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  • 251.
    Hossein, Moradi
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Simoff, Ivailo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Bartish, Galyna
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nygård, Odd
    Functional features of the C-terminal region of yeast ribosomal protein L52008In: Molecular Genetics and Genomics, ISSN 1617-4615, E-ISSN 1617-4623, Vol. 280, no 4, p. 337-350Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to analyze the functional importance of the C-terminus of the essential yeast ribosomal protein L5 (YrpL5). Previous studies have indicated that the C-terminal region of YrpL5 forms an α-helix with a positively charged surface that is involved in protein–5S rRNA interaction. Formation of an YrpL5·5S rRNA complex is a prerequisite for nuclear import of YrpL5. Here we have tested the importance of the α-helix and the positively charged surface for YrpL5 function in Saccharomyces cerevisiae using site directed mutagenesis in combination with functional complementation. Alterations in the sequence forming the putative α-helix affected the functional capacity of YrpL5. However, the effect did not correlate with a decreased ability of the protein to bind to 5S rRNA as all rpL5 mutants tested were imported to the nucleus whether or not the α-helix or the positively charged surface were intact. The alterations introduced in the C-terminal sequence affected the growth rate of cells expressing mutant but functional forms of YrpL5. The reduced growth rate was correlated with a reduced ribosomal content per cell indicating that the alterations introduced in the C-terminus interfered with ribosome assembly.

  • 252.
    Hu, Hui
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Mercury-induced autoimmunity: mechanisms of susceptibility/resistance1998Doctoral thesis, comprehensive summary (Other academic)
  • 253. Hutchinson, D.
    et al.
    Chernogubova, E.
    Dallner, O.S.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Cannon, B.
    Bengtsson, T.
    β-adrenoceptors, but not α-adrenoceptors, stimulate AMP-activated protein kinase in brown adipocytes independently of uncoupling protein-12005In: Diabetologia, ISSN 0012-186X, Vol. 48, no 11, p. 2386-95Article in journal (Refereed)
  • 254. Hutchinson, D S
    et al.
    Chernogubova, Ekaterina
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Cannon, B
    Bengtsson, T
    {beta}-Adrenoreceptors, but not {alpha}- Adrenoreceptors, Stimulate AMPK in Brown Adipocytes Independently of UCP1In: DiabetologiaArticle in journal (Refereed)
  • 255. Hutchinson, Dana S.
    et al.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Yamamoto, Daniel L.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Wikström, Per
    Wilcke, Mona
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Diphenylene iodonium stimulates glucose uptake in skeletal muscle cells through mitochondrial complex I inhibition and activation of AMP-activated protein kinase2007In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 19, no 7, p. 1610-1620Article in journal (Refereed)
    Abstract [en]

    NADPH oxidase inhibitors such as diphenylene iodonium (DPI) and apocynin lower whole body and blood glucose levels and improve diabetes when administered to rodents. Skeletal muscle has an important role in managing glucose homeostasis and we have used L6 cells, C2C12 cells and primary muscle cells as model systems to investigate whether these drugs regulate glucose uptake in skeletal muscle cells. The data presented in this study show that apocynin does not affect glucose uptake in skeletal muscle cells in culture. Tat gp91ds, a chimeric peptide that inhibits NADPH oxidase activity, also failed to affect glucose uptake and we found no significant evidence of NADPH oxidase (subunits tested were Nox4, p22phox, gp91phox and p47phox mRNA) in skeletal muscle cells in culture. However, DPI increases basal and insulin-stimulated glucose uptake in L6 cells, C2C12 cells and primary muscle cells. Detailed studies on L6 cells demonstrate that the increase of glucose uptake is via a mechanism independent of phosphoinositide-3 kinase (PI3K)/Akt but dependent on AMP-activated protein kinase (AMPK). We postulate that DPI through inhibition of mitochondrial complex 1 and decreases in oxygen consumption, leading to decreases of ATP and activation of AMPK, stimulates glucose uptake in skeletal muscle cells.

  • 256. Hutchinson, Dana S
    et al.
    Summers, Roger J
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Regulation of AMP-activated protein kinase activity by G-protein coupled receptors: potential utility in treatment of diabetes and heart disease.2008In: Pharmacol Ther, ISSN 0163-7258, Vol. 119, no 3, p. 291-310Article in journal (Refereed)
  • 257.
    Högberg, Helena
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Developmental Neurotoxicity Testing Using In vitro Approaches2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    There is a great concern about children’s health as the developing brain in foetuses and children is much more vulnerable to injury caused by different classes of chemicals than the adult brain. This vulnerability is partly due to the fact that the adult brain is well protected against chemicals by the blood brain barrier (BBB) and children have increased absorption rates and diminished ability to detoxify many exogenous compounds, in comparison to that of adults. Moreover, the development of the central nervous system (CNS) is a very complex process involving several different important events, e.g. proliferation, migration and differentiation of cells. These events are occurring within a strictly controlled time frame and therefore create different windows of vulnerability. Furthermore, the brain consists of numerous different cell types (neuronal, glial and endothelial cells) that have specific functions. The development of each cell type occurs within a specific time window and is therefore susceptible to environmental disturbances at different time periods.

    Evidence indicates that exposure to industrial chemicals, pesticides or drugs, contributes to the increasing incidence of neurodevelopment disorders. However, due to lack of studies only a few industrial chemicals have been identified as developmental neurotoxicants so far. The current developmental neurotoxicity (DNT) guidelines (OECD TG 426 and US EPA 712-C-98-239) are based entirely on in vivo studies that are time consuming, complex, costly and not suitable for the testing of a high number of chemicals. Applying alternative approaches such as in silico, in vitro and non-mammalian models as a part of an integrated test strategy, could speed up the process of DNT evaluation and reduce and refine animal usage. Both in vitro and non-mammalian test systems offer the possibility of providing an early screening for a large number of chemicals, and could be particularly useful in characterising the compound-induced mechanism of toxicity of various developmental processes.

    This thesis has characterised two primary neuronal cultures (cerebellar granule cells (CGCs) and cortical neuronal cultures) and identified them as relevant models for DNT testing, since the key processes of brain development are present, such as cell proliferation, migration and neuronal/glial differentiation. Furthermore, two emerging technologies (gene expression and electrical activity) have been evaluated and were identified as promising tools for in vitro DNT assessment. In combination with other assays they could be included into a DNT intelligent testing strategy to speed up the process of DNT evaluation mainly by prioritising chemicals with DNT potential for further testing.

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  • 258.
    Högberg, Helena T.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Bal-Price, Anna K.
    In-Vitro Methods Unit.
    Comparative toxicity induced by domoic acid in immature and mature mixed primarycultures of cerebellar granule cells: involvement of AMPA and NMDA receptorsManuscript (preprint) (Other academic)
    Abstract [en]

    Domoic acid is a naturally occurring shellfish toxin that can induce brain damage in mammalians. The toxic effects is thought to be mediated through activation of the AMPA/KA receptor, which induces increased levels of intracellular Ca2+ which in turn cause glutamate release and activates the NMDA receptor. Most studies have been performed in adult animals but neonates have been shown to be more sensitivity to domoic acid per body weight than adults. Prenatal exposure to domoic acid has been associated with damage to neurons in different brain regions, decreased brain GABA levels and increased glutamate levels. In this study we evaluated domoic acid induced toxicity in immature and mature cultures of primary rat cerebellar granule cells (CGCs) by measuring the mRNA levels of selected genes identified as specific glial and neuronal markers. Moreover, we assessed if the induced effects were mediated by activation of the AMPA/KA and/or the NMDA receptor. In addition the influence of the neurotransmitter GABA on domoic acid toxicity was evaluated. The mRNA levels of all the neuronal markers (NF-68, NF-200, NMDA receptor and GABAA receptor) were down-regulated after domoic acid exposure in both immature and mature cultures. However, the mature cultures seemed to be more sensitive to the treatment as the effects were observed at lower concentrations and at an earlier time point than for the immature ones. This could be due to lower expression in young cultures of the receptors that are mediating the toxicity. Indeed, the domoic acid effect could be prevented by the antagonist of the AMPA/KA receptor (NBQX) indicating that this receptor is involved, in contrast to the antagonist for the NMDA receptor (APV) that did not induced any effects. Interestingly, the astrocytic markers (GFAP and S100β) and the neural precursor marker (nestin) were only affected in the mature cultures. These effects could partly be prevented by NBQX, APV and the neurotransmitter GABA, indicating that domoic acid induced toxicity by different mechanisms in astrocytes compared to neurons.

