development of the uncoupling protein 1 (UCP1)-ablated mouse has it become possible to strictly delineate the physiological significance of the thermogenic capacity of brown adipose tissue. Considering the presence of active brown adipose tissue in adult humans, these insights may have direct human implications. In addition to classical nonshivering thermogenesis, all adaptive adrenergic thermogeneses, including diet-induced thermogenesis, is fully dependent on brown adipocyte activity. Any weight-reducing effect of β(3)-adrenergic agonists is fully dependent on UCP1 activity, as is any weight-reducing effect of leptin (in excess of its effect on reduction of food intake). Consequently, in the absence of the thermogenic activity of brown adipose tissue, obesity develops spontaneously. The ability of brown adipose tissue to contribute to glucose disposal is also mainly related to thermogenic activity. However, basal metabolic rate, cold-induced thermogenesis, acute cold tolerance, fevers, nonadaptive adrenergic thermogenesis and processes such as angiogenesis in brown adipose tissue itself are not dependent on UCP1 activity. Whereas it is likely that these conclusions are also qualitatively valid for adult humans, the quantitative significance of brown adipose tissue for human metabolism--and the metabolic consequences for a single individual possessing more or less brown adipose tissue--awaits clarification.

  • 123.
    Cannon, Barbara
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Neither brown nor white2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 488, no 7411, p. 286-287Article in journal (Other academic)
    Abstract [en]

    Fat cells are usually thought of as being either energy-storing white fat cells or food-burning brown fat cells. The identification of a third type of fat cell in mice and humans might open up new avenues for combating obesity.

  • 124.
    Cannon, Barbara
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nonshivering thermogenesis and its adequate measurement in metabolic studies2011In: Journal of Experimental Biology, ISSN 0022-0949, E-ISSN 1477-9145, Vol. 214, no Pt 2, p. 242-53Article in journal (Refereed)
    Abstract [en]

    Alterations in nonshivering thermogenesis are presently discussed as being both potentially causative of and able to counteract obesity. However, the necessity for mammals to defend their body temperature means that the ambient temperature profoundly affects the outcome and interpretation of metabolic experiments. An adequate understanding and assessment of nonshivering thermogenesis is therefore paramount for metabolic studies. Classical nonshivering thermogenesis is facultative, i.e. it is only activated when an animal acutely requires extra heat (switched on in minutes), and adaptive, i.e. it takes weeks for an increase in capacity to develop. Nonshivering thermogenesis is fully due to brown adipose tissue activity; adaptation corresponds to the recruitment of this tissue. Diet-induced thermogenesis is probably also facultative and adaptive and due to brown adipose tissue activity. Although all mammals respond to injected/infused norepinephrine (noradrenaline) with an increase in metabolism, in non-adapted mammals this increase mainly represents the response of organs not involved in nonshivering thermogenesis; only the increase after adaptation represents nonshivering thermogenesis. Thermogenesis (metabolism) should be expressed per animal, and not per body mass [not even to any power (0.75 or 0.66)]. A 'cold tolerance test' does not examine nonshivering thermogenesis capacity; rather it tests shivering capacity and endurance. For mice, normal animal house temperatures are markedly below thermoneutrality, and the mice therefore have a metabolic rate and food consumption about 1.5 times higher than their intrinsic requirements. Housing and examining mice at normal house temperatures carries a high risk of identifying false positives for intrinsic metabolic changes; in particular, mutations/treatments that affect the animal's insulation (fur, skin) may lead to such problems. Correspondingly, true alterations in intrinsic metabolic rate remain undetected when metabolism is examined at temperatures below thermoneutrality. Thus, experiments with animals kept and examined at thermoneutrality are likely to yield an improved possibility of identifying agents and genes important for human energy balance.

