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Sample records for type ii interferon

  1. Analysis of Pro-inflammatory Cytokine and Type II Interferon Induction by Nanoparticles.

    Science.gov (United States)

    Potter, Timothy M; Neun, Barry W; Rodriguez, Jamie C; Ilinskaya, Anna N; Dobrovolskaia, Marina A

    2018-01-01

    Cytokines, chemokines, and interferons are released by the immune cells in response to cellular stress, damage and/or pathogens, and are widely used as biomarkers of inflammation. Certain levels of cytokines are needed to stimulate an immune response in applications such as vaccines or immunotherapy where immune stimulation is desired. However, undesirable elevation of cytokine levels, as may occur in response to a drug or a device, may lead to severe side effects such as systemic inflammatory response syndrome or cytokine storm. Therefore, preclinical evaluation of a test material's propensity to cause cytokine secretion by healthy immune cells is an important parameter for establishing its safety profile. Herein, we describe in vitro methods for analysis of cytokines, chemokines, and type II interferon in whole blood cultures derived from healthy donor volunteers. First, whole blood is incubated with controls and tested nanomaterials for 24 h. Then, culture supernatants are analyzed by ELISA to detect IL-1β, TNFα, IL-8, and IFNγ. The culture supernatants can also be analyzed for the presence of other biomarkers secreted by the immune cells. Such testing would require additional assays not covered in this chapter and/or optimization of the test procedure to include relevant positive controls and/or cell types.

  2. Identification of Type II Interferon Receptors in Geese: Gene Structure, Phylogenetic Analysis, and Expression Patterns

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    Hao Zhou

    2015-01-01

    Full Text Available Interferon γ receptor 1 (IFNGR1 and IFNGR2 are two cell membrane molecules belonging to class II cytokines, which play important roles in the IFN-mediated antiviral signaling pathway. Here, goose IFNGR1 and IFNGR2 were cloned and identified for the first time. Tissue distribution analysis revealed that relatively high levels of goose IFNγ mRNA transcripts were detected in immune tissues, including the harderian gland, cecal tonsil, cecum, and thymus. Relatively high expression levels of both IFNGR1 and IFNGR2 were detected in the cecal tonsil, which implicated an important role of IFNγ in the secondary immune system of geese. No specific correlation between IFNγ, IFNGR1, and IFNGR2 expression levels was observed in the same tissues of healthy geese. IFNγ and its cognate receptors showed different expression profiles, although they appeared to maintain a relatively balanced state. Furthermore, the agonist R848 led to the upregulation of goose IFNγ but did not affect the expression of goose IFNGR1 or IFNGR2. In summary, trends in expression of goose IFNγ and its cognate receptors showed tissue specificity, as well as an age-related dependency. These findings may help us to better understand the age-related susceptibility to pathogens in birds.

  3. Human cytomegalovirus IE1 protein elicits a type II interferon-like host cell response that depends on activated STAT1 but not interferon-γ.

    Directory of Open Access Journals (Sweden)

    Theresa Knoblach

    2011-04-01

    Full Text Available Human cytomegalovirus (hCMV is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1 protein, a major transcriptional activator and antagonist of type I interferon (IFN signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1 and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity.

  4. Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon

    Science.gov (United States)

    Knoblach, Theresa; Grandel, Benedikt; Seiler, Jana

    2011-01-01

    Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity. PMID:21533215

  5. Dermatomyositis and Type 1 Interferons

    Science.gov (United States)

    2010-01-01

    Dermatomyositis is a poorly understood multisystem disease predominantly affecting skin and muscle. This review focuses on the potential role of a group of related cytokines, the type 1 interferons, in the pathogenesis of dermatomyositis. Type 1 interferon–inducible transcripts and proteins are uniquely elevated in dermatomyositis muscle compared with all other muscle diseases studied to date. The endothelial cell tubuloreticular inclusions present in affected dermatomyositis muscle are biomarkers of type 1 interferon exposure. The cell-poor lichenoid reaction in skin with predominant involvement of the basal epidermal cell layer and its topologic equivalent in muscle, perifascicular atrophy, may be lesions that develop directly in response to type 1 interferon signaling. PMID:20425524

  6. Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence.

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    Cameron R Cunningham

    2016-01-01

    Full Text Available Persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by IL-10 and PDL1 that attenuate antiviral T cell responses. Inhibiting these suppressive signals enhances T cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. Herein, we use lymphocytic choriomeningitis virus infection (LCMV to demonstrate that the induction and functional programming of immunosuppressive dendritic cells (DCs during viral persistence are separable mechanisms programmed by factors primarily considered pro-inflammatory. IFNγ first induces the de novo development of naive monocytes into DCs with immunosuppressive potential. Type I interferon (IFN-I then directly targets these newly generated DCs to program their potent T cell immunosuppressive functions while simultaneously inhibiting conventional DCs with T cell stimulating capacity. These mechanisms of monocyte conversion are constant throughout persistent infection, establishing a system to continuously interpret and shape the immunologic environment. MyD88 signaling was required for the differentiation of suppressive DCs, whereas inhibition of stimulatory DCs was dependent on MAVS signaling, demonstrating a bifurcation in the pathogen recognition pathways that promote distinct elements of IFN-I mediated immunosuppression. Further, a similar suppressive DC origin and differentiation was also observed in Mycobacterium tuberculosis infection, HIV infection and cancer. Ultimately, targeting the underlying mechanisms that induce immunosuppression could simultaneously prevent multiple suppressive signals to further restore T cell function and control persistent infections.

  7. Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence

    Science.gov (United States)

    Cunningham, Cameron R.; Champhekar, Ameya; Tullius, Michael V.; Dillon, Barbara Jane; Zhen, Anjie; de la Fuente, Justin Rafael; Herskovitz, Jonathan; Elsaesser, Heidi; Snell, Laura M.; Wilson, Elizabeth B.; de la Torre, Juan Carlos; Kitchen, Scott G.; Horwitz, Marcus A.; Bensinger, Steven J.; Smale, Stephen T.; Brooks, David G.

    2016-01-01

    Persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by IL-10 and PDL1 that attenuate antiviral T cell responses. Inhibiting these suppressive signals enhances T cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. Herein, we use lymphocytic choriomeningitis virus infection (LCMV) to demonstrate that the induction and functional programming of immunosuppressive dendritic cells (DCs) during viral persistence are separable mechanisms programmed by factors primarily considered pro-inflammatory. IFNγ first induces the de novo development of naive monocytes into DCs with immunosuppressive potential. Type I interferon (IFN-I) then directly targets these newly generated DCs to program their potent T cell immunosuppressive functions while simultaneously inhibiting conventional DCs with T cell stimulating capacity. These mechanisms of monocyte conversion are constant throughout persistent infection, establishing a system to continuously interpret and shape the immunologic environment. MyD88 signaling was required for the differentiation of suppressive DCs, whereas inhibition of stimulatory DCs was dependent on MAVS signaling, demonstrating a bifurcation in the pathogen recognition pathways that promote distinct elements of IFN-I mediated immunosuppression. Further, a similar suppressive DC origin and differentiation was also observed in Mycobacterium tuberculosis infection, HIV infection and cancer. Ultimately, targeting the underlying mechanisms that induce immunosuppression could simultaneously prevent multiple suppressive signals to further restore T cell function and control persistent infections. PMID:26808628

  8. Smac mimetics and type II interferon synergistically induce necroptosis in various cancer cell lines.

    Science.gov (United States)

    Cekay, Michael John; Roesler, Stefanie; Frank, Tanja; Knuth, Anne-Kathrin; Eckhardt, Ines; Fulda, Simone

    2017-12-01

    Since cancer cells often evade apoptosis, induction of necroptosis as another mode of programmed cell death is considered a promising therapeutic alternative. Here, we identify a novel synergistic interaction of Smac mimetics that antagonize x-linked Inhibitor of Apoptosis (XIAP), cellular Inhibitor of Apoptosis (cIAP) 1 and 2 with interferon (IFN)γ to induce necroptosis in apoptosis-resistant cancer cells in which caspase activation is blocked. This synergism is confirmed by calculation of combination indices (CIs) and found in both solid and hematological cancer cell lines as well as for different Smac mimetics (i.e. BV6, Birinapant), pointing to a broader relevance. Importantly, individual genetic knockdown of key components of necroptosis signaling, i.e. receptor-interacting protein (RIP) 1, RIP3 or mixed lineage kinase domain-like pseudokinase (MLKL), significantly protects from BV6/IFNγ-induced cell death. Similarly, pharmacological inhibitors of RIP1 (necrostatin-1(Nec-1)), RIP3 (GSK'872) or MLKL (necrosulfonamide (NSA)) significantly reduce BV6/IFNγ-stimulated cell death. Of note, IFN-regulatory factor (IRF)1 is required for BV6/IFNγ-mediated necroptosis, as IRF1 silencing provides protection from cell death. By comparison, antibodies blocking tumor necrosis factor (TNF)α, TNF-related apoptosis-inducing ligand (TRAIL) or CD95 ligand fail to inhibit BV6/IFNγ-induced cell death, pointing to a mechanism independently of death receptor ligands. This is the first report showing that Smac mimetics synergize with IFNγ to trigger necroptosis in apoptosis-resistant cancer cells with important implications for Smac mimetic-based strategies for the treatment of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Functional Interplay between Type I and II Interferons Is Essential to Limit Influenza A Virus-Induced Tissue Inflammation.

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    Sebastian A Stifter

    2016-01-01

    Full Text Available Host control of influenza A virus (IAV is associated with exuberant pulmonary inflammation characterized by the influx of myeloid cells and production of proinflammatory cytokines including interferons (IFNs. It is unclear, however, how the immune system clears the virus without causing lethal immunopathology. Here, we demonstrate that in addition to its known anti-viral activity, STAT1 signaling coordinates host inflammation during IAV infection in mice. This regulatory mechanism is dependent on both type I IFN and IFN-γ receptor signaling and, importantly, requires the functional interplay between the two pathways. The protective function of type I IFNs is associated with not only the recruitment of classical inflammatory Ly6Chi monocytes into IAV-infected lungs, but also the prevention of excessive monocyte activation by IFN-γ. Unexpectedly, type I IFNs preferentially regulate IFN-γ signaling in Ly6Clo rather than inflammatory Ly6Chi mononuclear cell populations. In the absence of type I IFN signaling, Ly6Clo monocytes/macrophages, become phenotypically and functionally more proinflammatory than Ly6Chi cells, revealing an unanticipated function of the Ly6Clo mononuclear cell subset in tissue inflammation. In addition, we show that type I IFNs employ distinct mechanisms to regulate monocyte and neutrophil trafficking. Type I IFN signaling is necessary, but not sufficient, for preventing neutrophil recruitment into the lungs of IAV-infected mice. Instead, the cooperation of type I IFNs and lymphocyte-produced IFN-γ is required to regulate the tissue neutrophilic response to IAV. Our study demonstrates that IFN interplay links innate and adaptive anti-viral immunity to orchestrate tissue inflammation and reveals an additional level of complexity for IFN-dependent regulatory mechanisms that function to prevent excessive immunopathology while preserving anti-microbial functions.

  10. The E5 protein of human papillomavirus type 16 perturbs MHC class II antigen maturation in human foreskin keratinocytes treated with interferon

    International Nuclear Information System (INIS)

    Zhang Benyue; Li Ping; Wang Exing; Brahmi, Zacharie; Dunn, Kenneth W.; Blum, Janice S.; Roman, Ann

    2003-01-01

    Major histocompatibility complex (MHC) class II antigens are expressed on human foreskin keratinocytes (HFKs) following exposure to interferon gamma. The expression of MHC class II proteins on the cell surface may allow keratinocytes to function as antigen-presenting cells and induce a subsequent immune response to virus infection. Invariant chain (Ii) is a chaperone protein which plays an important role in the maturation of MHC class II molecules. The sequential degradation of Ii within acidic endocytic compartments is a key process required for the successful loading of antigenic peptide onto MHC class II molecules. Since human papillomavirus (HPV) 16 E5 can inhibit the acidification of late endosomes in HFKs, the E5 protein may be able to affect proper peptide loading onto the MHC class II molecule. To test this hypothesis, HFKs were infected with either control virus or a recombinant virus expressing HPV16 E5 and the infected cells were subsequently treated with interferon-γ. ELISAs revealed a decrease of MHC class II expression on the surface of E5-expressing cells compared with control virus-infected cells after interferon treatment. Western blot analysis showed that, in cells treated with interferon gamma, E5 could prevent the breakdown of Ii and block the formation of peptide-loaded, SDS-stable mature MHC class II dimers, correlating with diminished surface MHC class II expression. These data suggest that HPV16 E5 may be able to decrease immune recognition of infected keratinocytes via disruption of MHC class II protein function

  11. DMPD: Type I interferon [corrected] gene induction by the interferon regulatory factorfamily of transcription factors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16979567 Type I interferon [corrected] gene induction by the interferon regulatory factorfamily...ng) (.svg) (.html) (.csml) Show Type I interferon [corrected] gene induction by the interferon regulatory factorfamily...orrected] gene induction by the interferon regulatory factorfamily of transcription factors. Authors Honda K

  12. Type I interferon pathway in adult and juvenile dermatomyositis

    Science.gov (United States)

    2011-01-01

    Gene expression profiling and protein studies of the type I interferon pathway have revealed important insights into the disease process in adult and juvenile dermatomyositis. The most prominent and consistent feature has been a characteristic whole blood gene signature indicating upregulation of the type I interferon pathway. Upregulation of the type I interferon protein signature has added additional markers of disease activity and insight into the pathogenesis of the disease. PMID:22192711

  13. Severe Dermatomyositis Triggered by Interferon Beta-1a Therapy and Associated With Enhanced Type I Interferon Signaling

    Science.gov (United States)

    Somani, Ally-Khan; Swick, Alan R.; Cooper, Kevin D.; McCormick, Thomas S.

    2013-01-01

    Background Type I interferons (IFNs) are common therapeutics for several diseases, including viral infections and multiple sclerosis (MS). Although numerous studies have implicated type I INFs with the production of autoantibodies and the development of certain autoimmune disorders, interferon beta has not previously been described in association with dermatomyositis, to our knowledge. Previous microarray studies of muscle biopsy specimens from patients with dermatomyositis disclosed a type I IFN–induced gene expression profile. The central role of plasmacytoid dendritic cell precursors, together with increased type IIFN production, suggests a pivotal role for type I IFNs in dermatomyositis. We report a case of dermatomyositis exacerbated or induced by interferon beta therapy for MS and provide evidence that demonstrates enhanced type I IFN signaling in this patient. Observations We observed new-onset dermatomyositis in a 57-year-old patient treated with interferon beta for MS. His symptoms were exacerbated temporally by interferon beta injections. Immunohistochemical staining of skin biopsy specimens for myxovirus-resistance protein A (a surrogate marker for cutaneous type I IFN signaling) showed increased staining that correlated temporally with interferon beta treatment and subsequent disease activity. In vitro treatment with interferon beta of peripheral blood mononuclear cells isolated from our patient revealed enhanced type I IFN signaling assessed by interferon-induced gene expression profiles. Conclusions To our knowledge, this is the first description of dermatomyositis exacerbated or induced by interferon beta treatment. Our results demonstrate enhanced type I IFN signaling following interferon beta treatment in our patient with dermatomyositis. PMID:18936398

  14. Guarding the frontiers: the biology of type III interferons

    DEFF Research Database (Denmark)

    Wack, Andreas; Terczynska-Dyla, Ewa; Hartmann, Rune

    2015-01-01

    Type III interferons (IFNs) or IFN-λs regulate a similar set of genes as type I IFNs, but whereas type I IFNs act globally, IFN-λs primarily target mucosal epithelial cells and protect them against the frequent viral attacks that are typical for barrier tissues. IFN-λs thereby help to maintain he...

  15. Morbillivirus v proteins exhibit multiple mechanisms to block type 1 and type 2 interferon signalling pathways.

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    Senthil K Chinnakannan

    Full Text Available Morbilliviruses form a closely related group of pathogenic viruses which encode three non-structural proteins V, W and C in their P gene. Previous studies with rinderpest virus (RPV and measles virus (MeV have demonstrated that these non-structural proteins play a crucial role in blocking type I (IFNα/β and type II (IFNγ interferon action, and various mechanisms have been proposed for these effects. We have directly compared four important morbilliviruses, rinderpest (RPV, measles virus (MeV, peste des petits ruminants virus (PPRV and canine distemper virus (CDV. These viruses and their V proteins could all block type I IFN action. However, the viruses and their V proteins had varying abilities to block type II IFN action. The ability to block type II IFN-induced gene transcription correlated with co-precipitation of STAT1 with the respective V protein, but there was no correlation between co-precipitation of either STAT1 or STAT2 and the abilities of the V proteins to block type I IFN-induced gene transcription or the creation of the antiviral state. Further study revealed that the V proteins of RPV, MeV, PPRV and CDV could all interfere with phosphorylation of the interferon-receptor-associated kinase Tyk2, and the V protein of highly virulent RPV could also block the phosphorylation of another such kinase, Jak1. Co-precipitation studies showed that morbillivirus V proteins all form a complex containing Tyk2 and Jak1. This study highlights the ability of morbillivirus V proteins to target multiple components of the IFN signalling pathways to control both type I and type II IFN action.

  16. DMPD: Type I interferon receptors: biochemistry and biological functions. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17502368 Type I interferon receptors: biochemistry and biological functions. de Wee...(.html) (.csml) Show Type I interferon receptors: biochemistry and biological functions. PubmedID 17502368 T...itle Type I interferon receptors: biochemistry and biological functions. Authors

  17. Opposing roles for interferon regulatory factor-3 (IRF-3 and type I interferon signaling during plague.

    Directory of Open Access Journals (Sweden)

    Ami A Patel

    Full Text Available Type I interferons (IFN-I broadly control innate immunity and are typically transcriptionally induced by Interferon Regulatory Factors (IRFs following stimulation of pattern recognition receptors within the cytosol of host cells. For bacterial infection, IFN-I signaling can result in widely variant responses, in some cases contributing to the pathogenesis of disease while in others contributing to host defense. In this work, we addressed the role of type I IFN during Yersinia pestis infection in a murine model of septicemic plague. Transcription of IFN-β was induced in vitro and in vivo and contributed to pathogenesis. Mice lacking the IFN-I receptor, Ifnar, were less sensitive to disease and harbored more neutrophils in the later stage of infection which correlated with protection from lethality. In contrast, IRF-3, a transcription factor commonly involved in inducing IFN-β following bacterial infection, was not necessary for IFN production but instead contributed to host defense. In vitro, phagocytosis of Y. pestis by macrophages and neutrophils was more effective in the presence of IRF-3 and was not affected by IFN-β signaling. This activity correlated with limited bacterial growth in vivo in the presence of IRF-3. Together the data demonstrate that IRF-3 is able to activate pathways of innate immunity against bacterial infection that extend beyond regulation of IFN-β production.

  18. Interferon

    CERN Multimedia

    De Somer,P

    1975-01-01

    Le Prof.Pierre de Somer est né en Belgique et a fait ses études de médecine à l'Université de Louvin où il a obtenu en 1942 son diplôme. En 1961 il a été nommé professeur ordinaire d'hygiène et de microbiologie à cette même Université et depuis 1967 il est recteur de l'Université catholique flamande de Louvin, président de la société belge de microbiologie et expert de l'O.M.S. Il nous parle de l'interferon et de ses perspectives dans le traitement de maladies virales avec présentation des clichées.

  19. Borna disease virus nucleoprotein inhibits type I interferon induction through the interferon regulatory factor 7 pathway

    International Nuclear Information System (INIS)

    Song, Wuqi; Kao, Wenping; Zhai, Aixia; Qian, Jun; Li, Yujun; Zhang, Qingmeng; Zhao, Hong; Hu, Yunlong; Li, Hui; Zhang, Fengmin

    2013-01-01

    Highlights: •IRF7 nuclear localisation was inhibited by BDV persistently infected. •BDV N protein resistant to IFN induction both in BDV infected OL cell and N protein plasmid transfected OL cell. •BDV N protein is related to the inhibition of IRF7 nuclear localisation. -- Abstract: The expression of type I interferon (IFN) is one of the most potent innate defences against viral infection in higher vertebrates. Borna disease virus (BDV) establishes persistent, noncytolytic infections in animals and in cultured cells. Early studies have shown that the BDV phosphoprotein can inhibit the activation of type I IFN through the TBK1–IRF3 pathway. The function of the BDV nucleoprotein in the inhibition of IFN activity is not yet clear. In this study, we demonstrated IRF7 activation and increased IFN-α/β expression in a BDV-persistently infected human oligodendroglia cell line following RNA interference-mediated BDV nucleoprotein silencing. Furthermore, we showed that BDV nucleoprotein prevented the nuclear localisation of IRF7 and inhibited endogenous IFN induction by poly(I:C), coxsackie virus B3 and IFN-β. Our findings provide evidence for a previously undescribed mechanism by which the BDV nucleoprotein inhibits type I IFN expression by interfering with the IRF7 pathway

  20. Borna disease virus nucleoprotein inhibits type I interferon induction through the interferon regulatory factor 7 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Song, Wuqi [The Heilongjiang Key Laboratory of Immunity and Infection, Heilongjiang (China); Department of Microbiology, Harbin Medical University (China); Kao, Wenping [The Key Laboratory of Pathogenic Biology, Heilongjiang Higher Education Institutions (China); Department of Microbiology, Harbin Medical University (China); Zhai, Aixia [The Heilongjiang Key Laboratory of Immunity and Infection, Heilongjiang (China); Qian, Jun; Li, Yujun [The Key Laboratory of Pathogenic Biology, Heilongjiang Higher Education Institutions (China); Zhang, Qingmeng [The Heilongjiang Key Laboratory of Immunity and Infection, Heilongjiang (China); Zhao, Hong; Hu, Yunlong; Li, Hui [Department of Microbiology, Harbin Medical University (China); Zhang, Fengmin, E-mail: fengminzhang@ems.hrbmu.edu.cn [The Heilongjiang Key Laboratory of Immunity and Infection, Heilongjiang (China); The Key Laboratory of Pathogenic Biology, Heilongjiang Higher Education Institutions (China); Department of Microbiology, Harbin Medical University (China)

    2013-09-06

    Highlights: •IRF7 nuclear localisation was inhibited by BDV persistently infected. •BDV N protein resistant to IFN induction both in BDV infected OL cell and N protein plasmid transfected OL cell. •BDV N protein is related to the inhibition of IRF7 nuclear localisation. -- Abstract: The expression of type I interferon (IFN) is one of the most potent innate defences against viral infection in higher vertebrates. Borna disease virus (BDV) establishes persistent, noncytolytic infections in animals and in cultured cells. Early studies have shown that the BDV phosphoprotein can inhibit the activation of type I IFN through the TBK1–IRF3 pathway. The function of the BDV nucleoprotein in the inhibition of IFN activity is not yet clear. In this study, we demonstrated IRF7 activation and increased IFN-α/β expression in a BDV-persistently infected human oligodendroglia cell line following RNA interference-mediated BDV nucleoprotein silencing. Furthermore, we showed that BDV nucleoprotein prevented the nuclear localisation of IRF7 and inhibited endogenous IFN induction by poly(I:C), coxsackie virus B3 and IFN-β. Our findings provide evidence for a previously undescribed mechanism by which the BDV nucleoprotein inhibits type I IFN expression by interfering with the IRF7 pathway.