  • 259.
    Högberg, Helena T.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Kinsner-Ovaskainen, Agnieszka
    In vitro methods unit.
    Coecke, Sandra
    In vitro methods unit.
    Hartung, Thomas
    Johns Hopkins University.
    Bal-Price, Anna
    In vitro methods unit.
    mRNA Expression is a Relevant Tool to Identify Developmental Neurotoxicants Using an In Vitro Approach2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 113, no 1, p. 95-115Article in journal (Refereed)
    Abstract [en]

    So far, only a few industrial chemicals have been identified as developmental neurotoxicants. Because the current developmental neurotoxicity (DNT) guideline (Organisation for Economic Cooperation and Development TG 426) is based entirely on in vivo studies that are both time consuming and costly, there is a need to develop alternative in vitro methods for initial screening to prioritize chemicals for further DNT testing. In this study, gene expression at the mRNA level was evaluated to determine whether this could be a suitable endpoint to detect potential developmental neurotoxicants. Primary cultures of rat cerebellar granule cells (CGCs) were exposed to well known (developmental) neurotoxicants (methyl mercury chloride, lead chloride, valproic acid, and tri-methyl tin chloride) for different time periods. A significant downregulation of the mRNA level for the neuronal markers (NF- 68, NF-200, N-methyl D-aspartate glutamate receptor, and gamma amino butyric acid receptor) was observed after exposure to methyl mercury chloride, valproic acid, and tri-methyl tin chloride. Moreover, a significant increase of the neural precursor marker nestin mRNA was also observed. The mRNA expression of the astrocytic markers (glial fibrillary acidic protein [GFAP] and S100b) was unchanged. In contrast, exposure to lead chloride significantly decreased the mRNA level of the astrocytic marker GFAP, whereas the neuronal markers were less affected. These results suggest that gene expression could be used as a sensitive tool for the initial identification of DNT effects induced by different mechanisms of toxicity in both cell types (neuronal and glial) and at various stages of cell development and maturation.

  • 260.
    Högberg, Helena T.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Kinsner-Ovaskainen, Agnieszka
    In vitro toxicology unit.
    Hartung, Thomas
    Traceability, Risk and Vulnerability Assessment.
    Coecke, Sandra
    In vitro toxicology unit.
    Bal-Price, Anna
    In vitro toxicology unit.
    Gene expression as a sensitive endpoint to evaluate cell differentiation andmaturation of the developing central nervous system in primary cultures of ratcerebellar granule cells (CGCs) exposed to pesticides2009In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 235, p. 268-286Article in journal (Refereed)
    Abstract [en]

    The major advantage of primary neuronal cultures for developmental neurotoxicity (DNT) testing is their ability to replicate the crucial stages of neurodevelopment. In our studies using primary culture of cerebellar granule cells (CGCs) we have evaluated whether the gene expression relevant to the most critical developmental processes such as neuronal differentiation (NF-68 and NF-200) and functional maturation (NMDA and GABA presence of neural precursor cells (nestin and Sox10) could be used as an endpoint for in vitro DNT. The expression of these genes was assessed after exposure to various pesticides (paraquat parathion, dichlorvos, pentachlorophenol and cycloheximide) that could induce developmental neurotoxicity through different mechanisms. All studied pesticides signi different stages of neuronal and/or glial cell development and maturation. The most signi observed after exposure to paraquat and parathion (i.e. down-regulation of mRNA expression of NF-68 and NF-200, NMDA and GABA expression of NF-68 and GABA as signi astrocyte marker (S100 multiple pathways of neurodevelopment can be identi in different stages of cell development and maturation, and that gene expression could be used as a sensitive endpoint for initial screening to identify the compounds with the potential to cause developmental neurotoxicity. A receptors), proliferation and differentiation of astrocytes (GFAP and S100β) as well as theficantly modified the expression of selected genes, related to theficant changes wereA receptors). Similarly, dichlorvos affected mainly neurons (decreased mRNAA receptors) whereas cycloheximide had an effect on neurons and astrocytes,ficant decreases in the mRNA expression of both neurofilaments (NF-68 and NF-200) and theβ) were observed. Our results suggest that toxicity induced by pesticides that targetfied by studying expression of genes that are involved

  • 261.
    Högberg, Helena T.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Sobanski, Tomasz
    System toxicology Unit.
    Novellino, Antonio
    System toxicology Unit.
    Whelan, Maurice
    System toxicology Unit.
    Bal-Price, Anna
    In-vitro Methods.
    Application of micro electrode arrays (MEAs) as an emerging technology for domoic acid- induced developmental neurotoxicity evaluation in primary cultures of rat cortical neuronsManuscript (preprint) (Other academic)
    Abstract [en]

    Due to lack of knowledge only a few industrial chemicals have been identified as developmental neurotoxicants. Current developmental neurotoxicity (DNT) guidelines (OECD TG 426 and EPA712-C-98-239) are based entirely on in vivo studies that are both time consuming and costly. Consequently, there is a high demand to develop alternative in vitro methods for initial screening to prioritise chemicals for further DNT testing. One of the most promising tools for neurotoxicity assessment is the measurement of electrical activity using micro electrode arrays (MEA) that provides a functional and neuronal specific endpoint that until now mainly has been used to detect acute neurotoxicity. Here, electrical activity measurements were evaluated to be a suitable endpoint for the detection of potential developmental neurotoxicants. Initially, primary cortical neurons grown on MEA were characterized for different cell markers (neural precursor cells, neurons and astrocytes) over time using immunocytochemistry to evaluate if the model could be suitable for DNT testing. Indeed, our results show that primary cortical neurons could be a promising in vitro model for DNT testing since some of the most critical neurodevelopment processes such as progenitor cell commitment, proliferation and differentiation of astrocytes and maturation of neurons are present. To evaluate if electrical activity could be a suitable endpoint to detect chemicals with DNT effects primary cortical neurons grown on MEA were exposed to domoic acid (DA), a potential developmental neurotoxicant for up to 4 weeks. Long term exposure to a low concentration (50 nM) of DA increased the basal spontaneous electrical activity as measured by spike and burst rates, as compared to the control cultures. Moreover, the effect induced by the GABAA receptor antagonist bicuculline was significantly lower in the DA treated cultures than in the untreated ones. Obtained data indicates that electrical activity measurements can be used as a tool to detect chemicals with DNT potential. However, more DNT chemicals as well as non-neurotoxic chemicals (negative controls) should be tested to confirm the use of electrical activity measurements for initial DNT screening purposes.

  • 262.
    Höglund, Anna-Stina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Cell motility: the dynamics of the cortical weave of microfilaments and its relation to microtubules and coated vesicles in fibroblasts and glial cells1985Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Actin and myosin, the major components of the microfilament system are found in most - if not all - eukaryotic cells. In muscle they form the basis of the contractile apparatus which generates the rapid, strong and unidirectional movements that characterizes muscle activity. Other cell types have developed their special arrangement of the microfilament system: some form what appears to be rather stable structures, while others undergo considerable reorganizations. Such reorganizations for instance are thought to be fundamental for the dynamic and flexible behavior shown by fibroblasts in vitro. How these reorganizations - which probably involve polymerization, bundling, debundling and depolymerization of actin - are regulated is beginning to be unravelled by the isolation and characterization of various actin-binding proteins.In addition to the various activities exerted by the microfilament system, the microtubules and most likely the intermediate filaments too contribute to non-muscle cell motile phenomena. Studies of the organization of these three fiber systems and their possible relationship are therefore important in order to understand cell moti1ity.This thesis describes the visualization of the peripheral microfilament organization in fibroblasts and glial cells by transmission electron microscopy of negatively- stained whole-cell mounts. Conditions for preparation of the specimen were developed in order to obtain a balanced solubilization and preservation of the cell components. The visualization of the cell ultrastructure was improved by using a mixture of detergent and fixative in combination with sodium si 1icotungstate as negative stain. This made it possible to make observations of the details in the microfilament arrangement in the periphery of spreading and translocating cells as well as of the surface structures induced by the growth-stimulating hormone, platelet-derived growth factor.The microtubules and their relation to the microfilament-based structures in the cell periphery were also visualized by this technique.Some observations concerning the possible involvement of the microfilament system in endocytosis, especially their relation to coated vesicles, are also described.

