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  • 301.
    Kanatani, Sachie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fuks, Jonas M.
    Olafsson, Einar B.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Westermark, Linda
    Chambers, Benedict
    Varas-Godoy, Manuel
    Uhlén, Per
    Barragan, Antonio
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Voltage-dependent calcium channel signaling mediates GABAA receptor-induced migratory activation of dendritic cells infected by Toxoplasma gondiiManuskript (preprint) (Annet vitenskapelig)
  • 302.
    Kanatani, Sachie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Karolinska Institutet, Sweden.
    Uhlén, Per
    Barragan, Antonio
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Karolinska Institutet, Sweden.
    Infection by Toxoplasma gondii Induces Amoeboid-Like Migration of Dendritic Cells in a Three-Dimensional Collagen Matrix2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 9, artikkel-id e0139104Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Toxoplasma gondii, an obligate intracellular parasite of humans and other warm-blooded vertebrates, invades a variety of cell types in the organism, including immune cells. Notably, dendritic cells (DCs) infected by T. gondii acquire a hypermigratory phenotype that potentiates parasite dissemination by a 'Trojan horse' type of mechanism in mice. Previous studies have demonstrated that, shortly after parasite invasion, infected DCs exhibit hypermotility in 2-dimensional confinements in vitro and enhanced transmigration in transwell systems. However, interstitial migration in vivo involves interactions with the extracellular matrix in a 3-dimensional (3D) space. We have developed a collagen matrix-based assay in a 96-well plate format that allows quantitative locomotion analyses of infected DCs in a 3D confinement over time. We report that active invasion of DCs by T. gondii tachyzoites induces enhanced migration of infected DCs in the collagen matrix. Parasites of genotype II induced superior DC migratory distances than type I parasites. Moreover, Toxoplasma-induced hypermigration of DCs was further potentiated in the presence of the CCR7 chemotactic cue CCL19. Blocking antibodies to integrins (CD11a, CD11b, CD18, CD29, CD49b) insignificantly affected migration of infected DCs in the 3D matrix, contrasting with their inhibitory effects on adhesion in 2D assays. Morphological analyses of infected DCs in the matrix were consistent with the acquisition of an amoeboid-like migratory phenotype. Altogether, the present data show that the Toxoplasma-induced hypermigratory phenotype in a 3D matrix is consistent with integrin-independent amoeboid DC migration with maintained responsiveness to chemotactic and chemokinetic cues. The data support the hypothesis that induction of amoeboid hypermigration and chemotaxis/chemokinesis in infected DCs potentiates the dissemination of T. gondii.

  • 303.
    Kandasamy, Ganapathi
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Andréasson, Claes
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hsp70-Hsp110 chaperones deliver ubiquitin-dependent and -independent substrates to the 26S proteasome for proteolysis in yeast2018Inngår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 131, nr 6, artikkel-id jcs210948Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During protein quality control, proteotoxic misfolded proteins are recognized by molecular chaperones, ubiquitylated by dedicated quality control ligases and delivered to the 26S proteasome for degradation. Proteins belonging to the Hsp70 chaperone and Hsp110 (the Hsp70 nucleotide exchange factor) families function in the degradation of misfolded proteins by the ubiquitin-proteasome system via poorly understood mechanisms. Here, we report that the Saccharomyces cerevisiae Hsp110 proteins (Sse1 and Sse2) function in the degradation of Hsp70-associated ubiquitin conjugates at the post-ubiquitylation step and are also required for ubiquitin-independent proteasomal degradation. Hsp110 associates with the 19S regulatory particle of the 26S proteasome and interacts with Hsp70 to f acilitate the delivery of Hsp70 substrates for proteasomal degradation. By using a highly defined ubiquitin-independent proteasome substrate, we show that the mere introduction of a single Hsp70-binding site renders its degradation dependent on Hsp110. The findings define a dedicated and chaperone-dependent pathway for the efficient shuttling of cellular proteins to the proteasome with profound implications for understanding protein quality control and cellular stress management.

  • 304. Kaneko, Akira
    et al.
    Chaves, Luis F.
    Taleo, George
    Kalkoa, Morris
    Isozumi, Rie
    Wickremasinghe, Renu
    Perlmann, Hedvig
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Takeo, Satoru
    Tsuboi, Takafumi
    Tachibana, Shin-Ichiro
    Kimura, Masatsugu
    Björkman, Anders
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Tanabe, Kazuyuki
    Drakeley, Chris
    Characteristic Age Distribution of Plasmodium vivax Infections after Malaria Elimination on Aneityum Island, Vanuatu2014Inngår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 82, nr 1, s. 243-252Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Resurgence is a major concern after malaria elimination. After the initiation of the elimination program on Aneityum Island in 1991, microscopy showed that Plasmodium falciparum disappeared immediately, whereas P. vivax disappeared from 1996 onward, until P. vivax cases were reported in January 2002. By conducting malariometric surveys of the entire population of Aneityum, we investigated the age distribution of individuals with parasites during this epidemic in the context of antimalarial antibody levels and parasite antigen diversity. In July 2002, P. vivax infections were detected by microscopy in 22/759 individuals: 20/298 born after the beginning of the elimination program in 1991, 2/126 born between 1982 and 1991, and none of 335 born before 1982. PCR increased the number of infections detected to 77, distributed among all age groups. Prevalences were 12.1%, 16.7%, and 6.0%, respectively (P<0.001). In November, a similar age pattern was found, but with fewer infections: 6/746 and 39/741 individuals were found to be infected by microscopy and PCR, respectively. The frequencies of antibody responses to P. vivax were significantly higher in individuals born before 1991 than in younger age groups and were similar to those on Malakula Island, an area of endemicity. Remarkably low antigen diversity (h, 0.15) of P. vivax infections was observed on Aneityum compared with the other islands (h, 0.89 to 1.0). A P. vivax resurgence was observed among children and teenagers on Aneityum, an age distribution similar to those before elimination and on islands where P. vivax is endemic, suggesting that in the absence of significant exposure, immunity may persist, limiting infection levels in adults. The limited parasite gene pool on islands may contribute to this protection.

  • 305.
    Kang, Wenjing
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Bang-Berthelsen, Claus Heiner
    Holm, Anja
    Houben, Anna J. S.
    Holt Müller, Anne
    Thymann, Thomas
    Pociot, Flemming
    Estivill, Xavier
    Friedländer, Marc R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Survey of 800+data sets from human tissue and body fluid reveals xenomiRs are likely artifacts2017Inngår i: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 23, nr 4, s. 433-445Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    miRNAs are small 22-nucleotide RNAs that can post-transcriptionally regulate gene expression. It has been proposed that dietary plant miRNAs can enter the human bloodstream and regulate host transcripts; however, these findings have been widely disputed. We here conduct the first comprehensive meta-study in the field, surveying the presence and abundances of cross-species miRNAs (xenomiRs) in 824 sequencing data sets from various human tissues and body fluids. We find that xenomiRs are commonly present in tissues (17%) and body fluids (69%); however, the abundances are low, comprising 0.001% of host human miRNA counts. Further, we do not detect a significant enrichment of xenomiRs in sequencing data originating from tissues and body fluids that are exposed to dietary intake (such as liver). Likewise, there is no significant depletion of xenomiRs in tissues and body fluids that are relatively separated from the main bloodstream (such as brain and cerebro-spinal fluids). Interestingly, the majority (81%) of body fluid xenomiRs stem from rodents, which are a rare human dietary contribution but common laboratory animals. Body fluid samples from the same studies tend to group together when clustered by xenomiR compositions, suggesting technical batch effects. Last, we performed carefully designed and controlled animal feeding studies, in which we detected no transfer of plant miRNAs into rat blood, or bovine milk sequences into piglet blood. In summary, our comprehensive computational and experimental results indicate that xenomiRs originate from technical artifacts rather than dietary intake.

  • 306.
    Kang, Wenjing
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Eldfjell, Yrin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fromm, Bastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Estivill, Xavier
    Biryukova, Inna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Friedländer, Marc R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    miRTrace reveals the organismal origins of microRNA sequencing data2018Inngår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 19, artikkel-id 213Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We present here miRTrace, the first algorithm to trace microRNA sequencing data back to their taxonomic origins. This is a challenge with profound implications for forensics, parasitology, food control, and research settings where cross-contamination can compromise results. miRTrace accurately (> 99%) assigns real and simulated data to 14 important animal and plant groups, sensitively detects parasitic infection in mammals, and discovers the primate origin of single cells. Applying our algorithm to over 700 public datasets, we find evidence that over 7% are cross-contaminated and present a novel solution to clean these computationally, even after sequencing has occurred.