  1. Antiviral Type I and Type III Interferon Responses in the Central Nervous System

    Science.gov (United States)

    Sorgeloos, Frédéric; Kreit, Marguerite; Hermant, Pascale; Lardinois, Cécile; Michiels, Thomas

    2013-01-01

    The central nervous system (CNS) harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB) from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs) are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i) preventing neuroinvasion and infection of CNS cells; ii) the identity of IFN-producing cells in the CNS; iii) the antiviral activity of ISGs; and iv) the activity of viral proteins of neurotropic viruses that target the IFN pathway. PMID:23503326

  2. Antiviral Type I and Type III Interferon Responses in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Thomas Michiels

    2013-03-01

    Full Text Available The central nervous system (CNS harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i preventing neuroinvasion and infection of CNS cells; ii the identity of IFN-producing cells in the CNS; iii the antiviral activity of ISGs; and iv the activity of viral proteins of neurotropic viruses that target the IFN pathway.

  3. Antiviral type I and type III interferon responses in the central nervous system.

    Science.gov (United States)

    Sorgeloos, Frédéric; Kreit, Marguerite; Hermant, Pascale; Lardinois, Cécile; Michiels, Thomas

    2013-03-15

    The central nervous system (CNS) harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB) from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs) are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i) preventing neuroinvasion and infection of CNS cells; ii) the identity of IFN-producing cells in the CNS; iii) the antiviral activity of ISGs; and iv) the activity of viral proteins of neurotropic viruses that target the IFN pathway.

  4. Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation

    Directory of Open Access Journals (Sweden)

    Alecia Seliga

    2018-02-01

    Full Text Available The Kallikrein–Kinin System (KKS, comprised of kallikreins (klks, bradykinins (BKs angiotensin-converting enzyme (ACE, and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand, R848 (TLR7 ligand, or recombinant IFN-α to induce interferon-stimulated genes (ISGs and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein, or captopril (an ACE inhibitor. BKs significantly decreased the ISGs induced by TLRs in vitro and in vivo (in normal and lupus-prone mice, and in human PBMCs, especially the induction of Irf7 gene (p < 0.05, the master regulator of Type I IFNs. ISGs induced by IFN-α were also suppressed by the KKS. MHC Class I upregulation, a classic response to Type I IFNs, was reduced by BKs in murine dendritic cells (DCs. BKs decreased phosphorylation of STAT2 molecules that mediate IFN signaling. Among the secreted pro-inflammatory cytokines/chemokines analyzed (IL-6, IL12p70, and CXCL10, the strongest suppressive effect was on CXCL10, a highly Type I IFN-dependent cytokine, upon CpG stimulation, both in normal and lupus-prone DCs. klks that break down into BKs, also suppressed CpG-induced ISGs in murine DCs. Captopril, a drug that inhibits ACE and increases BK, suppressed ISGs, both in mouse DCs and human PBMCs. The effects of BK were reversed with indomethacin (compound that inhibits production of PGE2, suggesting that BK suppression of IFN responses may be mediated via prostaglandins. These results highlight a novel regulatory mechanism in which members of the KKS control the Type I IFN response and suggest a role for modulators of IFNs in the pathogenesis of lupus and interferonopathies.

  5. The Peculiar Characteristics of Fish Type I Interferons

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    Pierre Boudinot

    2016-11-01

    Full Text Available Antiviral type I interferons (IFNs have been discovered in fish. Genomic studies revealed their considerable number in many species; some genes encode secreted and non-secreted isoforms. Based on cysteine motifs, fish type I IFNs fall in two subgroups, which use two different receptors. Mammalian type I IFN genes are intronless while type III have introns; in fish, all have introns, but structurally, both subgroups belong to type I. Type I IFNs likely appeared early in vertebrates as intron containing genes, and evolved in parallel in tetrapods and fishes. The diversity of their repertoires in fish and mammals is likely a convergent feature, selected as a response to the variety of viral strategies. Several alternative nomenclatures have been established for different taxonomic fish groups, calling for a unified system. The specific functions of each type I gene remains poorly understood, as well as their interactions in antiviral responses. However, distinct induction pathways, kinetics of response, and tissue specificity indicate that fish type I likely are highly specialized, especially in groups where they are numerous such as salmonids or cyprinids. Unravelling their functional integration constitutes the next challenge to understand how these cytokines evolved to orchestrate antiviral innate immunity in vertebrates.

  6. Type I Interferon in Chronic Virus Infection and Cancer.

    Science.gov (United States)

    Snell, Laura M; McGaha, Tracy L; Brooks, David G

    2017-08-01

    Type I interferons (IFN-Is) are emerging as key drivers of inflammation and immunosuppression in chronic infection. Control of these infections requires IFN-I signaling; however, prolonged IFN-I signaling can lead to immune dysfunction. IFN-Is are also emerging as double-edged swords in cancer, providing necessary inflammatory signals, while initiating feedback suppression in both immune and cancer cells. Here, we review the proinflammatory and suppressive mechanisms potentiated by IFN-Is during chronic virus infections and discuss the similar, newly emerging dichotomy in cancer. We then discuss how this understanding is leading to new therapeutic concepts and immunotherapy combinations. We propose that, by modulating the immune response at its foundation, it may be possible to widely reshape immunity to control these chronic diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Endometriosis and Type I Interferon & Characterization of a Mammalian Flippase

    DEFF Research Database (Denmark)

    Vestergaard, Anna Lindeløv

    2010-01-01

    Endometriosis and Type I Interferon   Endometriosis is a painful chronic disease in which endometrium-like lesions are located ectopically, frequently in the pelvic cavity but also in more distant sites. The pathogenesis of endometriosis is unclear and involves complex hormonal, genetic......) and in eutopic endometrium (Eu) and ectopic endometriosis lesions (Ec) of women with endometriosis. The four genes BST2, COL16A1, ISG20 and HOXB2 appeared significantly differentially regulated between the groups. However, after a thorough investigation of appropriate reference genes for normalization......, validation by qRT-PCR confirmed only that ISG20 and HOXB2 were significantly downregulated in the Ec group compared with the Eu and C groups. BST2 and COL16A1, as well as the highly IFN-stimulated genes ISG12A and 6-16, displayed merely insignificant variation between the groups. Endometriosis displays...

  8. Type I Interferon in the Pathogenesis of Lupus

    Science.gov (United States)

    Crow, Mary K.

    2014-01-01

    Investigations of patients with systemic lupus erythematosus (SLE) have applied insights from studies of the innate immune response to define type I interferon (IFN-I), with IFN-α the dominant mediator, as central to the pathogenesis of this prototype systemic autoimmune disease. Genetic association data identify regulators of nucleic acid degradation and components of TLR-independent, endosomal TLR-dependent, and IFN-I signaling pathways as contributors to lupus disease susceptibility. Together with a gene expression signature characterized by IFNI-induced gene transcripts in lupus blood and tissue, those data support the conclusion that many of the immunologic and pathologic features of this disease are a consequence of a persistent self-directed immune reaction driven by IFN-I and mimicking a sustained anti-virus response. This expanding knowledge of the role of IFN-I and the innate immune response suggests candidate therapeutic targets that are being tested in lupus patients. PMID:24907379

  9. DMPD: Signalling pathways mediating type I interferon gene expression. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17904888 Signalling pathways mediating type I interferon gene expression. Edwards M...hways mediating type I interferon gene expression. PubmedID 17904888 Title Signalling pathways...R, Slater L, Johnston SL. Microbes Infect. 2007 Sep;9(11):1245-51. Epub 2007 Jul 1. (.png) (.svg) (.html) (.csml) Show Signalling pat

  10. Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension

    Science.gov (United States)

    George, Peter M.; Oliver, Eduardo; Dorfmuller, Peter; Dubois, Olivier D.; Reed, Daniel M.; Kirkby, Nicholas S.; Mohamed, Nura A.; Perros, Frederic; Antigny, Fabrice; Fadel, Elie; Schreiber, Benjamin E.; Holmes, Alan M.; Southwood, Mark; Hagan, Guy; Wort, Stephen J.; Bartlett, Nathan; Morrell, Nicholas W.; Coghlan, John G.; Humbert, Marc; Zhao, Lan; Mitchell, Jane A.

    2014-01-01

    Rationale Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognized at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted. Objective To explore the role of type I IFN in PAH. Methods and Results Cells were cultured using standard approaches. Cytokines were measured by ELISA. Gene and protein expression were measured using reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knockout (IFNAR1−/−) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II, and III IFN levels were elevated in serum of patients with systemic sclerosis associated PAH. Serum interferon γ inducible protein 10 (IP10; CXCL10) and endothelin 1 were raised and strongly correlated together. IP10 correlated positively with pulmonary hemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1−/− mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum endothelin 1 levels. Conclusions These data indicate that type I IFN, via an action of IFNAR1, mediates PAH. PMID:24334027

  11. Neuromyelitis optica-like pathology is dependent on type I interferon response

    DEFF Research Database (Denmark)

    Khorooshi, Reza; Wlodarczyk, Agnieszka; Asgari, Nasrin

    2013-01-01

    Neuromyelitis optica is an antibody-mediated autoimmune inflammatory disease of the central nervous system. Reports have suggested that interferon beta which is beneficial for multiple sclerosis, exacerbates neuromyelitis optica. Our aim was to determine whether type I interferon plays a role in ...

  12. Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling

    International Nuclear Information System (INIS)

    Johnson, Karen E.; Song, Byeongwoon; Knipe, David M.

    2008-01-01

    Host cells respond to viral infection by many mechanisms, including the production of type I interferons which act in a paracrine and autocrine manner to induce the expression of antiviral interferon-stimulated genes (ISGs). Viruses have evolved means to inhibit interferon signaling to avoid induction of the innate immune response. Herpes simplex virus 1 (HSV-1) has several mechanisms to inhibit type I interferon production, the activities of ISGs, and the interferon signaling pathway itself. We report that the inhibition of the Jak/STAT pathway by HSV-1 requires viral gene expression and that viral immediate-early protein ICP27 plays a role in downregulating STAT-1 phosphorylation and in preventing the accumulation of STAT-1 in the nucleus. We also show that expression of ICP27 by transfection causes an inhibition of IFN-induced STAT-1 nuclear accumulation. Therefore, ICP27 is necessary and sufficient for at least some of the effects of HSV infection on STAT-1

  13. Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling.

    Directory of Open Access Journals (Sweden)

    In Ah Park

    Full Text Available Tumor-infiltrating lymphocytes (TILs have been known for their strong prognostic and predictive significance in triple-negative breast cancer (TNBC. Several mechanisms for TIL influx in TNBC have been elucidated. Major histocompatibility complex class II (MHC-II is an essential component of the adaptive immune system and is generally restricted to the surface of antigen-presenting cells. However, it has been reported that interferon-gamma signaling may induce MHC-II in almost all cell types, including those derived from cancer. We aimed to examine the relationship between MHC-II expression in tumor cells and the amount of TILs in 681 patients with TNBC. Further, the prognostic significance of MHC-II and the association of MHC-II with a couple of molecules involved in the interferon signaling pathway were investigated using immunohistochemical staining. Higher MHC-II expression in tumor cells was associated with the absence of lymphovascular invasion (p = 0.042; larger amounts of TILs (p < 0.001; frequent formations of tertiary lymphoid structures (p < 0.001; higher expression of myxovirus resistance gene A, one of the main mediators of the interferon signaling pathway (p < 0.001; and higher expression of double-stranded RNA-activated protein kinase, which can be induced by interferons (p = 0.008. Moreover, tumors that showed high MHC class I expression and any positivity for MHC-II had larger amounts of CD4- and CD8-positive T lymphocytes (p < 0.001. Positive MHC-II expression in tumor cells was associated with better disease-free survival in patients who had lymph node metastasis (p = 0.009. In conclusion, MHC-II expression in tumor cells was closely associated with an increase in TIL number and interferon signaling in TNBC. Further studies are warranted to improve our understanding regarding TIL influx, as well as patients' responses to immunotherapy.

  14. Activation of type III interferon genes by pathogenic bacteria in infected epithelial cells and mouse placenta.

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    Hélène Bierne

    Full Text Available Bacterial infections trigger the expression of type I and II interferon genes but little is known about their effect on type III interferon (IFN-λ genes, whose products play important roles in epithelial innate immunity against viruses. Here, we studied the expression of IFN-λ genes in cultured human epithelial cells infected with different pathogenic bacteria and in the mouse placenta infected with Listeria monocytogenes. We first showed that in intestinal LoVo cells, induction of IFN-λ genes by L. monocytogenes required bacterial entry and increased further during the bacterial intracellular phase of infection. Other Gram-positive bacteria, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis, also induced IFN-λ genes when internalized by LoVo cells. In contrast, Gram-negative bacteria Salmonella enterica serovar Typhimurium, Shigella flexneri and Chlamydia trachomatis did not substantially induce IFN-λ. We also found that IFN-λ genes were up-regulated in A549 lung epithelial cells infected with Mycobacterium tuberculosis and in HepG2 hepatocytes and BeWo trophoblastic cells infected with L. monocytogenes. In a humanized mouse line permissive to fetoplacental listeriosis, IFN-λ2/λ3 mRNA levels were enhanced in placentas infected with L. monocytogenes. In addition, the feto-placental tissue was responsive to IFN-λ2. Together, these results suggest that IFN-λ may be an important modulator of the immune response to Gram-positive intracellular bacteria in epithelial tissues.

  15. Interferon-free treatment for hepatitis C virus infection induces normalization of extrahepatic type I interferon signaling.

    Science.gov (United States)

    Sung, Pil Soo; Lee, Eun Byul; Park, Dong Jun; Lozada, Angelo; Jang, Jeong Won; Bae, Si Hyun; Choi, Jong Young; Yoon, Seung Kew

    2018-03-12

    Hepatitis C virus (HCV) replicates in the peripheral blood mononuclear cells (PBMCs), leading to the production of type I interferons (IFNs). It is well known that the gene expression profile of PBMC is similar to that of the liver. The present study explored the dynamic gene expression profile of PBMCs collected from HCV-infected patients undergoing direct-acting antiviral (DAA) therapy. A prospective cohort comprising 27 patients under DAA therapy was formed. Expression level of IFN-β and its downstream interferon-stimulated genes (ISGs) was measured in PBMCs before and after DAA treatment. Furthermore, immunoblotting was performed to identify the signaling molecules involved in the expression of ISGs. The pretreatment expression level of interferon-induced protein 44 (IFI44) and C-X-C motif chemokine ligand 10 (CXCL10) correlated with the pretreatment expression level of IFN-β. After DAA treatment, a significant decrease in the expression levels of IFN-β, IFI44, and CXCL10 was observed in the PBMCs. Furthermore, the pretreatment expression level of IFN-β and ISGs correlated with the level of signal transducer and activator of transcription 1 (STAT1) phosphorylation, and DAA treatment abrogated STAT1 phosphorylation. Pretreatment activation of IFN-β response is rapidly normalized after DAA treatment. The present study suggests that the decreased type I IFN response by the clearance of HCV might contribute to DAA-induced alleviation of extrahepatic manifestation of chronic HCV infection.

  16. TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis.

    Science.gov (United States)

    Conrad, Curdin; Di Domizio, Jeremy; Mylonas, Alessio; Belkhodja, Cyrine; Demaria, Olivier; Navarini, Alexander A; Lapointe, Anne-Karine; French, Lars E; Vernez, Maxime; Gilliet, Michel

    2018-01-02

    Although anti-tumor necrosis factor (TNF) agents are highly effective in the treatment of psoriasis, 2-5% of treated patients develop psoriasis-like skin lesions called paradoxical psoriasis. The pathogenesis of this side effect and its distinction from classical psoriasis remain unknown. Here we show that skin lesions from patients with paradoxical psoriasis are characterized by a selective overexpression of type I interferons, dermal accumulation of plasmacytoid dendritic cells (pDC), and reduced T-cell numbers, when compared to classical psoriasis. Anti-TNF treatment prolongs type I interferon production by pDCs through inhibition of their maturation. The resulting type I interferon overexpression is responsible for the skin phenotype of paradoxical psoriasis, which, unlike classical psoriasis, is independent of T cells. These findings indicate that paradoxical psoriasis represents an ongoing overactive innate inflammatory process, driven by pDC-derived type I interferon that does not lead to T-cell autoimmunity.

  17. Inhibition of type I interferon induction and signalling by mosquito-borne flaviviruses.

    Science.gov (United States)

    Cumberworth, Stephanie L; Clark, Jordan J; Kohl, Alain; Donald, Claire L

    2017-05-01

    The Flavivirus genus (Flaviviridae family) contains a number of important human pathogens, including dengue and Zika viruses, which have the potential to cause severe disease. In order to efficiently establish a productive infection in mammalian cells, flaviviruses have developed key strategies to counteract host immune defences, including the type I interferon response. They employ different mechanisms to control interferon signal transduction and effector pathways, and key research generated over the past couple of decades has uncovered new insights into their abilities to actively decrease interferon antiviral activity. Given the lack of antivirals or prophylactic treatments for many flaviviral infections, it is important to fully understand how these viruses affect cellular processes to influence pathogenesis and disease outcome. This review will discuss the strategies mosquito-borne flaviviruses have evolved to antagonise type I interferon mediated immune responses. © 2017 The Authors Cellular Microbiology Published by John Wiley & Sons Ltd.

  18. TYPE I INTERFERON REGULATES THE EXPRESSION OF LONG NONCODING RNAs

    Directory of Open Access Journals (Sweden)

    Elena eCarnero

    2014-11-01

    Full Text Available Interferons (IFNs are key players in the antiviral response. IFN sensing by the cell activates transcription of IFN-stimulated genes (ISGs able to induce an antiviral state by affecting viral replication and release. IFN also induces the expression of ISGs that function as negative regulators to limit the strength and duration of IFN response. The ISGs identified so far belong to coding genes. However, only a small proportion of the transcriptome corresponds to coding transcripts and it has been estimated that there could be as many coding as long noncoding RNAs (lncRNAs. To address whether IFN can also regulate the expression of lncRNAs, we analyzed the transcriptome of HuH7 cells treated or not with IFNα2 by expression arrays. Analysis of the arrays showed increased levels of several well-characterized coding genes that respond to IFN both at early or late times. Furthermore, we identified several IFN-stimulated or -downregulated lncRNAs (ISRs and IDRs. Further validation showed that ISR2, 8 and 12 expression mimics that of their neighboring genes GBP1, IRF1 and IL6, respectively, all related to the IFN response. These genes are induced in response to different doses of IFNα2 in different cell lines at early (ISR2 or 8 or later (ISR12 time points. IFNβ also induced the expression of these lncRNAs. ISR2 and 8 were also induced by an influenza virus unable to block the IFN response but not by other wild-type lytic viruses tested. Surprisingly, both ISR2 and 8 were significantly upregulated in cultured cells and livers from patients infected with HCV. Increased levels of ISR2 were also detected in patients chronically infected with HIV. This is relevant as genome-wide guilt-by-association studies predict that ISR2, 8 and 12 may function in viral processes, in the IFN pathway and the antiviral response. Therefore, we propose that these lncRNAs could be induced by IFN to function as positive or negative regulators of the antiviral response.

  19. Delayed polarization of mononuclear phagocyte transcriptional program by type I interferon isoforms

    Directory of Open Access Journals (Sweden)

    Wang Ena

    2005-06-01

    Full Text Available Abstract Background Interferon (IFN-α is considered a key modulator of immunopathological processes through a signature-specific activation of mononuclear phagocytes (MPs. This study utilized global transcript analysis to characterize the effects of the entire type I IFN family in comparison to a broad panel of other cytokines on MP previously exposed to Lipopolysaccharide (LPS stimulation in vitro. Results Immature peripheral blood CD14+ MPs were stimulated with LPS and 1 hour later with 42 separate soluble factors including cytokines, chemokines, interleukins, growth factors and IFNs. Gene expression profiling of MPs was analyzed 4 and 9 hours after cytokine stimulation. Four hours after stimulation, the transcriptional analysis of MPs revealed two main classes of cytokines: one associated with the alternative and the other with the classical pathway of MP activation without a clear polarization of type I IFNs effects. In contrast, after 9 hours of stimulation most type I IFN isoforms induced a characteristic and unique transcriptional pattern separate from other cytokines. These "signature" IFNs included; IFN-β, IFN-α2b/α2, IFN-αI, IFN-α2, IFN-αC, IFN-αJ1, IFN-αH2, and INF-α4B and induced the over-expression of 44 genes, all of which had known functional relationships with IFN such as myxovirus resistance (Mx-1, Mx-2, and interferon-induced hepatitis C-associated microtubular aggregation protein. A second group of type I IFNs segregated separately and in closer association with the type II IFN-γ. The phylogenetic relationship of amino acid sequences among type I IFNs did not explain their sub-classification, although differences at positions 94 through 109 and 175 through 189 were present between the signature and other IFNs. Conclusion Seven IFN-α isoforms and IFN-β participate in the late phase polarization of MPs conditioned by LPS. This information broadens the previous view of the central role played by IFN-α in

  20. DNA polymerase-α regulates type I interferon activation through cytosolic RNA:DNA synthesis

    Science.gov (United States)

    Starokadomskyy, Petro; Gemelli, Terry; Rios, Jonathan J.; Xing, Chao; Wang, Richard C.; Li, Haiying; Pokatayev, Vladislav; Dozmorov, Igor; Khan, Shaheen; Miyata, Naoteru; Fraile, Guadalupe; Raj, Prithvi; Xu, Zhe; Xu, Zigang; Ma, Lin; Lin, Zhimiao; Wang, Huijun; Yang, Yong; Ben-Amitai, Dan; Orenstein, Naama; Mussaffi, Huda; Baselga, Eulalia; Tadini, Gianluca; Grunebaum, Eyal; Sarajlija, Adrijan; Krzewski, Konrad; Wakeland, Edward K.; Yan, Nan; de la Morena, Maria Teresa; Zinn, Andrew R.; Burstein, Ezra

    2016-01-01

    Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations disrupting nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts expression of POLA1, the gene encoding the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency results in increased type I interferon production. This enzyme is necessary for RNA:DNA primer synthesis during DNA replication and strikingly, POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Altogether, this work identified POLA1 as a critical regulator of the type I interferon response. PMID:27019227

  1. Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling.

    Science.gov (United States)

    Park, In Ah; Hwang, Seong-Hye; Song, In Hye; Heo, Sun-Hee; Kim, Young-Ae; Bang, Won Seon; Park, Hye Seon; Lee, Miseon; Gong, Gyungyub; Lee, Hee Jin

    2017-01-01

    Tumor-infiltrating lymphocytes (TILs) have been known for their strong prognostic and predictive significance in triple-negative breast cancer (TNBC). Several mechanisms for TIL influx in TNBC have been elucidated. Major histocompatibility complex class II (MHC-II) is an essential component of the adaptive immune system and is generally restricted to the surface of antigen-presenting cells. However, it has been reported that interferon-gamma signaling may induce MHC-II in almost all cell types, including those derived from cancer. We aimed to examine the relationship between MHC-II expression in tumor cells and the amount of TILs in 681 patients with TNBC. Further, the prognostic significance of MHC-II and the association of MHC-II with a couple of molecules involved in the interferon signaling pathway were investigated using immunohistochemical staining. Higher MHC-II expression in tumor cells was associated with the absence of lymphovascular invasion (p = 0.042); larger amounts of TILs (p MHC class I expression and any positivity for MHC-II had larger amounts of CD4- and CD8-positive T lymphocytes (p MHC-II expression in tumor cells was associated with better disease-free survival in patients who had lymph node metastasis (p = 0.009). In conclusion, MHC-II expression in tumor cells was closely associated with an increase in TIL number and interferon signaling in TNBC. Further studies are warranted to improve our understanding regarding TIL influx, as well as patients' responses to immunotherapy.

  2. Mucopolysaccharidosis type II

    Science.gov (United States)

    Genetic counseling is recommended for couples who want to have children and who have a family history of MPS II. Prenatal testing is available. Carrier testing for female relatives of affected males is available at a few centers.