  • 263.
    Högstrand, Kari
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Gene conversion of the mouse MHC class II1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The major histocompatibility complex (MHC) is the most polymorphic vertebrate gene loci known to exist. Gene products of the MHC are responsible for presentation of antigen derived peptides to T cells of the immune system, which thereby become activated and involved in the elimination of particles recognised as non-self. The mechanism of acquiring this extensive polymorphism is not known, but gene conversion has been suggested as one possible molecular genetic mechanism employed to generate new MHC alleles. A strict definition of gene conversion, based on the phenomenon in yeast, involves the transfer of a DNA fragment from a donor gene to a homologous acceptor gene without the donor gene being changed in the process. For practical reasons, the term gene conversion in higher organisms is rather used in the context of ìtemplated segmental mutationì.

    This thesis describes the first direct evidence of gene conversion events between two endogenous MHC class II genes in a mouse system using sperm as a representative for future potential individuals. A PCR assay was developed using primers for the acceptor gene as well as the donor gene to obtain a detectable product only in cells where a gene conversion event had occurred. Interchromosomal gene conversion between a MHC class II Ab and Eb gene located on separate chromosomes was found to occur at a frequency of 1/500.000 sperm, whereas no gene conversion was detected in somatic liver cells. Intrachromosomal gene conversions between Ab and Eb genes located on the same chromosome were detected at frequencies ranging from 1/35.000 sperm to 1/830.000 sperm depending on the alleles in ves gat ed. This difference in frequency was found although the investigated alleles coexisted in the same cell, which indicates that there is sequence restraints acting on the genes involved in a gene conversion event. Both inter- and intra-chromosomal gene conversions transferred DNA fragments which varied in length, but the transfer breakpoints investigated were usually in regions where the donor and acceptor genes showed a high nucleotide similarity.

    Investigation of gene conversion during male gametogenesis showed that most gene conversion events detected between MHC class II genes were completed already in the premeiotic spermatogonia cell stage, which indicates that gene conversion relies on other molecular genetic mechanisms than normal meiotic recombination. Sequence analysis of several MHC mutants proposed to have been caused by gene conversion events revealed that both donor and acceptor sequences resided in regions where normal mammalian CpG suppression was absent. CpG dinucleotides have been shown to be relatively mutation prone, which accordingly suggests that regions with a high CpG content could be targeted for mutation events. Moreover, gene conversion could be induced and increased up to 15 times of the background level in a cell line by DNA damage, which indicates that the DNA repair system is involved in the gene conversion mechanism.

    From an evolutionary point of view, gene conversion thus is a very potent mechanism for creation of new MHC alleles by shuffling of already existing and functional parts of genes into new homologous locations. This mechanism can efficiently produce new functional MHC variants, which could give the population a selective advantage in terms of the ability to cope with various pathogens as well as being a mean to avoid inbreeding that could result in a reproductive loss.

  • 264.
    Höidén, Ingmarie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Regulation of superantigen-induced cytokine production1995Doctoral thesis, comprehensive summary (Other academic)
  • 265. Ibitokou, Samad
    et al.
    Oesterholt, Mayke
    Brutus, Laurent
    Borgella, Sophie
    Agbowaï, Carine
    Ezinmègnon, Sèm
    Lusingu, John
    Schmiegelow, Christentze
    Massougbodji, Achille
    Deloron, Philippe
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Varani, Stefania
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Luty, Adrian J. F.
    Fievet, Nadine
    Peripheral Blood Cell Signatures of Plasmodium falciparum Infection during Pregnancy2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 12, p. e49621-Article in journal (Refereed)
    Abstract [en]

    Sequestration of Plasmodium falciparum-infected erythrocytes in placental intervillous spaces causes inflammation and pathology. Knowledge of the profiles of immune cells associated with the physiopathology of pregnancy-associated malaria (PAM) is scarce. We conducted a longitudinal, prospective study, both in Benin and Tanzania, including ∼1000 pregnant women in each site with systematic follow-up at scheduled antenatal visits until delivery. We used ex vivo flow cytometry to identify peripheral blood mononuclear cell (PBMC) profiles that are associated with PAM and anaemia, determining the phenotypic composition and activation status of PBMC in selected sub-groups with and without PAM both at inclusion and at delivery in a total of 302 women. Both at inclusion and at delivery PAM was associated with significantly increased frequencies both of B cells overall and of activated B cells. Infection-related profiles were otherwise quite distinct at the two different time-points. At inclusion, PAM was associated with anaemia, with an increased frequency of immature monocytes and with a decreased frequency of regulatory T cells (Treg). At delivery, infected women presented with significantly fewer plasmacytoid dendritic cells (DC), more myeloid DC expressing low levels of HLA-DR, and more effector T cells (Teff) compared to uninfected women. Independent associations with an increased risk of anaemia were found for altered antigen-presenting cell frequencies at inclusion, but for an increased frequency of Teff at delivery. Our findings emphasize the prominent role played by B cells during PAM whenever it arises during pregnancy, whilst also revealing signature changes in other circulating cell types that, we conclude, primarily reflect the relative duration of the infections. Thus, the acute, recently-acquired infections present at delivery were marked by changes in DC and Teff frequencies, contrasting with infections at inclusion, considered chronic in nature, that were characterized by an abundance of immature monocytes and a paucity of Treg in PBMC.

  • 266. Imreh, Gabriela
    et al.
    Norberg, Helin Vakifahmetoglu
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Imreh, Stefan
    Zhivotovsky, Boris
    Chromosomal breaks during mitotic catastrophe trigger gamma H2AX-ATM-p53-mediated apoptosis2011In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 124, no 17, p. 2951-2963Article in journal (Refereed)
    Abstract [en]

    Although the cause and outcome of mitotic catastrophe (MC) has been thoroughly investigated, precisely how the ensuing lethality is regulated during or following this process and what signals are involved remain unknown. Moreover, the mechanism of the decision of cell death modalities following MC is still not well characterised. We demonstrate here a crucial role of the gamma H2AX-ATM-p53 pathway in the regulation of the apoptotic outcome of MC resulting from cells entering mitosis with damaged DNA. In addition to p53 deficiency, the depletion of ATM (ataxia telangiectasia mutated), but not ATR ( ataxia telangiectasia and Rad3-related protein), protected against apoptosis and shifted cell death towards necrosis. Activation of this pathway is triggered by the augmented chromosomal damage acquired during anaphase in doxorubicin-treated cells lacking 4-3-3 sigma (also known as epithelial cell marker protein-1 or stratifin). Moreover, cells that enter mitosis with damaged DNA encounter segregation problems because of their abnormal chromosomes, leading to defects in mitotic exit, and they therefore accumulate in G1 phase. These multi- or micronucleated cells are prevented from cycling again in a p53- and p21-dependent manner, and subsequently die. Because increased chromosomal damage resulting in extensive H2AX phosphorylation appears to be a direct cause of catastrophic mitosis, our results describe a mechanism that involves generation of additional DNA damage during MC to eliminate chromosomally unstable cells.

  • 267.
    Iriemenam, Nnaemeka C.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Antibody responses and Fc gamma receptor IIa polymorphism in relation to Plasmodium falciparum malaria2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Immunity to asexual blood-stage of Plasmodium falciparum malaria is believed to be associated with protective antibodies of certain immunoglobulin classes and subclasses. This thesis addressed the importance of antibodies in relation to malaria infection and their effective interactions with Fc gamma receptor IIa (FcyRIIa) polymorphisms. Our data indicate that the frequency of FcyRIIa-R/R131 genotype was statistically significantly higher in Sudanese patients with severe malaria, while the FcyRIIa-H/H131 genotype showed a significant association with mild malaria. The levels of IgG1 and IgG3 subclass antibodies were statistically higher in the mild malaria patients.

    The Fulani ethnic group in West Africa has been shown to be relatively resistant to malaria. We investigated the possible impact of FcyRIIa polymorphisms in the Fulani and non-Fulani in Mali and Sudan, and analysed their malaria-reactive IgG subclass profiles. The FcyRIIa-H/H131 genotype and H131-allele were found to be prevalent in the Fulani while R131-allele was prevalent in non-Fulani. The Fulani had higher serum levels of IgG1-3, with higher proportion of IgG2 than the non-Fulani.