  • 307. Kazemi, E.
    et al.
    Mortazavi, S. M. J.
    Ghanbari, A. Ali
    Mozdarani, H.
    Sharif-Zadeh, S.
    Mostafavi-pour, Z.
    Zal, F.
    Haghdoost, Siamak
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The effect of superposition of 900 MHz and incoherent noise electromagnetic fields on the induction of reactive oxygen species in SP2/0 cell line2015Inngår i: International journal of radiation research, ISSN 2322-3243, Vol. 13, nr 3, s. 275-280Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Induction of cellular response after exposure to electromagnetic fields is limited to coherent fields. An incoherent noise field is supposed to suppress the bioeffects of regular RF electromagnetic fields. The purpose of this study was to investigate the effect of GSM mobile phone-induced radiofrequency (RF) on the induction of oxidative stress in SP2/0 cell line. Materials and Methods: This study was also an attempt to assess whether these RF-induced effects can be blocked by superposing the RF radiation and an incoherent magnetic noise. Three groups of cultured cells were used in this study. The cells in the first group were only exposed to RF radiation emitted from a mobile phone simulator. The second group was only exposed to an incoherent noise field and the third group was simultaneously exposed to RF radiation and incoherent noise field. The exposure duration in all groups was 2 hours. The level of ROS production in the cells was quantified by the CM-H2DCFDA fluorescence probe, using flow cytometry technique. Results: Although our results showed increased ROS production after exposure to 900 MHz RF radiation, superposition of 900 MHz RF and the incoherent noise fields did not lead to increased levels of ROS in any experiment. However, the differences between RF exposure group and superposition of RF and noise exposure group were not statistically significant. Conclusion: Altogether our results cannot support the neutralizing effect of noise theory but may confirm the concept that just the coherent fields can be bioeffective while the incoherent noise fields cannot cause any biological effects.

  • 308.
    Keehnen, Naomi L. P.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Rolff, Jens
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wheat, Christopher W.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Insect Antimicrobial Defences: A Brief History, Recent Findings, Biases, and a Way Forward in Evolutionary Studies2017Inngår i: Advances in Insect Physiology, ISSN 0065-2806, E-ISSN 2213-6800, Vol. 52, s. 1-33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We propose that an evolutionary and phenotype-driven approach, harnessing current technological developments, has much to offer for our understanding of insect immunity. After briefly reviewing the history of the discovery of canonical immune system, the current understanding of its components is reviewed and then we argue that the current paradigm of research may be biassed due to (a) its limited taxonomic perspective, (b) the evolutionary time scale being studied, and (c) a focus primarily if not exclusively, upon the canonical, humoural gene set. For the rest of the review, we then discuss the importance of a phenotype down approach as an understudied perspective, exemplified by the need for understanding the basis of cellular responses and wounding as a source of selection on immunity in the wild. We propose that research on those topics almost certainly will provide new insights into the evolution of the insect immune system.

  • 309. Khairalla, Ahmed S.
    et al.
    Omer, Sherko A.
    Mahdavi, Jafar
    Aslam, Akhmed
    Dufailu, Osman A.
    Self, Tim
    Jonsson, Ann-Beth
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Geörg, Miriam
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sjölinder, Hong
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Royer, Pierre-Joseph
    Martinez-Pomares, Luisa
    Ghaemmaghami, Amir M.
    Wooldridge, Karl G.
    Oldfield, Neil J.
    Ala'Aldeen, Dlawer A. A.
    Nuclear trafficking, histone cleavage and induction of apoptosis by the meningococcal App and MspA autotransporters2015Inngår i: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 17, nr 7, s. 1008-1020Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neisseria meningitidis, a major cause of bacterial meningitis and septicaemia, secretes multiple virulence factors, including the adhesion and penetration protein (App) and meningococcal serine protease A (MspA). Both are conserved, immunogenic, type Va autotransporters harbouring S6-family serine endopeptidase domains. Previous work suggested that both could mediate adherence to human cells, but their precise contribution to meningococcal pathogenesis was unclear. Here, we confirm that App and MspA are in vivo virulence factors since human CD46-expressing transgenic mice infected with meningococcal mutants lacking App, MspA or both had improved survival rates compared with mice infected with wild type. Confocal imaging showed that App and MspA were internalized by human cells and trafficked to the nucleus. Cross-linking and enzyme-linked immuno assay (ELISA) confirmed that mannose receptor (MR), transferrin receptor 1 (TfR1) and histones interact with MspA and App. Dendritic cell (DC) uptake could be blocked using mannan and transferrin, the specific physiological ligands for MR and TfR1, whereas in vitro clipping assays confirmed the ability of both proteins to proteolytically cleave the core histone H3. Finally, we show that App and MspA induce a dose-dependent increase in DC death via caspase-dependent apoptosis. Our data provide novel insights into the roles of App and MspA in meningococcal infection.

  • 310. Khan, Md Kawsar
    et al.
    Zaman, Shabnam
    Chakraborty, Sajib
    Chakravorty, Rajib
    Alam, Mohammad Murshid
    Bhuiyan, Taufiqur Rahman
    Rahman, Muhammad Jubayer
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fernández, Carmen
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Qadri, Firdausi
    Seraj, Zeba I.
    In silico predicted mycobacterial epitope elicits in vitro T-cell responses2014Inngår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 61, nr 1, s. 16-22Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Epitope-based vaccines permit the selection of only a specific subset of epitopes to induce the necessary immune response, thus providing a rational alternative to conventional design approaches. Using a range of immunoinformatics tools, we identified a novel, contiguous 28 amino acid multi-epitope cluster within the highly conserved secretory protein Ag85B of Mycobacterium tuberculosis, the causative agent of TB. This cluster, named Ep85B, is composed of epitopes which bind to three HLA Class I and 15 Class II molecules, and harbors the potential to generate 99% population coverage in TB-endemic regions. We experimentally evaluated the capacity of Ep85B to elicit T-cell immune responses using whole blood cells and, as predicted, observed significant increases in populations of both CD4+ and memory CD4+ CD45RO+ T-cells. Our results demonstrate the practical utility of an epitope-based design methodology - a strategy that, following further evaluation, may serve as an additional tool for the development of novel vaccine candidates against TB and other diseases.

  • 311.
    Khan Mirzaei, Mohammadali
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Study of phages for phage therapy: An Escherichia coli experience2014Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The world is rapidly moving toward a post-antibiotic era as effective antibiotics are becoming fewer. phage therapy is a potentially possible method for treating infectious diseases and counts as an alternative method for antibiotic therapy. Phages' number on earth is estimated to be 1031 which ensures a great variety for these entities, and a never ending source for new phages. However, phages vary in their morphology, life cycle and virulent ability, and thus phage therapy will be unsuccessful without enough knowledge in phage biology. Only phages with a good virulence and broad host ranges are fitted for phage therapy applications, host range being one the most important factors that needs a careful study. There is no common method for studying the host range of phages and host range measurements are consequently dependent on the method that was used to study it. In our study, six polyvalent phages were selected from thirty virulent phages isolated using strains from E. coli reference collection (ECOR) as hostes. The selected phages were tested for their host range across 234 strains of E.coli (both sensetive and resistant to antibiotics) and Salmonella (reference collection SARA and SARB) using both spot test and efficiency of plating (EOP) method. Spot test results show no correlation to results of EOP analyses. One way to explain why spot test results are uncorrelated to EOP is the effects of resistant mechanisms of the host. In spot test, phages of a high concentration lystae might absorb, degrade the cell wall and kill the bacteria but the intrinsic resistant mechanisms of the host can recognize and degrade the genome, and stop phage replication and reproduction, which is visualized in the EOP analysis. Based on our studies, it is possible that prophages can contribute to bacterial defence against phages. Phages cannot in most cases produce a high EOP on those E. coli strains that have a P2 prophage in their genome.

    The phage SU10 had the highest EOP/spot test ratio among six selected phages. Transmission electron microscopy images revealed a very rare morphology for SU10, a short tail of 19 nm long and a 137 elongated head, and it was classified as a member of Podoviridae family. Genomic analysis of the phage show a genome size of 77,327 kb, 123 ORF encodes 38 proteins with known function. Twenty-two of theses proteins were identified using a mass-spectrometry based proteomics. The size of the tail was measured to be longer, 41 nm, in ultra-thin sectioning transmission electron microscopy images. A honeycomb structure is formed by the phage capsids during structural assembly, which is very rare for bacteriophages. The honeycomb structure of SU10 capsids might work as an aid or and external scaffolding protein during morphogenesis. The SU10 capsid is elongated before its genome is packed into the head according to the ultra-thin sectioning transmission electrographs which indicates that the genome packaging process has no role in elongation of the head. Based on our phylogenetic analysis, the scaffolding protein and major head protein have coevolved and the scaffolding protein in SU10 is not a recent attachment to the major head protein. According to the phylogenetic analysis of two proteins, the C1 and C3 morphotypes diverged 280 million years.