  • 125.
    Cannon, Barbara
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Studies of thermogenesis and mitochondrial function in adipose tissues.2008In: Methods Mol Biol, ISSN 1064-3745, Vol. 456, p. 109-21Article in journal (Refereed)
  • 126.
    Cannon, Barbara
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Thermogenesis challenges the adipostat hypothesis for body-weight control.2009In: Proceedings of the Nutrition Society, ISSN 0029-6651, E-ISSN 1475-2719, Vol. 68, no 4, p. 401-7Article in journal (Refereed)
    Abstract [en]

    According to the adipostat hypothesis for body-weight control, alterations in body weight should always be compensated by adequate alterations in food intake and thermogenesis. Thus, increased thermogenesis should not be able to counteract obesity because food intake would be increased. However evidence is presented here that thermogenesis in different forms (through artificial uncouplers, exercise, cold exposure) may counteract obesity and is not always fully compensated by increased food intake. Correspondingly, a decreased capacity for metaboloregulatory thermogenesis (i.e. non-functional brown adipose tissue) may in itself lead to obesity. This is evident in mice and may be valid for human subjects, as a substantial proportion of adults possess brown adipose tissue, and those with less or without brown adipose tissue would seem to be more prone to obesity. Thus, increased thermogenesis may counteract obesity, without dietary intervention.

  • 127.
    Cannon, Barbara
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Thyroid hormones: igniting brown fat via the brain.2010In: Nature medicine, ISSN 1546-170X, Vol. 16, no 9, p. 965-7Article in journal (Refereed)
  • 128.
    Cannon, Barbara
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Yes, even human brown fat is on fire!2012In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 122, no 2, p. 486-489Article in journal (Other academic)
    Abstract [en]

    That adult humans possess brown fat is now accepted - but is the brown fat metabolically active? Does human brown fat actually combust fat to release heat? In this issue of the JCI, Ouellet et al. demonstrate that metabolism in brown fat really is increased when adult humans are exposed to cold. This boosts the possibility that calorie combustion in brown fat may be of significance for our metabolism and, correspondingly, that the absence of brown fat may increase our proneness to obesity - provided that brown fat becomes activated not only by cold but also through food-related stimuli.

  • 129.
    Cardell, Susanna
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    T lymphocyte subsets: a study on heterogeneity based on lymphokine production1992Doctoral thesis, comprehensive summary (Other academic)
  • 130. Carpenter, Danielle
    et al.
    Abushama, Hind
    Bereczky, Sándor
    Färnert, Anna
    Rooth, Ingegerd
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Quinnell, Rupert J
    Shaw, Marie-Anne
    Immunogenetic control of antibody responsiveness in a malaria endemic area.2007In: Hum Immunol, ISSN 0198-8859, Vol. 68, no 3, p. 165-9Article in journal (Refereed)
  • 131.
    Carter, Sidney
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Characterization of Budding Yeast Nonhomologous End-Joining at DNA Double-Strand Breaks and Telomeres2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The yeast K. lactis efficiently integrates DNA by illegitimate recombination (IR). IR was completely dependent upon nonhomologous end-joining (NHEJ). In contrast to S. cerevisiae, NHEJ in K. lactis repaired a wide variety of DNA ends, and was not regulated by cell-type. IR events occurred primarily in 5’ intergenic regions. Deletion of RAD52 did not affect the distribution of IR sites. IR events could be targeted to an ectopic DNA double-strand break (DSB). We interpret the genomic distribution of IR events as a map of mitotic DSBs.

    K. lactis mre11 and rad50 strains displayed a shortened telomere phenotype, and a ku80 strain displayed shortened telomeres within a background of telomere elongation. Deletion of KU80 also resulted in excess 3’ overhangs, indicative of a role in telomere end protection. Substantial increases in subtelomeric recombination were observed in rad50 and mre11 strains, while ku80 and lig4 strains displayed modest increases. Telomere-telomere fusions (T-Tfs) induced by loss of Rap1 binding at telomeres were dependent on LIG4 and KU80, but occurred independently of NEJ1. Circularized chromosomes severely inhibited passage of a diploid strain through meiosis. We conclude that K. lactis NHEJ proteins both mediate T-Tfs and contribute to telomere capping.

    The Srs2 helicase was identified as a Nej1 interaction partner. Mutational analysis of Nej1 suggested that the interaction was dependent on phosphorylation of Nej1 serines 297/298 by the Dun1 kinase. Deletion of NEJ1 or DUN1 impaired Srs2 recruitment to an HO induced DSB. Srs2 recruitment was unaffected by deletion of SIZ1, implicated in promoting Srs2 recruitment to replication forks. Both srs2 and nej1 strains were deficient in a RAD52-dependent repair event similar to single-strand annealing. Additionally, srs2 and dun1 strains performed NHEJ less efficiently than a wild-type strain. We propose that Nej1 promotes Srs2 recruitment to DSBs, and supports efficient NHEJ/SSA by antagonizing Rad51.