    Most clinico-epidemiology studies have been in areas with holo- and hyper-malaria endemicity. We have analysed antibody responses to a panel of six blood-stage antigens in relation to clinical malaria outcome in mesoendemic Sudan. Our results revealed a linear association with anti-AMA-1 IgG1 antibodies and reduced risk of severe malaria while a non-linear relationship with IgG3 antibodies was observed for MSP-2, MSP-3 and GLURP. In the combined final model, the highest levels of IgG1 subclass antibodies to AMA-1, GLURP-R0, and the highest levels of IgG3 subclass antibodies reactive to 3D7 MSP-2 were independently associated with a reduced risk of clinical malaria.

    Taken together, these data suggest a possible association between FcyRIIa-R/H131 and anti-malarial antibody responses in the clinical outcome of malaria.

     

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  • 268.
    Iriemenam, Nnaemeka C.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Khirelsied, Atif H.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    ElGhazali, Gehad
    Giha, Haider A.
    Elhassan A-Elgadir, Thoraya
    Agab-Aldour, Ahmed A.
    Montgomery, Scott M.
    Anders, Robin F.
    Theisen, Michael
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Elbashir, Mustafa I.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Antibody responses to a panel of Plasmodium falciparum malaria blood-stage antigens in relation to clinical disease outcome in Sudan2009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, no 1, p. 62-71Article in journal (Refereed)
    Abstract [en]

    Despite many intervention programmes aimed at curtailing the scourge, malaria remains a formidable problem of human health. Immunity to asexual blood-stage of Plasmodium falciparum malaria is thought to be associated with protective antibodies of certain immunoglobulin classes and subclasses. We have analysed immunoglobulin G profiles to six leading blood-stage antigens in relation to clinical malaria outcome in a hospital-based study in Sudan. Our results revealed a linear association with anti-AMA-1-IgG1 antibodies in children <5 years and reduced risk of severe malaria, while the responses of the IgG3 antibodies against MSP-2, MSP-3, GLURP in individuals above 5 years were bi-modal. A dominance of IgG3 antibodies in >5 years was also observed. In the final combined model, the highest levels of IgG1 antibodies to AMA-1, GLURP-R0, and the highest levels of IgG3 antibodies to 3D7 MSP-2 were independently associated with protection from clinical malaria. The study provides further support for the potential importance of the studied merozoite vaccine candidate antigens as targets for parasite neutralizing antibody responses of the IgG1 and IgG3 subclasses.

  • 269.
    Iriemenam, Nnaemeka C
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Okafor, Christian M F
    Balogun, Halima A
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ayede, Idowu
    Omosun, Yusuf
    Persson, Jan-Olov
    Hagstedt, Margareta
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Anumudu, Chiaka I
    Nwuba, Roseangela I
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Cytokine profiles and antibody responses to Plasmodium falciparum malaria infection in individuals living in Ibadan, southwest Nigeria.2009In: African Health Sciences, ISSN 1680-6905, E-ISSN 1729-0503, Vol. 9, no 2, p. 66-74Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The ability of the host immune system to efficiently clear Plasmodium falciparum parasites during a malaria infection depends on the type of immune response mounted by the host. STUDY DESIGN: In a cross-sectional study, we investigated the cellular-and antibody responses in individuals with P. falciparum infection, in an attempt to identify immunological signs indicative of the development of natural immunity against malaria in Ibadan, Nigeria. Levels of IL-10, IL-12(p70), IFN-gamma, and IgM, IgG and IgG1-4 subclasses in the serum of 36 symptomatic children with microscopically confirmed malaria parasitaemia and 54 asymptomatic controls were analysed by ELISA. RESULTS: IFN-gamma and IL-10 were significantly higher in the symptomatic children (p=0.009, p=0.025 respectively) than in the asymptomatic controls but no differences were seen for IL-12(p70). Estimated higher ratios of IFN-gamma/IL-10 and IFN-gamma/IL-12 were also observed in the symptomatic children while the asymptomatic controls had higher IL-12/IL-10 ratio. The mean concentration levels of anti-P. falciparum IgG1, IgG2, IgG3 antibodies were statistically significantly higher in the individuals >5 years of age than <5 years while anti-P. falciparum IgG3 antibodies were notably low in <5 years category. Children <5 years had higher IgM antibodies than IgG and the expression of IgG subclasses increased with age. CONCLUSION: Taken together, malaria infection is on a delicate balance of pro- and anti-inflammatory cytokines. The higher levels of IFN-gamma seen in the symptomatic children (<6 months) may be instrumental in immune-protection against malaria by limiting parasite replication. The observed variations in immunoglobulin subclass levels were age-dependent and exposure-related.

  • 270.
    Israelsson, E.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Balogun, Halima
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Vasconcelos, N.-M.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Beser, J.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Roussilhon, C
    Rogier, C
    Trape, J F
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Antibody responses to a C-terminal fragment of the Plasmodium falciparum blood-stage antigen Pf332 in Senegalese individuals naturally primed to the parasite2008In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 152, no 1, p. 64-71Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that antibodies from humans exposed continuously to malaria recognize the Plasmodium falciparum asexual blood-stage antigen Pf332. Here we analysed the antibody responses to a C-terminal fragment of Pf332, designated C231, in individuals from Senegal, by measuring the serum levels of immunoglobulin M (IgM), IgG class and subclass and IgE antibodies. IgG antibody reactivity with crude P. falciparum antigen was detected in all the donors, while many of the children lacked or had low levels of such antibodies against C231. The antibody levels increased significantly with age for both crude P. falciparum antigen and C231, and in the older age groups most of the donors displayed antibodies to C231. This was also true for IgM, IgE and IgG subclass reactivity against C231. Moreover, the ratio of IgG1/IgG2 was considerably lower for C231 than for crude P. falciparum antigen, and in age groups 10–14 and 15–19 years the levels of IgG2 against C231 even exceeded that of IgG1. The IgG2/IgG3 ratios suggest that C231 gives similar levels of IgG2 and IgG3, except for children aged 4–9 years, where IgG3 was higher. Raw IgM, IgG class and subclass and IgE antibody levels to C231 tended to be higher in those who did not experience a malaria attack, but following linear multivariate analysis the trends were not significant.

  • 271. Israelsson, E.
    et al.
    Ekström, M.
    Nasr, A.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Arambepola, G.
    Maiga, B.
    Dolo, A.
    Doumbo, O.K.
    Giha, H.A.
    Troye-Blomberg, M.
    Berzins, K.
    Tornvall, P.
    Polymorphism in the CRP gene may contribute to the lower susceptibility to malaria of the Fulani ethnic group in AfricaManuscript (Other academic)
  • 272.
    Israelsson, Elisabeth
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Host genetic factors and antibody responses with potential involvement in the susceptibility to malaria2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The relatively lower susceptibility to malaria seen in the Fulani ethnic group in Africa, as compared to other sympatric ethnic groups, has been related to genetic regulation of the immune responses. This thesis aimed to describe important pathways related to the regulation of antibodies in the immune responses during a malaria infection. Our results suggest that the higher anti-malarial immune responses seen in the Fulani are not a general hyper-responsiveness in this group, but neither a malaria specific response. Fcγ receptors are important structures in the immune responses, and polymorphisms in these genes were associated with IgG subclass levels, P. falciparum parasitemia and haemoglobin levels, suggesting that these polymorphisms may be a contributing factor to the differential susceptibility to malaria. C-reactive protein levels rise immediately in response to inflammatory stimuli, and the -286 CRP polymorphism was indicated to influence parasite levels, suggesting a possible involvement in the lower susceptibility to malaria seen in the Fulani ethnic group. Several cytokines are important in maintaining the optimal parasite-neutralizing milieu in the host, and we investigated polymorphisms in some of these cytokine genes, in order to establish a possible influence of these on malaria susceptibility. Several of these polymorphisms showed associations with haemoglobin levels, IgG subclass antibody levels and parasitemia, suggesting that IL-1β, IL-6, IL-10 and TNF could affect the susceptibility to malaria and the severity of the malaria infection.

    Taken together, these data suggest that genetic factors have the ability to affect the antibody responses, and that several pathways can be affected. Moreover, the Fulani have a genetic predisposition for a higher inflammatory response during a malaria infection, which could lower their susceptibility to the disease. However, the control measures for this inflammation still have to be established and evaluated.