  • 312.
    Khan Mirzaei, Mohammadali
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The efficacy of bacterial viruses against multi-resistant Escherichia coli: from isolation to pharmacology2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The increase of multi-resistant bacteria highlights that the golden era of antibiotics is ending and that alternative treatmentsare urgently needed. Phages have been historically used to treat bacterial infections prior to the discovery of antibiotics and have gained renewed interest in the past decade. Despite the advantages of phage therapy over traditional antibiotic usage, a number of concerns persist over their clinical application centring on their efficacy and safety. This thesis presents four papers that focus on the isolation and characterization of phages that target reference strains and drug-resistant strains of E. coli as well as their infection dynamics and kinetics. In Paper I, six of thirty isolated phages were selected to be characterized for their growth parameters and host range using two commonly used methods. The study showed that the host range (an important selection criteria for phages) of the phages can change based on the assessment method and that the lysis efficiency of phages is host-dependent. The study suggests that standardised methods to assess the host range and lytic activity of phages are required to reduce result variability between research groups. Paper II investigated a rare phage with C3 morphotype from the Podoviridae family and characterised it via genomic, proteomic, morphologic and phylogenetic analysis. The study revealed previously unseen aspects including the formation of a honeycomb structure comprised of phage head during DNA packaging, the possible contractile nature of the tail and the 280 million year co-evolution between the major head protein and the scaffolding protein. Paper III highlights the need to take the immune system into consideration when designing phage therapeutics. In the study, four purified structurally distinct phages (selected from the three main phage families) were exposed to human cells (HT-29 and Caco-2 immortalised intestinal epithelial cell lines and donor-derived peripheral blood mononuclear cells) and the immunogenicity of the phages determined. Phage immunogenicity was shown to vary in a concentration and phage dependent manner with SU63 (a Myoviridae) being the most immunogenic phage and SU32 (a Siphoviridae) the least immunogenic. In the presence of human cells and a suitable host, phages were shown to maintain their killing efficacy as well as the ability to proliferate. Paper IV studies the infection dynamics of an experimental two-phage cocktail against a single bacterial host in vitro and in silico. However, in silico analysis and in vitro analysis produced conflicting results, in which mathematical modelling predicted the complete clearance of bacteria for all treatment scenarios whereas experimental results showed a 1-3log10 reduction in bacterial content. Practical experiments also showed increased anti-bacterial activity when the time between the additions of each phage was varied. This discrepancy suggests that the current mathematical model is unsuitable due to the inability to account for discrete variables such as interference.

  • 313.
    Khan Mirzaei, Mohammadali
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ek Blom, Linnea
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cooper, Callum J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Weiss, Howard
    Udekwu, Klas I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nilsson, Anders S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Infection Dynamics within a Two Phage One Bacterium System: 1 Implications for TherapyManuskript (preprint) (Annet vitenskapelig)
  • 314.
    Khan Mirzaei, Mohammadali
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Eriksson, Harald
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kasuga, Kie
    Haggård-Ljungquist, Elisabeth
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nilsson, Anders S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Genomic, Proteomic, Morphological, and Phylogenetic Analyses of vB_EcoP_SU10, a Podoviridae Phage with C3 Morphology2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 12, artikkel-id e116294Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A recently isolated phage, vB_EcoP_SU10 (SU10), with the unusual elongated C3 morphotype, can infect a wide range of Escherichia coli strains. We have sequenced the genome of this phage and characterized it further by mass spectrometry based proteomics, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and ultra-thin section electron microscopy. The genome size is 77,327 base pairs and its genes, and genome architecture, show high similarity to the phiEco32 phage genes and genome. The TEM images reveal that SU10 have a quite long tail for being a Podoviridae phage, and that the tail also changes conformation upon infection. The ultra-thin section electron microscopy images of phages at the stage of replication within the host cell show that the phages form a honeycomb-like structure under packaging of genomes and assembly of mature capsids. This implies a tight link between the replication and cutting of the concatemeric genome, genome packaging, and capsid assembly. We have also performed a phylogenetic analysis of the structural genes common between Podoviridae phages of the C1 and C3 morphotypes. The result shows that the structural genes have coevolved, and that they form two distinct groups linked to their morphotypes. The structural genes of C1 and C3 phages appear to have diverged around 280 million years ago applying a molecular clock calibrated according to the presumed split between the Escherichia - Salmonella genera.

  • 315.
    Khan Mirzaei, Mohammadali
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Haileselassie, Yeneneh
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Navis, Marit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cooper, Callum
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nilsson, Anders S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Immunogenic profiling of structurally distinct bacteriophages and their interaction with human cellsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Due to a global increase in the range and number of infections caused by multi-resistant bacteria, 11 phage therapy is currently experiencing a resurgence of interest. However, there are a number of 12 well-known concerns over the use of phages to treat bacterial infections. In order to address concerns 13 over safety and the poorly understood pharmacokinetics of phages and their associated cocktails, 14 immunological characterization is required. In the current investigation, the immunogenicity of four 15 distinct phages and their interaction with donor derived peripheral blood mononuclear cells and 16 immortalized cell lines (HT-29 and Caco-2 intestinal epithelial cells) were investigated using 17 standard immunological techniques. When exposed to high phage concentrations (109 PFU/well), 18 cytokine driven inflammatory responses were induced from all cell types. Although phages appeared 19 to inhibit the growth of intestinal epithelial cell lines, they also appear to be non-cytotoxic. Despite 20 co-incubation with different cell types, phages maintained a high killing efficiency, reducing 21 extended-spectrum beta-lactamase-producing Escherichia coli numbers by 1-4 log10 compared to 22 untreated controls. Phages were also able to actively reproduce in the presence of human cells 23 resulting in an approximately 2 log10 increase in phage titer compared to the initial inoculum. 24 Through an increased understanding of the complex pharmacokinetics of phages, it may be possible 25 to address some of the safety concerns surrounding phage preparations prior to creating new 26 therapeutic strategies.

  • 316.
    Khan Mirzaei, Mohammadali
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Haileselassie, Yeneneh
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Navis, Marit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cooper, Callum
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nilsson, Anders S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Morphologically Distinct Escherichia coli Bacteriophages Differ in Their Efficacy and Ability to Stimulate Cytokine Release In Vitro2016Inngår i: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 7, artikkel-id 437Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Due to a global increase in the range and number of infections caused by multi resistant bacteria, phage therapy is currently experiencing a resurgence of interest. However, there are a number of well-known concerns over the use of phages to treat bacterial infections. In order to address concerns over safety and the poorly understood pharmacokinetics of phages and their associated cocktails, immunological characterization is required. In the current investigation, the immunogenicity of four distinct phages (taken from the main families that comprise the Caudovirales order) and their interaction with donor derived peripheral blood mononuclear cells and immortalized cell lines (HT-29 and Caco-2 intestinal epithelial cells) were investigated using standard immunological techniques. When exposed to high phage concentrations (10(9) PFU/well), cytokine driven inflammatory responses were induced from all cell types. Although phages appeared to inhibit the growth of intestinal epithelial cell lines, they also appear to be non-cytotoxic. Despite co-incubation with different cell types, phages maintained a high killing efficiency, reducing extended-spectrum betalactamase-producing Escherichia colinumbers by 1-4 log(10) compared to untreated controls. When provided with a suitable bacterial host, phages were also able to actively reproduce in the presence of human cells resulting in an approximately 2 log10 increase in phage titer compared to the initial inoculum. Through an increased understanding of the complex pharmacokinetics of phages, it may be possible to address some of the safety concerns surrounding phage preparations prior to creating new therapeutic strategies.

  • 317.
    Khan Mirzaei, Mohammadali
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nilsson, Anders S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Isolation of Phages for Phage Therapy: A Comparison of Spot Tests and Efficiency of Plating Analyses for Determination of Host Range and Efficacy2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 3, artikkel-id e0118557Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Phage therapy, treating bacterial infections with bacteriophages, could be a future alternative to antibiotic treatment of bacterial infections. There are, however, several problems to be solved, mainly associated to the biology of phages, the interaction between phages and their bacterial hosts, but also to the vast variation of pathogenic bacteria which implies that large numbers of different phages are going to be needed. All of these phages must under present regulation of medical products undergo extensive clinical testing before they can be applied. It will consequently be of great economic importance that effective and versatile phages are selected and collected into phage libraries, i.e., the selection must be carried out in a way that it results in highly virulent phages with broad host ranges. We have isolated phages using the Escherichia coli reference (ECOR) collection and compared two methods, spot testing and efficiency of plating (EOP), which are frequently used to identify phages suitable for phage therapy. The analyses of the differences between the two methods show that spot tests often overestimate both the overall virulence and the host range and that the results are not correlated to the results of EOP assays. The conclusion is that single dilution spot tests cannot be used for identification and selection of phages to a phage library and should be replaced by EOP assays. The difference between the two methods can be caused by many factors. We have analysed if the differences and lack of correlation could be caused by lysis from without, bacteriocins in the phage lysate, or by the presence of pro-phages harbouring genes coding for phage resistance systems in the genomes of the bacteria in the ECOR collection.

  • 318. Khmelinskii, Anton
    et al.
    Blaszczak, Ewa
    Pantazopoulou, Marina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fischer, Bernd
    Omnus, Deike J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Le Dez, Gaelle
    Brossard, Audrey
    Gunnarsson, Alexander
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Barry, Joseph D.
    Meurer, Matthias
    Kirrmaier, Daniel
    Boone, Charles
    Huber, Wolfgang
    Rabut, Gwenael
    Ljungdahl, Per O.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Knop, Michael
    Protein quality control at the inner nuclear membrane2014Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 516, nr 7531, s. 410-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The nuclear envelope is a double membrane that separates the nucleus from the cytoplasm. The inner nuclear membrane (INM) functions in essential nuclear processes including chromatin organization and regulation of gene expression(1). The outer nuclear membrane is continuous with the endoplasmic reticulum and is the site of membrane protein synthesis. Protein homeostasis in this compartment is ensured by endoplasmic-reticulum-associated protein degradation (ERAD) pathways that in yeast involve the integral membrane E3 ubiquitin ligases Hrd1 and Doa10 operating with the E2 ubiquitin-conjugating enzymes Ubc6 and Ubc7 (refs 2, 3). However, little is known about protein quality control at the INM. Here we describe a protein degradation pathway at the INM in yeast (Saccharomyces cerevisiae) mediated by the Asicomplex consisting of the RING domain proteins Asi1 and Asi3 (ref. 4). We report that the Asi complex functions together with the ubiquitin-conjugating enzymes Ubc6 and Ubc7 to degrade soluble and integral membrane proteins. Genetic evidence suggests that the Asi ubiquitin ligase defines a pathway distinct from, but complementary to, ERAD. Using unbiased screening with a novel genome-wide yeast library based on a tandem fluorescent protein timer(5), we identify more than 50 substrates of the Asi, Hrd1 and Doa10 E3 ubiquitin ligases. We show that the Asi ubiquitin ligase is involved in degradation of mislocalized integral membrane proteins, thus acting to maintain and safeguard the identity of the INM.