  • 132. Carter, Sidney D
    et al.
    Iyer, Shilpa
    Xu, Jianing
    McEachern, Michael J
    Aström, Stefan U
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    The role of nonhomologous end-joining components in telomere metabolism in Kluyveromyces lactis.2007In: Genetics, ISSN 0016-6731, Vol. 175, no 3, p. 1035-45Article in journal (Refereed)
  • 133.
    Carter, Sidney D.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Vigasova, Dana
    Chen, Jiang
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Chovanec, Miroslav
    Åström, Stefan U.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Nej1 recruits the Srs2 helicase to DNA double-strand breaks and supports repair by a single-strand annealing-like mechanism2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 29, p. 12037-12042Article in journal (Refereed)
    Abstract [en]

    Double-strand breaks (DSBs) represent the most severe DNA lesion a cell can suffer, as they pose the risk of inducing loss of genomic integrity and promote oncogenesis in mammals. Two pathways repair DSBs, nonhomologous end joining (NHEJ) and homologous recombination (HR). With respect to mechanism and genetic requirements, characterization of these pathways has revealed a large degree of functional separation between the two. Nej1 is a cell-type specific regulator essential to NHEJ in Saccharomyces cerevisiae. Srs2 is a DNA helicase with multiple roles in HR. In this study, we show that Nej1 physically interacts with Srs2. Furthermore, mutational analysis of Nej1 suggests that the interaction was strengthened by Dun1-dependent phosphorylation of Nej1 serines 297/298. Srs2 was previously shown to be recruited to replication forks, where it promotes translesion DNA synthesis. We demonstrate that Srs2 was also efficiently recruited to DSBs generated by the HO endonuclease. Additionally, efficient Srs2 recruitment to this DSB was dependent on Nej1, but independent of mechanisms facilitating Srs2 recruitment to replication forks. Functionally, both Nej1 and Srs2 were required for efficient repair of DSBs with 15-bp overhangs, a repair event reminiscent of a specific type of HR called single-strand annealing (SSA). Moreover, absence of Rad51 suppressed the SSA-defect in srs2 and nej1 strains. We suggest a model in which Nej1 recruits Srs2 to DSBs to promote NHEJ/SSA-like repair by dismantling inappropriately formed Rad51 nucleoprotein filaments. This unexpected link between NHEJ and HR components may represent cross-talk between DSB repair pathways to ensure efficient repair.

  • 134.
    Carter, Sidney
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Shilpa, Iyer
    Xu, Jianing
    McEachern, Michael
    Åström, Stefan
    The Role of Nonhomologous End-Joining Components in Telomere Metabolism in Kluyveromyces lactis2007In: Genetics, ISSN 1091-6490, Vol. 175, no 3, p. 1035-1045Article in journal (Refereed)
  • 135.
    Cavellán, Erica
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Chromatin remodelling in Pol I and III transcription2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Compaction of chromosomes in the eukaryotic cell is due to interactions between DNA and proteins and interactions between proteins. These two types of interaction form a dynamic structure, known as "chromatin". The condensation of chromatin must be carefully regulated, since the structure is an obstacle for factors that need access to the DNA. An extensive range of components, one group of which is the ATP-dependent chromatin remodel-ling complexes, controls the accessibility of DNA. These complexes have been studied in a variety of eukaryotic systems, and their functions in major events in the cell, such as replication, DNA-repair and transcription have been established, as have their roles in the assembly and maintenance of chromatin. All of the complexes contain a highly conserved ATPase, which belongs to the SWI2/SNF2 family of proteins, one group of which is known as the ISWI proteins. There are two forms of ISWI in human, known as "SNF2h" and "SNF2l".