  3. Antagonism of type I interferon responses by new world hantaviruses.

    Science.gov (United States)

    Levine, Jessica R; Prescott, Joseph; Brown, Kyle S; Best, Sonja M; Ebihara, Hideki; Feldmann, Heinz

    2010-11-01

    Evasion of interferon (IFN)-mediated antiviral signaling is a common defense strategy for pathogenic RNA viruses. To date, research on IFN antagonism by hantaviruses is limited and has focused on only a subset of the numerous recognized hantavirus species. The host IFN response has two phases, an initiation phase, resulting in the induction of alpha/beta IFN (IFN-α/β), and an amplification phase, whereby IFN-α/β signals through the Jak/STAT pathway, resulting in the establishment of the cellular antiviral state. We examined interactions between these critical host responses and the New World hantaviruses. We observed delayed cellular responses in both Andes virus (ANDV)- and Sin Nombre virus (SNV)-infected A549 and Huh7-TLR3 cells. We found that IFN-β induction is inhibited by coexpression of ANDV nucleocapsid protein (NP) and glycoprotein precursor (GPC) and is robustly inhibited by SNV GPC alone. Downstream amplification by Jak/STAT signaling is also inhibited by SNV GPC and by either NP or GPC of ANDV. Therefore, ANDV- and SNV-encoded proteins have the potential for inhibiting both IFN-β induction and signaling, with SNV exhibiting the more potent antagonism ability. Herein we identify ANDV NP, a previously unrecognized inhibitor of Jak/STAT signaling, and show that IFN antagonism by ANDV relies on expression of both the glycoproteins and NP, whereas the glycoproteins appear to be sufficient for antagonism by SNV. These data suggest that IFN antagonism strategies by hantaviruses are quite variable, even between species with similar disease phenotypes, and may help to better elucidate species-specific pathogenesis.

  4. A type I interferon signature characterizes chronic antibody-mediated rejection in kidney transplantation.

    Science.gov (United States)

    Rascio, Federica; Pontrelli, Paola; Accetturo, Matteo; Oranger, Annarita; Gigante, Margherita; Castellano, Giuseppe; Gigante, Maddalena; Zito, Anna; Zaza, Gianluigi; Lupo, Antonio; Ranieri, Elena; Stallone, Giovanni; Gesualdo, Loreto; Grandaliano, Giuseppe

    2015-09-01

    Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss. To uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of peripheral blood mononuclear cells (PBMCs) and, separately, of CD4(+) T lymphocytes isolated from CAMR patients, compared to kidney transplant recipients with normal graft function and histology. We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls), and 8 transplant recipients with clinical and histological evidence of interstitial fibrosis/tubular atrophy. Messenger RNA and microRNA profiling of PBMCs and CD4(+) T lymphocytes was performed using Agilent microarrays in eight randomly selected patients per group from CAMR and control subjects. Results were evaluated statistically and by functional pathway analysis (Ingenuity Pathway Analysis) and validated in the remaining subjects. In PBMCs, 45 genes were differentially expressed between the two groups, most of which were up-regulated in CAMR and were involved in type I interferon signalling. In the same patients, 16 microRNAs were down-regulated in CAMR subjects compared to controls: four were predicted modulators of six mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signalling. To further confirm this result, we investigated the transcriptomic profiles of CD4(+) T lymphocytes in an independent group of patients, observing that the activation of type I interferon signalling was a specific hallmark of CAMR. In addition, in CAMR patients, we detected a reduction of circulating BDCA2(+) dendritic cells, the natural type I interferon-producing cells, and their recruitment into the graft along with increased expression of MXA, a type I interferon-induced protein, at the tubulointerstitial and vascular level. Finally, interferon alpha mRNA expression was significantly increased in CAMR compared to control

  5. Identification, Characterization, and Developmental Expression Pattern of Type III Interferon Receptor Gene in the Chinese Goose

    Directory of Open Access Journals (Sweden)

    Qin Zhou

    2015-01-01

    Full Text Available Interferons, as the first line of defense against the viral infection, play an important role in innate immune responses. Type III interferon (IFN-λ was a newly identified member of IFN family, which plays IFN-like antiviral activity. Towards a better understanding of the type III interferon system in birds, type III interferon lambda receptor (IFNLR1 was first identified in the Chinese goose. In this paper, we had cloned 1952 bp for goose IFNLR1 (goIFNLR1, including an ORF of 1539 bp, encoding a 512-amino acid protein with a 20 aa predict signal peptide at its N terminal and a 23 aa transmembrane region. The predicted amino acid sequence of goIFNLR1 has 90%, 73%, and 34% identity with duck IFNLR1 (predicted sequence, chicken IFNLR1, and human IFNLR1, respectively. And the age-related tissue distribution of goIFNLR1 was identified by Real Time quantitative PCR (RT-qPCR, we found that the goIFNLR1 has a mainly expression in epithelium-rich tissues similar to other species’, such as small intestinal, lung, liver, and stomach. Moreover, a relatively high expression of goIFNLR1 was also observed in the secondary immune tissues (harderian gland and cecal tonsil. The identification and tissue distribution of goIFNLR1 will facilitate further study of the role of IFN-λ in goose antiviral defense.

  6. Type I Interferons Induce T Regulatory 1 Responses and Restrict Humoral Immunity during Experimental Malaria.

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    Ryan A Zander

    2016-10-01

    Full Text Available CD4 T cell-dependent antibody responses are essential for limiting Plasmodium parasite replication and the severity of malaria; however, the factors that regulate humoral immunity during highly inflammatory, Th1-biased systemic infections are poorly understood. Using genetic and biochemical approaches, we show that Plasmodium infection-induced type I interferons limit T follicular helper accumulation and constrain anti-malarial humoral immunity. Mechanistically we show that CD4 T cell-intrinsic type I interferon signaling induces T-bet and Blimp-1 expression, thereby promoting T regulatory 1 responses. We further show that the secreted effector cytokines of T regulatory 1 cells, IL-10 and IFN-γ, collaborate to restrict T follicular helper accumulation, limit parasite-specific antibody responses, and diminish parasite control. This circuit of interferon-mediated Blimp-1 induction is also operational during chronic virus infection and can occur independently of IL-2 signaling. Thus, type I interferon-mediated induction of Blimp-1 and subsequent expansion of T regulatory 1 cells represent generalizable features of systemic, inflammatory Th1-biased viral and parasitic infections that are associated with suppression of humoral immunity.

  7. The tiers and dimensions of evasion of the type I interferon response by human cytomegalovirus.

    Science.gov (United States)

    Amsler, Lisi; Verweij, Marieke; DeFilippis, Victor R

    2013-12-13

    Human cytomegalovirus (HCMV) is a member of the β-herpesvirus family that invariably occupies hosts for life despite a consistent multi-pronged antiviral immune response that targets the infection. This persistence is enabled by the large viral genome that encodes factors conferring a wide assortment of sophisticated, often redundant phenotypes that disable or otherwise manipulate impactful immune effector processes. The type I interferon system represents a first line of host defense against infecting viruses. The physiological reactions induced by secreted interferon act to effectively block replication of a broad spectrum of virus types, including HCMV. As such, the virus must exhibit counteractive mechanisms to these responses that involve their inhibition, tolerance, or re-purposing. The goal of this review is to describe the impact of the type I interferon system on HCMV replication and to showcase the number and diversity of strategies employed by the virus that allow infection of hosts in the presence of interferon-dependent activity. © 2013.

  8. Simvastatin inhibits interferon-γ-induced MHC class II up-regulation in cultured astrocytes

    Directory of Open Access Journals (Sweden)

    Glazenburg Lisa

    2006-07-01

    Full Text Available Abstract Based on their potent anti-inflammatory properties and a preliminary clinical trial, statins (HMG-CoA reductase inhibitors are being studied as possible candidates for multiple sclerosis (MS therapy. The pathogenesis of MS is unclear. One theory suggests that the development of autoimmune lesions in the central nervous system may be due to a failure of endogenous inhibitory control of MHC class II expression on astrocytes, allowing these cells to adapt an interferon (IFN-γ-induced antigen presenting phenotype. By using immunocytochemistry in cultured astrocytes derived from newborn Wistar rats we found that simvastatin at nanomolar concentrations inhibited, in a dose-response fashion, up to 70% of IFN-γ-induced MHC class II expression. This effect was reversed by the HMG-CoA reductase product mevalonate. Suppression of the antigen presenting function of astrocytes might contribute to the beneficial effects of statins in MS.

  9. Intrahepatic expression of interferon alpha & interferon alpha ...

    African Journals Online (AJOL)

    kemrilib

    Alpha m-RNA while 30% only expressed Interferon Alpha Receptor m-RNA. Responders and non-responders to Interferon therapy ... expression of IFN Alpha Receptor mRNA. Regardless of the response to interferon, histological .... generation reverse hybridisation, line probe assay. (Inno-LiPA HCV II; Innogenetics, Ghent,.

  10. Immune- and miRNA-response to recombinant interferon beta-1a: a biomarker evaluation study to guide the development of novel type I interferon- based therapies.

    Science.gov (United States)

    Coenen, Martin; Hinze, Annette Viktoria; Mengel, Martin; Fuhrmann, Christine; Lüdenbach, Bastian; Zimmermann, Julian; Dykstra, Verena; Fimmers, Rolf; Viviani, Roberto; Stingl, Julia; Holdenrieder, Stefan; Müller, Marcus; Hartmann, Gunther; Coch, Christoph

    2015-09-22

    The innate immune receptor RIG-I detects viral RNA within the cytosol of infected cells. Activation of RIG-I leads to the induction of antiviral cytokines, in particular type I interferon, the inhibition of a T(H)17 response as well as to the suppression of tumor growth. Therefore, RIG-I is a promising drug target for the treatment of cancer as well as multiple sclerosis. A specific ligand for RIG-I is currently in preclinical testing. The first-in-human trial will need to be carefully designed to avoid an overshooting cytokine response. Therefore, the ResI study was set up to analyze the human immune response to standard treatment with recombinant interferon-beta to establish biomarkers for safety and efficacy of the upcoming first-in-human trial investigating the RIG-I ligand. ResI is a single center, prospective, open label, non-randomized phase I clinical trial. Three different cohorts (20 healthy volunteers, 20 patients with RRMS and ongoing interferon-beta treatment and 10 patients starting on interferon-beta) will receive standard interferon-beta-1a therapy for nine days. The study will be conducted according to the principles of the german medicinal products act, ICH-GCP, and the Declaration of Helsinki on the phase I unit of the Institute of Clinical Chemistry and Clinical Pharmacology and in the Department of Neurology, both University Hospital Bonn. Interferon-beta-induced cytokine levels, surface marker on immune cells, mRNA- and miRNA-expression as well as psychometric response will be investigated as target variables. The ResI study will assess biomarkers in response to interferon-β treatment to guide the dose steps within the first-in-human trial with a newly developed RIG-I ligand. Thus, ResI is a biomarker study to enhance the safety of the clinical development of a first-in-class compound. The data can additionally be used for the development of other therapies based on type I interferon induction such as TLR ligands. Moreover, it will help to

  11. Case 22:Type II diabetes

    Science.gov (United States)

    Diabetes mellitus is characterized by elevated blood glucose levels. It is composed of two types depending on the pathogenesis. Type I diabetes is characterized by insulin deficiency and usually has its onset during childhood or teenage years. This is also called ketosis-prone diabetes. Type II diab...

  12. Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo.

    Science.gov (United States)

    Douam, Florian; Soto Albrecht, Yentli E; Hrebikova, Gabriela; Sadimin, Evita; Davidson, Christian; Kotenko, Sergei V; Ploss, Alexander

    2017-08-15

    Yellow fever virus (YFV) is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths. The live attenuated vaccine strain, YFV-17D, has significantly contributed in controlling the global burden of yellow fever worldwide. However, the viral and host contributions to YFV-17D attenuation remain elusive. Type I interferon (IFN-α/β) signaling and type II interferon (IFN-γ) signaling have been shown to be mutually supportive in controlling YFV-17D infection despite distinct mechanisms of action in viral infection. However, it remains unclear how type III IFN (IFN-λ) integrates into this antiviral system. Here, we report that while wild-type (WT) and IFN-λ receptor knockout (λR -/- ) mice were largely resistant to YFV-17D, deficiency in type I IFN signaling resulted in robust infection. Although IFN-α/β receptor knockout (α/βR -/- ) mice survived the infection, mice with combined deficiencies in both type I signaling and type III IFN signaling were hypersusceptible to YFV-17D and succumbed to the infection. Mortality was associated with viral neuroinvasion and increased permeability of the blood-brain barrier (BBB). α/βR -/- λR -/- mice also exhibited distinct changes in the frequencies of multiple immune cell lineages, impaired T-cell activation, and severe perturbation of the proinflammatory cytokine balance. Taken together, our data highlight that type III IFN has critical immunomodulatory and neuroprotective functions that prevent viral neuroinvasion during active YFV-17D replication. Type III IFN thus likely represents a safeguard mechanism crucial for controlling YFV-17D infection and contributing to shaping vaccine immunogenicity. IMPORTANCE YFV-17D is a live attenuated flavivirus vaccine strain recognized as one of the most effective vaccines ever developed. However, the host and viral determinants governing YFV-17D attenuation and its potent immunogenicity are still unknown. Here, we analyzed the

  13. MDP up-regulates the gene expression of type I interferons in human aortic endothelial cells.

    Science.gov (United States)

    Lv, Qingshan; Yang, Mei; Liu, Xueting; Zhou, Lina; Xiao, Zhilin; Chen, Xiaobin; Chen, Meifang; Xie, Xiumei; Hu, Jinyue

    2012-03-23

    Muramyldipeptide (MDP), the minimum essential structure responsible for the immuno-adjuvant activity of peptidoglycan, is recognized by intracellular nuclear-binding oligomerization domain 2 (NOD2). Here, we obtained evidence that the treatment of human aortic endothelial cells (HAECs) with MDP up-regulated the gene expression of type I interferons in a dose- and time-dependent manner. MDP also up-regulated the expression of the receptor NOD2, suggesting that MDP may induce a positive feedback response. The up-regulation of interferons was not dependent on the TNFa signaling, as HAECs did not express TNFa with the stimulation of MDP, and TNFa neutralizing antibody did not decrease the induction of IFNs induced by MDP. RT-PCR results showed that HAECs expressed the gene transcripts of interferon regulatory factor (IRF) 1, 2, 3, 9. The western blot results showed that MDP induced the phosphorylation of IRF3. These results suggested that MDP induced the up-regulation of gene transcript of interferons through the activation of IRF3 signaling pathway. Meanwhile, MDP induced the gene expression of pro-inflammatory cytokines, including IL-1ß, IL-8, and MCP-1. Taken together, these results suggested that HAECs may play roles in the anti-infection immune response and in the induction of innate immunity.

  14. MDP Up-Regulates the Gene Expression of Type I Interferons in Human Aortic Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Xiumei Xie

    2012-03-01

    Full Text Available Muramyldipeptide (MDP, the minimum essential structure responsible for the immuno-adjuvant activity of peptidoglycan, is recognized by intracellular nuclear-binding oligomerization domain 2 (NOD2. Here, we obtained evidence that the treatment of human aortic endothelial cells (HAECs with MDP up-regulated the gene expression of type I interferons in a dose- and time-dependent manner. MDP also up-regulated the expression of the receptor NOD2, suggesting that MDP may induce a positive feedback response. The up-regulation of interferons was not dependent on the TNFa signaling, as HAECs did not express TNFa with the stimulation of MDP, and TNFa neutralizing antibody did not decrease the induction of IFNs induced by MDP. RT-PCR results showed that HAECs expressed the gene transcripts of interferon regulatory factor (IRF 1, 2, 3, 9. The western blot results showed that MDP induced the phosphorylation of IRF3. These results suggested that MDP induced the up-regulation of gene transcript of interferons through the activation of IRF3 signaling pathway. Meanwhile, MDP induced the gene expression of pro-inflammatory cytokines, including IL-1ß, IL-8, and MCP-1. Taken together, these results suggested that HAECs may play roles in the anti-infection immune response and in the induction of innate immunity.

  15. Success of measles virotherapy in ATL depends on type I interferon secretion and responsiveness.

    Science.gov (United States)

    M Parrula, M Cecilia; Fernandez, Soledad A; Landes, Kristina; Huey, Devra; Lairmore, Michael; Niewiesk, Stefan

    2014-08-30

    Adult T cell leukemia/lymphoma (ATL) is a highly aggressive CD4+/CD25+ T-cell malignancy caused by human T cell lymphotropic virus type 1 (HTLV-1). Previous studies in the MET-1 cell/NOD/SCID mouse model of ATL demonstrated that MET-1 cells are very susceptible to measles virus (MV) oncolytic therapy. To further evaluate the potential of MV therapy in ATL, the susceptibility of several HTLV-1 transformed CD4+ T cell lines (MT-1, MT-2, MT-4 and C8166-45) as well as HTLV-1 negative CD4+ T cell lines (Jurkat and CCRF-CEM) to infection with MV was tested in vitro. All cell lines were permissive to MV infection and subsequent cell death, except MT-1 and CCRF-CEM cells which were susceptible and permissive to MV infection, but resistant to cell death. The resistance to MV-mediated cell death was associated with IFNβ produced by MT-1 and CCRF-CEM cells. Inhibition of IFNβ rendered MT-1 and CCRF-CEM cells susceptible to MV-mediated cell death. Cells susceptible to MV-induced cell death did not produce nor were responsive to IFNβ. Upon infection with Newcastle Disease Virus (NDV), MT-1 and CCRF-CEM but not the susceptible cell lines up-regulated pSTAT-2. In vivo, treatment of tumors induced by MT-1 cell lines which produce IFNβ demonstrated only small increases in mean survival time, while only two treatments prolonged mean survival time in mice with MET-1 tumors deficient in type I interferon production. These results indicate that type I interferon production is closely linked with the inability of tumor cells to respond to type I interferon. Screening of tumor cells for type I interferon could be a useful strategy to select candidate patients for MV virotherapy. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Human B cells fail to secrete type I interferons upon cytoplasmic DNA exposure.

    Science.gov (United States)

    Gram, Anna M; Sun, Chenglong; Landman, Sanne L; Oosenbrug, Timo; Koppejan, Hester J; Kwakkenbos, Mark J; Hoeben, Rob C; Paludan, Søren R; Ressing, Maaike E

    2017-11-01

    Most cells are believed to be capable of producing type I interferons (IFN I) as part of an innate immune response against, for instance, viral infections. In macrophages, IFN I is potently induced upon cytoplasmic exposure to foreign nucleic acids. Infection of these cells with herpesviruses leads to triggering of the DNA sensors interferon-inducible protein 16 (IFI16) and cyclic GMP-AMP (cGAMP) synthase (cGAS). Thereby, the stimulator of interferon genes (STING) and the downstream molecules TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) are sequentially activated culminating in IFN I secretion. Human gamma-herpesviruses, such as Epstein-Barr virus (EBV), exploit B cells as a reservoir for persistent infection. In this study, we investigated whether human B cells, similar to macrophages, engage the cytoplasmic DNA sensing pathway to induce an innate immune response. We found that the B cells fail to secrete IFN I upon cytoplasmic DNA exposure, although they express the DNA sensors cGAS and IFI16 and the signaling components TBK1 and IRF3. In primary human B lymphocytes and EBV-negative B cell lines, this deficiency is explained by a lack of detectable levels of the central adaptor protein STING. In contrast, EBV-transformed B cell lines did express STING, yet both these lines as well as STING-reconstituted EBV-negative B cells did not produce IFN I upon dsDNA or cGAMP stimulation. Our combined data show that the cytoplasmic DNA sensing pathway is dysfunctional in human B cells. This exemplifies that certain cell types cannot induce IFN I in response to cytoplasmic DNA exposure providing a potential niche for viral persistence. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion.

    Science.gov (United States)

    Luthra, Priya; Aguirre, Sebastian; Yen, Benjamin C; Pietzsch, Colette A; Sanchez-Aparicio, Maria T; Tigabu, Bersabeh; Morlock, Lorraine K; García-Sastre, Adolfo; Leung, Daisy W; Williams, Noelle S; Fernandez-Sesma, Ana; Bukreyev, Alexander; Basler, Christopher F

    2017-04-04

    Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication. IMPORTANCE Ebola virus and other emerging RNA viruses are significant but unpredictable public health threats. Therapeutic approaches with broad-spectrum activity could provide an attractive response to such infections. We describe a novel assay that can identify small molecules that overcome Ebola virus-encoded innate immune evasion mechanisms. This assay identified as hits cancer chemotherapeutic drugs, including doxorubicin. Follow-up studies provide new insight into how doxorubicin induces interferon (IFN) responses, revealing activation of both the DNA damage response kinase ATM and the DNA sensor cGAS and its partner signaling protein STING. The studies further demonstrate that the ATM and cGAS-STING pathways of IFN induction are a point of vulnerability not only for Ebola virus but for other RNA viruses as well, because viral innate immune antagonists consistently fail to

  18. USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon α response.

    Directory of Open Access Journals (Sweden)

    Véronique François-Newton

    Full Text Available Type I interferons (IFN are cytokines that are rapidly secreted upon microbial infections and regulate all aspects of the immune response. In humans 15 type I IFN subtypes exist, of which IFN α2 and IFN β are used in the clinic for treatment of different pathologies. IFN α2 and IFN β are non redundant in their expression and in their potency to exert specific bioactivities. The more recently identified type III IFNs (3 IFN λ or IL-28/IL-29 bind an unrelated cell-type restricted receptor. Downstream of these two receptor complexes is a shared Jak/Stat pathway. Several mechanisms that contribute to the shut down of the IFN-induced signaling have been described at the molecular level. In particular, it has long been known that type I IFN induces the establishment of a desensitized state. In this work we asked how the IFN-induced desensitization integrates into the network built by the multiple type I IFN subtypes and type III IFNs. We show that priming of cells with either type I IFN or type III IFN interferes with the cell's ability to further respond to all IFN α subtypes. Importantly, primed cells are differentially desensitized in that they retain sensitivity to IFN β. We show that USP18 is necessary and sufficient to induce differential desensitization, by impairing the formation of functional binding sites for IFN α2. Our data highlight a new type of differential between IFNs α and IFN β and underline a cross-talk between type I and type III IFN. This cross-talk could shed light on the reported genetic variation in the IFN λ loci, which has been associated with persistence of hepatitis C virus and patient's response to IFN α2 therapy.

  19. MCPIP1 is a positive regulator of type I interferons antiviral activity.

    Science.gov (United States)

    Qian, Liping; Zuo, Yibo; Deng, Wenjun; Miao, Ying; Liu, Jin; Yuan, Yukang; Guo, Tingting; Zhang, Liting; Jin, Jun; Wang, Jun; Zheng, Hui

    2018-04-15

    Type-I interferons (IFN-I) are widely used for antiviral immunotherapy in clinic. Therefore, identification of the regulators of IFN-I antiviral activity is important for developing novel targets for IFN-based antiviral therapy. Monocyte chemoattractant protein 1-induced protein 1 (MCPIP1) is critical for cellular inflammatory responses. However, the roles of MCPIP1 in interferons (IFNs)-mediated antiviral immunity are unexplored. In this study, we demonstrate for the first time that MCPIP1 is an important positive regulator of IFNs antiviral activity. We found that MCPIP1 can promote innate antiviral immunity independently of both its RNase and deubiquitinase activity. Furthermore, we reveal that MCPIP1 is an IFN-induced positive feedback signal molecule which promotes IFN-I-mediated antiviral efficacy. Mechanistically, MCPIP1 does not affect the activation of JAK/STAT upstream of IFN-I signaling, but significantly promotes IFN-I signaling by enhancing ISRE promoter activity and expression of interferon-stimulated genes (ISGs). And MCPIP1-mediated activation of IFN-I signaling is independently of its RNase and deubiquitinase activity. These findings uncover a novel innate antiviral mechanism mediated by the IFN-MCPIP1 axis, and may provide potential targets for enhancing IFNs antiviral therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Role of type I interferon receptor signaling on NK cell development and functions.