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  • 273.
    Israelsson, Elisabeth
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    The role of antibody mediated parasite neutralization in protective immunity against malaria2007Licentiate thesis, comprehensive summary (Other academic)
    Download full text (pdf)
    FULLTEXT01
  • 274.
    Israelsson, Elisabeth
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ekström, Mattias
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dolo, Amagana
    Kearsley, Susannah
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Arambepola, Gishanthi
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Homann, Manijeh V.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Maiga, Bakary
    Doumbo, Ogobara K.
    ElGhazali, Gehad
    Giha, Hayder A.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Tornvall, Per
    Marked differences in CRP genotype frequencies between the Fulani and sympatric ethnic groups in Africa2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, no 136Article in journal (Refereed)
    Abstract [en]

    Background

    C-reactive protein (CRP) is an acute phase protein that can activate various immune cells and bind to certain Fcγ receptors. The latter may compete with the binding of IgG antibodies to these receptors and could thereby interfere with the antigen-specific immune response. Polymorphisms in the promoter region of the CRP gene have been strongly associated with the plasma concentration of CRP. The known lower susceptibility to malaria in the Fulani ethnic group, as compared to their sympatric neighbours in Africa, has been linked to different genetic backgrounds. The present study was performed to investigate if polymorphisms in the CRP gene could contribute to the lower susceptibility to malaria seen in the Fulani ethnic group.

    Methods

    The CRP -717 T>C, -286 C>T>A, and +1444 C>T polymorphisms were analysed in asymptomatic Fulani and non-Fulani individuals from Mali and Sudan using Pyrosequencing T and TaqMan r MGB probes.

    Results

    The rare -286 A allele, previously shown to be associated with increased CRP expression and plasma levels, was shown to be more frequent in the non-Fulani ethnic groups as compared to the sympatric Fulani ethnic group both in Mali and Sudan. The common -717 T allele was more prevalent in the non-Fulani ethnic group compared to the sympatric Fulani ethnic group, but only in Mali. The parasite prevalence was increased for the -286 A allele, but not for the -717 T allele. No differences regarding genotype frequency or parasite prevalence were seen for +1444 C>T.

    Conclusion

    This study indicate that CRP may play an important role in the immune responses to malaria, and that the -286 C/T/A CRP polymorphism may be a contributing factor to the lower susceptibility to malaria seen in the Fulani.

  • 275.
    Israelsson, Elisabeth
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Kearsley, Susannah
    Berzins, Klavs
    Maiga, Bakary
    Nasr, Amre
    Dolo, Amagana
    Doumbo, Ogobara K.
    ElGhazali, Gehad
    Giha, Hayder A.
    Troye-Blomberg, Marita
    Tornvall, Per
    Cytokine polymorphisms: influences on C-reactive protein levels, and a possible influence on malaria susceptibilityManuscript (Other academic)
  • 276.
    Israelsson, Elisabeth
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Kearsley, Susannah
    Vafa, Manijeh
    Maiga, Bakary
    Dolo, Amagana
    Doumbo, Ogobara K.
    Troye-Blomberg, Marita
    Berzins, Klavs
    Fcγ-receptor genotypes in two ethnic groups showing different susceptibility against malaria in Mali, West AfricaManuscript (Other academic)
  • 277.
    Israelsson, Elisabeth
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Maiga, Bakary
    Kearsley, Susannah
    Dolo, Amagana
    Homann, Manijeh Vafa
    Doumbo, Ogobara K
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Tornvall, Per
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Cytokine gene haplotypes with a potential effect on susceptibility to malaria in sympatric ethnic groups in Mali2011In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 11, no 7, p. 1608-1615Article in journal (Refereed)
    Abstract [en]

    Cytokines are important players in the immune responses, and an unbalance in pro- and anti-inflammatory cytokine responses may affect parasitemia and pathology in a Plasmodium falciparum infection. Polymorphisms in cytokine genes may affect not only the levels of the protein, but many down-stream functions, such as production of C-reactive protein and immunoglobulin isotype switching. Susceptibility to malaria has been shown to differ between individuals with different genetic backgrounds, as indicated by studies in Fulani and non-Fulani ethnic groups. The aim of this study was to investigate possible interethnic differences in totally twelve single nucleotide polymorphisms (SNPs) in the genes encoding the cytokines IL-1β, IL-6, IL-10 and TNF. These SNPs are present in the promoter region of the genes, and have previously been associated with cytokine expression and with disease outcome in malaria. The results from the present study suggest that the Fulani ethnic group has a more pro-inflammatory response, due to high frequencies of high-producing alleles of IL1β and low-producing alleles of IL10. IL-6 could potentially also contribute to the relatively lower susceptibility to malaria in the Fulani ethnic group, whereas the TNF polymorphisms analysed in this study rather seem to associate with the severity of the infection and not the susceptibility for the infection itself. We therefore suggest that the polymorphisms analysed in this study all show a potential to influence the relatively lower susceptibility to malaria seen in the Fulani ethnic group as compared to the other sympatric ethnic groups.

  • 278.
    Israelsson, Elisabeth
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Vafa, Manijeh
    Maiga, Bakary
    Lysén, Anna
    Iriemenam, Nnaemeka C.
    Dolo, Amagana
    Doumbo, Ogobara K.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Berzins, Klavs
    Differences in Fcγ receptor IIa genotypes and IgG subclass pattern of anti-malarial antibodies between sympatric ethnic groups in Mali2008In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 7, no 175Article in journal (Refereed)
  • 279. Jacobson, Eva
    et al.
    Masjedi, Khosro
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Ahlborg, Niklas
    Lundeberg, Lena
    Karlberg, Ann-Therese
    Scheynius, Annika
    Cytokine production in nickel-sensitized individuals analysed with enzyme-linked immunospot assay: possible implication for diagnosis2002In: British Journal of Dermatology, Vol. 147, no 3, p. 442-9Article in journal (Refereed)
  • 280.
    Jacobsson, Anders
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Jakobsson, Andreas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Jörgensen, Johanna
    Differential regulation of fatty acid elongation enzymes in brown adipocytes imply an unique role for Elovl3 during increased fatty acid oxidation2005In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 289, p. 517-526Article in journal (Refereed)
    Abstract [en]

    The expression of the Elovl3 gene, which belongs to the Elovl gene family coding for microsomal enzymes involved in very long-chain fatty acid (VLCFA) elongation, is dramatically increased in mouse brown adipose tissue upon cold stimulation. In the present study, we show that the cold-induced Elovl3 expression is under the control of peroxisome proliferator-activated receptor- (PPAR) and that this regulation is part of a fundamental divergence in the regulation of expression for the different members of the Elovl gene family. In cultured brown adipocytes, a mixture of norepinephrine, dexamethasone, and the PPAR ligand Wy-14643, which rendered the adipocytes a high oxidative state, was required for substantial induction of Elovl3 expression, whereas the same treatment suppressed Elovl1 mRNA levels. The nuclear liver X receptor (LXR) has been implicated in the control of fatty acid synthesis and subsequent lipogenic processes in several tissues. This regulation is also exerted in part by sterol regulatory element-binding protein (SREBP-1), which is a target gene of LXR. We found that stimulation of Elovl3 expression was independent of LXR and SREBP-1 activation. In addition, exposure to the LXR agonist TO-901317 increased nuclear abundance of LXR and mature SREBP-1 as well as expression of the elongases Lce and Elovl1 in a lipogenic fashion but repressed Elovl3 expression. A functional consequence of this was seen on the level of esterified saturated fatty acids, such as C22:0, which was coupled to Elovl3 expression. These data demonstrate differential transcriptional regulation and concomitantly different functional roles for fatty acid elongases in lipid metabolism of brown adipocytes, which reflects the metabolic status of the cells.