    We have identified a human SNF2h-assembly, B-WICH, that consists of SNF2h, William’s syndrome transcription factor (WSTF), nuclear myosin (NM1), and a number of additional nuclear proteins including the Myb-binding protein 1a (Myb bp1a), SF3b155/SAP155, the RNA helicase II/Guα, the proto-oncogene Dek, and the Cockayne Syndrome protein B (CSB). The 45S rRNA, 5S rRNA and 7SL RNA are all parts of the B-WICH assembly. The formation of B-WICH depends on active transcription, and is implicated in the regulation of both RNA transcription by both pol I and pol III. The B-WICH provides a link between RNA and the chromatin structure.

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  • 136.
    Cavellán, Erica
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Asp, Patrik
    Percipalle, Pergiorgio
    Östlund Farrants, Ann-Kristin
    The WSTF-SNF2h chromatin remodelling complex interacts with several nuclear proteins in transcription2006In: The Journal of biological chemistry, ISSN 0021-9258, no April, 9Article in journal (Refereed)
  • 137. Cavellán, Erica
    et al.
    Asp, Patrik
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Östlund Farrants, Ann-Kristin
    WSTF-SNF2h interacts ith several nuclear proteins in a transcription dependent manner, to form a functional unit B-WICHManuscript (Other academic)
  • 138.
    Cavellán, Erica
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Östlund Farrants, Ann-Kristin
    The WSTF-SNF2h assembly regulates Pol I transcriptionManuscript (Other academic)
  • 139.
    Chen, Jiang
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    DNA double-strand break repair in ascomycetes2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Nonhomologous end joining (NHEJ) and homologous recombination (HR) are two pathways for DNA double strand break (DSB) repair. We found that the NHEJ protein Nej1 interacted physically with the HR protein Srs2, which was dependent on phosphorylation of Nej1 by Dun1. Srs2 recruitment to a DSB partly relied on Nej1 and Dun1. Both Nej1 and Srs2 contributed to efficient single strand annealing (SSA). We suggest that Nej1 and Srs2 facilitate SSA-like repair by disassembling Rad51 nucleoprotein filaments.

    Yen1 is a nuclease that can cleave branched recombination intermediates such as Holliday junctions (HJs). We demonstrated that yen1Δ displayed a negative genetic interaction with mus81 and sgs1 mutants. Mus81 and Sgs1 promoted HJ disjoining by alternative routes, explaining the genetic interaction. Interestingly, catalytically inactive Yen1 had residual functions in DNA repair, suggesting that Yen1 also has a structural role. We discovered that Yen1 interacted physically with Uls1 a potential SUMO targeted ubiquitin ligase. The interaction partly depended on SUMO-modification of the carboxyl terminus of Yen1 and consistent with an ubiquitin ligase function for Uls1, absence of Uls1 stabilized Yen1 after extensive DNA damage. In addition, uls1Δ shared several phenotypes with yen1Δ, including negative genetic interactions with Mus81 after DNA damage and in meiosis. We suggest that Yen1 and Uls1 act together in a DNA repair pathway that is responsible for resolving complex repair intermediates in the absence of Mus81.

    We found that phosphorylation of histone H2A serine 129 promoted DSB repair. Moreover, cells lacking acetylation of lysine residues in the histone H3 NH2-terminus was defective for HR. Interestingly; leaving a single lysine residue intact protected cells from DNA damage. These findings indicate that both histone H2A phosphorylation and histone H3 acetylation are important for the efficiency of the HR-pathway probably by increasing the accessibility of chromatin.

  • 140.
    Chen, Jiang
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Bauer, Stefanie
    Åström, Stefan U.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    The helicase/SUMO-targeted ubiquitin ligase Uls1 interacts both physically and functionally with the Holliday junction resolvase Yen1Manuscript (preprint) (Other academic)
    Abstract [en]