    Directory of Open Access Journals (Sweden)

    Jean Guan

    Full Text Available Type I interferons (IFN are unique cytokines transcribed from intronless genes. They have been extensively studied because of their anti-viral functions. The anti-viral effects of type I IFN are mediated in part by natural killer (NK cells. However, the exact contribution of type I IFN on NK cell development, maturation and activation has been somewhat difficult to assess. In this study, we used a variety of approaches to define the consequences of the lack of type I interferon receptor (IFNAR signaling on NK cells. Using IFNAR deficient mice, we found that type I IFN affect NK cell development at the pre-pro NK stage. We also found that systemic absence of IFNAR signaling impacts NK cell maturation with a significant increase in the CD27+CD11b+ double positive (DP compartment in all organs. However, there is tissue specificity, and only in liver and bone marrow is the maturation defect strictly dependent on cell intrinsic IFNAR signaling. Finally, using adoptive transfer and mixed bone marrow approaches, we also show that cell intrinsic IFNAR signaling is not required for NK cell IFN-γ production in the context of MCMV infection. Taken together, our studies provide novel insights on how type I IFN receptor signaling regulates NK cell development and functions.

  1. Type I interferon protects against pneumococcal invasive disease by inhibiting bacterial transmigration across the lung.

    Directory of Open Access Journals (Sweden)

    Kim S LeMessurier

    Full Text Available Streptococcus pneumoniae infection is a leading cause of bacterial pneumonia, sepsis and meningitis and is associated with high morbidity and mortality. Type I interferon (IFN-I, whose contribution to antiviral and intracellular bacterial immunity is well established, is also elicited during pneumococcal infection, yet its functional significance is not well defined. Here, we show that IFN-I plays an important role in the host defense against pneumococci by counteracting the transmigration of bacteria from the lung to the blood. Mice that lack the type I interferon receptor (Ifnar1 (-/- or mice that were treated with a neutralizing antibody against the type I interferon receptor, exhibited enhanced development of bacteremia following intranasal pneumococcal infection, while maintaining comparable bacterial numbers in the lung. In turn, treatment of mice with IFNβ or IFN-I-inducing synthetic double stranded RNA (poly(I:C, dramatically reduced the development of bacteremia following intranasal infection with S. pneumoniae. IFNβ treatment led to upregulation of tight junction proteins and downregulation of the pneumococcal uptake receptor, platelet activating factor receptor (PAF receptor. In accordance with these findings, IFN-I reduced pneumococcal cell invasion and transmigration across epithelial and endothelial layers, and Ifnar1 (-/- mice showed overall enhanced lung permeability. As such, our data identify IFN-I as an important component of the host immune defense that regulates two possible mechanisms involved in pneumococcal invasion, i.e. PAF receptor-mediated transcytosis and tight junction-dependent pericellular migration, ultimately limiting progression from a site-restricted lung infection to invasive, lethal disease.

  2. Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion

    Directory of Open Access Journals (Sweden)

    Priya Luthra

    2017-04-01

    Full Text Available Ebola virus (EBOV protein VP35 inhibits production of interferon alpha/beta (IFN by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication.

  3. Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord

    DEFF Research Database (Denmark)

    Oji, Satoru; Nicolussi, Eva-Maria; Kaufmann, Nathalie

    2016-01-01

    ) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from therapies involving type I interferons (I-IFN), NMO patients typically do......, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation...

  4. Activation of Type I Interferon Pathway in Systemic Lupus Erythematosus: Association with Distinct Clinical Phenotypes

    Science.gov (United States)

    Karageorgas, Theophanis P.; Tseronis, Dimitrios D.; Mavragani, Clio P.

    2011-01-01

    Growing evidence over the last few years suggests a central role of type I IFN pathway in the pathogenesis of systemic autoimmune disorders. Data from clinical and genetic studies in patients with systemic lupus erythematosus (SLE) and lupus-prone mouse models, indicates that the type I interferon system may play a pivotal role in the pathogenesis of several lupus and associated clinical features, such as nephritis, neuropsychiatric and cutaneous lupus, premature atherosclerosis as well as lupus-specific autoantibodies particularly against ribonucleoproteins. In the current paper, our aim is to summarize the latest findings supporting the association of type I IFN pathway with specific clinical manifestations in the setting of SLE providing insights on the potential use of type I IFN as a therapeutic target. PMID:22162633

  5. Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response.

    Directory of Open Access Journals (Sweden)

    Scott A Read

    Full Text Available Treatment of chronic hepatitis C virus (HCV infection is evolving rapidly with the development of novel direct acting antivirals (DAAs, however viral clearance remains intimately linked to the hepatic innate immune system. Patients demonstrating a high baseline activation of interferon stimulated genes (ISGs, termed interferon refractoriness, are less likely to mount a strong antiviral response and achieve viral clearance when placed on treatment. As a result, suppressor of cytokine signalling (SOCS 3 and other regulators of the IFN response have been identified as key candidates for the IFN refractory phenotype due to their regulatory role on the IFN response. AXL is a receptor tyrosine kinase that has been identified as a key regulator of interferon (IFN signalling in myeloid cells of the immune system, but has not been examined in the context of chronic HCV infection. Here, we show that AXL is up-regulated following HCV infection, both in vitro and in vivo and is likely induced by type I/III IFNs and inflammatory signalling pathways. AXL inhibited type IFNα mediated ISG expression resulting in a decrease in its antiviral efficacy against HCV in vitro. Furthermore, patients possessing the favourable IFNL3 rs12979860 genotype associated with treatment response, showed lower AXL expression in the liver and a stronger induction of AXL in the blood, following their first dose of IFN. Together, these data suggest that elevated AXL expression in the liver may mediate an IFN-refractory phenotype characteristic of patients possessing the unfavourable rs12979860 genotype, which is associated with lower rates of viral clearance.

  6. Type I interferon and pattern recognition receptor signaling following particulate matter inhalation

    Directory of Open Access Journals (Sweden)

    Erdely Aaron

    2012-07-01

    Full Text Available Abstract Background Welding, a process that generates an aerosol containing gases and metal-rich particulates, induces adverse physiological effects including inflammation, immunosuppression and cardiovascular dysfunction. This study utilized microarray technology and subsequent pathway analysis as an exploratory search for markers/mechanisms of in vivo systemic effects following inhalation. Mice were exposed by inhalation to gas metal arc – stainless steel (GMA-SS welding fume at 40 mg/m3 for 3 hr/d for 10 d and sacrificed 4 hr, 14 d and 28 d post-exposure. Whole blood cells, aorta and lung were harvested for global gene expression analysis with subsequent Ingenuity Pathway Analysis and confirmatory qRT-PCR. Serum was collected for protein profiling. Results The novel finding was a dominant type I interferon signaling network with the transcription factor Irf7 as a central component maintained through 28 d. Remarkably, these effects showed consistency across all tissues indicating a systemic type I interferon response that was complemented by changes in serum proteins (decreased MMP-9, CRP and increased VCAM1, oncostatin M, IP-10. In addition, pulmonary expression of interferon α and β and Irf7 specific pattern recognition receptors (PRR and signaling molecules (Ddx58, Ifih1, Dhx58, ISGF3 were induced, an effect that showed specificity when compared to other inflammatory exposures. Also, a canonical pathway indicated a coordinated response of multiple PRR and associated signaling molecules (Tlr7, Tlr2, Clec7a, Nlrp3, Myd88 to inhalation of GMA-SS. Conclusion This methodological approach has the potential to identify consistent, prominent and/or novel pathways and provides insight into mechanisms that contribute to pulmonary and systemic effects following toxicant exposure.

  7. Bridging the species divide: transgenic mice humanized for type-I interferon response.

    Directory of Open Access Journals (Sweden)

    Daniel Harari

    Full Text Available We have generated transgenic mice that harbor humanized type I interferon receptors (IFNARs enabling the study of type I human interferons (Hu-IFN-Is in mice. These "HyBNAR" (Hybrid IFNAR mice encode transgenic variants of IFNAR1 and IFNAR2 with the human extracellular domains being fused to transmembrane and cytoplasmic segments of mouse sequence. B16F1 mouse melanoma cells harboring the HyBNAR construct specifically bound Hu-IFN-Is and were rendered sensitive to Hu-IFN-I stimulated anti-proliferation, STAT1 activation and activation of a prototypical IFN-I response gene (MX2. HyBNAR mice were crossed with a transgenic strain expressing the luciferase reporter gene under the control of the IFN-responsive MX2 promoter (MX2-Luciferase. Both the HyBNAR and HyBNAR/MX2-Luciferase mice were responsive to all Hu-IFN-Is tested, inclusive of IFNα2A, IFNβ, and a human superagonist termed YNSα8. The mice displayed dose-dependent pharmacodynamic responses to Hu-IFN-I injection, as assessed by measuring the expression of IFN-responsive genes. Our studies also demonstrated a weak activation of endogenous mouse interferon response, especially after high dose administration of Hu-IFNs. In sharp contrast to data published for humans, our pharmacodynamic readouts demonstrate a very short-lived IFN-I response in mice, which is not enhanced by sub-cutaneous (SC injections in comparison to other administration routes. With algometric differences between humans and mice taken into account, the HyBNAR mice provides a convenient non-primate pre-clinical model to advance the study of human IFN-Is.

  8. Downregulation of angiotensin II type 1 receptors during sepsis.

    Science.gov (United States)

    Bucher, M; Ittner, K P; Hobbhahn, J; Taeger, K; Kurtz, A

    2001-08-01

    Our study aimed to characterize the mechanisms underlying the attenuated cardiovascular responsiveness toward the renin-angiotensin system during sepsis. For this purpose, we determined the effects of experimental Gram-negative and Gram-positive sepsis in rats. We found that sepsis led to a ubiquitous upregulation of NO synthase isoform II expression and to pronounced hypotension. Despite increased plasma renin activity and plasma angiotensin (Ang) II levels, plasma aldosterone concentrations were normal, and the blood pressure response to exogenous Ang II was markedly diminished in septic rats. Mimicking the fall of blood pressure during sepsis by short-term infusion of the NO donor sodium nitroprusside in normal rats did not alter their blood pressure response to exogenous Ang II. Therefore, we considered the possibility of an altered expression of Ang II receptors during sepsis. It turned out that Ang II type 1 receptor expression was markedly downregulated in all organs of septic rats. Further in vitro studies with rat renal mesangial cells showed that NO and a combination of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma) downregulated Ang II type 1 receptor expression in a synergistic fashion. In summary, our data suggest that sepsis causes a systemic downregulation of Ang II type 1 receptors that is likely mediated by proinflammatory cytokines and NO. We suggest that this downregulation of Ang II type 1 receptors is the main reason for the attenuated responsiveness of blood pressure and of aldosterone formation to Ang II and, therefore, contributes to the characteristic septic shock.

  9. T-helper 17 cell cytokines and interferon type I: Partners in crime in systemic lupus erythematosus?

    NARCIS (Netherlands)

    Z. Brkic (Zana); O.B.J. Corneth (Odilia); C.G. van Helden-Meeuwsen; R.J.E.M. Dolhain (Radboud); M. de Maria; S.M.J. Paulissen (Sandra); N. Davelaar (Nadine); J.P. van Hamburg (Jan Piet); P.L.A. van Daele (Paul); V.A.S.H. Dalm (Virgil); P.M. van Hagen (Martin); J.M.W. Hazes (Mieke); M.A. Versnel (Marjan); E.W. Lubberts (Erik)

    2014-01-01

    textabstractIntroduction: A hallmark of systemic autoimmune diseases like systemic lupus erythematosus (SLE) is the increased expression of interferon (IFN) type I inducible genes, so-called IFN type I signature. Recently, T-helper 17 subset (Th17 cells), which produces IL-17A, IL-17F, IL-21, and

  10. Transcriptional expression of type I interferon response genes and stability of housekeeping genes in the human endometrium and endometriosis

    DEFF Research Database (Denmark)

    Vestergaard, Anna L; Knudsen, Ulla B; Munk, Torben

    2011-01-01

    Endometriosis is a painful chronic female disease defined by the presence of endometrial tissue implants in ectopic locations. The pathogenesis is much debated, and type I interferons could be involved. The expression of genes of the type I interferon response were profiled by a specific PCR Array...... of RNA obtained from ectopic and eutopic endometrium collected from 9 endometriosis patients and 9 healthy control women. Transcriptional expression levels of selected interferon-regulated and housekeeping genes were investigated by real-time quantitative reverse transcriptase PCR (qRT-PCR). Stably...... expressed housekeeping genes for valid normalization of transcriptional studies of endometrium and endometriosis have not yet been published. Here, seven housekeeping genes were evaluated for stability using the GeNorm and NormFinder software. A normalization factor based on HMBS, TBP, and YWHAZ expression...

  11. Analysis of Transcriptional Signatures in Response to Listeria monocytogenes Infection Reveals Temporal Changes That Result from Type I Interferon Signaling

    Science.gov (United States)

    Potempa, Krzysztof; Graham, Christine M.; Moreira-Teixeira, Lucia; McNab, Finlay W.; Howes, Ashleigh; Stavropoulos, Evangelos; Pascual, Virginia; Banchereau, Jacques; Chaussabel, Damien; O’Garra, Anne

    2016-01-01

    Analysis of the mouse transcriptional response to Listeria monocytogenes infection reveals that a large set of genes are perturbed in both blood and tissue and that these transcriptional responses are enriched for pathways of the immune response. Further we identified enrichment for both type I and type II interferon (IFN) signaling molecules in the blood and tissues upon infection. Since type I IFN signaling has been reported widely to impair bacterial clearance we examined gene expression from blood and tissues of wild type (WT) and type I IFNαβ receptor-deficient (Ifnar1-/-) mice at the basal level and upon infection with L. monocytogenes. Measurement of the fold change response upon infection in the absence of type I IFN signaling demonstrated an upregulation of specific genes at day 1 post infection. A less marked reduction of the global gene expression signature in blood or tissues from infected Ifnar1-/- as compared to WT mice was observed at days 2 and 3 after infection, with marked reduction in key genes such as Oasg1 and Stat2. Moreover, on in depth analysis, changes in gene expression in uninfected mice of key IFN regulatory genes including Irf9, Irf7, Stat1 and others were identified, and although induced by an equivalent degree upon infection this resulted in significantly lower final gene expression levels upon infection of Ifnar1-/- mice. These data highlight how dysregulation of this network in the steady state and temporally upon infection may determine the outcome of this bacterial infection and how basal levels of type I IFN-inducible genes may perturb an optimal host immune response to control intracellular bacterial infections such as L. monocytogenes. PMID:26918359

  12. DNA-Damage-Induced Type I Interferon Promotes Senescence and Inhibits Stem Cell Function

    Directory of Open Access Journals (Sweden)

    Qiujing Yu

    2015-05-01

    Full Text Available Expression of type I interferons (IFNs can be induced by DNA-damaging agents, but the mechanisms and significance of this regulation are not completely understood. We found that the transcription factor IRF3, activated in an ATM-IKKα/β-dependent manner, stimulates cell-autonomous IFN-β expression in response to double-stranded DNA breaks. Cells and tissues with accumulating DNA damage produce endogenous IFN-β and stimulate IFN signaling in vitro and in vivo. In turn, IFN acts to amplify DNA-damage responses, activate the p53 pathway, promote senescence, and inhibit stem cell function in response to telomere shortening. Inactivation of the IFN pathway abrogates the development of diverse progeric phenotypes and extends the lifespan of Terc knockout mice. These data identify DNA-damage-response-induced IFN signaling as a critical mechanism that links accumulating DNA damage with senescence and premature aging.

  13. Enterovirus 71 protease 2Apro targets MAVS to inhibit anti-viral type I interferon responses.

    Directory of Open Access Journals (Sweden)

    Bei Wang

    2013-03-01

    Full Text Available Enterovirus 71 (EV71 is the major causative pathogen of hand, foot, and mouth disease (HFMD. Its pathogenicity is not fully understood, but innate immune evasion is likely a key factor. Strategies to circumvent the initiation and effector phases of anti-viral innate immunity are well known; less well known is whether EV71 evades the signal transduction phase regulated by a sophisticated interplay of cellular and viral proteins. Here, we show that EV71 inhibits anti-viral type I interferon (IFN responses by targeting the mitochondrial anti-viral signaling (MAVS protein--a unique adaptor molecule activated upon retinoic acid induced gene-I (RIG-I and melanoma differentiation associated gene (MDA-5 viral recognition receptor signaling--upstream of type I interferon production. MAVS was cleaved and released from mitochondria during EV71 infection. An in vitro cleavage assay demonstrated that the viral 2A protease (2A(pro, but not the mutant 2A(pro (2A(pro-110 containing an inactivated catalytic site, cleaved MAVS. The Protease-Glo assay revealed that MAVS was cleaved at 3 residues between the proline-rich and transmembrane domains, and the resulting fragmentation effectively inactivated downstream signaling. In addition to MAVS cleavage, we found that EV71 infection also induced morphologic and functional changes to the mitochondria. The EV71 structural protein VP1 was detected on purified mitochondria, suggesting not only a novel role for mitochondria in the EV71 replication cycle but also an explanation of how EV71-derived 2A(pro could approach MAVS. Taken together, our findings reveal a novel strategy employed by EV71 to escape host anti-viral innate immunity that complements the known EV71-mediated immune-evasion mechanisms.

  14. West Nile virus noncoding subgenomic RNA contributes to viral evasion of the type I interferon-mediated antiviral response.

    Science.gov (United States)

    Schuessler, Andrea; Funk, Anneke; Lazear, Helen M; Cooper, Daphne A; Torres, Shessy; Daffis, Stephane; Jha, Babal Kant; Kumagai, Yutaro; Takeuchi, Osamu; Hertzog, Paul; Silverman, Robert; Akira, Shizuo; Barton, David J; Diamond, Michael S; Khromykh, Alexander A

    2012-05-01

    We previously showed that a noncoding subgenomic flavivirus RNA (sfRNA) is required for viral pathogenicity, as a mutant West Nile virus (WNV) deficient in sfRNA production replicated poorly in wild-type mice. To investigate the possible immunomodulatory or immune evasive functions of sfRNA, we utilized mice and cells deficient in elements of the type I interferon (IFN) response. Replication of the sfRNA mutant WNV was rescued in mice and cells lacking interferon regulatory factor 3 (IRF-3) and IRF-7 and in mice lacking the type I alpha/beta interferon receptor (IFNAR), suggesting a contribution for sfRNA in overcoming the antiviral response mediated by type I IFN. This was confirmed by demonstrating rescue of mutant virus replication in the presence of IFNAR neutralizing antibodies, greater sensitivity of mutant virus replication to IFN-α pretreatment, partial rescue of its infectivity in cells deficient in RNase L, and direct effects of transfected sfRNA on rescuing replication of unrelated Semliki Forest virus in cells pretreated with IFN-α. The results define a novel function of sfRNA in flavivirus pathogenesis via its contribution to viral evasion of the type I interferon response.

  15. Interferon-γ induces expression of MHC class II on intestinal epithelial cells and protects mice from colitis.

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    Christoph Thelemann

    Full Text Available Immune responses against intestinal microbiota contribute to the pathogenesis of inflammatory bowel diseases (IBD and involve CD4(+ T cells, which are activated by major histocompatibility complex class II (MHCII molecules on antigen-presenting cells (APCs. However, it is largely unexplored how inflammation-induced MHCII expression by intestinal epithelial cells (IEC affects CD4(+ T cell-mediated immunity or tolerance induction in vivo. Here, we investigated how epithelial MHCII expression is induced and how a deficiency in inducible epithelial MHCII expression alters susceptibility to colitis and the outcome of colon-specific immune responses. Colitis was induced in mice that lacked inducible expression of MHCII molecules on all nonhematopoietic cells, or specifically on IECs, by continuous infection with Helicobacter hepaticus and administration of interleukin (IL-10 receptor-blocking antibodies (anti-IL10R mAb. To assess the role of interferon (IFN-γ in inducing epithelial MHCII expression, the T cell adoptive transfer model of colitis was used. Abrogation of MHCII expression by nonhematopoietic cells or IECs induces colitis associated with increased colonic frequencies of innate immune cells and expression of proinflammatory cytokines. CD4(+ T-helper type (Th1 cells - but not group 3 innate lymphoid cells (ILCs or Th17 cells - are elevated, resulting in an unfavourably altered ratio between CD4(+ T cells and forkhead box P3 (FoxP3(+ regulatory T (Treg cells. IFN-γ produced mainly by CD4(+ T cells is required to upregulate MHCII expression by IECs. These results suggest that, in addition to its proinflammatory roles, IFN-γ exerts a critical anti-inflammatory function in the intestine which protects against colitis by inducing MHCII expression on IECs. This may explain the failure of anti-IFN-γ treatment to induce remission in IBD patients, despite the association of elevated IFN-γ and IBD.

  16. Differential Impact of Interferon Regulatory Factor 7 in Initiation of the Type I Interferon Response in the Lymphocytic Choriomeningitis Virus-Infected Central Nervous System versus the Periphery

    DEFF Research Database (Denmark)

    Christensen, Jeanette Erbo; Fenger, Christina; Issazadeh-Navikas, Shohreh

    2012-01-01

    Interferon (IFN) regulatory factors (IRFs) are a family of transcription factors involved in regulating type I IFN genes and other genes participating in the early antiviral host response. To better understand the mechanisms involved in virus-induced central nervous system (CNS) inflammation, we...... studied the influence of IRF1, -3, -7, and -9 on the transcriptional activity of key genes encoding antiviral host factors in the CNS of mice infected with lymphocytic choriomeningitis virus (LCMV). A key finding is that neither IRF3 nor IRF7 is absolutely required for induction of a type I IFN response...... in the LCMV-infected CNS, whereas concurrent elimination of both factors markedly reduces the virus-induced host response. This is unlike the situation in the periphery, where deficiency of IRF7 almost eliminates the LCMV-induced production of the type I IFNs. This difference is seemingly related to the local...

  17. Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Khorooshi, Reza; Mørch, Marlene Thorsen; Holm, Thomas

    2015-01-01

    The Type I interferons (IFN), beta (IFN-β) and the alpha family (IFN-α), act through a common receptor and have anti-inflammatory effects. IFN-β is used to treat multiple sclerosis (MS) and is effective against experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice with EAE...

  18. DMPD: The role of type I interferon production by dendritic cells in host defense. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17544561 The role of type I interferon production by dendritic cells in host defense. Fitzgerald-Bocars...fense. Authors Fitzgerald-Bocarsly P, Feng D. Publication Biochimie. 2007 Jun-Jul;89(6-7):843-55. Epub 2007

  19. Association of interferon-gamma and interleukin 10 genotypes and serum levels with partial clinical remission in type 1 diabetes

    DEFF Research Database (Denmark)

    Alizadeh, B Z; Hanifi-Moghaddam, P; Eerligh, P

    2006-01-01

    We studied whether serum interferon (IFN)-gamma or interleukin (IL)-10 levels and their corresponding functional polymorphic genotypes are associated with partial remission of type 1 diabetes (T1D). A multi-centre study was undertaken in patients with newly diagnosed T1D and matched controls. T1D...

  20. Post-Transcriptional Control of Type I Interferon Induction by Porcine Reproductive and Respiratory Syndrome Virus in Its Natural Host Cells

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    Xiuqing Wang

    2012-05-01

    Full Text Available Porcine reproductive and respiratory syndrome virus (PRRSV is not only a poor inducer of type I interferon but also inhibits the efficient induction of type I interferon by porcine transmissible gastroenteritis virus (TGEV and synthetic dsRNA molecules, Poly I:C. However, the mechanistic basis by which PRRSV interferes with the induction of type I interferon in its natural host cells remains less well defined. The purposes of this review are to summarize the key findings in supporting the post-transcriptional control of type I interferon in its natural host cells and to propose the possible role of translational control in the regulation of type I interferon induction by PRRSV.