  • 281. Jacobsson, Anders
    et al.
    Jakobsson, Andreas
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Napier, Johnathan
    Westerberg, Rolf
    Impaired substrate utilization for triglyceride formation in cultured brown adipocytes of Elovl3-ablated miceManuscript (Other academic)
  • 282.
    Jain, Shruti
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Planells, Jordi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Regadas, Isabel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Barrett, Donal
    Stockholm University, Science for Life Laboratory (SciLifeLab).
    von Euler, Anne
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Lindberg, Bo G.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Pelechano, Vicent
    Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mannervik, Mattias
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Faculty of Science, The Wenner-Gren Institute, Developmental Biology.
    Visa, Neus
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    SnoRNA:U3:9B is required for the activation of immune response genes in Drosophila melanogasterManuscript (preprint) (Other academic)
    Abstract [en]

    Small nucleolar RNAs (snoRNAs) are prevailing components of the chromatin-associatedtranscriptome and many orphan snoRNAs are associated with protein coding genes in the genome ofDrosophila melanogaster. We have studied a specific chromatin-associated snoRNA, snoRNA:U3:9B,that binds to immune response genes. Using a Sindbis virus replicon model, we have shownthat snoRNA:U3:9B depletion in S2 cells leads to reduced immune response gene expression andreduced chromatin accessibility at target immune response genes. We have used CRISPR/Cas9 tocreate a snoRNA:U3:9B knock-out fly strain and revealed that snoRNA:U3:9B-deficient larvae areviable in control conditions, but fail to develop into pupae when challenged by expression of the Sindbisvirus replicon, which suggests that this snoRNA is essential for the activation of an effective antiviralresponse. In agreement with this proposal, the chromatin decompaction and gene activation normallyobserved at immune response gene loci in response to Sindbis replicon expression are abolished inthe snoRNA:U3:9B-deficient larvae, as shown by ATAC-qPCR and RT-qPCR analyses. Moreover,ChIRP-qPCR experiments have shown that snoRNA:U3:9B associates with the immune responsegenes in vivo, which suggests that the defects observed on chromatin compaction and gene expressionare due to direct regulatory events. In summary, our results reveal the existence of an epigeneticmechanism that requires snoRNA:U3:9B to modulate local chromatin accessibility and enable theinduction of immune response genes.

  • 283. Jakobson, Eva
    et al.
    Masjedi, Khosro
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Ahlborg, Niklas
    Lundeberg, Lena
    Karlberg, Ann-Therese
    Scheynius, Annika
    Cytokine production in nickel-sensitized individuals analysed with enzyme-linked immunospot assay: possible implication for diagnosis2002In: British Journal of Dermatology, Vol. 147, no 3, p. 442-9Article in journal (Refereed)
  • 284.
    Jakobsson, Andreas
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Elovl3 and very long chain fatty acids; role in metabolism2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fatty acids (FA) are important in several aspects of cellular function, for example as structural molecules and metabolic substrates. The bulk of FA up to 16 carbons (palmitic acid) in length are synthesised by a cytosolic enzyme complex called fatty acid synthase (FAS), while FA can be further elongated into very long-chain fatty acids (VLCFA) by membrane-bound enzymes in the endoplasmatic reticulum (ER). Individual enzymes perform the four different steps of the elongation cycle to extend VLCFA, where condensation enzymes (first step) are suggested to be rate-limiting as well as in control of substrate specificity. Six mammalian condensation enzymes, encoded by Elovl (Elogation of very long chain fatty acids) genes in mouse, have presently been identified which suggests multiple elongation pathways.

    In this report, I present data from studies performed mainly in brown adipose tissue and skin on the role of ELOVL3 in metabolic and structure-related processes. This enzyme is suggested to be involved in the synthesis of saturated and monounsaturated VLCFA, which are incorporated into different classes of lipids. Acyl-specific structural functions of sphingolipids, essential for proper membrane integrity, constitute a requirement for endogenous synthesis of VLCFA. We have demonstrated complementary functions between yeast and murine elongation enzymes in the synthesis of sphingolipids with corresponding alterations in cell viability. This indicates a conserved function for elongation enzymes in eukaryotic cells, which implicates cellular growth and maintenance of membrane structures.

    Investigations of the lipid composition in Elovl3-ablated mice, generated by homologous recombination, support a role for ELOVL3 in the synthesis of neutral lipids, such as triglycerides and sterol-esters. The phenotype of these mice includes impaired skin barrier function and altered VLCFA elongation activity in liver and brown adipose tissue, which is consistent with the tissue-specific expression pattern of this gene.

    Regulation of Elovl3 mRNA expression in brown adipocytes was found to differ from what was seen for other Elovl gene family members, which suggests divergent functional roles within the family of elongases. Elovl3 expression correlated with a high oxidative state, therefore, the function of this enzyme may be to replenish specific lipids under conditions of intense FA turnover. In addition, channeling of metabolic substrates is altered in brown adipocytes lacking ELOVL3, indicating important functions of specific VLCFA in nutritional homeostasis and substrate utilization.

  • 285. Jallow, Muminatou
    et al.
    Teo, Yik Ying
    Small, Kerrin S
    Rockett, Kirk A
    Deloukas, Panos
    Clark, Taane G
    Kivinen, Katja
    Bojang, Kalifa A
    Conway, David J
    Pinder, Margaret
    Sirugo, Giorgio
    Sisay-Joof, Fatou
    Usen, Stanley
    Auburn, Sarah
    Bumpstead, Suzannah J
    Campino, Susana
    Coffey, Alison
    Dunham, Andrew
    Fry, Andrew E
    Green, Angela
    Gwilliam, Rhian
    Hunt, Sarah E
    Inouye, Michael
    Jeffreys, Anna E
    Mendy, Alieu
    Palotie, Aarno
    Potter, Simon
    Ragoussis, Jiannis
    Rogers, Jane
    Rowlands, Kate
    Somaskantharajah, Elilan
    Whittaker, Pamela
    Widden, Claire
    Donnelly, Peter
    Howie, Bryan
    Marchini, Jonathan
    Morris, Andrew
    Sanjoaquin, Miguel
    Achidi, Eric Akum
    Agbenyega, Tsiri
    Allen, Angela
    Amodu, Olukemi
    Corran, Patrick
    Djimde, Abdoulaye
    Dolo, Amagana
    Doumbo, Ogobara K
    Drakeley, Chris
    Dunstan, Sarah
    Evans, Jennifer
    Farrar, Jeremy
    Fernando, Deepika
    Hien, Tran Tinh
    Horstmann, Rolf D
    Ibrahim, Muntaser
    Karunaweera, Nadira
    Kokwaro, Gilbert
    Koram, Kwadwo A
    Lemnge, Martha
    Makani, Julie
    Marsh, Kevin
    Michon, Pascal
    Modiano, David
    Molyneux, Malcolm E
    Mueller, Ivo
    Parker, Michael
    Peshu, Norbert
    Plowe, Christopher V
    Puijalon, Odile
    Reeder, John
    Reyburn, Hugh
    Riley, Eleanor M
    Sakuntabhai, Anavaj
    Singhasivanon, Pratap
    Sirima, Sodiomon
    Tall, Adama
    Taylor, Terrie E
    Thera, Mahamadou
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Williams, Thomas N
    Wilson, Michael
    Kwiatkowski, Dominic P
    Genome-wide and fine-resolution association analysis of malaria in West Africa.2009In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, p. 657-665Article in journal (Refereed)
    Abstract [en]

    We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 x 10(-7) to P = 4 x 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

  • 286. Jangpatarapongsa, Kulachart
    et al.
    Chootong, Patchanee
    Sattabongkot, Jetsumon
    Chotivanich, Kesinee
    Sirichaisinthop, Jeeraphat
    Tungpradabkul, Sumalee
    Hisaeda, Hajime
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Cui, Liwang
    Udomsangpetch, Rachanee
    Plasmodium vivax parasites alter the balance of myeloid and plasmacytoid dendritic cells and the induction of regulatory T cells.2008In: Eur J Immunol, ISSN 0014-2980, Vol. 38, no 10, p. 2697-705Article in journal (Refereed)
  • 287.
    Jayaram, S. A.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Tiklová, K.
    Samakovlis, C.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Selective requirement of a deacetylase domain for Emp24independent luminal secretion in the Drosophila tracheaManuscript (preprint) (Other academic)
    Abstract [en]

    Vermiform and Serpentine are secreted putative chitin deacetylases (ChLDs). They are deposited into the tracheal lumen to terminate tube elongation during morphogenesis. Deletion analysis of a Serp-GFP reporter had revealed that the deacetylase domain is essential for its luminal localization. We transferred the deacetylase domain from Serp to Gasp, another tracheal luminal protein, which requires the Emp24 adaptor for ER exit. The GaspDeac-GFP chimera was normally secreted in emp24 mutants indicating that the deacetylase domain contains potential ER-exit signals. To explore this possibility we identified and characterized conserved sequence motifs in Serp deacetylase domain. We generated amino acid substitution mutants altering the three putative Nglycosylation sites, the predicted enzymatic activity cluster and three phylogenetically conserved motifs. We tested the cellular localization of the constructs in S2 cultured cells and the trachea of transgenic Drosophila embryos. Residue substitutions in the putative catalytic site neither interfered with Serp secretion nor with its ability to rescue the tracheal tube elongation defects of serp mutants. Mutations of the N-glycosylation sites gradually reduced the luminal deposition of Serp-GFP constructs suggesting that increased glycosylation enhances apical Serp secretion. By contrast, substitutions in each of the three uncharacterized amino acid stretches completely blocked the ER-exit of Serp-GFP constructs. The mutated proteins were N-glycosylated suggesting that the motifs may be involved in a subsequent protein-folding step or facilitate ER exit through interactions with unidentified specific adaptors.