    Yen1 is nuclease that can cleave the Holliday junction (HJ), an important DNA intermediate formed during homologous recombination. Here, we show that Yen1 interacts molecularly with Uls1, a SUMO targeted ubiquitin ligase that also belongs to the SWI/SNF-family of DNA-dependent ATPases. We demonstrate that Yen1 is SUMO modified in its carboxyl terminus and that this modification strengthens the interaction between Yen1 and Uls1. Absence of Uls1 increased the steady-state levels of Yen1, but only after extensive DNA damage, suggesting that Uls1 has a role in damage-induced degradation of Yen1. Consistent with a shared role for Uls1 and Yen1, mutations in the two enzymes display similar phenotypes. Both uls1 and yen1 have a negative genetic interaction with the alternative HJ-cleaving nuclease Mus81. This negative genetic interaction is manifested in supersensitivity to DNA damaging agents, but also in a meiotic defect. Neither mus81 uls1 nor mus81 yen1 double mutant diploids can complete meiosis. Moreover, both uls1 and yen1 exacerbates the chromosome mis-segregation phenotype of mus81. However, the mus81 uls1 yen1 triple mutant strain was slightly more sensitive to DNA damage compared to any double mutant combination, indicating that Uls1 and Yen1 also have independent roles in DNA repair. Point mutant alleles of Uls1 (uls1K975R and uls1C1330S/C1333S) that inactivates the ATPase and potential ubiquitin ligase activities are also supersensitive to DNA damage when combined with mus81, indicating that both activities of Uls1 are essential for function. We suggest that Yen1 and Uls1 are involved in an alternative pathway that is responsible for resolving complex DNA repair intermediates in the absence of Mus81.

  • 141.
    Chen, Jiang
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Åström, Stefan U.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    A catalytic and non-catalytic role for the Yen1 nuclease in maintaining genome integrity in Kluyveromyces lactis2012In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 11, no 10, p. 833-843Article in journal (Refereed)
    Abstract [en]

    Yen1 is a nuclease identified in Saccharomyces cerevisiae that cleaves the Holliday junction (HJ) intermediate formed during homologous recombination. Alternative routes to disjoin HJs are performed by the Mus81/Mms4- and Sgs1/Top3/Rmi1-complexes. Here, we investigate the role of the Yen1 protein in the yeast Kluyveromyces lactis. We demonstrate that both yen1 mus81 and yen1 sgs1 double mutants displayed negative genetic interactions in the presence of DNA-damaging chemicals. To test if these phenotypes required the catalytic activity of Yen1, we introduced point mutations targeting the catalytic site of Yen1, which abolished the nuclease activity in vitro. Remarkably, catalytically inactive Yen1 did not exacerbate the hydroxyurea sensitivity of the sgs1Δ strain, which the yen1Δ allele did. In addition, overexpression of catalytically inactive Yen1 partially rescued the DNA damage sensitivity of both mus81 and sgs1 mutant strains albeit less efficiently than WT Yen1. These results suggest that Yen1 serves both a catalytic and non-catalytic role in its redundant function with Mus81 and Sgs1. Diploids lacking Mus81 had a severe defect in sporulation efficiency and crossover frequency, but diploids lacking both Mus81 and Yen1 showed no further reduction in spore formation. Hence, Yen1 had no evident role in meiosis. However, overexpression of WT Yen1, but not catalytically inactive Yen1 partially rescued the crossover defect in mus81/mus81 mutant diploids. Yen1 is a member of the RAD2/XPG-family of nucleases, but genetic analyses revealed no genetic interaction between yen1 and other family members (rad2, exo1 and rad27). In addition, yen1 mutants had normal nonhomologous end-joining efficiency. We discuss the similarities and differences between K. lactis Yen1 and Yen1/GEN1 from other organisms.

  • 142.
    Chen, Jiang
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Åström, Stefan U.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Acetylation of the histone H3 N-terminus promotes DNA double-strand break repair in Kluyveromyces lactisManuscript (preprint) (Other academic)
    Abstract [en]

    Condensed chromatin hinders proteins from accessing the DNA, hence posing a block to processes like DNA repair. In this study, we investigate how histone modifications influence DNA double-strand break (DSB) repair. We show that blocking phosphorylation of serine 129 of histone H2A impairs DSB-repair, probably by reducing the efficiency of homologous recombination (HR). The lysine residues of histone H3 and H4 are subjected to reversible acetylation and methylation and we exchanged the lysines for either arginine (mimicking non-acetylated lysine) or glutamine (mimicking acetylated lysine). A histone H3 mutant with five N-terminal lysines exchanged for arginine showed reduced gene conversion and perturbed cell cycle progression. Leaving a single lysine residue intact was sufficient for protecting cells from DNA damage. In addition, exchanging the five lysines for glutamine did not result in these defects, indicating that one lysine residue in the histone H3 N-terminus must be acetylated for efficient DSB-repair. We find no evidence for that histone modification reduces the efficiency of nonhomologous end joining. Furthermore, the histone H3 K9, 14, 18, 23, 27R mutation is not defective in transcription of DSB repair genes indicating that the defects we observe in DSB-repair is unlikely to be due to indirect regulatory effects. These findings indicate that both histone H2A phosphorylation and histone H3 acetylation is important for the efficiency of the HR-pathway.