  1. Type I interferon induction is detrimental during infection with the Whipple's disease bacterium, Tropheryma whipplei.

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    Khatoun Al Moussawi

    2010-01-01

    Full Text Available Macrophages are the first line of defense against pathogens. Upon infection macrophages usually produce high levels of proinflammatory mediators. However, macrophages can undergo an alternate polarization leading to a permissive state. In assessing global macrophage responses to the bacterial agent of Whipple's disease, Tropheryma whipplei, we found that T. whipplei induced M2 macrophage polarization which was compatible with bacterial replication. Surprisingly, this M2 polarization of infected macrophages was associated with apoptosis induction and a functional type I interferon (IFN response, through IRF3 activation and STAT1 phosphorylation. Using macrophages from mice deficient for the type I IFN receptor, we found that this type I IFN response was required for T. whipplei-induced macrophage apoptosis in a JNK-dependent manner and was associated with the intracellular replication of T. whipplei independently of JNK. This study underscores the role of macrophage polarization in host responses and highlights the detrimental role of type I IFN during T. whipplei infection.

  2. Distinct Effects of Type I and III Interferons on Enteric Viruses

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    Harshad Ingle

    2018-01-01

    Full Text Available Interferons (IFNs are key host cytokines in the innate immune response to viral infection, and recent work has identified unique roles for IFN subtypes in regulating different aspects of infection. Currently emerging is a common theme that type III IFNs are critical in localized control of infection at mucosal barrier sites, while type I IFNs are important for broad systemic control of infections. The intestine is a particular site of interest for exploring these effects, as in addition to being the port of entry for a multitude of pathogens, it is a complex tissue with a variety of cell types as well as the presence of the intestinal microbiota. Here we focus on the roles of type I and III IFNs in control of enteric viruses, discussing what is known about signaling downstream from these cytokines, including induction of specific IFN-stimulated genes. We review viral strategies to evade IFN responses, effects of IFNs on the intestine, interactions between IFNs and the microbiota, and briefly discuss the role of IFNs in controlling viral infections at other barrier sites. Enhanced understanding of the coordinate roles of IFNs in control of viral infections may facilitate development of antiviral therapeutic strategies; here we highlight potential avenues for future exploration.

  3. Endogenous and recombinant type I interferons and disease activity in multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, Finn; Krakauer, Martin; Limborg, Signe

    2012-01-01

    Although treatment of multiple sclerosis (MS) with the type I interferon (IFN) IFN-ß lowers disease activity, the role of endogenous type I IFN in MS remains controversial. We studied CD4+ T cells and CD4+ T cell subsets, monocytes and dendritic cells by flow cytometry and analysed the relationship...... with endogenous type I IFN-like activity, the effect of IFN-ß therapy, and clinical and magnetic resonance imaging (MRI) disease activity in MS patients. Endogenous type I IFN activity was associated with decreased expression of the integrin subunit CD49d (VLA-4) on CD4+CD26(high) T cells (Th1 helper cells......), and this effect was associated with less MRI disease activity. IFN-ß therapy reduced CD49d expression on CD4+CD26(high) T cells, and the percentage of CD4+CD26(high) T cells that were CD49d(high) correlated with clinical and MRI disease activity in patients treated with IFN-ß. Treatment with IFN-ß also increased...

  4. Distinct Effects of Type I and III Interferons on Enteric Viruses.

    Science.gov (United States)

    Ingle, Harshad; Peterson, Stefan T; Baldridge, Megan T

    2018-01-20

    Interferons (IFNs) are key host cytokines in the innate immune response to viral infection, and recent work has identified unique roles for IFN subtypes in regulating different aspects of infection. Currently emerging is a common theme that type III IFNs are critical in localized control of infection at mucosal barrier sites, while type I IFNs are important for broad systemic control of infections. The intestine is a particular site of interest for exploring these effects, as in addition to being the port of entry for a multitude of pathogens, it is a complex tissue with a variety of cell types as well as the presence of the intestinal microbiota. Here we focus on the roles of type I and III IFNs in control of enteric viruses, discussing what is known about signaling downstream from these cytokines, including induction of specific IFN-stimulated genes. We review viral strategies to evade IFN responses, effects of IFNs on the intestine, interactions between IFNs and the microbiota, and briefly discuss the role of IFNs in controlling viral infections at other barrier sites. Enhanced understanding of the coordinate roles of IFNs in control of viral infections may facilitate development of antiviral therapeutic strategies; here we highlight potential avenues for future exploration.

  5. Avian influenza A virus PB2 promotes interferon type I inducing properties of a swine strain in porcine dendritic cells

    Energy Technology Data Exchange (ETDEWEB)

    Ocana-Macchi, Manuela; Ricklin, Meret E.; Python, Sylvie; Monika, Gsell-Albert [Institute of Virology and Immunoprophylaxis, Mittelhaeusern (Switzerland); Stech, Juergen; Stech, Olga [Friedrich-Loeffler Institut, Greifswald-Insel Riems (Germany); Summerfield, Artur, E-mail: artur.summerfield@ivi.admin.ch [Institute of Virology and Immunoprophylaxis, Mittelhaeusern (Switzerland)

    2012-05-25

    The 2009 influenza A virus (IAV) pandemic resulted from reassortment of avian, human and swine strains probably in pigs. To elucidate the role of viral genes in host adaptation regarding innate immune responses, we focussed on the effect of genes from an avian H5N1 and a porcine H1N1 IAV on infectivity and activation of porcine GM-CSF-induced dendritic cells (DC). The highest interferon type I responses were achieved by the porcine virus reassortant containing the avian polymerase gene PB2. This finding was not due to differential tropism since all viruses infected DC equally. All viruses equally induced MHC class II, but porcine H1N1 expressing the avian viral PB2 induced more prominent nuclear NF-{kappa}B translocation compared to its parent IAV. The enhanced activation of DC may be detrimental or beneficial. An over-stimulation of innate responses could result in either pronounced tissue damage or increased resistance against IAV reassortants carrying avian PB2.

  6. Avian influenza A virus PB2 promotes interferon type I inducing properties of a swine strain in porcine dendritic cells

    International Nuclear Information System (INIS)

    Ocaña-Macchi, Manuela; Ricklin, Meret E.; Python, Sylvie; Monika, Gsell-Albert; Stech, Jürgen; Stech, Olga; Summerfield, Artur

    2012-01-01

    The 2009 influenza A virus (IAV) pandemic resulted from reassortment of avian, human and swine strains probably in pigs. To elucidate the role of viral genes in host adaptation regarding innate immune responses, we focussed on the effect of genes from an avian H5N1 and a porcine H1N1 IAV on infectivity and activation of porcine GM-CSF-induced dendritic cells (DC). The highest interferon type I responses were achieved by the porcine virus reassortant containing the avian polymerase gene PB2. This finding was not due to differential tropism since all viruses infected DC equally. All viruses equally induced MHC class II, but porcine H1N1 expressing the avian viral PB2 induced more prominent nuclear NF-κB translocation compared to its parent IAV. The enhanced activation of DC may be detrimental or beneficial. An over-stimulation of innate responses could result in either pronounced tissue damage or increased resistance against IAV reassortants carrying avian PB2.

  7. Indoleamine 2,3-dioxygenase (IDO): the antagonist of type I interferon-driven skin inflammation?

    Science.gov (United States)

    Scheler, Marina; Wenzel, Joerg; Tüting, Thomas; Takikawa, Osamu; Bieber, Thomas; von Bubnoff, Dagmar

    2007-12-01

    Recent studies have provided evidence that a type I interferon (IFN)-driven immune response might play an important role in the pathogenesis of lichen planus (LP), an inflammatory disorder of the skin of unclear etiology. Plasmacytoid dendritic cells in affected skin from LP have been proposed to produce IFN-alpha/beta locally, which leads to the expression of IFN-inducible chemokines such as IP10/CXCL10 in the epidermis. This chemokine recruits chemokine receptor CXCR3-expressing T-lymphocytes into the skin via CXCR3/IP10 interactions. Indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan and suppresses T-cell proliferation, is induced by IFNs and other inflammatory cytokines. We show that type I IFN-mediated skin disorders, such as LP, strongly express IDO in lesional skin. This expression closely correlates to the expression of the highly specific type I IFN marker MxA. We further demonstrate that the IDO+ cells in LP are large myeloid CD11c+S100+CD68(-) dendritic cells. Accordingly, CD11c+ antigen-presenting cells significantly up-regulate IDO gene expression and intracellular IDO protein expression after stimulation with IFN-alpha in vitro. These findings reveal that both proinflammatory and counterregulatory mechanisms are operative in cutaneous lesions of LP. We propose that the balance of these mechanisms may be involved in the pathogenesis of this disorder.

  8. C7L family of poxvirus host range genes inhibits antiviral activities induced by type I interferons and interferon regulatory factor 1.

    Science.gov (United States)

    Meng, Xiangzhi; Schoggins, John; Rose, Lloyd; Cao, Jingxin; Ploss, Alexander; Rice, Charles M; Xiang, Yan

    2012-04-01

    Vaccinia virus (VACV) K1L and C7L function equivalently in many mammalian cells to support VACV replication and antagonize antiviral activities induced by type I interferons (IFNs). While K1L is limited to orthopoxviruses, genes that are homologous to C7L are found in diverse mammalian poxviruses. In this study, we showed that the C7L homologues from sheeppox virus and swinepox virus could rescue the replication defect of a VACV mutant deleted of both K1L and C7L (vK1L(-)C7L(-)). Interestingly, the sheeppox virus C7L homologue could rescue the replication of vK1L(-)C7L(-) in human HeLa cells but not in murine 3T3 and LA-4 cells, in contrast to all other C7L homologues. Replacing amino acids 134 and 135 of the sheeppox virus C7L homologue, however, made it functional in the two murine cell lines, suggesting that these two residues are critical for antagonizing a putative host restriction factor which has some subtle sequence variation in human and murine cells. Furthermore, the C7L family of host range genes from diverse mammalian poxviruses were all capable of antagonizing type I IFN-induced antiviral activities against VACV. Screening of a library of more than 350 IFN-stimulated genes (ISGs) identified interferon-regulated factor 1 (IRF1) as an inhibitor of vK1L(-)C7L(-) but not wild-type VACV. Expression of either K1L or C7L, however, rendered vK1L(-)C7L(-) resistant to IRF1-induced antiviral activities. Altogether, our data show that K1L and C7L antagonize IRF1-induced antiviral activities and that the host modulation function of C7L is evolutionally conserved in all poxviruses that can readily replicate in tissue-cultured mammalian cells.

  9. Critical role of constitutive type I interferon response in bronchial epithelial cell to influenza infection.

    Directory of Open Access Journals (Sweden)

    Alan C-Y Hsu

    Full Text Available Innate antiviral responses in bronchial epithelial cells (BECs provide the first line of defense against respiratory viral infection and the effectiveness of this response is critically dependent on the type I interferons (IFNs. However the importance of the antiviral responses in BECs during influenza infection is not well understood. We profiled the innate immune response to infection with H3N2 and H5N1 virus using Calu-3 cells and primary BECs to model proximal airway cells. The susceptibility of BECs to influenza infection was not solely dependent on the sialic acid-bearing glycoprotein, and antiviral responses that occurred after viral endocytosis was more important in limiting viral replication. The early antiviral response and apoptosis correlated with the ability to limit viral replication. Both viruses reduced RIG-I associated antiviral responses and subsequent induction of IFN-β. However it was found that there was constitutive release of IFN-β by BECs and this was critical in inducing late antiviral signaling via type I IFN receptors, and was crucial in limiting viral infection. This study characterizes anti-influenza virus responses in airway epithelial cells and shows that constitutive IFN-β release plays a more important role in initiating protective late IFN-stimulated responses during human influenza infection in bronchial epithelial cells.

  10. Viewpoint: factors involved in type I interferon responses during porcine virus infections.

    Science.gov (United States)

    Summerfield, Artur

    2012-07-15

    Since type I interferon (IFN-I) is considered a potent antiviral defence mechanism, it is not surprising that during evolution viruses have development of various mechanisms to counteract IFN-I induction or release. Despite this, certain virus infections are associated with very high levels of systemic IFN-I. One explanation for this observation is the presence of plasmacytoid dendritic cells (pDC), which are able to produce high levels of IFN-I despite the presence of viral IFN-I antagonists. Examples of virus infection in pigs including classical swine fever virus, influenza virus, foot-and-mouth disease virus, and porcine circo virus type 2 highlight factors involved in controlling such responses and illustrate potential negative and positive effects for the host. Based on published data, we propose that in addition to the ability to activate pDC, the ability to spread systemically, and the tropism for lymphoid tissue also represent important factors contributing to strong systemic IFN-I responses during certain virus infections. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Constitutive overexpressed type I interferon induced downregulation of antiviral activity in medaka fish (Oryzias latipes).

    Science.gov (United States)

    Maekawa, Shun; Aoki, Takashi; Wang, Han-Ching

    2017-03-01

    In fish, as well as vertebrates, type I interferons (IFNs) are important cytokines that help to provide innate, antiviral immunity. Although low amounts of IFN are constitutively secreted under normal physiological conditions, long-term and excessive IFN stimulation leads to reduced sensitivity to the IFN signal. This provides a negative feedback mechanism that prevents inappropriate responses and autoimmunity. At present, however, neither IFN desensitization nor the normal physiological role of constitutive IFN are well characterized in fish. The objective here was therefore to produce and characterize a transgenic medaka fish (Oryzias latipes), designated IFNd-Tg, that constitutively overexpressed the IFNd gene. A dual promoter expression vector was constructed for overexpression of IFNd under an EF1α promoter and a DsRed reporter gene under control of a γF-crystaline promoter. The phenotype of the IFNd-Tg fish had a lower response to poly(I:C) and increased susceptibility to nervous necrosis virus (NNV) infection compared to wild-type (WT). Furthermore, transduction of IFN signals for STAT1b, STAT2 and IRF9 were down-regulated in the IFNd-Tg fish, and expression levels of RLR signal molecules (MDA5, MITA, IRF1 and IRF3) were lower than in WT. The constitutive overexpression of IFNd resulted in desensitization of IFN-stimulation, apparently due to downregulation of IFN signal transduction, and this caused increased susceptibility to NNV. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. The clinical effect of neutralizing antibodies against interferon-beta is independent of the type of interferon-beta used for patients with relapsing-remitting multiple sclerosis

    DEFF Research Database (Denmark)

    Koch-Henriksen, N.; Sorensen, P.S.; Bendtzen, K.

    2009-01-01

    OBJECTIVE: To establish whether the clinical effect of neutralizing antibodies (NAbs) against interferon-beta (IFN beta) depends on the type of IFNbeta (1a or 1b) used for treatment of patients with relapsing-remitting multiple sclerosis (MS). INTRODUCTION: NAbs against IFN beta-1b appear faster...... was considered as NAb-positive. We used a mixed logistic regression analysis in which NAb-status (three levels), IFN beta-preparation, and time since treatment started were included as explanatory variables, and relapse rate as response variable. RESULTS: In 1,309 patients, who were observed for 21,958 months......, 32.3% were classified as NAb-positive. The odds-ratio (OR) for relapses in NAb-positive months compared with NAb-negative months was 1.25; P = 0.02. The risk of relapses was higher with Betaferon than with Rebif22 (OR 1.26; P independent of whether...

  13. Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells.

    Directory of Open Access Journals (Sweden)

    James R Bowen

    2017-02-01

    Full Text Available Zika virus (ZIKV is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects, including microcephaly, and is associated with Guillain-Barre syndrome in adults. Dendritic cells (DCs are an important cell type during infection by multiple mosquito-borne flaviviruses, including dengue virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus. Despite this, the interplay between ZIKV and DCs remains poorly defined. Here, we found human DCs supported productive infection by a contemporary Puerto Rican isolate with considerable variability in viral replication, but not viral binding, between DCs from different donors. Historic isolates from Africa and Asia also infected DCs with distinct viral replication kinetics between strains. African lineage viruses displayed more rapid replication kinetics and infection magnitude as compared to Asian lineage viruses, and uniquely induced cell death. Infection of DCs with both contemporary and historic ZIKV isolates led to minimal up-regulation of T cell co-stimulatory and MHC molecules, along with limited secretion of inflammatory cytokines. Inhibition of type I interferon (IFN protein translation was observed during ZIKV infection, despite strong induction at the RNA transcript level and up-regulation of other host antiviral proteins. Treatment of human DCs with RIG-I agonist potently restricted ZIKV replication, while type I IFN had only modest effects. Mechanistically, we found all strains of ZIKV antagonized type I IFN-mediated phosphorylation of STAT1 and STAT2. Combined, our findings show that ZIKV subverts DC immunogenicity during infection, in part through evasion of type I IFN responses, but that the RLR signaling pathway is still capable of inducing an antiviral state, and therefore may serve as an antiviral therapeutic target.

  14. Tumor-suppressive effects of natural-type interferon-β through CXCL10 in melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, Hikaru; Nobeyama, Yoshimasa, E-mail: nobederm@jikei.ac.jp; Nakagawa, Hidemi

    2015-08-21

    Introduction: Type 1 interferon is in widespread use as adjuvant therapy to inhibit melanoma progression. Considering the tumor-suppressive effects of local administration of interferon-β (IFN-β) on lymphatic metastasis, the present study was conducted to identify melanoma-suppressive molecules that are up-regulated by IFN-β treatment of lymphatic endothelial cells. Materials and methods: Lymphatic endothelial cells, fibroblasts, and melanoma cells were treated with natural-type IFN-β, and melanoma cells were treated with CXCL10. Genome-wide oligonucleotide microarray analysis was performed using lymphatic endothelial cells with or without IFN-β treatment. Quantitative real-time reverse transcription-PCR and an enzyme-linked immunosorbent assay were performed to examine CXCL10 expression. A proliferation assay was performed to examine the effects of IFN-β and CXCL10 in melanoma cells. Results: Genome-wide microarray analyses detected CXCL10 as a gene encoding a secretory protein that was up-regulated by IFN-β in lymphatic endothelial cells. IFN-β treatment significantly induced CXCL10 in dermal lymphatic endothelial cells and melanoma cells that are highly sensitive to IFN-β. CXCL10 reduced melanoma cell proliferation in IFN-β-sensitive cells as well as resistant cells. Melanoma cells in which CXCL10 was knocked down were sensitive to IFN-β. CXCR3-B, which encodes the CXCL10 receptor, was up-regulated in melanoma cells with high sensitivity to IFN-β and down-regulated in melanoma cells with medium to low sensitivity. Conclusions: Our data suggest that IFN-β suppresses proliferation and metastasis from the local lymphatic system and melanoma cells via CXCL10. Down-regulation of CXCR3-B by IFN-β may be associated with resistance to IFN-β. - Highlights: • We search melanoma-suppressive molecules induced by IFN-β. • IFN-β induces a high amount of CXCL10 from lymphatic endothelial cells. • CXCL10 induction level in melanoma cells is correlated

  15. Interferon alpha treatment stimulates interferon gamma expression in type I NKT cells and enhances their antiviral effect against hepatitis C virus.

    Science.gov (United States)

    Miyaki, Eisuke; Hiraga, Nobuhiko; Imamura, Michio; Uchida, Takuro; Kan, Hiromi; Tsuge, Masataka; Abe-Chayama, Hiromi; Hayes, C Nelson; Makokha, Grace Naswa; Serikawa, Masahiro; Aikata, Hiroshi; Ochi, Hidenori; Ishida, Yuji; Tateno, Chise; Ohdan, Hideki; Chayama, Kazuaki

    2017-01-01

    Interferon (IFN) inhibits hepatitis C virus (HCV) replication through up-regulation of intrahepatic IFN-stimulated gene expression but also through activation of host immune cells. In the present study, we analyzed the immune cell-mediated antiviral effects of IFN-α using HCV-infected mice. Urokinase-type plasminogen activator (uPA)-severe combined immunodeficiency (SCID) mice with transplanted human hepatocytes were infected with genotype 1b HCV and injected with human peripheral blood mononuclear cells (PBMCs). IFN-α treatment following human PBMC transplantation resulted in a significant reduction in serum HCV RNA titers and a higher human CD45-positive mononuclear cell chimerism compared to mice without human PBMC transplantation. In mice with human PBMCs treated with IFN-α, serum concentrations of IFN-γ increased, and natural killer T (NKT) cells, especially type I NKT cells, produced IFN-γ. Mice in which IFN-γ signaling was blocked using antibody or in which transplanted PBMCs were depleted for type I NKT cells showed similar levels of anti-HCV effect compared with mice treated only with IFN-α. These results show that IFN-α stimulates IFN-γ expression in type 1 NKT cells and enhances the inhibition of HCV replication. We propose that type 1 NKT cells might represent a new therapeutic target for chronic hepatitis C patients.

  16. Expression and biological activity of two types of interferon genes in medaka (Oryzias latipes).

    Science.gov (United States)

    Maekawa, Shun; Chiang, Yi-An; Hikima, Jun-ichi; Sakai, Masahiro; Lo, Chu-Fang; Wang, Han-Ching; Aoki, Takashi

    2016-01-01

    Type I interferon (IFN) is one of most important cytokines for antiviral responses in fish innate immunity, after the induction pathway following pattern recognition. In this study, 2 types of type I IFN mRNA from a medaka (Japanese rice fish; Oryzias latipes) were identified and classified (phylogenetic analysis) into subgroup-a and -d by (designated olIFNa and olIFNd, respectively). Both olIFNa and olIFNd (encoding 197 and 187 amino acid residues, respectively) contained 2 cysteines. Gene expression pattern of olIFNa, olIFNd and IFN-stimulated genes (ISGs) was assessed (quantitative real-time reverse transcriptase PCR, qRT-PCR) in various organs (i.e., whole kidney, liver and spleen) of medaka stimulated by polyI:C or infected with nervous necrosis virus (NNV). Expression of olIFNa, olIFNd and ISGs, especially the ISG15 gene, were significantly upregulated after NNV-infection. Furthermore, olIFNa, olIFNd and ISGs mRNAs were sufficiently induced in DIT cells (i.e., medaka hepatoma cell line) transfected with polyI:C or infected with NNV. In addition, in vitro biological activities of recombinant olIFNa and olIFNd (rolIFNa and rolIFNd) produced by mammalian cell line HEK293T were also characterized. Expression of GIG1a and ISG15 genes in kidney cells of adult medaka were induced by rolIFNa or rolIFNd. The olIFNs-overexpressing DIT cells had reduced viral titers following NNV infection. Therefore, we inferred that 2 type I IFNs were involved in innate immunity (antiviral response) in medaka fish. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. The type I interferon response during viral infections: a "SWOT" analysis.

    Science.gov (United States)

    Gaajetaan, Giel R; Bruggeman, Cathrien A; Stassen, Frank R

    2012-03-01

    The type I interferon (IFN) response is a strong and crucial moderator for the control of viral infections. The strength of this system is illustrated by the fact that, despite some temporary discomfort like a common cold or diarrhea, most viral infections will not cause major harm to the healthy immunocompetent host. To achieve this, the immune system is equipped with a wide array of pattern recognition receptors and the subsequent coordinated type I IFN response orchestrated by plasmacytoid dendritic cells (pDCs) and conventional dendritic cells (cDCs). The production of type I IFN subtypes by dendritic cells (DCs), but also other cells is crucial for the execution of many antiviral processes. Despite this coordinated response, morbidity and mortality are still common in viral disease due to the ability of viruses to exploit the weaknesses of the immune system. Viruses successfully evade immunity and infection can result in aberrant immune responses. However, these weaknesses also open opportunities for improvement via clinical interventions as can be seen in current vaccination and antiviral treatment programs. The application of IFNs, Toll-like receptor ligands, DCs, and antiviral proteins is now being investigated to further limit viral infections. Unfortunately, a common threat during stimulation of immunity is the possible initiation or aggravation of autoimmunity. Also the translation from animal models to the human situation remains difficult. With a Strengths-Weaknesses-Opportunities-Threats ("SWOT") analysis, we discuss the interaction between host and virus as well as (future) therapeutic options, related to the type I IFN system. Copyright © 2011 John Wiley & Sons, Ltd.