  • 288.
    Jayaram, Satish Arcot
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Senti, Kirsten-André
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Tiklová, Katarina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Tsarouhas, Vasilios
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Hemphälä, Johanna
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Samakovlis, Christos
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    COPI Vesicle Transport Is a Common Requirement for Tube Expansion in Drosophila2008In: PLOS ONE, E-ISSN 1932-6203, Vol. 09 AprArticle in journal (Refereed)
    Abstract [en]

    Background Tube expansion defects like stenoses and atresias cause devastating human diseases. Luminal expansion during organogenesis begins to be elucidated in several systems but we still lack a mechanistic view of the process in many organs. The Drosophila tracheal respiratory system provides an amenable model to study tube size regulation. In the trachea, COPII anterograde transport of luminal proteins is required for extracellular matrix assembly and the concurrent tube expansion.

    Principal Findings We identified and analyzed Drosophila COPI retrograde transport mutants with narrow tracheal tubes. γCOP mutants fail to efficiently secrete luminal components and assemble the luminal chitinous matrix during tracheal tube expansion. Likewise, tube extension is defective in salivary glands, where it also coincides with a failure in the luminal deposition and assembly of a distinct, transient intraluminal matrix. Drosophila γCOP colocalizes with cis-Golgi markers and in γCOP mutant embryos the ER and Golgi structures are severely disrupted. Analysis of γCOP and Sar1 double mutants suggests that bidirectional ER-Golgi traffic maintains the ER and Golgi compartments and is required for secretion and assembly of luminal matrixes during tube expansion.

    Conclusions/Significance Our results demonstrate the function of COPI components in organ morphogenesis and highlight the common role of apical secretion and assembly of transient organotypic matrices in tube expansion. Intraluminal matrices have been detected in the notochord of ascidians and zebrafish COPI mutants show defects in notochord expansion. Thus, the programmed deposition and growth of distinct luminal molds may provide distending forces during tube expansion in diverse organs.

  • 289.
    Jenvert, Rose-Marie
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    The ribosome, stringent factor and the bacterial stringent response2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The stringent response plays a significant role in the survival of bacteria during different environmental conditions. It is activated by the binding of stringent factor (SF) to stalled ribosomes that have an unacylated tRNA in the ribosomal A-site which leads to the synthesis of (p)ppGpp. ppGpp binds to the RNA polymerase, resulting in a rapid down-regulation of rRNA and tRNA transcription and up-regulation of mRNAs coding for enzymes involved in amino acid biosynthesis. The importance of the A-site and unacylated tRNA in the activation of SF was confirmed by chemical modification and subsequent primer extension experiments (footprinting experiments) which showed that binding of SF to ribosomes resulted in the protection of regions in 23S rRNA, the A-loop and helix 89 that are involved in the binding of the A-site tRNA. An in vitro assay showed that the ribosomal protein L11 and its flexible N-terminal part was important in the activation of SF. Interestingly the N-terminal part of L11 was shown to activate SF on its own and this activation was dependent on both ribosomes and an unacylated tRNA in the A-site. The N-terminal part of L11 was suggested to mediate an interaction between ribosome-bound SF and the unacylated tRNA in the A-site or interact with SF and the unacylated tRNA independently of each other. Footprinting experiments showed that SF bound to the ribosome protected bases in the L11 binding domain of the ribosome that were not involved in an interaction with ribosomal protein L11. The sarcin/ricin loop, in close contact with the L11 binding domain on the ribosome and essential for the binding and activation of translation elongation factors was also found to be protected by the binding of SF. Altogether the presented results suggest that SF binds to the factor-binding stalk of the ribosome and that activation of SF is dependent on the flexible N-terminal domain of L11 and an interaction of SF with the unacylated tRNA in the A-site of the 50S subunit.

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  • 290.
    Jenvert, Rose-Marie
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Holmberg Schiavone, Lovisa
    The flexible N-terminal domain of ribosomal protein L11 from Escherichia coli is necessary for the activation of stringent factor2007In: Journal of molecular biology, ISSN 0022-2836, Vol. 365, no 3, p. 764-772Article in journal (Refereed)
  • 291.
    Jenvert, Rose-Marie
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Homberg Schiavone, Lovisa
    Mapping the interaction between stringent factor and the ribosome by footprinting of ribosomal RNAManuscript (Other academic)
  • 292.
    Jiang, Yun
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Heavy Metal Superantigen: Genetic Regulation of Lymphocyte Activation by HgC121998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Injections of subtoxic doses of HgCl2 (mercuric chloride) cause a systemic autoimmune disease in genetically predisposed rats and mice. My work was designed to elucidate how HgCl2 induces lymphocyte activation and how the response to HgCl2 is regulated in susceptible and resistant strains.

    We showed that HgCl2 at a very low dose (10 mM) primarily activated murine T lymphocytes to proliferation in the presence of adherent cells in a primary in vitro culture, reaching a peak by day 5. Consistent with the in vivo findings, lymphocytes from different strains differed in their capability of responding to HgCl2. Anti-CD4 antibody completely inhibited the proliferation induced by HgCl2, which indicates that CD8+ T cells cannot be activated to division without the help from CD4+ T cells. Moreover, CD4+ T cells from susceptible A.SW and BALB/c mice, but not from resistant DBA/2 mice, were preferentially activated by HgCl2, as indicated by expression of the very early activation antigen CD69 and transformation to blast cells. Unlike CD4+ T cells, CD8+ T cells were activated by HgCl2 irrespective of the origin of the cells. Thus, helper T cells play a crucial role in the immunological effects caused by HgCl2 and may determine the ability of different strains to respond to HgCl2.

    We found that HgCl2 selectively activated T cells expressing certain TCR Vb elements. Depletion of Vb8+ T cells strongly suppressed HgCl2 -induced proliferation and transformation in spleen cells from BALB/c mice, indicating a specific correlation between Vb usage and the response to HgCl2. It seems unlikely that a specific TCR repertoire predisposes to the development of autoimmunity caused by HgCl2. We also verified that the unresponsiveness of CD4+ T cells from DBA/2 mice to HgCl2 was not due to immunosuppression mediated by CD8+ T cells.

    We further investigated the production of IL-2, IL-4, IFN-g, and IL-10 after activation by HgCl2, but found no evidence for the suggestion that HgCl2 induces a Th1/Th2 imbalance in resistant/ susceptible strains. A high frequency of IL-2-secreting cells was observed in spleen cells from the high responder A.SW mice, followed by cells from the intermediate responder BALB/c mice, whereas the frequency was low in cells from the non-responder DBA/2 mice. We showed that neutralizing anti-IL-2 antibody profoundly inhibited the proliferative response to HgCl2. Supplement of exogenous IL-2 enabled spleen cells from DBA/2 mice to respond to HgCl2 to a level comparable with cells from BALB/c mice. These findings indicate that lymphocytes from resistant mice have the potential of responding to HgCl2, but the response is limited due to an insufficient source of IL-2.

    HgCl2 activated B cells from susceptible mice, but not from resistant mice, to produce IgM antibody in a primary in vitro culture.

    We hypothesize that mercuric ions bind to certain molecules and transform them to super-antigens which in turn polyclonally activate T cells in a Vb-specific manner. This is followed by a polyclonal activation of B cells, resulting in autoantibody production and pathological manifestations in susceptible strains. IL-2 may be a limiting factor that precludes lymphocytes from resistant strains from responding to HgCl2.