  • 143. Cherif, M. K.
    et al.
    Sanou, G. S.
    Maiga, B.
    Israelsson, E.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ouedraogo, A. L.
    Bougouma, E. C.
    Diarra, A.
    Ouedraogo, A.
    Ouattara, A. S.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dolo, A.
    Cavanagh, D. R.
    Theisen, M.
    Modiano, D.
    Sirima, S. B.
    Nebie, I.
    Fc gamma RIIa Polymorphism and Anti-Malaria-Specific IgG and IgG Subclass Responses in Populations Differing in Susceptibility to Malaria in Burkina Faso2012In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 75, no 6, p. 606-613Article in journal (Refereed)
    Abstract [en]

    Fc?RIIa is known to be polymorphic; and certain variants are associated with different susceptibilities to malaria. Studies involving the Fulani ethnic group reported an ethnic difference in Fc?RIIa-R131H genotype frequencies between the Fulani and other sympatric groups. No previous studies have addressed these questions in Burkina Faso. This study aimed to assess the influence of Fc?RIIa-R131H polymorphism on anti-falciparum malaria IgG and IgG subclass responses in the Fulani and the Mossi ethnic groups living in Burkina Faso. Healthy adults more than 20 years old belonging to the Mossi or the Fulani ethnic groups were enrolled for the assessment of selected parasitological, immunological and genetic variables in relation to their susceptibility to malaria. The prevalence of the Plasmodium falciparum infection frequency was relatively low in the Fulani ethnic group compared to the Mossi ethnic group. For all tested antigens, the Fulani had higher antibody levels than the Mossi group. In both ethnic groups, a similar distribution of Fc?RIIa R131H polymorphism was found. Individuals with the R allele of Fc?RIIa had higher antibody levels than those with the H allele. This study confirmed that malaria infection affected less the Fulani group than the Mossi group. Fc?RIIa-R131H allele distribution is similar in both ethnic groups, and higher antibody levels are associated with the Fc?RIIa R allele compared to the H allele.

  • 144.
    Chernogubova, Ekaterina
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Adrenergic stimulation of glucose uptake in brown adipocytes2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this study was to investigate adrenergically stimulated glucose uptake in brown adipose tissue (BAT) with the focus on receptor subtypes and intracellular signalling pathways. As a model system, we used primary cultured brown adipocytes.

    Adrenergic stimulation of glucose uptake occurs via β3-AR in wild type cells and β1-/α1-ARs in β3-KO cells, includes activation of adenylyl cyclase and cAMP formation, activation of PKA, PI3K, PKC and AMPK (Paper I, II, III). Interestingly, UCP1 activity is not required for the AMPK function in brown adipocytes (Paper III). Long-term adrenergic stimulation of glucose uptake induces an increase in GLUT1 mRNA and protein levels stimulating GLUT1 translocation to the plasma membrane (Paper IV).

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    FULLTEXT01
  • 145.
    Chernogubova, Ekaterina
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Cannon, B
    Bengtsson, T
    Norepinephrine increases glucose transport in brown adipocytes via {beta3}-adrenoceptors through a cAMP, PKA, and PI3-kinasedependent pathway stimulating conventional and novel PKCs2004In: Endocrinology, ISSN 0013-7227, Vol. 145, no 1, p. 269-280Article in journal (Refereed)
  • 146.
    Chernogubova, Ekaterina
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Hutchinson, D S
    Nedergaard, J
    Bengtsson, T
    {alpha}1- and {beta}1-Adrenoceptor Signaling Fully Compensates for {beta}3-Adrenoceptor Deficiency in Brown Adipocyte Norepinephrine-Stimulated Glucose Uptake2005In: Endocrinology, ISSN 0013-7227, Vol. 146, no 5, p. 2271-2284Article in journal (Refereed)
  • 147. Chuangchaiya, S
    et al.
    Jangpatarapongsa, K
    Chootong, P
    Sirichaisinthop, J
    Sattabongkot, J
    Pattanapanyasat, K
    Chotivanich, K
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Cui, L
    Udomsangpetch, R
    Immune response to Plasmodium vivax has a potential to reduce malaria severity2010In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 160, no 2, p. 233-239Article in journal (Refereed)
    Abstract [en]