  18. Type I interferon receptor in peripheral blood mononuclear cells may predict response to intra-arterial 5-fluorouracil + interferon therapy for advanced hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Korenaga K

    2011-04-01

    Full Text Available Yasuyuki Tomiyama1, Naoko Yoshioka1, Yoshiaki Yanai2,3, Tomoya Kawase1, Sohji Nishina1, Yuichi Hara1, Koji Yoshida1, Keiko Korenaga1, Masaaki Korenaga1, Keisuke Hino11Department of Hepatology and Pancreatology, Kawasaki Medical University, Kurashiki, Japan; 2Institute of Fujisaki, Hayashibara Biochemical Lab Inc, Okayama, Japan; 3Pharmaceutical Marketing Division, Otsuka Pharmaceutical Co Ltd, Tokyo, JapanBackground: Type 1 interferon alpha receptor 2 (IFNAR2 in the liver has been reported to be a predictive factor for the response to intra-arterial 5-fluorouracil (5-FU + systemic interferon (IFN-alpha combination therapy in patients with advanced hepatocellular carcinoma. We tested whether IFNAR2 expression in peripheral blood mononuclear cells could predict the response to 5-FU + IFN.Methods: Predictive factors for survival and response to therapy were determined in 30 patients with advanced hepatocellular carcinoma who underwent treatment with 5-FU + IFN. IFNAR2 expression in peripheral blood mononuclear cells was measured in 11 of the 30 patients.Results: With a mean number of 4.2 courses of combination therapy, one patient (3% showed a complete response, eight (27% showed partial responses, 13 (43% had stable disease, and eight (27% showed progressive disease. The median survival time of responders (complete response/partial response was 12.7 months and that of nonresponders (stable disease/progressive disease was 7.5 months. The one-year and two-year cumulative survival rates of responders and nonresponders were 87/69% and 40/11%, respectively (P = 0.019. Multivariate analysis identified response to therapy (P = 0.037 as the sole independent determinant of survival. The expression level of IFNAR2 in peripheral blood mononuclear cells was significantly (P = 0.012 higher in responders (6.5 ± 2.4 than in nonresponders (2.4 ± 0.6, even though no clinical factors were identified as being associated with the response to the combination

  19. Type I Versus Type II Endometrial Cancer

    DEFF Research Database (Denmark)

    Noer, Mette Calundann; Antonsen, Sofie Leisby; Ottesen, Bent

    2018-01-01

    OBJECTIVE: Two distinct types of endometrial carcinoma (EC) with different etiology, tumor characteristics, and prognosis are recognized. We investigated if the prognostic impact of comorbidity varies between these 2 types of EC. Furthermore, we studied if the recently developed ovarian cancer....... A consistent association between increasing levels of comorbidity and poorer survival was observed for both types. Cox regression analyses revealed a significant interaction between cancer stage and comorbidity indicating that the impact of comorbidity varied with stage. In contrast, the interaction between...

  20. Reversible silencing of cytomegalovirus genomes by type I interferon governs virus latency.

    Directory of Open Access Journals (Sweden)

    Franziska Dağ

    2014-02-01

    Full Text Available Herpesviruses establish a lifelong latent infection posing the risk for virus reactivation and disease. In cytomegalovirus infection, expression of the major immediate early (IE genes is a critical checkpoint, driving the lytic replication cycle upon primary infection or reactivation from latency. While it is known that type I interferon (IFN limits lytic CMV replication, its role in latency and reactivation has not been explored. In the model of mouse CMV infection, we show here that IFNβ blocks mouse CMV replication at the level of IE transcription in IFN-responding endothelial cells and fibroblasts. The IFN-mediated inhibition of IE genes was entirely reversible, arguing that the IFN-effect may be consistent with viral latency. Importantly, the response to IFNβ is stochastic, and MCMV IE transcription and replication were repressed only in IFN-responsive cells, while the IFN-unresponsive cells remained permissive for lytic MCMV infection. IFN blocked the viral lytic replication cycle by upregulating the nuclear domain 10 (ND10 components, PML, Sp100 and Daxx, and their knockdown by shRNA rescued viral replication in the presence of IFNβ. Finally, IFNβ prevented MCMV reactivation from endothelial cells derived from latently infected mice, validating our results in a biologically relevant setting. Therefore, our data do not only define for the first time the molecular mechanism of IFN-mediated control of CMV infection, but also indicate that the reversible inhibition of the virus lytic cycle by IFNβ is consistent with the establishment of CMV latency.

  1. Bovine parainfluenza virus type 3 accessory proteins that suppress beta interferon production.

    Science.gov (United States)

    Komatsu, Takayuki; Takeuchi, Kenji; Gotoh, Bin

    2007-07-01

    The paramyxovirus P gene encodes accessory proteins antagonistic to interferon (IFN). Viral proteins responsible for the IFN antagonism, however, are distinct among paramyxoviruses. Here we determine bovine parainfluenza virus type 3 (bPIV3) IFN antagonists that suppress IFN-beta production, and investigate the underlying molecular mechanism. Of bPIV3 P gene products, C and V proteins were found to suppress double-stranded RNA-stimulated IFN-beta production. The V protein of bPIV3 and Sendai virus in the same genus Respirovirus significantly inhibits double-stranded RNA-stimulated IFN-beta production and the IFN-beta promoter activation enhanced by overexpression of MDA5 but not RIG-I, and yet does not suppress IFN-beta production induced by TRIF, TBK1, and IKKi. The V protein of both viruses specifically binds to MDA5 but not RIG-I. These results suggest that the V protein targets MDA5 for blockage of the IFN-beta gene activation signal. On the other hand, both bPIV3 and Sendai virus C proteins modestly inhibited IFN-beta production irrespective of a species of the signaling molecules used as an inducer. Interestingly, reporter gene expression driven by various promoters was also suppressed by the C proteins irrespective of the promoter species. These results demonstrate that the target of the respirovirus C protein is undoubtedly different from that of the V protein.

  2. Targeting type I interferon-mediated activation restores immune function in chronic HIV infection.

    Science.gov (United States)

    Zhen, Anjie; Rezek, Valerie; Youn, Cindy; Lam, Brianna; Chang, Nelson; Rick, Jonathan; Carrillo, Mayra; Martin, Heather; Kasparian, Saro; Syed, Philip; Rice, Nicholas; Brooks, David G; Kitchen, Scott G

    2017-01-03

    Chronic immune activation, immunosuppression, and T cell exhaustion are hallmarks of HIV infection, yet the mechanisms driving these processes are unclear. Chronic activation can be a driving force in immune exhaustion, and type I interferons (IFN-I) are emerging as critical components underlying ongoing activation in HIV infection. Here, we have tested the effect of blocking IFN-I signaling on T cell responses and virus replication in a murine model of chronic HIV infection. Using HIV-infected humanized mice, we demonstrated that in vivo blockade of IFN-I signaling during chronic HIV infection diminished HIV-driven immune activation, decreased T cell exhaustion marker expression, restored HIV-specific CD8 T cell function, and led to decreased viral replication. Antiretroviral therapy (ART) in combination with IFN-I blockade accelerated viral suppression, further decreased viral loads, and reduced the persistently infected HIV reservoir compared with ART treatment alone. Our data suggest that blocking IFN-I signaling in conjunction with ART treatment can restore immune function and may reduce viral reservoirs during chronic HIV infection, providing validation for IFN-I blockade as a potential therapy for HIV infection.

  3. Foot-and-mouth disease virus leader proteinase inhibits dsRNA-induced type I interferon transcription by decreasing interferon regulatory factor 3/7 in protein levels

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Dang; Fang, Liurong; Luo, Rui; Ye, Rui; Fang, Ying; Xie, Lilan; Chen, Huanchun [Division of Animal Infectious Diseases, State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China); Xiao, Shaobo, E-mail: shaoboxiao@yahoo.com [Division of Animal Infectious Diseases, State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China)

    2010-08-13

    Research highlights: {yields} FMDV L{sup pro} inhibits poly(I:C)-induced IFN-{alpha}1/{beta} mRNA expression. {yields} L{sup pro} inhibits MDA5-mediated activation of the IFN-{alpha}1/{beta} promoter. {yields} L{sup pro} significantly reduced the transcription of multiple IRF-responsive genes. {yields} L{sup pro} inhibits IFN-{alpha}1/{beta} promoter activation by decreasing IRF-3/7 in protein levels. {yields} The ability to process eIF-4G of L{sup pro} is not necessary to inhibit IFN-{alpha}1/{beta} activation. -- Abstract: The leader proteinase (L{sup pro}) of foot-and-mouth disease virus (FMDV) has been identified as an interferon-{beta} (IFN-{beta}) antagonist that disrupts the integrity of transcription factor nuclear factor {kappa}B (NF-{kappa}B). In this study, we showed that the reduction of double stranded RNA (dsRNA)-induced IFN-{alpha}1/{beta} expression caused by L{sup pro} was also associated with a decrease of interferon regulatory factor 3/7 (IRF-3/7) in protein levels, two critical transcription factors for activation of IFN-{alpha}/{beta}. Furthermore, overexpression of L{sup pro} significantly reduced the transcription of multiple IRF-responsive genes including 2',5'-OAS, ISG54, IP-10, and RANTES. Screening L{sup pro} mutants indicated that the ability to process eIF-4G of L{sup pro} is not required for suppressing dsRNA-induced activation of the IFN-{alpha}1/{beta} promoter and decreasing IRF-3/7 expression. Taken together, our results demonstrate that, in addition to disrupting NF-{kappa}B, L{sup pro} also decreases IRF-3/7 expression to suppress dsRNA-induced type I IFN production, suggesting multiple strategies used by FMDV to counteract the immune response to viral infection.

  4. Foot-and-mouth disease virus leader proteinase inhibits dsRNA-induced type I interferon transcription by decreasing interferon regulatory factor 3/7 in protein levels

    International Nuclear Information System (INIS)

    Wang, Dang; Fang, Liurong; Luo, Rui; Ye, Rui; Fang, Ying; Xie, Lilan; Chen, Huanchun; Xiao, Shaobo

    2010-01-01

    Research highlights: → FMDV L pro inhibits poly(I:C)-induced IFN-α1/β mRNA expression. → L pro inhibits MDA5-mediated activation of the IFN-α1/β promoter. → L pro significantly reduced the transcription of multiple IRF-responsive genes. → L pro inhibits IFN-α1/β promoter activation by decreasing IRF-3/7 in protein levels. → The ability to process eIF-4G of L pro is not necessary to inhibit IFN-α1/β activation. -- Abstract: The leader proteinase (L pro ) of foot-and-mouth disease virus (FMDV) has been identified as an interferon-β (IFN-β) antagonist that disrupts the integrity of transcription factor nuclear factor κB (NF-κB). In this study, we showed that the reduction of double stranded RNA (dsRNA)-induced IFN-α1/β expression caused by L pro was also associated with a decrease of interferon regulatory factor 3/7 (IRF-3/7) in protein levels, two critical transcription factors for activation of IFN-α/β. Furthermore, overexpression of L pro significantly reduced the transcription of multiple IRF-responsive genes including 2',5'-OAS, ISG54, IP-10, and RANTES. Screening L pro mutants indicated that the ability to process eIF-4G of L pro is not required for suppressing dsRNA-induced activation of the IFN-α1/β promoter and decreasing IRF-3/7 expression. Taken together, our results demonstrate that, in addition to disrupting NF-κB, L pro also decreases IRF-3/7 expression to suppress dsRNA-induced type I IFN production, suggesting multiple strategies used by FMDV to counteract the immune response to viral infection.

  5. A Versatile Vector for In Vivo Monitoring of Type I Interferon Induction and Signaling.

    Directory of Open Access Journals (Sweden)

    Estanislao Nistal-Villan

    Full Text Available Development of reporter systems for in vivo examination of IFN-β induction or signaling of type I interferon (IFN-I pathways is of great interest in order to characterize biological responses to different inducers such as viral infections. Several reporter mice have been developed to monitor the induction of both pathways in response to different agonists. However, alternative strategies that do not require transgenic mice breeding have to date not been reported. In addition, detection of these pathways in vivo in animal species other than mice has not yet been addressed. Herein we describe a simple method based on the use of an adeno-associated viral vector (AAV8-3xIRF-ISRE-Luc containing an IFN-β induction and signaling-sensitive promoter sequence controlling the expression of the reporter gene luciferase. This vector is valid for monitoring IFN-I responses in vivo elicited by diverse stimuli in different organs. Intravenous administration of the vector in C57BL/6 mice and Syrian hamsters was able to detect activation of the IFN pathway in the liver upon systemic treatment with different pro-inflammatory agents and infection with Newcastle disease virus (NDV. In addition, intranasal instillation of AAV8-3xIRF-ISRE-Luc showed a rapid and transient IFN-I response in the respiratory tract of mice infected with the influenza A/PR8/34 virus lacking the NS1 protein. In comparison, this response was delayed and exacerbated in mice infected with influenza A/PR/8 wild type virus. In conclusion, the AAV8-3xIRF-ISRE-Luc vector offers the possibility of detecting IFN-I activation in response to different stimuli and in different animal models with no need for reporter transgenic animals.

  6. 5HT(4) agonists inhibit interferon-gamma-induced MHC class II and B7 costimulatory molecules expression on cultured astrocytes

    NARCIS (Netherlands)

    Zeinstra, Esther M.; Wilczak, Nadine; Wilschut, Jan C.; Glazenburg, Lisa; Chesik, Daniel; Kroese, Frans G. M.; De Keyser, Jacques

    2006-01-01

    A failure of tight control of MHC class II expression on astrocytes may play a role in the development of autoimmune responses in multiple sclerosis. The 5-HT4 serotonin receptor agonists cisapride and prucalopride, at concentrations between 10(-10) M and 10(-8) M, reduced interferon-gamma-induced

  7. The C protein of measles virus inhibits the type I interferon response

    International Nuclear Information System (INIS)

    Shaffer, Jessica A.; Bellini, William J.; Rota, Paul A.

    2003-01-01

    Type I interferons (IFNα/β) are an important part of innate immunity to viral infections because they induce an antiviral response and limit viral replication until the adaptive response clears the infection. Since the nonstructural proteins of several paramyxoviruses inhibit the IFNα/β response, we chose to explore the role of the C protein of measles virus (MV) in such inhibition. Previous studies have suggested that the MV C protein may serve as a virulence factor, but its role in the pathogenesis of MV remains undefined. In the present study, a recombinant MV strain that does not express the C protein (MV C-) and its parental strain (Ed Tag) were used. Growth of MV C- was restricted in human peripheral blood mononuclear cells and HeLa cells, but in the presence of neutralizing antibodies to IFNα/β, MV C- produced titers that were equivalent to those of Ed Tag. In addition, expression of the MV C protein from plasmid DNA inhibited the production of an IFNα/β responsive reporter gene and, to a lesser extent, inhibited an IFNγ responsive reporter gene. The ability of the MV C protein to suppress the IFNα/β response was confirmed using a biologic assay. After IFNβ stimulation, HeLa cells infected with Ed Tag produced five-fold less IFNα/β than cells infected with MV C-. While the mechanism of inhibition remains unclear, these data suggest that the MV C protein plays an important role in the pathogenesis of MV by inhibiting IFNα/β signaling

  8. Cell-autonomous cytotoxicity of type I interferon responseviainduction of endoplasmic reticulum stress.

    Science.gov (United States)

    Mihailidou, Chrysovalantou; Papavassiliou, Athanasios G; Kiaris, Hippokratis

    2017-12-01

    The interaction of IFN with specific membrane receptors that transduce death-inducing signals is considered to be the principle mechanism of IFN-induced cytotoxicity. In this study, the classic non-cell-autonomous cytotoxicity of IFN was augmented by cell-autonomous mechanisms that operated independently of the interaction of IFN with its receptors. Cells primed to produce IFN by 5-azacytidine (5-aza) underwent endoplasmic reticulum (ER) stress. The chemical chaperones tauroursodeoxycholate (TUDCA) and 4-phenylbutyrate (4-PBA), as well as the iron chelator ciclopirox (CPX), which reduces ER stress, alleviated the cytotoxicity of 5-aza. Ablation of CCAAT-enhancer-binding protein homologous protein (CHOP), the major ER stress-associated proapoptotic transcription factor, protected fibroblasts from 5-aza only when the cytotoxicity was examined cell autonomously. In a medium-transfer experiment in which the cell-autonomous effects of 5-aza was dissociated, CHOP ablation was incapable of modulating cytotoxicity; however, neutralization of IFN receptor was highly effective. Also the levels of caspase activation showed a distinct profile between the cell-autonomous and the medium-transfer experiments. We suggest that besides the classic paracrine mechanism, cell-autonomous mechanisms that involve induction of ER stress also participate. These results have implications in the development of anti-IFN-based therapies and expand the class of pathologic states that are viewed as protein-misfolding diseases.-Mihailidou, C., Papavassiliou, A. G., Kiaris, H. Cell-autonomous cytotoxicity of type I interferon response via induction of endoplasmic reticulum stress. © FASEB.

  9. Type I Interferon Regulates the Expression of Long Non-Coding RNAs

    Science.gov (United States)

    Carnero, Elena; Barriocanal, Marina; Segura, Victor; Guruceaga, Elizabeth; Prior, Celia; Börner, Kathleen; Grimm, Dirk; Fortes, Puri

    2014-01-01

    Interferons (IFNs) are key players in the antiviral response. IFN sensing by the cell activates transcription of IFN-stimulated genes (ISGs) able to induce an antiviral state by affecting viral replication and release. IFN also induces the expression of ISGs that function as negative regulators to limit the strength and duration of IFN response. The ISGs identified so far belong to coding genes. However, only a small proportion of the transcriptome corresponds to coding transcripts and it has been estimated that there could be as many coding as long non-coding RNAs (lncRNAs). To address whether IFN can also regulate the expression of lncRNAs, we analyzed the transcriptome of HuH7 cells treated or not with IFNα2 by expression arrays. Analysis of the arrays showed increased levels of several well-characterized coding genes that respond to IFN both at early or late times. Furthermore, we identified several IFN-stimulated or -downregulated lncRNAs (ISRs and IDRs). Further validation showed that ISR2, 8, and 12 expression mimics that of their neighboring genes GBP1, IRF1, and IL6, respectively, all related to the IFN response. These genes are induced in response to different doses of IFNα2 in different cell lines at early (ISR2 or 8) or later (ISR12) time points. IFNβ also induced the expression of these lncRNAs. ISR2 and 8 were also induced by an influenza virus unable to block the IFN response but not by other wild-type lytic viruses tested. Surprisingly, both ISR2 and 8 were significantly upregulated in cultured cells and livers from patients infected with HCV. Increased levels of ISR2 were also detected in patients chronically infected with HIV. This is relevant as genome-wide guilt-by-association studies predict that ISR2, 8, and 12 may function in viral processes, in the IFN pathway and the antiviral response. Therefore, we propose that these lncRNAs could be induced by IFN to function as positive or negative regulators of the antiviral response. PMID:25414701

  10. Endothelial dysfunction is associated with activation of the type i interferon system and platelets in patients with systemic lupus erythematosus

    DEFF Research Database (Denmark)

    Tydén, Helena; Lood, Christian; Gullstrand, Birgitta

    2017-01-01

    Objectives Endothelial dysfunction may be connected to cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Type I interferons (IFNs) are central in SLE pathogenesis and are suggested to induce both endothelial dysfunction and platelet activation. In this study, we investigated...... the interplay between endothelial dysfunction, platelets and type I IFN in SLE. Methods We enrolled 148 patients with SLE and 79 sex-matched and age-matched healthy controls (HCs). Type I IFN activity was assessed with a reporter cell assay and platelet activation by flow cytometry. Endothelial dysfunction...... with activation of platelets and the type I IFN system. We suggest that an interplay between the type I IFN system, injured endothelium and activated platelets may contribute to development of CVD in SLE....

  11. Clash of the Cytokine Titans: counter-regulation of interleukin-1 and type I interferon-mediated inflammatory responses.

    Science.gov (United States)

    Mayer-Barber, Katrin D; Yan, Bo

    2017-01-01

    Over the past decades the notion of 'inflammation' has been extended beyond the original hallmarks of rubor (redness), calor (heat), tumor (swelling) and dolor (pain) described by Celsus. We have gained a more detailed understanding of the cellular players and molecular mediators of inflammation which is now being applied and extended to areas of biomedical research such as cancer, obesity, heart disease, metabolism, auto-inflammatory disorders, autoimmunity and infectious diseases. Innate cytokines are often central components of inflammatory responses. Here, we discuss how the type I interferon and interleukin-1 cytokine pathways represent distinct and specialized categories of inflammatory responses and how these key mediators of inflammation counter-regulate each other.

  12. DO GIANT PLANETS SURVIVE TYPE II MIGRATION?

    International Nuclear Information System (INIS)

    Hasegawa, Yasuhiro; Ida, Shigeru

    2013-01-01

    Planetary migration is one of the most serious problems to systematically understand the observations of exoplanets. We clarify that the theoretically predicted type II, migration (like type I migration) is too fast, by developing detailed analytical arguments in which the timescale of type II migration is compared with the disk lifetime. In the disk-dominated regime, the type II migration timescale is characterized by a local viscous diffusion timescale, while the disk lifetime is characterized by a global diffusion timescale that is much longer than the local one. Even in the planet-dominated regime where the inertia of the planet mass reduces the migration speed, the timescale is still shorter than the disk lifetime except in the final disk evolution stage where the total disk mass decays below the planet mass. This suggests that most giant planets plunge into the central stars within the disk lifetime, and it contradicts the exoplanet observations that gas giants are piled up at r ∼> 1 AU. We examine additional processes that may arise in protoplanetary disks: dead zones, photoevaporation of gas, and gas flow across a gap formed by a type II migrator. Although they make the type II migration timescale closer to the disk lifetime, we show that none of them can act as an effective barrier for rapid type II migration with the current knowledge of these processes. We point out that gas flow across a gap and the fraction of the flow accreted onto the planets are uncertain and they may have the potential to solve the problem. Much more detailed investigation for each process may be needed to explain the observed distribution of gas giants in extrasolar planetary systems

  13. Metformin activates type I interferon signaling against HCV via activation of adenosine monophosphate-activated protein kinase.

    Science.gov (United States)

    Tsai, Wei-Lun; Chang, Tsung-Hsien; Sun, Wei-Chi; Chan, Hoi-Hung; Wu, Chun-Ching; Hsu, Ping-I; Cheng, Jin-Shiung; Yu, Ming-Lung

    2017-11-03

    Activation of the type I interferon (IFN) signaling pathway is essential for the eradication of hepatitis C virus (HCV). Metformin can activate adenosine monophosphate-activated protein kinase (AMPK) to reduce insulin resistance. Cross talks between AMPK and IFN signaling remain unclear. To understand the influence of metformin on the type I IFN signaling pathway and HCV infection, the full-length HCV replicon OR6 cells and the infectious HCV clones JFH1 were used to assess the anti-HCV effect of the insulin sensitizers, metformin and pioglitazone. Immunofluorescence staining and the immunoblotting of HCV viral protein demonstrated that metformin, but not pioglitazone, inhibited HCV replication in OR-6 and JFH-1-infected Huh 7.5.1 cells. Immunoblotting data showed that metformin activated the phosphorylation of STAT-1 and STAT-2 in OR-6 and JFH-1 infected Huh 7.5.1 cells. Metformin enhanced the phosphorylation of AMPK, and the metformin-activated IFN signaling was down-regulated by AMPK inhibitor. After treatment of AMPK inhibitor, the level of HCV core protein decreased by metformin can be rescued. In conclusion, metformin activates type I interferon signaling and inhibits the replication of HCV via activation of AMPK.