  • 319. Kohler, Verena
    et al.
    Goessweiner-Mohr, Nikolaus
    Aufschnaiter, Andreas
    Fercher, Christian
    Probst, Ines
    Pavkov-Keller, Tea
    Hunger, Kristin
    Wolinski, Heimo
    Büttner, Sabrina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Graz, Austria.
    Grohmann, Elisabeth
    Keller, Walter
    TraN: A novel repressor of an Enterococcus conjugative type IV secretion system2018Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, nr 17, s. 9201-9219Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The dissemination of multi-resistant bacteria represents an enormous burden on modern healthcare. Plasmid-borne conjugative transfer is the most prevalent mechanism, requiring a type IV secretion system that enables bacteria to spread beneficial traits, such as resistance to last-line antibiotics, among different genera. Inc18 plasmids, like the Gram-positive broad host-range plasmid pIP501, are substantially involved in propagation of vancomycin resistance from Enterococci to methicillin-resistant strains of Staphylococcus aureus. Here, we identified the small cytosolic protein TraN as a repressor of the pIP501-encoded conjugative transfer system, since deletion of traN resulted in upregulation of transfer factors, leading to highly enhanced conjugative transfer. Furthermore, we report the complex structure of TraN with DNA and define the exact sequence of its binding motif. Targeting this protein-DNA interaction might represent a novel therapeutic approach against the spreading of antibiotic resistances.

  • 320. Kohler, Verena
    et al.
    Probst, Ines
    Aufschnaiter, Andreas
    Büttner, Sabrina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Graz, Austria.
    Schaden, Lisa
    Rechberger, Gerald N.
    Koraimann, Günther
    Grohmann, Elisabeth
    Keller, Walter
    Conjugative type IV secretion in Gram-positive pathogens: TraG, a lytic transglycosylase and endopeptidase, interacts with translocation channel protein TraM2017Inngår i: Plasmid, ISSN 0147-619X, E-ISSN 1095-9890, Vol. 91, s. 9-18Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Conjugative transfer plays a major role in the transmission of antibiotic resistance in bacteria. pIP501 is a Grampositive conjugative model plasmid with the broadest transfer host-range known so far and is frequently found in Enterococcus faecalis and Enterococcus faecium clinical isolates. The pIP501 type IV secretion system is encoded by 15 transfer genes. In this work, we focus on the VirB1-like protein TraG, a modular peptidoglycan metabolizing enzyme, and the VirB8-homolog TraM, a potential member of the translocation channel. By providing full-length traG in trans, but not with a truncated variant, we achieved full recovery of wild type transfer efficiency in the traG-knockout mutant E. faecalis pIP501AtraG. With peptidoglycan digestion experiments and tandem mass spectrometry we could assign lytic transglycosylase and endopeptidase activity to TraG, with the CHAP domain alone displaying endopeptidase activity. We identified a novel interaction between TraG and TraM in a bacterial 2-hybrid assay. In addition we found that both proteins localize in focal spots at the E. faecalis cell membrane using immunostaining and fluorescence microscopy. Extracellular protease digestion to evaluate protein cell surface exposure revealed that correct membrane localization of TraM requires the transmembrane helix of TraG. Thus, we suggest an essential role for TraG in the assembly of the pIP501 type IV secretion system.

  • 321.
    Kotova, Natalia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. The Swedish National Food Agency, Sweden.
    Frostne, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Abramsson-Zetterberg, Lilianne
    Tareke, Eden
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Bergman, Rolf
    Haghdoost, Siamak
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Paulsson, Birgit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Törnqvist, Margareta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Segerbäck, Dan
    Jenssen, Dag
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Grawé, Jan
    Differences in micronucleus frequency and acrylamide adduct levels with hemoglobin between vegetarians and non-vegetarians2015Inngår i: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 54, nr 7, s. 1181-1190Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nutrients and food constituents can prevent or contribute to genotoxicity. In this study, the possible influence of a vegetarian/non-vegetarian diet on genotoxic effects was investigated in 58 non-smoking healthy vegetarians (V) and non-vegetarians (NV), age 21-37 years from the Stockholm area in Sweden. Physical activity and dietary habits were similar in both groups, with the exception of the intake of meat and fish. Using flow cytometry, we determined the formation of micronuclei (MN) in transferrin-positive immature peripheral blood reticulocytes (Trf-Ret) (Total: n = 53; V: n = 27; NV: n = 26). Dietary exposure to acrylamide was measured through hemoglobin (Hb) adducts in peripheral erythrocytes (Total: n = 53; V: n = 29; NV: n = 24). Hb adducts of both acrylamide and its genotoxic metabolite glycidamide were monitored as a measure of the corresponding in vivo doses. Our data demonstrated that compared with the non-vegetarians, the vegetarians exhibited lower frequencies of MN (fMN) in the Trf-Ret (p < 0.01, Student's t test). A multivariate analysis demonstrated that there was no association between the fMN and factors such as age, sex, intake of vitamins/minerals, serum folic acid and vitamin B12 levels, physical activity, and body mass index. The mean Hb adduct levels of acrylamide and glycidamide showed no significant differences between vegetarians and non-vegetarians. Furthermore, there were no significant relationships between the adduct levels and fMN in the individuals. The ratio of the Hb adduct levels from glycidamide and acrylamide, however, showed a significant difference (p < 0.04) between the two groups. These data suggest that the vegetarian diet might be beneficial in lowering genomic instability in healthy individuals. The measured Hb adduct levels indicate that the total intake of acrylamide does not differ between the two studied groups and does not contribute to the observed difference in fMN, although an influence of the diet on the metabolic rates of acrylamide was indicated. In addition, the observed significant difference in the background fMN in the two groups demonstrated that the MN analysis method has a sensitivity applicable to the biomonitoring of human lifestyle factors.

  • 322.
    Kotova, Natalia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hebert, N.
    Härnwall, Eva-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Vare, Daniel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mazurier, C.
    Douay, L.
    Jenssen, Dag
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Grawe, J.
    A novel micronucleus in vitro assay utilizing human hematopoietic stem cells2015Inngår i: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 29, nr 7, s. 1897-1905Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The induction of micronucleated reticulocytes in the bone marrow is a sensitive indicator of chromosomal damage. Therefore, the micronucleus assay in rodents is widely used in genotoxicity and carcinogenicity testing. A test system based on cultured human primary cells could potentially provide better prediction compared to animal tests, increasing patient safety while also implementing the 3Rs principle, i.e. replace, reduce and refine. Hereby, we describe the development of an in vitro micronucleus assay based on animal-free ex vivo culture of human red blood cells from hematopoietic stem cells. To validate the method, five clastogens with direct action, three clastogens requiring metabolic activation, four aneugenic and three non-genotoxic compounds have been tested. Also, different metabolic systems have been applied. Flow cytometry was used for detection and enumeration of micronuclei. Altogether, the results were in agreement with the published data and indicated that a sensitive and cost effective in vitro assay to assess genotoxicity with a potential to high-throughput screening has been developed.

  • 323.
    Krautz, Robert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Drosophila immune responses in a model for epithelial hypertrophy2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Apoptosis, differentiation and proliferation have to be tightly balanced and thus regulated to maintain tissue homeostasis. Stress, metabolic cues, genetic variability, infections and physiological host-commensal interactions influence this balance and thus need to be integrated. Therefore, beyond the discrimination between self and non-self (i.e., foreign) also damage inflicted on tissues under sterile conditions is perceived by the immune system due to altered tissue integrity. Growing knowledge of the interaction between the immune system and wounded or more generally altered tissues allows inferring on anti-tumorous immune responses, too. Despite the lack of adaptive immunity, Drosophila mounts solid and versatile innate immune responses that functionally and molecularly share many properties with their vertebrate counterparts. In fact, tissue overgrowth, tissue dysplasia or endogenous danger signaling activate systemic Toll-signaling in the fat body indicating a role for the Drosophila immune system in maintaining tissue homeostasis.

    Here we characterize systemic and local immune responses towards altered or transformed tissues by using a Drosophila hypertrophy model, which is based on the overexpression of a dominant-active variant of the small GTPase Ras (Ras85DG12V) in salivary glands and wing discs. We characterized the strong induction of hemocyte recruitment to the glands as a consequence of JNK-dependent MMP1-expression and basal membrane degradation. Apart from this cellular immune reaction, transcriptome profiling revealed comprehensive humoral immune responses mounted by the fat body that involved signatures of Toll- and imd-activation. Moreover, a novel tissue-autonomous response that was spatially restricted to the anterior end of the RasV12-expressing salivary gland itself was identified. While multiple immune genes were found to be upregulated in the anterior compartment as detected by RNA sequencing, particular focus was given to the effector peptide Drosomycin (Drs). Overexpression of Drs with RasV12 in the entire gland similar to the inhibition of the JNK-pathway was able to selectively rescue a characteristic set of RasV12-induced phenotypes, which ultimately blocks the recruitment of hemocytes. Thereby, local immune-related responses in RasV12-expressing salivary glands are able to restrict the tissue damage induced by hypertrophic growth.