  • 293. Johansson, Catharina
    et al.
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Andersson, Anna
    Lundeberg, Lena
    Karlsson, Maria A.
    Scheynius, Annika
    Linder, Maria Tengvall
    Elevated Peripheral Allergen-Specific T Cell Response Is Crucial for a Positive Atopy Patch Test Reaction2009In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 150, no 1, p. 51-58Article in journal (Refereed)
    Abstract [en]

    Background: Atopic eczema is a chronic inflammatory skin disease in which several subgroups of cases can be identified. Atopy patch testing (APT) reveals allergen sensitization also in atopic eczema patients devoid of detectable allergen-specific IgE, suggesting the importance of factors other than IgE in the reaction. Here we investigate the relationship between APT reactions and allergen-specific peripheral IgE and T cell reactivity in atopic eczema patients. Methods: Adult patients with atopic eczema (n = 64) and healthy controls (n = 24) were analyzed for reactivity to Malassezia sympodialis extract by APT, measurement of specific plasma IgE and in vitro determination of the frequency of allergen-reactive peripheral blood mononuclear cells producing interleukin-4 and interleukin-5 using the ELISpot method. Results: When combining the results of the APT, IgE measurements and the ELISpot analyses, reactivity to M. sympodialis was found in a majority of the atopic eczema patients (69%), whereas the healthy controls were negative throughout. T cell reactivity to M. sympodialis, manifested by production of both interleukins 4 and 5, was highly predictive for a positive APT reaction and displayed a strongly positive correlation with the APT score. In contrast, the allergen-specific IgE levels did not predict the APT outcome, and no correlation could be found between the IgE levels and the APT score. Conclusion: Peripheral allergen-specific T helper 2 cell-mediated reactivity appears to be required for a positive APT reaction to M. sympodialis. The diagnostic potential of measuring peripheral allergen-specific T cell responses should be considered in atopic eczema. 

  • 294.
    Johansson, Maria
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Early gut microbiota in relation to cytokine responses and allergic disease2011Licentiate thesis, comprehensive summary (Other academic)
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    FULLTEXT01
  • 295.
    Johansson, Maria A
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Haileselassie, Yeneneh
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Roos, Stefan
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Nilsson, Caroline
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Early-Life Gut Bacteria Associate with IL-4-, IL-10- and IFN-γ Production at Two Years of Age2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 11, p. e49315-(9 pp)Article in journal (Refereed)
    Abstract [en]

    Microbial exposure early in life influences immune maturation and potentially also the development of immune-mediated disease. Here we studied early-life gut colonization in relation to cytokine responses at two years of age. Fecal samples were collected from infants during the first two months of life. DNA was extracted from the fecal samples and Bifidobacterium (B.) adolescentis, B. breve, B. bifidum, a group of lactobacilli (L. casei, L. paracasei and L. rhamnosus) as well as Staphylococcus (S.) aureus were detected with real time PCR. Peripheral mononuclear cells were stimulated with phytohaemagglutinin (PHA) and numbers of IL-4-, IL-10- and IFN-γ secreting cells were evaluated using ELISpot. We further stimulated peripheral blood mononuclear cells with bacterial supernatants in vitro and assessed the IL-4-, IL-10- and IFN-γ inducing capacity by flow cytometry and ELISA. Early S. aureus colonization associated with higher numbers of IL-4- (p = 0.022) and IL-10 (p = 0.016) producing cells at two years of age. In contrast to colonization with S. aureus alone, co-colonization with lactobacilli associated with suppression of IL-4- (p = 0.004), IL-10- (p = 0.004) and IFN-γ (p = 0.034) secreting cells. In vitro stimulations of mononuclear cells with bacterial supernatants supported a suppressive role of L. rhamnosus GG on S. aureus-induced cytokine responses. We demonstrate that the early gut colonization pattern associates with the PHA-induced cytokine profile at two years of age and our in vitro findings support that specific bacterial species influence the T helper cell subsets. This suggests that dysbiosis in the early microbiota may modulate the risk of developing inflammatory conditions like allergy.

  • 296.
    Johansson, Maria A.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Sjögren, Ylva M.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Nilsson, Caroline
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Early colonization with a group of Lactobacilli decreases the risk for allergy at five years of age despite allergic heredity.2011In: PLOS ONE, E-ISSN 1932-6203, Vol. 6, no 8, p. e23031-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Microbial deprivation early in life can potentially influence immune mediated disease development such as allergy. The aims of this study were to investigate the influence of parental allergy on the infant gut colonization and associations between infant gut microbiota and allergic disease at five years of age.

    METHODS AND FINDINGS: Fecal samples were collected from 58 infants, with allergic or non-allergic parents respectively, at one and two weeks as well as at one, two and twelve months of life. DNA was extracted from the fecal samples and Real time PCR, using species-specific primers, was used for detection of Bifidobacterium (B.) adolescentis, B. breve, B. bifidum, Clostridium (C.) difficile, a group of Lactobacilli (Lactobacillus (L.) casei, L. paracasei and L. rhamnosus) as well as Staphylococcus (S.) aureus. Infants with non-allergic parents were more frequently colonized by Lactobacilli compared to infants with allergic parents (p = 0.014). However, non-allergic five-year olds acquired Lactobacilli more frequently during their first weeks of life, than their allergic counterparts, irrespectively of parental allergy (p = 0.009, p = 0.028). Further the non-allergic children were colonized with Lactobacilli on more occasions during the first two months of life (p = 0.038). Also, significantly more non-allergic children were colonized with B. bifidum at one week of age than the children allergic at five years (p = 0.048).

    CONCLUSION: In this study we show that heredity for allergy has an impact on the gut microbiota in infants but also that early Lactobacilli (L. casei, L. paracasei, L. rhamnosus) colonization seems to decrease the risk for allergy at five years of age despite allergic heredity.

  • 297.
    Johansson, Thomas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Profilin:actin in cell motility: A search for profilin:actin binding proteins2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The profilin:actin complex is a major source of actin for actin filament growth in vivo. A number of proteins regulating either profilin or actin has been described since profilin:actin was isolated during the 1970s. Since then, profilin and actin and their binding partners have been intensively studied. The ability of profilin:actin to interact with the fast polymerizing end of actin filaments focus the interest to components that regulates this interaction; this is the theme in this thesis.

    A chemically cross-linked and therefore non-dissociable profilin:actin complex, called PxA, was used in these studies which led to development of a rapid screening method to search for proteins that bind to profilin:actin. The method allows a simultaneous detection of proteins that separately interact with profilin, actin and/or profilin:actin. Here the technique was used to screen cell and tissue extracts, before and after gel filtration, for components that showed a unique interaction with the profilin:actin complex. Mass spectrometry was then used for their identification. Furthermore it was demonstrated that profilin:actin binding components are present in RNA containing, large molecular weight complexes.

    Two different PxA immunizations generated two separate populations of affinity purified profilin and actin antibodies. The actin antibodies from these two populations showed significant differences in the staining pattern when used for fluorescence microscopy of tissue cultured cells. One of these appeared to bind monomeric actin while the other bound to filamentous actin. Both of the profilin antibody preparations stained cells in a dotted pattern. The distribution of epitopes recognized by the different actin antibody preparations was determined using a combination of protease digestion, gel electrophoresis and mass spectrometry. The result demonstrated partially different epitope recognition.

    The actin associated protein palladin contains sequence motifs typical for profilin-binding proteins suggesting that profilin may bind palladin. The potential profilin-palladin interaction was studied using a combination of biochemical and histochemical techniques. The interaction was observed in vitro, and the two proteins co-distributed in actin rich regions in tissue cultured cells. These results suggest that palladin recruits profilin and/or profilin:actin to sites of actin dynamics.

  • 298.
    Johansson, Thomas
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Grenklo, Staffan
    Karlsson, Roger
    Detection of binding partners to the profilin:actin complex by far Western and mass spectrometry analyses2004In: Anal Biochem, Vol. 335, no 2, p. 228-234Article in journal (Refereed)
  • 299. Johansson, Thomas
    et al.
    Grenklo, Staffan
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Karlsson, Roger
    Detection of Binding Partners to the Profilin:actin Complex by Far western and MS-analysesManuscript (Other academic)
  • 300.
    Johansson, Thomas
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Karlsson, Roger
    Profilin:actin binding proteins are present in cell extracts in high molecular weight RNA-containing complexesManuscript (Other academic)
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