  14. Temozolomide and interferon-alpha in metastatic melanoma: a phase II study of the Italian Melanoma Intergroup.

    Science.gov (United States)

    Ridolfi, Ruggero; Romanini, Antonella; Sileni, Vanna Chiarion; Michiara, Maria; Guida, Michele; Biasco, Guido; Poletti, Paola; Amaducci, Laura; Leoni, Maurizio; Ravaioli, Alessandra

    2004-08-01

    Temozolomide (TMZ) is a new oral alkylating agent which has proven to be as active as dacarbazine (DTIC) in the treatment of melanoma, but with a lower toxicity. A multicentric phase II trial was conducted in an out-patient setting to determine the therapeutic activity and safety of TMZ in combination with interferon-alpha (IFN-alpha). From June 2000 to July 2001, 41 patients were recruited to receive TMZ 200 mg/m orally on days 1-5 every 28 days and with 5 MU IFN-alpha subcutaneously three times a week, continuously for eight cycles or until disease progression occurred. Of the 40 treated patients, two complete responses (5%) and three partial responses (7.5%) were observed, with a median duration of 4 months (range, 1.5-13.5 months). Thirteen patients (32.5%) had stable disease for a median of 2.5 months. Time to progression was 2.6 months and the median overall survival was 11.8 months. Nine patients (22.5%) developed brain metastases. The grade 4 toxicity observed in seven patients was of a transient haematological nature. This combination therapy is well tolerated but does not appear to increase the response rate or overall survival with respect to TMZ alone or to chemotherapeutic regimens. Further and more complex associations of these two drugs could be investigated in specific subsets of patients, in particular to evaluate its real efficacy in preventing brain metastases. Copyright 2004 Lippincott Williams & Wilkins

  15. The type I interferon signature in leukocyte subsets from peripheral blood of patients with early arthritis: a major contribution by granulocytes

    NARCIS (Netherlands)

    de Jong, Tamarah D.; Lübbers, Joyce; Turk, Samina; Vosslamber, Saskia; Mantel, Elise; Bontkes, Hetty J.; van der Laken, Conny J.; Bijlsma, Johannes W.; van Schaardenburg, Dirkjan; Verweij, Cornelis L.

    2016-01-01

    The type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response. Identification of the cell type(s) contributing to this IFN signature could provide insight into the signature's functional consequences. The aim of

  16. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo

    DEFF Research Database (Denmark)

    Ank, Nina; West, Hans; Bartholdy, Christina

    2006-01-01

    -alpha/beta)-induced directly by stimulation with IFN-alpha or -lambda, thus identifying type III IFNs as IFN-stimulated genes. In vitro assays revealed that IFN-lambdas have appreciable antiviral activity against encephalomyocarditis virus (EMCV) but limited activity against herpes simplex virus type 2 (HSV-2), whereas IFN......Type III interferons (IFNs) (interleukin-28/29 or lambda interferon [IFN-lambda]) are cytokines with IFN-like activities. Here we show that several classes of viruses induce expression of IFN-lambda1 and -lambda2/3 in similar patterns. The IFN-lambdas were-unlike alpha/beta interferon (IFN...... had a more modest antiviral activity. Finally, pretreatment with IFN-lambda enhanced the levels of IFN-gamma in serum after HSV-2 infection. Thus, type III IFNs are expressed in response to most viruses and display potent antiviral activity in vivo against select viruses. The discrepancy between...

  17. Lambda Interferon (IFN-gamma), a Type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo

    DEFF Research Database (Denmark)

    Ank, Nina; West, Hans; Bartholdy, C.

    2006-01-01

    -alpha/beta)-induced directly by stimulation with IFN-alpha or -lambda, thus identifying type III IFNs as IFN-stimulated genes. In vitro assays revealed that IFN-lambdas have appreciable antiviral activity against encephalomyocarditis virus (EMCV) but limited activity against herpes simplex virus type 2 (HSV-2), whereas IFN......Type III interferons (IFNs) (interleukin-28/29 or lambda interferon [IFN-lambda]) are cytokines with IFN-like activities. Here we show that several classes of viruses induce expression of IFN-lambda1 and -lambda2/3 in similar patterns. The IFN-lambdas were-unlike alpha/beta interferon (IFN...... had a more modest antiviral activity. Finally, pretreatment with IFN-lambda enhanced the levels of IFN-gamma in serum after HSV-2 infection. Thus, type III IFNs are expressed in response to most viruses and display potent antiviral activity in vivo against select viruses. The discrepancy between...

  18. Microarray analyses demonstrate the involvement of type I interferons in psoriasiform pathology development in D6-deficient mice.

    Science.gov (United States)

    Baldwin, Helen M; Pallas, Kenneth; King, Vicky; Jamieson, Thomas; McKimmie, Clive S; Nibbs, Robert J B; Carballido, José M; Jaritz, Marcus; Rot, Antal; Graham, Gerard J

    2013-12-20

    The inflammatory response is normally limited by mechanisms regulating its resolution. In the absence of resolution, inflammatory pathologies can emerge, resulting in substantial morbidity and mortality. We have been studying the D6 chemokine scavenging receptor, which played an indispensable role in the resolution phase of inflammatory responses and does so by facilitating removal of inflammatory CC chemokines. In D6-deficient mice, otherwise innocuous cutaneous inflammatory stimuli induce a grossly exaggerated inflammatory response that bears many similarities to human psoriasis. In the present study, we have used transcriptomic approaches to define the molecular make up of this response. The data presented highlight potential roles for a number of cytokines in initiating and maintaining the psoriasis-like pathology. Most compellingly, we provide data indicating a key role for the type I interferon pathway in the emergence of this pathology. Neutralizing antibodies to type I interferons are able to ameliorate the psoriasis-like pathology, confirming a role in its development. Comparison of transcriptional data generated from this mouse model with equivalent data obtained from human psoriasis further demonstrates the strong similarities between the experimental and clinical systems. As such, the transcriptional data obtained in this preclinical model provide insights into the cytokine network active in exaggerated inflammatory responses and offer an excellent tool to evaluate the efficacy of compounds designed to therapeutically interfere with inflammatory processes.

  19. Heroin use is associated with lower levels of restriction factors and type I interferon expression and facilitates HIV-1 replication.

    Science.gov (United States)

    Zhu, Jia-Wu; Liu, Feng-Liang; Mu, Dan; Deng, De-Yao; Zheng, Yong-Tang

    Heroin use is associated with increased incidence of infectious diseases such as HIV-1 infection, as a result of immunosuppression to a certain extent. Host restriction factors are recently identified cellular proteins with potent antiviral activities. Whether heroin use impacts on the in vivo expression of restriction factors that result in facilitating HIV-1 replication is poorly understood. Here we recruited 432 intravenous drug users (IDUs) and 164 non-IDUs at high-risk behaviors. Based on serological tests, significantly higher prevalence of HIV-1 infection was observed among IDUs compared with non-IDUs. We included those IDUs and non-IDUs without HIV-1 infection, and found IDUs had significantly lower levels of TRIM5α, TRIM22, APOBEC3G, and IFN-α, -β expression than did non-IDUs. We also directly examined plasma viral load in HIV-1 mono-infected IDUs and non-IDUs and found HIV-1 mono-infected IDUs had significantly higher plasma viral load than did non-IDUs. Moreover, intrinsically positive correlation between type I interferon and TRIM5α or TRIM22 was observed, however, which was dysregulated following heroin use. Collectively, heroin use benefits HIV-1 replication that may be partly due to suppression of host restriction factors and type I interferon expression. Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  20. NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosis

    Science.gov (United States)

    Jiang, Zhaozhao; Fortune, Sarah M.; Coulombe, Francois; Behr, Marcel A.; Fitzgerald, Katherine A.; Sassetti, Christopher M.; Kelliher, Michelle A.

    2009-01-01

    While the recognition of microbial infection often occurs at the cell surface via Toll-like receptors, the cytosol of the cell is also under surveillance for microbial products that breach the cell membrane. An important outcome of cytosolic recognition is the induction of IFNα and IFNβ, which are critical mediators of immunity against both bacteria and viruses. Like many intracellular pathogens, a significant fraction of the transcriptional response to Mycobacterium tuberculosis infection depends on these type I interferons, but the recognition pathways responsible remain elusive. In this work, we demonstrate that intraphagosomal M. tuberculosis stimulates the cytosolic Nod2 pathway that responds to bacterial peptidoglycan, and this event requires membrane damage that is actively inflicted by the bacterium. Unexpectedly, this recognition triggers the expression of type I interferons in a Tbk1- and Irf5-dependent manner. This response is only partially impaired by the loss of Irf3 and therefore, differs fundamentally from those stimulated by bacterial DNA, which depend entirely on this transcription factor. This difference appears to result from the unusual peptidoglycan produced by mycobacteria, which we show is a uniquely potent agonist of the Nod2/Rip2/Irf5 pathway. Thus, the Nod2 system is specialized to recognize bacteria that actively perturb host membranes and is remarkably sensitive to mycobacteria, perhaps reflecting the strong evolutionary pressure exerted by these pathogens on the mammalian immune system. PMID:19578435

  1. An updated Type II supernova Hubble diagram

    Science.gov (United States)

    Gall, E. E. E.; Kotak, R.; Leibundgut, B.; Taubenberger, S.; Hillebrandt, W.; Kromer, M.; Burgett, W. S.; Chambers, K.; Flewelling, H.; Huber, M. E.; Kaiser, N.; Kudritzki, R. P.; Magnier, E. A.; Metcalfe, N.; Smith, K.; Tonry, J. L.; Wainscoat, R. J.; Waters, C.

    2018-03-01

    We present photometry and spectroscopy of nine Type II-P/L supernovae (SNe) with redshifts in the 0.045 ≲ z ≲ 0.335 range, with a view to re-examining their utility as distance indicators. Specifically, we apply the expanding photosphere method (EPM) and the standardized candle method (SCM) to each target, and find that both methods yield distances that are in reasonable agreement with each other. The current record-holder for the highest-redshift spectroscopically confirmed supernova (SN) II-P is PS1-13bni (z = 0.335-0.012+0.009), and illustrates the promise of Type II SNe as cosmological tools. We updated existing EPM and SCM Hubble diagrams by adding our sample to those previously published. Within the context of Type II SN distance measuring techniques, we investigated two related questions. First, we explored the possibility of utilising spectral lines other than the traditionally used Fe IIλ5169 to infer the photospheric velocity of SN ejecta. Using local well-observed objects, we derive an epoch-dependent relation between the strong Balmer line and Fe IIλ5169 velocities that is applicable 30 to 40 days post-explosion. Motivated in part by the continuum of key observables such as rise time and decline rates exhibited from II-P to II-L SNe, we assessed the possibility of using Hubble-flow Type II-L SNe as distance indicators. These yield similar distances as the Type II-P SNe. Although these initial results are encouraging, a significantly larger sample of SNe II-L would be required to draw definitive conclusions. Tables A.1, A.3, A.5, A.7, A.9, A.11, A.13, A.15 and A.17 are also available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (http://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/611/A25

  2. Measuring type II stresses using 3DXRD

    DEFF Research Database (Denmark)

    Oddershede, Jette; Schmidt, Søren; Poulsen, Henning Friis

    2010-01-01

    An algorithm is presented for characterization of the grain resolved (type II) stress states in a polycrystalline sample based on monochromatic X-ray diffraction data. The algorithm is a robust 12-parameter-per-grain fit of the centre-of-mass grain positions, orientations and stress tensors...

  3. Ester alkaloids from Cephalotaxus interfere with the 2'3'-cGAMP-induced type I interferon pathway in vitro.

    Directory of Open Access Journals (Sweden)

    Gayoung Park

    Full Text Available Dysregulated activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING pathway by self-DNA contributes to interferonopathy and promotes autoimmune diseases. To identify potential suppressors of STING-induced type I interferon (IFN induction, ethanol extracts of medicinal plants were screened for inhibitory activity against IFN-ß promoter activation. Notably, 70% ethanol extract of Cephalotaxus koreana specifically down-regulated STING-induced, but not TBK1- or IRF3-induced, IFN-ß promoter activity. The compounds exerting inhibitory activity specifically against STING-mediated IFN-ß promoter activation were identified as ester alkaloids isolated from the genus, Cephalotaxus, homoharringtonine and harringtonine. Furthermore, these two compounds inhibited 2'3'-cGAMP-induced IFN-stimulated gene expression and interaction between STING and TBK1. These suppressive effects were not observed with cephalotaxine devoid of the ester side-chain. Our data support the potential utility of homoharringtonine and harringtonine to treat STING-associated interferonopathy and autoimmune diseases.

  4. Intact type I Interferon production and IRF7 function in sooty mangabeys.

    Directory of Open Access Journals (Sweden)

    Steven E Bosinger

    Full Text Available In contrast to pathogenic HIV/SIV infections of humans and rhesus macaques (RMs, natural SIV infection of sooty mangabeys (SMs is typically non-pathogenic despite high viremia. Several studies suggested that low immune activation and relative resistance of CD4+ central memory T-cells from virus infection are mechanisms that protect SMs from AIDS. In 2008 it was reported that plasmacytoid dendritic cells (pDCs of SMs exhibit attenuated interferon-alpha (IFN-α responses to TLR7/9 ligands in vitro, and that species-specific amino acid substitutions in SM Interferon Regulatory Factor-7 (IRF7 are responsible for this observation. Based on these findings, these authors proposed that "muted" IFN-α responses are responsible for the benign nature of SIV infection in SMs. However, other studies indicated that acutely SIV-infected SMs show robust IFN-α responses and marked upregulation of Interferon Stimulated Genes (ISGs. To investigate this apparent disparity, we first examined the role of the reported IRF7 amino acid substitutions in SMs. To this end, we sequenced all IRF7 exons in 16 breeders, and exons displaying variability (exons 2,3,5,6,7,8 in the remainder of the colony (177 animals. We found that the reported Ser-Gly substitution at position 191 was a sequencing error, and that several of the remaining substitutions represent only minor alleles. In addition, functional assays using recombinant SM IRF7 showed no defect in its ability to translocate in the nucleus and drive transcription from an IFN-α promoter. Furthermore, in vitro stimulation of SM peripheral blood mononuclear cells with either the TLR7 agonist CL097 or SIV(mac239 induced an 500-800-fold induction of IFN-α and IFN-β mRNA, and levels of IFN-α production by pDCs similar to those of RMs or humans. These data establish that IFN-α and IRF7 signaling in SMs are largely intact, with differences with RMs that are minor and unlikely to play any role in the AIDS resistance of SIV

  5. Scalar dark matter with type II seesaw

    Directory of Open Access Journals (Sweden)

    Arnab Dasgupta

    2014-12-01

    Full Text Available We study the possibility of generating tiny neutrino mass through a combination of type I and type II seesaw mechanism within the framework of an abelian extension of standard model. The model also provides a naturally stable dark matter candidate in terms of the lightest neutral component of a scalar doublet. We compute the relic abundance of such a dark matter candidate and also point out how the strength of type II seesaw term can affect the relic abundance of dark matter. Such a model which connects neutrino mass and dark matter abundance has the potential of being verified or ruled out in the ongoing neutrino, dark matter, as well as accelerator experiments.

  6. The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis

    NARCIS (Netherlands)

    Brkic, Z.; Bon, L. van; Cossu, M.; Helden-Meeuwsen, C.G. van; Vonk, M.C.; Knaapen, H.; Berg, W. van den; Dalm, V.A.; Daele, P.L. van; Severino, A.; Maria, N.I.; Guillen, S.; Dik, W.A.; Beretta, L.; Versnel, M.A.; Radstake, T.

    2016-01-01

    BACKGROUND: Interferon (IFN) signature has been reported in definite systemic sclerosis (SSc) but it has not been characterised in early SSc (EaSSc). We aim at characterising IFN type I signature in SSc before overt skin fibrosis develops. METHODS: The expression of 11 IFN type I inducible genes was

  7. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren's syndrome and association with disease activity and BAFF gene expression

    NARCIS (Netherlands)

    Z. Brkic (Zana); M. de Maria; C.G. van Helden-Meeuwsen; J.P. van de Merwe (Joop); P.L.A. van Daele (Paul); V.A.S.H. Dalm (Virgil); M.E. Wildenberg; W. Beumer (Wouter); H.A. Drexhage (Hemmo); M.A. Versnel (Marjan)

    2013-01-01

    textabstractObjective To determine the prevalence of upregulation of interferon (IFN) type I inducible genes, the so called "IFN type I signature", in CD14 monocytes in 69 patients with primary Sjögren's syndrome (pSS) and 44 healthy controls (HC) and correlate it with disease manifestations and

  8. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjogren's syndrome and association with disease activity and BAFF gene expression

    NARCIS (Netherlands)

    Brkic, Zana; Maria, Naomi I.; van Helden-Meeuwsen, Cornelia G.; van de Merwe, Joop P.; van Daele, Paul L.; Dalm, Virgil A.; Wildenberg, Manon E.; Beumer, Wouter; Drexhage, Hemmo A.; Versnel, Marjan A.

    2013-01-01

    To determine the prevalence of upregulation of interferon (IFN) type I inducible genes, the so called 'IFN type I signature', in CD14 monocytes in 69 patients with primary Sjögren's syndrome (pSS) and 44 healthy controls (HC) and correlate it with disease manifestations and expression of B cell

  9. Type I interferon signals in macrophages and dendritic cells control dengue virus infection: implications for a new mouse model to test dengue vaccines.

    Science.gov (United States)

    Züst, Roland; Toh, Ying-Xiu; Valdés, Iris; Cerny, Daniela; Heinrich, Julia; Hermida, Lisset; Marcos, Ernesto; Guillén, Gerardo; Kalinke, Ulrich; Shi, Pei-Yong; Fink, Katja

    2014-07-01

    Dengue virus (DENV) infects an estimated 400 million people every year, causing prolonged morbidity and sometimes mortality. Development of an effective vaccine has been hampered by the lack of appropriate small animal models; mice are naturally not susceptible to DENV and only become infected if highly immunocompromised. Mouse models lacking both type I and type II interferon (IFN) receptors (AG129 mice) or the type I IFN receptor (IFNAR(-/-) mice) are susceptible to infection with mouse-adapted DENV strains but are severely impaired in mounting functional immune responses to the virus and thus are of limited use for study. Here we used conditional deletion of the type I IFN receptor (IFNAR) on individual immune cell subtypes to generate a minimally manipulated mouse model that is susceptible to DENV while retaining global immune competence. Mice lacking IFNAR expression on CD11c(+) dendritic cells and LysM(+) macrophages succumbed completely to DENV infection, while mice deficient in the receptor on either CD11c(+) or LysM(+) cells were susceptible to infection but often resolved viremia and recovered fully from infection. Conditional IFNAR mice responded with a swift and strong CD8(+) T-cell response to viral infection, compared to a weak response in IFNAR(-/-) mice. Furthermore, mice lacking IFNAR on either CD11c(+) or LysM(+) cells were also sufficiently immunocompetent to raise a protective immune response to a candidate subunit vaccine against DENV-2. These data demonstrate that mice with conditional deficiencies in expression of the IFNAR represent improved models for the study of DENV immunology and screening of vaccine candidates. Dengue virus infects 400 million people every year worldwide, causing 100 million clinically apparent infections, which can be fatal if untreated. Despite many years of research, there are no effective vaccine and no antiviral treatment available for dengue. Development of vaccines has been hampered in particular by the lack of

  10. KAP1 regulates type I interferon/STAT1-mediated IRF-1 gene expression

    International Nuclear Information System (INIS)

    Kamitani, Shinya; Ohbayashi, Norihiko; Ikeda, Osamu; Togi, Sumihito; Muromoto, Ryuta; Sekine, Yuichi; Ohta, Kazuhide; Ishiyama, Hironobu; Matsuda, Tadashi

    2008-01-01

    Signal transducers and activators of transcription (STATs) mediate cell proliferation, differentiation, and survival in immune responses, hematopoiesis, neurogenesis, and other biological processes. Recently, we showed that KAP1 is a novel STAT-binding partner that regulates STAT3-mediated transactivation. KAP1 is a universal co-repressor protein for the KRAB zinc finger protein superfamily of transcriptional repressors. In this study, we found KAP1-dependent repression of interferon (IFN)/STAT1-mediated signaling. We also demonstrated that endogenous KAP1 associates with endogenous STAT1 in vivo. Importantly, a small-interfering RNA-mediated reduction in KAP1 expression enhanced IFN-induced STAT1-dependent IRF-1 gene expression. These results indicate that KAP1 may act as an endogenous regulator of the IFN/STAT1 signaling pathway

  11. Müllerian inhibiting substance type II receptor (MISIIR): a novel, tissue-specific target expressed by gynecologic cancers.

    Science.gov (United States)

    Bakkum-Gamez, Jamie N; Aletti, Giovanni; Lewis, Kriste A; Keeney, Gary L; Thomas, Bijoy M; Navarro-Teulon, Isabelle; Cliby, William A

    2008-01-01

    Müllerian inhibiting substance type II receptor (MISIIR) is expressed by ovarian, breast, and prostate cancers [Masiakos PT, et al. Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) Type II Receptor, bind, and are responsive to MIS. Clin Cancer Res 1999;5:3488-99; Hoshiya Y, et al. Mullerian inhibiting substance promotes interferon {gamma}-induced gene expression and apoptosis in breast cancer cells. J Biol Chem 2003;278:51703-12; Hoshiya Y, et al. Mullerian inhibiting substance induces NFkB signaling in breast and prostate cancer cells. Mol. Cell. Endocrinol. 2003;211:43-9. [1-3

  12. Peculiar Type II supernovae from blue supergiants

    Science.gov (United States)

    Kleiser, Io K. W.; Poznanski, Dovi; Kasen, Daniel; Young, Timothy R.; Chornock, Ryan; Filippenko, Alexei V.; Challis, Peter; Ganeshalingam, Mohan; Kirshner, Robert P.; Li, Weidong; Matheson, Thomas; Nugent, Peter E.; Silverman, Jeffrey M.

    2011-07-01

    The vast majority of Type II supernovae (SNeII) are produced by red supergiants, but SN 1987A revealed that blue supergiants (BSGs) can produce members of this class as well, albeit with some peculiar properties. This best-studied event revolutionized our understanding of SNe and linking it to the bulk of Type II events is essential. We present here the optical photometry and spectroscopy gathered for SN 2000cb, which is clearly not a standard SNII and yet is not a SN 1987A analogue. The light curve of SN 2000cb is reminiscent of that of SN 1987A in shape, with a slow rise to a late optical peak, but on substantially different time-scales. Spectroscopically, SN 2000cb resembles a normal SNII, but with ejecta velocities that far exceed those measured for SN 1987A or normal SNeII, above 18 000 km s-1 for Hα at early times. The red colours, high velocities, late photometric peak and our modelling of this object all point towards a scenario involving the high-energy explosion of a small-radius star, most likely a BSG, producing 0.1 M⊙ of 56Ni. Adding a similar object to the sample, SN 2005ci, we derive a rate of ˜2 per cent of the core-collapse rate for this loosely defined class of BSG explosions.