  • 324.
    Krautz, Robert
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Arefin, Badrul
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Damage signals in the insect immune response2014Inngår i: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 5, artikkel-id 342Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Insects and mammals share an ancient innate immune system comprising both humoral and cellular responses. The insect immune system consists of the fat body, which secretes effector molecules into the hemolymph and several classes of hemocytes, which reside in the hemolymph and of protective border epithelia. Key features of wound- and immune responses are shared between insect and mammalian immune systems including the mode of activation by commonly shared microbial (non-self) patterns and the recognition of these patterns by dedicated receptors. It is unclear how metazoan parasites in insects, which lack these shared motifs, are recognized. Research in recent years has demonstrated that during entry into the insect host, many eukaryotic pathogens leave traces that alert potential hosts of the damage they have afflicted. In accordance with terminology used in the mammalian immune systems, these signals have been dubbed danger- or damage-associated signals. Damage signals are necessary byproducts generated during entering hosts either by mechanical or proteolytic damage. Here, we briefly review the current stage of knowledge on how wound closure and wound healing during mechanical damage is regulated and how damage-related signals contribute to these processes. We also discuss how sensors of proteolytic activity induce insect innate immune responses. Strikingly damage-associated signals are also released from cells that have aberrant growth, including tumor cells. These signals may induce apoptosis in the damaged cells, the recruitment of immune cells to the aberrant tissue and even activate humoral responses. Thus, this ensures the removal of aberrant cells and compensatory proliferation to replace lost tissue. Several of these pathways may have been co-opted from wound healing and developmental processes.

  • 325.
    Krautz, Robert
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Khalili, Dilan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hauling, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Söll, Iris
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hauptmann, Giselbert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    An innate immune response against dysplasia in a secretory organManuskript (preprint) (Annet vitenskapelig)
  • 326.
    Krautz, Robert
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Khalili, Dilan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Söll, Iris
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hauptmann, Giselbert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Drosophila larval fat body preparations to reveal regionalized gene expression​Manuskript (preprint) (Annet vitenskapelig)
  • 327. Kreuzer, M.
    et al.
    Auvinen, A.
    Cardis, E.
    Durante, M.
    Harms-Ringdahl, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Jourdain, J. R.
    Madas, B. G.
    Ottolenghi, A.
    Pazzaglia, S.
    Prise, K. M.
    Quintens, R.
    Sabatier, L.
    Bouffler, S.
    Multidisciplinary European Low Dose Initiative (MELODI): strategic research agenda for low dose radiation risk research2018Inngår i: Radiation and Environmental Biophysics, ISSN 0301-634X, E-ISSN 1432-2099, Vol. 57, nr 1, s. 5-15Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    MELODI (Multidisciplinary European Low Dose Initiative) is a European radiation protection research platform with focus on research on health risks after exposure to low-dose ionising radiation. It was founded in 2010 and currently includes 44 members from 18 countries. A major activity of MELODI is the continuous development of a long-term European Strategic Research Agenda (SRA) on low-dose risk for radiation protection. The SRA is intended to identify priorities for national and European radiation protection research programs as a basis for the preparation of competitive calls at the European level. Among those key priorities is the improvement of health risk estimates for exposures close to the dose limits for workers and to reference levels for the population in emergency situations. Another activity of MELODI is to ensure the availability of European key infrastructures for research activities, and the long-term maintenance of competences in radiation research via an integrated European approach for training and education. The MELODI SRA identifies three key research topics in low dose or low dose-rate radiation risk research: (1) dose and dose rate dependence of cancer risk, (2) radiation-induced non-cancer effects and (3) individual radiation sensitivity. The research required to improve the evidence base for each of the three key topics relates to three research lines: (1) research to improve understanding of the mechanisms contributing to radiogenic diseases, (2) epidemiological research to improve health risk evaluation of radiation exposure and (3) research to address the effects and risks associated with internal exposures, differing radiation qualities and inhomogeneous exposures. The full SRA and associated documents can be downloaded from the MELODI website (http://www.melodi-online.eu/sra.html).

  • 328.
    Kubrak, Olga I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Kucerova, Lucie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nylin, Sören
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Characterization of Reproductive Dormancy in Male Drosophila melanogaster2016Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, artikkel-id 572Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insects are known to respond to seasonal and adverse environmental changes by entering dormancy, also known as diapause. In some insect species, including Drosophila melanogaster, dormancy occurs in the adult organism and postpones reproduction. This adult dormancy has been studied in female flies where it is characterized by arrested development of ovaries, altered nutrient stores, lowered metabolism, increased stress and immune resistance and drastically extended lifespan. Male dormancy, however, has not been investigated in D. melanogaster, and its physiology is poorly known in most insects. Here we show that unmated 3-6 h old male flies placed at low temperature (11 degrees C) and short photoperiod (10 Light:14 Dark) enter a state of dormancy with arrested spermatogenesis and development of testes and male accessory glands. Over 3 weeks of diapause we see a dynamic increase in stored carbohydrates and an initial increase and then a decrease in lipids. We also note an up-regulated expression of genes involved in metabolism, stress responses and innate immunity. Interestingly, we found that male flies that entered reproductive dormancy do not attempt to mate females kept under non-diapause conditions (25 degrees C, 1 2L:1 2D), and conversely non-diapausing males do not mate females in dormancy. In summary, our study shows that male D. melanogaster can enter reproductive dormancy. However, our data suggest that dormant male flies deplete stored nutrients faster than females, studied earlier, and that males take longer to recover reproductive capacity after reintroduction to non-diapause conditions.

  • 329.
    Kubrak, Olga I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Kucerova, Lucie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    The Sleeping Beauty: How Reproductive Diapause Affects Hormone Signaling, Metabolism, Immune Response and Somatic Maintenance in Drosophila melanogaster2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, artikkel-id e113051Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Some organisms can adapt to seasonal and other environmental challenges by entering a state of dormancy, diapause. Thus, insects exposed to decreased temperature and short photoperiod enter a state of arrested development, lowered metabolism, and increased stress resistance. Drosophila melanogaster females can enter a shallow reproductive diapause in the adult stage, which drastically reduces organismal senescence, but little is known about the physiology and endocrinology associated with this dormancy, and the genes involved in its regulation. We induced diapause in D. melanogaster and monitored effects over 12 weeks on dynamics of ovary development, carbohydrate and lipid metabolism, as well as expression of genes involved in endocrine signaling, metabolism and innate immunity. During diapause food intake diminishes drastically, but circulating and stored carbohydrates and lipids are elevated. Gene transcripts of glucagonand insulin-like peptides increase, and expression of several target genes of these peptides also change. Four key genes in innate immunity can be induced by infection in diapausing flies, and two of these, drosomycin and cecropin A1, are upregulated by diapause independently of infection. Diapausing flies display very low mortality, extended lifespan and decreased aging of the intestinal epithelium. Many phenotypes induced by diapause are reversed after one week of recovery from diapause conditions. Furthermore, mutant flies lacking specific insulin-like peptides (dilp5 and dilp2-3) display increased diapause incidence. Our study provides a first comprehensive characterization of reproductive diapause in D. melanogaster, and evidence that glucagon- and insulin-like signaling are among the key regulators of the altered physiology during this dormancy.

  • 330.
    Kucerova, Lucie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of South Bohemia, Czech Republic.
    Broz, Vaclav
    Arefin, Badrul
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Maaroufi, Houda Ouns
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hurychova, Jana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Masaryk University, Czech Republic.
    Strnad, Hynek
    Zurovec, Michal
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The Drosophila Chitinase-Like Protein IDGF3 Is Involved in Protection against Nematodes and in Wound Healing2016Inngår i: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 8, nr 2, s. 199-210Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chitinase-like proteins (CLPs) of the 18 glycosyl hydrolase family retain structural similarity to chitinases but lack enzymatic activity. Although CLPs are upregulated in several human disorders that affect regenerative and inflammatory processes, very little is known about their normal physiological function. We show that an insect CLP (Drosophila imaginal disc growth factor 3, IDGF3) plays an immune-protective role during entomopathogenic nematode (EPN) infections. During these infections, nematodes force their entry into the host via border tissues, thus creating wounds. Whole-genome transcriptional analysis of nematode-infected wildtype and Idgf3 mutant larvae have shown that, in addition to the regulation of genes related to immunity and wound closure, IDGF3 represses Jak/STAT and Wingless signaling. Further experiments have confirmed that IDGF3 has multiple roles in innate immunity. It serves as an essential component required for the formation of hemolymph clots that seal wounds, and Idgf3 mutants display an extended developmental delay during wound healing. Altogether, our findings indicate that vertebrate and invertebrate CLP proteins function in analogous settings and have a broad impact on inflammatory reactions and infections. This opens the way to further genetic analysis of Drosophila IDGF3 and will help to elucidate the exact molecular context of CLP function.