    Summary Plasmodium falciparum infection causes transient immunosuppression during the parasitaemic stage. However, the immune response during simultaneous infections with both P. vivax and P. falciparum has been investigated rarely. In particular, it is not clear whether the host's immune response to malaria will be different when infected with a single or mixed malaria species. Phenotypes of T cells from mixed P. vivax-P. falciparum (PV-PF) infection were characterized by flow cytometry, and anti-malarial antibodies in the plasma were determined by an enzyme-linked immunosorbent assay. We found the percentage of CD3(+)delta2(+)-T cell receptor (TCR) T cells in the acute-mixed PV-PF infection and single P. vivax infection three times higher than in the single P. falciparum infection. This implied that P. vivax might lead to the host immune response to the production of effector T killer cells. During the parasitaemic stage, the mixed PV-PF infection had the highest number of plasma antibodies against both P. vivax and P. falciparum. Interestingly, plasma from the group of single P. vivax or P. falciparum malaria infections had both anti-P. vivax and anti-P. falciparum antibodies. In addition, antigenic cross-reactivity of P. vivax or P. falciparum resulting in antibodies against both malaria species was shown in the supernatant of lymphocyte cultures cross-stimulated with either antigen of P. vivax or P. falciparum. The role of delta2 +/- TCR T cells and the antibodies against both species during acute mixed malaria infection could have an impact on the immunity to malaria infection.

  • 148.
    Chuquimia Flores, Olga Daniela
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Innate and adaptive immune responses in the lungs. Contribution to protection against mycobacterial infections2011Licentiate thesis, monograph (Other academic)
    Abstract [en]

    Host defense against Mycobacterium tuberculosis (Mtb) is mediated by a combination of innate and adaptive immunity. In this thesis we investigated the role of components of innate system such as TLR2 signalling and alveolar epithelial cells type II (AEC II) in the immune responses against mycobacterial infections.

    Since TLR2 has been shown to be important in the defense against mycobacterial infections; in paper I we investigated the role of TLR2 to generate acquired immune responses. We compared both humoral and cellular immune responses in TLR2-/- and WT (wild type) mice immunized with the mycobacterial antigens 19kDa (TLR2 ligand) or Ag85A (non-TLR2 ligand). We did not find any differences in the humoral responses in both mouse strains. However, we found some deficiencies in the T cell memory compartment of TLR2-/- mice immunized with 19kDa. In addition, the antigen presenting cells (APC) compartment in TLR2-/- mice, for instance bone marrow derived macrophages (BMM) and pulmonary macrophages (PM) in this study, has also shown deficiencies. This effect was more evident when PM were used as APC. We next evaluated the responses in both BMM and PM upon stimulation with anti-CD40 and TLR ligands where PM were the low responders to TLR2 ligand and to anti-CD40 both in the production of different cytokines and in the up-regulation of the co-stimulatory molecules. Together, our results have demonstrated the importance of TLR2 in the generation of specific immune responses.

    In paper II, we investigated the role of AEC II in the defense against mycobacterial infections. AEC II have been suggested to play an important role in the local immune responses to inhaled pathogens. First, we compared murine AEC II with PM in their ability to take up and control mycobacterial growth and their capacity as APCs. AEC II were able to internalize and control bacterial growth as well as presenting antigen to memory T cells. In addition, both cells types were compared in their capacity to produce cytokines, chemokines and other factors where AEC II exhibited a different pattern of secretion than PM. Also, a more complete profile of AEC II responses reveled that AEC II were able to secrete different factors important to generated various effects in others cells. The major finding in this study was that upon TNF, AEC II produced MCP-1 a chemokine involved in the recruitment monocytes/macrophages to the sites of infection. Since TNF is predominantely produced by macrophages, we speculate that both cell types may communicate and influence each other. In conclusion, our results provide more evidence of the important role of AEC II in the immune responses in the respiratory tract.