  • 331.
    Kucerova, Lucie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kubrak, Olga I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Bengtsson, Jonas M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Strnad, Hynek
    Nylin, Sören
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Slowed aging during reproductive dormancy is reflected in genome-wide transcriptome changes in Drosophila melanogaster2016Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, artikkel-id 50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In models extensively used in studies of aging and extended lifespan, such as C. elegans and Drosophila, adult senescence is regulated by gene networks that are likely to be similar to ones that underlie lifespan extension during dormancy. These include the evolutionarily conserved insulin/IGF, TOR and germ line-signaling pathways. Dormancy, also known as dauer stage in the larval worm or adult diapause in the fly, is triggered by adverse environmental conditions, and results in drastically extended lifespan with negligible senescence. It is furthermore characterized by increased stress resistance and somatic maintenance, developmental arrest and reallocated energy resources. In the fly Drosophila melanogaster adult reproductive diapause is additionally manifested in arrested ovary development, improved immune defense and altered metabolism. However, the molecular mechanisms behind this adaptive lifespan extension are not well understood. Results: A genome wide analysis of transcript changes in diapausing D. melanogaster revealed a differential regulation of more than 4600 genes. Gene ontology (GO) and KEGG pathway analysis reveal that many of these genes are part of signaling pathways that regulate metabolism, stress responses, detoxification, immunity, protein synthesis and processes during aging. More specifically, gene readouts and detailed mapping of the pathways indicate downregulation of insulin-IGF (IIS), target of rapamycin (TOR) and MAP kinase signaling, whereas Toll-dependent immune signaling, Jun-N-terminal kinase (JNK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways are upregulated during diapause. Furthermore, we detected transcriptional regulation of a large number of genes specifically associated with aging and longevity. Conclusions: We find that many affected genes and signal pathways are shared between dormancy, aging and lifespan extension, including IIS, TOR, JAK/STAT and JNK. A substantial fraction of the genes affected by diapause have also been found to alter their expression in response to starvation and cold exposure in D. melanogaster, and the pathways overlap those reported in GO analysis of other invertebrates in dormancy or even hibernating mammals. Our study, thus, shows that D. melanogaster is a genetically tractable model for dormancy in other organisms and effects of dormancy on aging and lifespan.

  • 332. Kukutla, Phanidhar
    et al.
    Lindberg, Bo G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Pei, Dong
    Rayl, Melanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Yu, Wanqin
    Steritz, Matthew
    Faye, Ingrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Xu, Jiannong
    Draft Genome Sequences of Elizabethkingia anophelis Strains R26T and Ag1 from the Midgut of the Malaria Mosquito Anopheles gambiae2013Inngår i: Genome Announcements, ISSN 2169-8287, Vol. 1, nr 6, s. e01030-13-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elizabethkingia anophelis is a species in the family Flavobacteriaceae. It is a dominant resident in the mosquito gut and also a human pathogen. We present the draft genome sequences of two strains of E. anophelis, R26T and Ag1, which were isolated from the midgut of the malaria mosquito Anopheles gambiae.

  • 333. Kukutla, Phanidhar
    et al.
    Lindberg, Bo G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Pei, Dong
    Rayl, Melanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Yu, Wanqin
    Steritz, Matthew
    Faye, Ingrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Xu, Jiannong
    Insights from the Genome Annotation of Elizabethkingia anophelis from the Malaria Vector Anopheles gambiae2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 5, s. e97715-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elizabethkingia anophelis is a dominant bacterial species in the gut ecosystem of the malaria vector mosquito Anopheles gambiae. We recently sequenced the genomes of two strains of E. anophelis, R26(T) and Ag1, isolated from different strains of A. gambiae. The two bacterial strains are identical with a few exceptions. Phylogenetically, Elizabethkingia is closer to Chryseobacterium and Riemerella than to Flavobacterium. In line with other Bacteroidetes known to utilize various polymers in their ecological niches, the E. anophelis genome contains numerous TonB dependent transporters with various substrate specificities. In addition, several genes belonging to the polysaccharide utilization system and the glycoside hydrolase family were identified that could potentially be of benefit for the mosquito carbohydrate metabolism. In agreement with previous reports of broad antibiotic resistance in E. anophelis, a large number of genes encoding efflux pumps and blactamases are present in the genome. The component genes of resistance-nodulation-division type efflux pumps were found to be syntenic and conserved in different taxa of Bacteroidetes. The bacterium also displays hemolytic activity and encodes several hemolysins that may participate in the digestion of erythrocytes in the mosquito gut. At the same time, the OxyR regulon and antioxidant genes could provide defense against the oxidative stress that is associated with blood digestion. The genome annotation and comparative genomic analysis revealed functional characteristics associated with the symbiotic relationship with the mosquito host.

  • 334. Kulka, U.
    et al.
    Ainsbury, L.
    Atkinson, M.
    Barnard, S.
    Smith, R.
    Barquinero, J. F.
    Barrios, L.
    Bassinet, C.
    Beinke, C.
    Cucu, A.
    Darroudi, F.
    Fattibene, P.
    Bortolin, E.
    Della Monaca, S.
    Gil, O.
    Gregoire, E.
    Hadjidekova, V.
    Haghdoost, Siamak
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hatzi, V.
    Hempel, W.
    Herranz, R.
    Jaworska, A.
    Lindholm, C.
    Lumniczky, K.
    M'kacher, R.
    Moertl, S.
    Montoro, A.
    Moquet, J.
    Moreno, M.
    Noditi, M.
    Ogbazghi, A.
    Oestreicher, U.
    Palitti, F.
    Pantelias, G.
    Popescu, I.
    Prieto, M. J.
    Roch-Lefevre, S.
    Roessler, U.
    Romm, H.
    Rothkamm, K.
    Sabatier, L.
    Sebastia, N.
    Sommer, S.
    Terzoudi, G.
    Testa, A.
    Thierens, H.
    Trompier, F.
    Turai, I.
    Vandevoorde, C.
    Vaz, P.
    Voisin, P.
    Vral, A.
    Ugletveit, F.
    Wieser, A.
    Woda, C.
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Realising the European network of biodosimetry: RENEB-status quo2015Inngår i: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 164, nr 1-2, s. 42-45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Creating a sustainable network in biological and retrospective dosimetry that involves a large number of experienced laboratories throughout the European Union (EU) will significantly improve the accident and emergency response capabilities in case of a large-scale radiological emergency. A well-organised cooperative action involving EU laboratories will offer the best chance for fast and trustworthy dose assessments that are urgently needed in an emergency situation. To this end, the EC supports the establishment of a European network in biological dosimetry (RENEB). The RENEB project started in January 2012 involving cooperation of 23 organisations from 16 European countries. The purpose of RENEB is to increase the biodosimetry capacities in case of large-scale radiological emergency scenarios. The progress of the project since its inception is presented, comprising the consolidation process of the network with its operational platform, intercomparison exercises, training activities, proceedings in quality assurance and horizon scanning for new methods and partners. Additionally, the benefit of the network for the radiation research community as a whole is addressed.

  • 335. Kulka, Ulrike
    et al.
    Abend, Michael
    Ainsbury, Elizabeth
    Badie, Christophe
    Francesc Barquinero, Joan
    Barrios, Lleonard
    Beinke, Christina
    Bortolin, Emanuela
    Cucu, Alexandra
    De Amicis, Andrea
    Dominguez, Inmaculada
    Fattibene, Paola
    Frovig, Anne Marie
    Gregoire, Eric
    Guogyte, Kamile
    Hadjidekova, Valeria
    Jaworska, Alicja
    Kriehuber, Ralf
    Lindholm, Carita
    Lloyd, David
    Lumniczky, Katalin
    Lyng, Fiona
    Meschini, Roberta
    Moertl, Simone
    Della Monaca, Sara
    Gil, Octavia Monteiro
    Montoro, Alegria
    Moquet, Jayne
    Moren, Mercedes
    Oestreicher, Ursula
    Palitti, Fabrizio
    Pantelias, Gabriel
    Patrono, Clarice
    Piqueret-Stephan, Laure
    Port, Matthias
    Jesus Prieto, Maria
    Quintens, Roel
    Ricoul, Michelle
    Romm, Horst
    Roy, Laurence
    Safrany, Geza
    Sabatier, Laure
    Sebastia, Natividad
    Sommer, Sylwester
    Terzoudi, Georgia
    Testa, Antonella
    Thierens, Hubert
    Turai, Istvan
    Trompier, Francois
    Valente, Marco
    Vaz, Pedro
    Voisin, Philippe
    Vral, Anne
    Woda, Clemens
    Zafiropoulos, Demetre
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    RENEB - Running the European Network of biological dosimetry and physical retrospective dosimetry2017Inngår i: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 93, nr 1, s. 2-14Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: A European network was initiated in 2012 by 23 partners from 16 European countries with the aim to significantly increase individualized dose reconstruction in case of large-scale radiological emergency scenarios. Results: The network was built on three complementary pillars: (1) an operational basis with seven biological and physical dosimetric assays in ready-to-use mode, (2) a basis for education, training and quality assurance, and (3) a basis for further network development regarding new techniques and members. Techniques for individual dose estimation based on biological samples and/or inert personalized devices as mobile phones or smart phones were optimized to support rapid categorization of many potential victims according to the received dose to the blood or personal devices. Communication and cross-border collaboration were also standardized. To assure long-term sustainability of the network, cooperation with national and international emergency preparedness organizations was initiated and links to radiation protection and research platforms have been developed. A legal framework, based on a Memorandum of Understanding, was established and signed by 27 organizations by the end of 2015. Conclusions: RENEB is a European Network of biological and physical-retrospective dosimetry, with the capacity and capability to perform large-scale rapid individualized dose estimation. Specialized to handle large numbers of samples, RENEB is able to contribute to radiological emergency preparedness and wider large-scale research projects.

  • 336. Kumsiri, Ratchanok
    et al.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Pattanapanyasat, Kovit
    Krudsood, Srivicha
    Maneerat, Yaowapa
    IgE low affinity receptor (CD23) expression, Plasmodium falciparum specific IgE and tumor necrosis factor-alpha production in Thai uncomplicated and severe falciparum malaria patients2016Inngår i: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 154, s. 25-33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previous studies have suggested that Plasmodium falciparum (P. falciparum) specific IgE in the form of immune complexes crosslinking the low-affinity receptor (CD23) on monocyte results in tumor necrosis factor (TNF)-alpha and nitric oxide (NO) production. However, the roles of these parameters in severity and immune protection are still unclear. This study aimed to determine the association between CD23 expression on monocytes, plasma soluble CD23 (sCD23), total IgE, malaria-specific IgE and IgG, and TNF-alpha levels in P. falciparum infected patients. We evaluated 64 uncomplicated (UC) and 25 severe patients (S), admitted at the Hospital for Tropical Diseases, Mahidol University, and 34 healthy controls (C) enrolled in 2001. Flow cytometry and enzyme linked immunosorbent assays (ELISA) demonstrated that trends of the CD23 expression, levels of sCD23 and specific IgE were higher in the S group as compared to those in the UC and C groups. Plasma levels of P. falciparum specific IgE in the UC (p = 0.011) and S groups (p = 0.025) were significantly higher than those in C group. In contrast the TNF-alpha levels tended to be higher in the UC than those in the S (p = 0343) and significantly higher than those in C (p = 0.004) groups. The specific IgG levels in UC were significantly higher than those in S and C (p < 0.001) groups. At admission, a strong significant negative correlation was found between specific IgG and sCD23 (r = -0.762, p = 0.028), and TNF-alpha and IgE-IgG complexes (r=-0.715, p = 0.002). Significant positive correlations between levels of specific IgE and TNF-alpha (r=0.575, p = 0.010); and sCD23 (r=0.597, p = 0.000) were also observed. In conclusion, our data suggest that CD23 expression and malaria-specific IgE levels may be involved in the severity of the disease while TNF-alpha and the malaria-specific IgG may correlate with protection against falciparum malaria.

  • 337.
    Kunc, Martin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Masaryk University, Czech Republic.
    Arefin, Badrul
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hyrsl, Pavel
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Monitoring the effect of pathogenic nematodes on locomotion of Drosophila larvae2017Inngår i: fly, ISSN 1933-6934, Vol. 11, nr 3, s. 208-217Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    One of the key factors that determine the interaction between hosts and their parasites is the frequency of their interactions, which depends on the locomotory behavior of both parts. To address host behavior we used natural infections involving insect pathogenic nematodes and Drosophila melanogaster larvae as hosts. Using a modified version of a recently described method (FIMTrack) to assess several parameters in larger sets of animals, we initially detected specific differences in larval food searching when comparing Drosophila strains. These differences were further influenced by the presence of nematodes. Given a choice, Drosophila larvae clearly avoided nematodes irrespective of their genetic background. Our newly developed methods will be useful to test candidate genes and pathways involved in host/pathogen interactions in general and to assess specific parameters of their interaction.

  • 338. Kunc, Martin
    et al.
    Arefin, Badrul
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hyrsl, Pavel
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Monitoring the effect of pathogenic nematodes on locomotion of Drosophila larvaeManuskript (preprint) (Annet vitenskapelig)
  • 339. Kupferschmidt, Natalia
    et al.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ballell, Lluis
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Garcia-Bennett, Alfonso E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Large pore mesoporous silica induced weight loss in obese mice2014Inngår i: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 9, nr 9, s. 1353-1362Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There is a need for medical treatments to curb the rising rate of obesity. Weight reduction is correlated with a decrease in associated risk factors and cholesterol levels in humans. Amorphous silica particles have been found to exert a hypocholesterolemic effect in humans, making them popular dietary additives. Aim: To investigate the effect of mesoporous silica, which possess sharp pore size distributions, on: weight loss, cholesterol, triglycerides and glucose blood levels in obese mice. Materials & methods: Mesoporous silicas with differing pore size were mixed in the high-fat diet of obese mice. Results: Animals receiving large pore mesoporous silica with a high-fat diet show a significant reduction in body weight and fat composition, with no observable negative effects. Conclusion: Pore size is an important parameter for reduction of body weight and body fat composition by mesoporous silica, demonstrating promising signs for the treatment of obesity.

  • 340. Kurioka, Ayako
    et al.
    Cosgrove, Cormac
    Simoni, Yannick
    van Wilgenburg, Bonnie
    Geremia, Alessandra
    Björkander, Sophia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Thurnheer, Christine
    Günthard, Huldrych F.
    Khanna, Nina
    Walker, Lucy Jane
    Arancibia-Cárcamo, Carolina V.
    Newell, Evan W.
    Willberg, Christian B.
    Klenerman, Paul
    CD161 Defines a Functionally Distinct Subset of Pro-Inflammatory Natural Killer Cells2018Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, artikkel-id 486Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. Recently, we found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations. Using mass cytometry and microarray experiments, we demonstrate that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression. Thus, CD161 expression identifies NK cells that may contribute to inflammatory disease pathogenesis and correlates with an innate responsiveness to cytokines in both T and NK cells.

  • 341. Kurioka, Ayako
    et al.
    Jahun, Aminu S.
    Hannaway, Rachel F.
    Walker, Lucy J.
    Fergusson, Joannah R.
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Corbett, Alexandra J.
    Ussher, James E.
    Willberg, Christian B.
    Klenerman, Paul
    Shared and Distinct Phenotypes and Functions of Human CD161++ V alpha 7.2+T Cell Subsets2017Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, artikkel-id 1031Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human mucosal-associated invariant T (MAIT) cells are an important T cell subset that are enriched in tissues and possess potent effector functions. Typically such cells are marked by their expression of V alpha 7.2-J alpha 33/J alpha 20/J alpha 12 T cell receptors, and functionally they are major histocompatibility complex class I-related protein 1 (MR1)-restricted, responding to bacterially derived riboflavin synthesis intermediates. MAIT cells are contained within the CD161++ V alpha 7.2+ T cell population, the majority of which express the CD8 receptor (CD8+), while a smaller fraction expresses neither CD8 or CD4 coreceptor (double negative; DN) and a further minority are CD4+. Whether these cells have distinct homing patterns, phenotype and functions have not been examined in detail. We used a combination of phenotypic staining and functional assays to address the similarities and differences between these CD161++ V alpha 7.2+ T cell subsets. We find that most features are shared between CD8+ and DN CD161++ V alpha 7.2+ T cells, with a small but detectable role evident for CD8 binding in tuning functional responsiveness. By contrast, the CD4+ CD161++ V alpha 7.2+ T cell population, although showing MR1-dependent responsiveness to bacterial stimuli, display reduced T helper 1 effector functions, including cytolytic machinery, while retaining the capacity to secrete interleukin-4 (IL-4) and IL-13. This was consistent with underlying changes in transcription factor (TF) expression. Although we found that only a proportion of CD4+ CD161++ V alpha 7.2+ T cells stained for the MR1-tetramer, explaining some of the heterogeneity of CD4+ CD161++ V alpha 7.2+ T cells, these differences in TF expression were shared with CD4+ CD161++ MR1-tetramer+ cells. These data reveal the functional diversity of human CD161++ V alpha 7.2+ T cells and indicate potentially distinct roles for the different subsets in vivo.

  • 342.
    Kutsenko, Alexey
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Svensson, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Nystedt, Björn
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Lundeberg, Joakim
    Björk, Petra
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sonnhammer, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Giacomello, Stefania
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Visa, Neus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wieslander, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The Chironomus tentans genome sequence and the organization of the Balbiani ring genes2014Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, s. 819-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The polytene nuclei of the dipteran Chironomus tentans (Ch. tentans) with their Balbiani ring (BR) genes constitute an exceptional model system for studies of the expression of endogenous eukaryotic genes. Here, we report the first draft genome of Ch. tentans and characterize its gene expression machineries and genomic architecture of the BR genes. Results: The genome of Ch. tentans is approximately 200 Mb in size, and has a low GC content (31%) and a low repeat fraction (15%) compared to other Dipteran species. Phylogenetic inference revealed that Ch. tentans is a sister clade to mosquitoes, with a split 150-250 million years ago. To characterize the Ch. tentans gene expression machineries, we identified potential orthologus sequences to more than 600 Drosophila melanogaster (D. melanogaster) proteins involved in the expression of protein-coding genes. We report novel data on the organization of the BR gene loci, including a novel putative BR gene, and we present a model for the organization of chromatin bundles in the BR2 puff based on genic and intergenic in situ hybridizations. Conclusions: We show that the molecular machineries operating in gene expression are largely conserved between Ch. tentans and D. melanogaster, and we provide enhanced insight into the organization and expression of the BR genes. Our data strengthen the generality of the BR genes as a unique model system and provide essential background for in-depth studies of the biogenesis of messenger ribonucleoprotein complexes.