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    Olga Chuquimia Licentiate thesis-2011
  • 149.
    Chuquimia, Olga D.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Petursdottir, Dagbjort H.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Periolo, Natalia
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Fernandéz, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Alveolar epithelial cells are critical in protection of the respiratory tract by secretion of factors able to modulate the activity of pulmonary macrophages and directly control bacterial growth2013In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 81, no 1, p. 381-389Article in journal (Refereed)
    Abstract [en]

    The respiratory epithelium is a physical and functional barrier actively involved in the clearance of environmental agents. The alveolar compartment is lined with membranous pneumocytes known as type I alveolar epithelial cells (AEC I), and granular pneumocytes, type II alveolar epithelial cells (AEC II). AEC II are responsible for epithelial reparation upon injury and ion transport and are very active immunologically contributing to lung defense by secreting antimicrobial factors. AEC II also secrete a broad variety of factors such as cytokines and chemokines involved in activation and differentiation of immune cells and are able to present antigen to specific T cells. Another cell type important in lung defense is the pulmonary macrophage (PuM). Considering the architecture of the alveoli, a good communication between the external and the internal compartments is crucial to mount effective responses. Our hypothesis is that being in the interface; AEC may play an important role in transmitting signals from the external to the internal compartment and in modulating the activity of PuM. For this, we collected supernatants from AEC unstimulated or stimulated in vitro with lipopolysaccharide (LPS). These AEC-conditioned media were used in various setups to test for the effect on a number of macrophage functions: a) migration; b) phagocytosis and intracellular control of bacterial growth and c) phenotypic changes and morphology. Finally, we tested the direct effect of AEC-conditioned media on bacterial growth. We found that AEC-secreted factors had a dual effect, in one hand controlling bacterial growth and on the other hand increasing macrophage activity.

  • 150.
    Chuquimia, Olga D.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Petursdottir, Dagbjort H.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Rahman, Muhammad J.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Hartl, Katharina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Singh, Mahavir
    Fernandez, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    The Role of Alveolar Epithelial Cells in Initiating and Shaping Pulmonary Immune Responses: Communication between Innate and Adaptive Immune Systems2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 2, p. e32125-Article in journal (Refereed)
    Abstract [en]

    Macrophages and dendritic cells have been recognized as key players in the defense against mycobacterial infection. However, more recently, other cells in the lungs such as alveolar epithelial cells (AEC) have been found to play important roles in the defense and pathogenesis of infection. In the present study we first compared AEC with pulmonary macrophages (PuM) isolated from mice in their ability to internalize and control Bacillus Calmette-Guerin (BCG) growth and their capacity as APCs. AEC were able to internalize and control bacterial growth as well as present antigen to primed T cells. Secondly, we compared both cell types in their capacity to secrete cytokines and chemokines upon stimulation with various molecules including mycobacterial products. Activated PuM and AEC displayed different patterns of secretion. Finally, we analyzed the profile of response of AEC to diverse stimuli. AEC responded to both microbial and internal stimuli exemplified by TLR ligands and IFNs, respectively. The response included synthesis by AEC of several factors, known to have various effects in other cells. Interestingly, TNF could stimulate the production of CCL2/MCP-1. Since MCP-1 plays a role in the recruitment of monocytes and macrophages to sites of infection and macrophages are the main producers of TNF, we speculate that both cell types can stimulate each other. Also, another cell-cell interaction was suggested when IFNs (produced mainly by lymphocytes) were able to induce expression of chemokines (IP-10 and RANTES) by AEC involved in the recruitment of circulating lymphocytes to areas of injury, inflammation, or viral infection. In the current paper we confirm previous data on the capacity of AEC regarding internalization of mycobacteria and their role as APC, and extend the knowledge of AEC as a multifunctional cell type by assessing the secretion of a broad array of factors in response to several different types of stimuli.

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