  • 343.
    Lackmann, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    High-throughput RNA structure probing reveals critical folding events during early 60S ribosome assembly in yeastManuskript (preprint) (Annet vitenskapelig)
  • 344.
    Lackmann, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mrd1 is involved in restructuring the U3 snoRNP and central regions in the 90S pre-ribosomeManuskript (preprint) (Annet vitenskapelig)
  • 345.
    Lackmann, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nucleolar Ribosome Assembly2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Ribosomes are macromolecular machines that are responsible for production of every protein in a living cell. Yet we do not know the details about how these machines are formed. The ribosome consists of four RNA strands and roughly 80 proteins that associate with each other in the nucleolus and form pre-ribosomal complexes. Eukaryotes, in contrast to prokaryotes, need more than 200 non-ribosomal factors to assemble ribosomes. These associate with pre-ribosomal complexes at different stages as they travel from the nucleolus to the cytoplasm and are required for pre-rRNA processing. We do however lack knowledge about the molecular function of most of these factors and what enables pre-rRNA processing. Especially, information is missing about how non-ribosomal factors influence folding of the pre-rRNA and to what extent the pre-ribosomal complexes are restructured during their maturation. 

    This thesis aims to obtain a better understanding of the earliest events of ribosome assembly, namely those that take place in the nucleolus. This has been achieved by studying the essential protein Mrd1 by mutational analysis in the yeast Saccharomyces cerevisiae as well as by obtaining structural information of nucleolar pre-ribosomal complexes. Mrd1 has a modular structure consisting of multiple RNA binding domains (RBDs) that we find is conserved throughout eukarya. We show that an evolutionary conserved linker region of Mrd1 is crucial for function of the protein and likely forms an essential module together with adjacent RBDs. By obtaining structural information of pre-ribosomal complexes at different stages, we elucidate what structuring events occur in the nucleolus.  We uncover a direct role of Mrd1 in structuring the pre-rRNA in early pre-ribosomal complexes, which provides an explanation for why pre-rRNA cannot be processed in Mrd1 mutants.

  • 346.
    Lackmann, Fredrik
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Belikov, Sergey
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Burlacu, Elena
    Granneman, Sander
    Wieslander, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Maturation of the 90S pre-ribosome requires Mrd1 dependent U3 snoRNA and 35S pre-rRNA structural rearrangements2018Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, nr 7, s. 3692-3706Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In eukaryotes, ribosome biogenesis requires folding and assembly of the precursor rRNA (pre-rRNA) with a large number of proteins and snoRNPs into huge RNA-protein complexes. In spite of intense genetic, biochemical and high-resolution cryo-EM studies in Saccharomyces cerevisiae, information about the structure of the 35S pre-rRNA is limited. To overcome this, we performed high-throughput SHAPE chemical probing on the 35S pre-rRNA within 90S pre-ribosomes. We focused our analyses on external (5' ETS) and internal (ITS1) transcribed spacers as well as the 18S rRNA region. We show that in the 35S pre-rRNA, the central pseudoknot is not formed and the central core of the 18S rRNA is in an open configuration but becomes more constrained in 20S pre-rRNA. The essential ribosome biogenesis protein Mrd1 influences the structure of the 18S rRNA region locally and is involved in organizing the central pseudoknot and surrounding structures. We demonstrate that U3 snoRNA dynamically interacts with the 35S pre-rRNA and that Mrd1 is required for disrupting U3 snoRNA base pairing interactions in the 5' ETS. We propose that the dynamic U3 snoRNA interactions and Mrd1 are essential for establishing the structure of the central core of 18S rRNA that is required for processing and 40S subunit function.

  • 347.
    Lackmann, Fredrik
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Belikov, Sergey
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wieslander, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Linker 2 of the eukaryotic pre-ribosomal processing factor Mrd1p is an essential interdomain functionally coupled to upstream RNA Binding Domain 2 (RBD2)2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 4, artikkel-id e0175506Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ribosome synthesis is an essential process in all cells. In Sacharomyces cerevisiae, the precursor rRNA, 35S pre-rRNA, is folded and assembled into a 90S pre-ribosomal complex. The 40S ribosomal subunit is processed from the pre-ribosomal complex. This requires concerted action of small nucleolar RNAs, such as U3 snoRNA, and a large number of transacting factors. Mrd1p, one of the essential small ribosomal subunit synthesis factors is required for cleavage of the 35S pre-rRNA to generate 18S rRNA of the small ribosomal subunit. Mrd1p is evolutionary conserved in all eukaryotes and in yeast it contains five RNA Binding Domains (RBDs) separated by linker regions. One of these linkers, Linker 2 between RBD2 and RBD3, is conserved in length, predicted to be structured and contains conserved clusters of amino acid residues. In this report, we have analysed Linker 2 mutations and demonstrate that it is essential for Mrd1p function during pre-ribosomal processing. Extensive changes of amino acid residues as well as specific changes of conserved clusters of amino acid residues were found to be incompatible with synthesis of pre-40S ribosomes and cell growth. In addition, gross changes in primary sequence of Linker 2 resulted in Mrd1p instability, leading to degradation of the N-terminal part of the protein. Our data indicates that Linker 2 is functionally coupled to RBD2 and argues for that these domains constitute a functional module in Mrd1p. We conclude that Linker 2 has an essential role for Mrd1p beyond just providing a defined length between RBD2 and RBD3.

  • 348. Langlet, Fanny
    et al.
    Tarbier, Marcel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Haeusler, Rebecca A.
    Camastra, Stefania
    Ferrannini, Eleuterio
    Friedländer, Marc R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Accili, Domenico
    microRNA-205-5p is a modulator of insulin sensitivity that inhibits FOXO function2018Inngår i: Molecular metabolism, ISSN 2212-8778, Vol. 17, s. 49-60Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: Hepatic insulin resistance is a hallmark of type 2 diabetes and obesity. Insulin receptor signaling through AKT and FOXO has important metabolic effects that have traditionally been ascribed to regulation of gene expression. However, whether all the metabolic effects of FOXO arise from its regulation of protein-encoding mRNAs is unknown. Methods: To address this question, we obtained expression profiles of FOXO-regulated murine hepatic microRNAs (miRNAs) during fasting and refeeding using mice lacking Foxo1, 3a, and 4 in liver (L-Foxo1,3a, 4). Results: Out of 439 miRNA analyzed, 175 were differentially expressed in Foxo knockouts. Their functions were associated with insulin, Wnt, Mapk signaling, and aging. Among them, we report a striking increase of miR-205-5p expression in L-Foxo1,3a,4 knockouts, as well as in obese mice. We show that miR-205-5p gain-of-function increases AKT phosphorylation and decreases SHIP2 in primary hepatocytes, resulting in FOXO inhibition. This results in decreased hepatocyte glucose production. Consistent with these observations, miR-205-5p gain-of-function in mice lowered glucose levels and improved pyruvate tolerance. Conclusions: These findings reveal a homeostatic miRNA loop regulating insulin signaling, with potential implications for in vivo glucose metabolism.

  • 349.
    Lasaviciute, Gintare
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Björkander, Sophia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Carvalho-Queiroz, Claudia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hed Myrberg, Ida
    Nussbaum, Bianca
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nilsson, Caroline
    Bemark, Mats
    Nilsson, Anna
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Saghafian-Hedengren, Shanie
    Epstein-Barr Virus, but Not Cytomegalovirus, Latency Accelerates the Decay of Childhood Measles and Rubella Vaccine Responses-A 10-Year Follow-up of a Swedish Birth Cohort2017Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, artikkel-id 1865Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are ubiquitous and persistent herpesviruses commonly acquired during childhood. Both viruses have a significant impact on the immune system, especially through mediating the establishment of cellular immunity, which keeps these viruses under control for life. Far less is known about how these viruses influence B-cell responses. Objectives: To evaluate the impact of latent EBV and CMV infection on rubella- and measles-specific antibody responses as well as on the B-cell compartment in a prospective birth cohort followed during the first 10 years of life. Methods: IgG titers against rubella and measles vaccines were measured in plasma obtained from the same donors at 2, 5, and 10 years of age. Peripheral B-cell subsets were evaluated ex vivo at 2 and 5 years of age. Factors related to optimal B-cell responses including IL-21 and CXCL13 levels in plasma were measured at all-time points. Results: EBV carriage in the absence of CMV associated with an accelerated decline of rubella and measles-specific IgG levels (p = 0.003 and p = 0.019, respectively, linear mixed model analysis), while CMV carriage in the absence of EBV associated with delayed IgG decay over time for rubella (p = 0.034). At 5 years of age, EBV but not CMV latency associated with a lower percentage of plasmablasts, but higher IL-21 levels in the circulation. Conclusion: Our findings suggest that EBV carriage in the absence of CMV influences the B-cell compartment and the dynamics of antibody responses over time during steady state in the otherwise healthy host.

  • 350. Lateef, Dalya M.
    et al.
    Abreu-Vieira, Gustavo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Xiao, Cuiying
    Reitman, Marc L.
    Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-32014Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 306, nr 6, s. E681-E687Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, with Brs3 knockout (Brs3(-/y)) mice being hypometabolic, hypothermic, and hyperphagic and developing obesity. We now report that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 min later. The Brs3(-/y) metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3(-/y) mice have intact thermogenic responses to stress, acute cold exposure, and beta 3-adrenergic activation, and Brs3(-/y) mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3(-/y) mice. Intrahypothalamic infusion of MK5046 increased body temperature. These data indicate that the BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3(-/y) mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue.

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