  13. Aase-Smith Syndrome type II

    International Nuclear Information System (INIS)

    Soker, Murat; Ayyildiz, Orhan; Isikdogan, Abdurrahman

    2004-01-01

    Aase-Smith syndrome type II is a rare in childhood and there a few reported cases. Here, we report an 8-months-old boy with congenital red cell aplasia and triphalangeal thumbs. In addition to thumb anomalies. He presented with growth failure, hypertelorism and novel osseous radiologic abnormalities, large fontanelles and micrognathia as extraordinary. Some clinical symptoms had complete clinical remission with deflazacort treatment. (author)

  14. NNMSM type-II and -III

    Energy Technology Data Exchange (ETDEWEB)

    Haba, Naoyuki [Graduate School of Science and Engineering, Shimane University, Matsue, Shimane (Japan); Hokkaido University, Department of Physics, Faculty of Science, Sapporo, Hokkaido (Japan); Kaneta, Kunio [Hokkaido University, Department of Physics, Faculty of Science, Sapporo, Hokkaido (Japan); University of Tokyo, Kavli Institute for the Physics and Mathematics of the Universe (WPI), Kashiwa, Chiba (Japan); Osaka University, Department of Physics, Graduate School of Science, Toyonaka, Osaka (Japan); Takahashi, Ryo [Hokkaido University, Department of Physics, Faculty of Science, Sapporo, Hokkaido (Japan)

    2014-01-15

    We suggest two types of extension of the standard model, which are the so-called next to new minimal standard model type-II and -III. They can achieve gauge coupling unification as well as suitable dark matter abundance, small neutrino masses, baryon asymmetry of the universe, inflation, and dark energy. The gauge coupling unification can be realized by introducing two or three extra new fields, and they could explain charge quantization. We also show that there are regions in which the vacuum stability, coupling perturbativity, and correct dark matter abundance can be realized with current experimental data at the same time. (orig.)

  15. Exosome-mediated miR-146a transfer suppresses type I interferon response and facilitates EV71 infection.

    Directory of Open Access Journals (Sweden)

    Yuxuan Fu

    2017-09-01

    Full Text Available Exosomes can transfer genetic materials between cells. Their roles in viral infections are beginning to be appreciated. Researches have shown that exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modulate recipient's cellular response and result in productive infection of the recipient host. Here, we showed that EV71 infection resulted in upregulated exosome secretion and differential packaging of the viral genomic RNA and miR-146a into exosomes. We provided evidence showing that miR-146a was preferentially enriched in exosomes while the viral RNA was not in infected cells. Moreover, the exosomes contained replication-competent EV71 RNA in complex with miR-146a, Ago2, and GW182 and could mediate EV71 transmission independent of virus-specific receptor. The exosomal viral RNA could be transferred to and replicate in a new target cell while the exosomal miR-146a suppressed type I interferon response in the target cell, thus facilitating the viral replication. Additionally, we found that the IFN-stimulated gene factors (ISGs, BST-2/tetherin, were involved in regulating EV71-induced upregulation of exosome secretion. Importantly, in vivo study showed that exosomal viral RNA exhibited differential tissue accumulation as compared to the free virus particles. Together, our findings provide evidence that exosomes secreted by EV71-infected cells selectively packaged high level miR-146a that can be functionally transferred to and facilitate exosomal EV71 RNA to replicate in the recipient cells by suppressing type I interferon response.

  16. DMPD: TICAM-1 and TICAM-2: toll-like receptor adapters that participate in inductionof type 1 interferons. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15618008 TICAM-1 and TICAM-2: toll-like receptor adapters that participate in induc... Mar;37(3):524-9. (.png) (.svg) (.html) (.csml) Show TICAM-1 and TICAM-2: toll-like receptor adapters that p...articipate in inductionof type 1 interferons. PubmedID 15618008 Title TICAM-1 and TIC

  17. Type II canal configuration and Type I Dens invaginatus.

    Science.gov (United States)

    Liji, Mele Puthukudy; Chandrababu, Krishnankutty; Kumar, Maroli Ramesh; Jayashree, Santhadevi

    2014-07-01

    The prevalent notion about maxillary central incisor with normal external morphology is a tooth with single root and root canal. A case in which all four maxillary incisors were having Type II canal configurations (Vertucci's classification) is reported, in addition, the lateral incisors revealed dens invaginatus with a Type I pattern as suggested by Ohler's classification and a large periapical lesion was seen in relation to the right lateral incisor. The diagnosis was confirmed with the aid of spiral computed tomography (CT) and canals obturated. Nonsurgical healing of the lesion was assessed by reviewing the case at prefixed intervals of time.

  18. Cesarean Section and Interferon-Induced Helicase Gene Polymorphisms Combine to Increase Childhood Type 1 Diabetes Risk

    Science.gov (United States)

    Bonifacio, Ezio; Warncke, Katharina; Winkler, Christiane; Wallner, Maike; Ziegler, Anette-G.

    2011-01-01

    OBJECTIVE The incidence of type 1 diabetes is increasing. Delivery by cesarean section is also more prevalent, and it is suggested that cesarean section is associated with type 1 diabetes risk. We examine associations between cesarean delivery, islet autoimmunity and type 1 diabetes, and genes involved in type 1 diabetes susceptibility. RESEARCH DESIGN AND METHODS Cesarean section was examined as a risk factor in 1,650 children born to a parent with type 1 diabetes and followed from birth for the development of islet autoantibodies and type 1 diabetes. RESULTS Children delivered by cesarean section (n = 495) had more than twofold higher risk for type 1 diabetes than children born by vaginal delivery (hazard ratio [HR] 2.5; 95% CI 1.4–4.3; P = 0.001). Cesarean section did not increase the risk for islet autoantibodies (P = 0.6) but was associated with a faster progression to diabetes after the appearance of autoimmunity (P = 0.015). Cesarean section–associated risk was independent of potential confounder variables (adjusted HR 2.7;1.5–5.0; P = 0.001) and observed in children with and without high-risk HLA genotypes. Interestingly, cesarean section appeared to interact with immune response genes, including CD25 and in particular the interferon-induced helicase 1 gene, where increased risk for type 1 diabetes was only seen in children who were delivered by cesarean section and had type 1 diabetes–susceptible IFIH1 genotypes (12-year risk, 9.1 vs. cesarean section may be linked to viral responses in the preclinical autoantibody-positive disease phase. PMID:22110093

  19. Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity.

    Science.gov (United States)

    Nice, Timothy J; Osborne, Lisa C; Tomov, Vesselin T; Artis, David; Wherry, E John; Virgin, Herbert W

    2016-06-01

    In order for a virus to persist, there must be a balance between viral replication and immune clearance. It is commonly believed that adaptive immunity drives clearance of viral infections and, thus, dysfunction or viral evasion of adaptive immunity is required for a virus to persist. Type I interferons (IFNs) play pleiotropic roles in the antiviral response, including through innate control of viral replication. Murine norovirus (MNoV) replicates in dendritic cells (DCs) and type I IFN signaling in DCs is important for early control of MNoV replication. We show here that the non-persistent MNoV strain CW3 persists systemically when CD11c positive DCs are unable to respond to type I IFN. Persistence in this setting is associated with increased early viral titers, maintenance of DC numbers, increased expression of DC activation markers and an increase in CD8 T cell and antibody responses. Furthermore, CD8 T cell function is maintained during the persistent phase of infection and adaptive immune cells from persistently infected mice are functional when transferred to Rag1-/- recipients. Finally, increased early replication and persistence are also observed in mixed bone marrow chimeras where only half of the CD11c positive DCs are unable to respond to type I IFN. These findings demonstrate that increased early viral replication due to a cell-intrinsic innate immune deficiency is sufficient for persistence and a functional adaptive immune response is not sufficient for viral clearance.

  20. Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity.

    Directory of Open Access Journals (Sweden)

    Timothy J Nice

    2016-06-01

    Full Text Available In order for a virus to persist, there must be a balance between viral replication and immune clearance. It is commonly believed that adaptive immunity drives clearance of viral infections and, thus, dysfunction or viral evasion of adaptive immunity is required for a virus to persist. Type I interferons (IFNs play pleiotropic roles in the antiviral response, including through innate control of viral replication. Murine norovirus (MNoV replicates in dendritic cells (DCs and type I IFN signaling in DCs is important for early control of MNoV replication. We show here that the non-persistent MNoV strain CW3 persists systemically when CD11c positive DCs are unable to respond to type I IFN. Persistence in this setting is associated with increased early viral titers, maintenance of DC numbers, increased expression of DC activation markers and an increase in CD8 T cell and antibody responses. Furthermore, CD8 T cell function is maintained during the persistent phase of infection and adaptive immune cells from persistently infected mice are functional when transferred to Rag1-/- recipients. Finally, increased early replication and persistence are also observed in mixed bone marrow chimeras where only half of the CD11c positive DCs are unable to respond to type I IFN. These findings demonstrate that increased early viral replication due to a cell-intrinsic innate immune deficiency is sufficient for persistence and a functional adaptive immune response is not sufficient for viral clearance.

  1. Type I Interferon Production Induced by Streptococcus pyogenes-Derived Nucleic Acids Is Required for Host Protection

    Science.gov (United States)

    Gratz, Nina; Hartweger, Harald; Matt, Ulrich; Kratochvill, Franz; Janos, Marton; Sigel, Stefanie; Drobits, Barbara; Li, Xiao-Dong; Knapp, Sylvia; Kovarik, Pavel

    2011-01-01

    Streptococcus pyogenes is a Gram-positive human pathogen that is recognized by yet unknown pattern recognition receptors (PRRs). Engagement of these receptor molecules during infection with S. pyogenes, a largely extracellular bacterium with limited capacity for intracellular survival, causes innate immune cells to produce inflammatory mediators such as TNF, but also type I interferon (IFN). Here we show that signaling elicited by type I IFNs is required for successful defense of mice against lethal subcutaneous cellulitis caused by S. pyogenes. Type I IFN signaling was accompanied with reduced neutrophil recruitment to the site of infection. Mechanistic analysis revealed that macrophages and conventional dendritic cells (cDCs) employ different signaling pathways leading to IFN-beta production. Macrophages required IRF3, STING, TBK1 and partially MyD88, whereas in cDCs the IFN-beta production was fully dependent on IRF5 and MyD88. Furthermore, IFN-beta production by macrophages was dependent on the endosomal delivery of streptococcal DNA, while in cDCs streptococcal RNA was identified as the IFN-beta inducer. Despite a role of MyD88 in both cell types, the known IFN-inducing TLRs were individually not required for generation of the IFN-beta response. These results demonstrate that the innate immune system employs several strategies to efficiently recognize S. pyogenes, a pathogenic bacterium that succeeded in avoiding recognition by the standard arsenal of TLRs. PMID:21625574

  2. Type I interferon production induced by Streptococcus pyogenes-derived nucleic acids is required for host protection.

    Directory of Open Access Journals (Sweden)

    Nina Gratz

    2011-05-01

    Full Text Available Streptococcus pyogenes is a Gram-positive human pathogen that is recognized by yet unknown pattern recognition receptors (PRRs. Engagement of these receptor molecules during infection with S. pyogenes, a largely extracellular bacterium with limited capacity for intracellular survival, causes innate immune cells to produce inflammatory mediators such as TNF, but also type I interferon (IFN. Here we show that signaling elicited by type I IFNs is required for successful defense of mice against lethal subcutaneous cellulitis caused by S. pyogenes. Type I IFN signaling was accompanied with reduced neutrophil recruitment to the site of infection. Mechanistic analysis revealed that macrophages and conventional dendritic cells (cDCs employ different signaling pathways leading to IFN-beta production. Macrophages required IRF3, STING, TBK1 and partially MyD88, whereas in cDCs the IFN-beta production was fully dependent on IRF5 and MyD88. Furthermore, IFN-beta production by macrophages was dependent on the endosomal delivery of streptococcal DNA, while in cDCs streptococcal RNA was identified as the IFN-beta inducer. Despite a role of MyD88 in both cell types, the known IFN-inducing TLRs were individually not required for generation of the IFN-beta response. These results demonstrate that the innate immune system employs several strategies to efficiently recognize S. pyogenes, a pathogenic bacterium that succeeded in avoiding recognition by the standard arsenal of TLRs.

  3. Spectral modeling of Type II SNe

    Science.gov (United States)

    Dessart, Luc

    2015-08-01

    The red supergiant phase represents the final stage of evolution in the life of moderate mass (8-25Msun) massive stars. Hidden from view, the core changes considerably its structure, progressing through the advanced stages of nuclear burning, and eventually becomes degenerate. Upon reaching the Chandrasekhar mass, this Fe or ONeMg core collapses, leading to the formation of a proto neutron star. A type II supernova results if the shock that forms at core bounce, eventually wins over the envelope accretion and reaches the progenitor surface.The electromagnetic display of such core-collapse SNe starts with this shock breakout, and persists for months as the ejecta releases the energy deposited initially by the shock or continuously through radioactive decay. Over a timescale of weeks to months, the originally optically-thick ejecta thins out and turns nebular. SN radiation contains a wealth of information about the explosion physics (energy, explosive nucleosynthesis), the progenitor properties (structure and composition). Polarised radiation also offers signatures that can help constrain the morphology of the ejecta.In this talk, I will review the current status of type II SN spectral modelling, and emphasise that a proper solution requires a time dependent treatment of the radiative transfer problem. I will discuss the wealth of information that can be gleaned from spectra as well as light curves, from both the early times (photospheric phase) and late times (nebular phase). I will discuss the diversity of Type SNe properties and how they are related to the diversity of red supergiant stars from which they originate.SN radiation offers an alternate means of constraining the properties of red-supergiant stars. To wrap up, I will illustrate how SNe II-P can also be used as probes, for example to constrain the metallicity of their environment.

  4. Safety, tolerability, and mechanisms of antiretroviral activity of pegylated interferon Alfa-2a in HIV-1-monoinfected participants: a phase II clinical trial.

    Science.gov (United States)

    Asmuth, David M; Murphy, Robert L; Rosenkranz, Susan L; Lertora, Juan J L; Kottilil, Shyam; Cramer, Yoninah; Chan, Ellen S; Schooley, Robert T; Rinaldo, Charles R; Thielman, Nathan; Li, Xiao-Dong; Wahl, Sharon M; Shore, Jessica; Janik, Jennifer; Lempicki, Richard A; Simpson, Yaa; Pollard, Richard B

    2010-06-01

    To our knowledge, the antiviral activity of pegylated interferon alfa-2a has not been studied in participants with untreated human immunodeficiency virus type 1 (HIV-1) infection but without chronic hepatitis C virus (HCV) infection. Untreated HIV-1-infected volunteers without HCV infection received 180 microg of pegylated interferon alfa-2a weekly for 12 weeks. Changes in plasma HIV-1 RNA load, CD4(+) T cell counts, pharmacokinetics, pharmacodynamic measurements of 2',5'-oligoadenylate synthetase (OAS) activity, and induction levels of interferon-inducible genes (IFIGs) were measured. Nonparametric statistical analysis was performed. Eleven participants completed 12 weeks of therapy. The median plasma viral load decrease and change in CD4(+) T cell counts at week 12 were 0.61 log(10) copies/mL (90% confidence interval [CI], 0.20-1.18 log(10) copies/mL) and -44 cells/microL (90% CI, -95 to 85 cells/microL), respectively. There was no correlation between plasma viral load decreases and concurrent pegylated interferon plasma concentrations. However, participants with larger increases in OAS level exhibited greater decreases in plasma viral load at weeks 1 and 2 (r = -0.75 [90% CI, -0.93 to -0.28] and r = -0.61 [90% CI, -0.87 to -0.09], respectively; estimated Spearman rank correlation). Participants with higher baseline IFIG levels had smaller week 12 decreases in plasma viral load (0.66 log(10) copies/mL [90% CI, 0.06-0.91 log(10) copies/mL]), whereas those with larger IFIG induction levels exhibited larger decreases in plasma viral load (-0.74 log(10) copies/mL [90% CI, -0.93 to -0.21 log(10) copies/mL]). Pegylated interferon alfa-2a was well tolerated and exhibited statistically significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein levels (weeks 1 and 2) and IFIG induction levels (week 12) but not with pegylated interferon concentrations.

  5. Over-expression of mitochondrial antiviral signaling protein inhibits coxsackievirus B3 infection by enhancing type-I interferons production

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    Zhang Qing-Meng

    2012-12-01

    Full Text Available Abstract Background Recent studies have revealed that Mitochondrial Antiviral Signaling (MAVS protein plays an essential role in the inhibition of viral infection through type I interferon (IFN pathway. It has been shown that 3C (pro cysteine protease of coxsackievirus B3 (CVB3 cleaves MAVS to inhibit type I IFNs induction. Other workers also found that MAVS knock-out mice suffered CVB3 susceptibility and severe histopathological change. Accordingly,our experiments were designed to explore the protection of over-expressing MAVS against CVB3 infection and the possible mechanism. Results In this study, HeLa cells (transfected with MAVS constructs pre- or post- exposure to CVB3 were used to analyze the function of exogenous MAVS on CVB3 infection. The results revealed that though CVB3 infection induced production of type I IFNs, viral replication and cell death were not effectively inhibited. Similarly, exogenous MAVS increased type I IFNs moderately. Morever, we observed robust production of type I IFNs in CVB3 post-infected HeLa cells thereby successfully inhibiting CVB3 infection, as well formation of cytopathic effect (CPE and cell death. Finally, introduction of exogenous MAVS into CVB3 pre-infected cells also restricted viral infection efficiently by greatly up-regulating IFNs. Conclusions In summary, exogenous MAVS effectively prevents and controls CVB3 infection by modulating and promoting the production of type I IFNs. The IFNs level in MAVS over-expressing cells is still tightly regulated by CVB3 infection. Thus, the factors that up-regulate MAVS might be an alternative prescription in CVB3-related syndromes by enhancing IFNs production.

  6. Type I interferons are associated with subclinical markers of cardiovascular disease in a cohort of systemic lupus erythematosus patients.

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    Emily C Somers

    Full Text Available Systemic lupus erythematosus (SLE patients have a striking increase in cardiovascular (CV comorbidity not fully explained by the Framingham risk score. Recent evidence from in vitro studies suggests that type I interferons (IFN could promote premature CV disease (CVD in SLE. We assessed the association of type I IFN signatures with functional and anatomical evidence of vascular damage, and with biomarkers of CV risk in a cohort of lupus patients without overt CVD.Serum type I IFN activity (induction of five IFN-inducible genes; IFIGs from 95 SLE patient and 38 controls was quantified by real-time PCR. Flow mediated dilatation (FMD of the brachial artery and carotid intima media thickness (CIMT were quantified by ultrasound, and coronary calcification by computed tomography. Serum vascular biomarkers were measured by ELISA. We evaluated the effect of type I IFNs on FMD, CIMT and coronary calcification by first applying principal components analysis to combine data from five IFIGs into summary components that could be simultaneously modeled. Three components were derived explaining 97.1% of the total IFIG variation. Multivariable linear regression was utilized to investigate the association between the three components and other covariates, with the outcomes of FMD and CIMT; zero-inflated Poisson regression was used for modeling of coronary calcification. After controlling for traditional CV risk factors, enhanced serum IFN activity was significantly associated with decreased endothelial function in SLE patients and controls (p<0.05 for component 3, increased CIMT among SLE patients (p<0.01 for components 1 and 2, and severity of coronary calcification among SLE patients (p<0.001 for component 3.Type I IFNs are independently associated with atherosclerosis development in lupus patients without history of overt CVD and after controlling for Framingham risk factors. This study further supports the hypothesis that type I IFNs promote premature

  7. RNA-Seq Based Transcriptome Analysis of the Type I Interferon Host Response upon Vaccinia Virus Infection of Mouse Cells

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    Bruno Hernáez

    2017-01-01

    Full Text Available Vaccinia virus (VACV encodes the soluble type I interferon (IFN binding protein B18 that is secreted from infected cells and also attaches to the cell surface, as an immunomodulatory strategy to inhibit the host IFN response. By using next generation sequencing technologies, we performed a detailed RNA-seq study to dissect at the transcriptional level the modulation of the IFN based host response by VACV and B18. Transcriptome profiling of L929 cells after incubation with purified recombinant B18 protein showed that attachment of B18 to the cell surface does not trigger cell signalling leading to transcriptional activation. Consistent with its ability to bind type I IFN, B18 completely inhibited the IFN-mediated modulation of host gene expression. Addition of UV-inactivated virus particles to cell cultures altered the expression of a set of 53 cellular genes, including genes involved in innate immunity. Differential gene expression analyses of cells infected with replication competent VACV identified the activation of a broad range of host genes involved in multiple cellular pathways. Interestingly, we did not detect an IFN-mediated response among the transcriptional changes induced by VACV, even after the addition of IFN to cells infected with a mutant VACV lacking B18. This is consistent with additional viral mechanisms acting at different levels to block IFN responses during VACV infection.

  8. Identification of host cytosolic sensors and bacterial factors regulating the type I interferon response to Legionella pneumophila.

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    Kathryn M Monroe

    2009-11-01

    Full Text Available Legionella pneumophila is a gram-negative bacterial pathogen that replicates in host macrophages and causes a severe pneumonia called Legionnaires' Disease. The innate immune response to L. pneumophila remains poorly understood. Here we focused on identifying host and bacterial factors involved in the production of type I interferons (IFN in response to L. pneumophila. It was previously suggested that the delivery of L. pneumophila DNA to the host cell cytosol is the primary signal that induces the type I IFN response. However, our data are not easily reconciled with this model. We provide genetic evidence that two RNA-sensing proteins, RIG-I and MDA5, participate in the IFN response to L. pneumophila. Importantly, these sensors do not seem to be required for the IFN response to L. pneumophila DNA, whereas we found that RIG-I was required for the response to L. pneumophila RNA. Thus, we hypothesize that bacterial RNA, or perhaps an induced host RNA, is the primary stimulus inducing the IFN response to L. pneumophila. Our study also identified a secreted effector protein, SdhA, as a key suppressor of the IFN response to L. pneumophila. Although viral suppressors of cytosolic RNA-sensing pathways have been previously identified, analogous bacterial factors have not been described. Thus, our results provide new insights into the molecular mechanisms by which an intracellular bacterial pathogen activates and also represses innate immune responses.

  9. Characteristics of alpha/beta interferon induction after infection of murine fibroblasts with wild-type and mutant alphaviruses

    International Nuclear Information System (INIS)

    Burke, Crystal W.; Gardner, Christina L.; Steffan, Joshua J.; Ryman, Kate D.; Klimstra, William B.

    2009-01-01

    We examined the characteristics of interferon alpha/beta (IFN-α/β) induction after alphavirus or control Sendai virus (SeV) infection of murine fibroblasts (MEFs). As expected, SeV infection of wild-type (wt) MEFs resulted in strong dimerization of IRF3 and the production of high levels of IFN-α/β. In contrast, infection of MEFs with multiple alphaviruses failed to elicit detectable IFN-α/β. In more detailed studies, Sindbis virus (SINV) infection caused dimerization and nuclear migration of IRF3, but minimal IFN-β promoter activity, although surprisingly, the infected cells were competent for IFN production by other stimuli early after infection. A SINV mutant defective in host macromolecular synthesis shutoff induced IFN-α/β in the MEF cultures dependent upon the activities of the TBK1 IRF3 activating kinase and host pattern recognition receptors (PRRs) PKR and MDA5 but not RIG-I. These results suggest that wild-type alphaviruses antagonize IFN induction after IRF3 activation but also may avoid detection by host PRRs early after infection.

  10. Type I Interferon-Mediated Skewing of the Serotonin Synthesis Is Associated with Severe Disease in Systemic Lupus Erythematosus

    Science.gov (United States)

    Lood, Christian; Tydén, Helena; Gullstrand, Birgitta; Klint, Cecilia; Wenglén, Christina; Nielsen, Christoffer T.; Heegaard, Niels H. H.; Jönsen, Andreas; Kahn, Robin; Bengtsson, Anders A.

    2015-01-01

    Serotonin, a highly pro-inflammatory molecule released by activated platelets, is formed by tryptophan. Tryptophan is also needed in the production of kynurenine, a process mediated by the type I interferon (IFN)-regulated rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO). The aim of this study was to investigate levels of serotonin in patients with the autoimmune disease systemic lupus erythematosus (SLE), association to clinical phenotype and possible involvement of IDO in regulation of serotonin synthesis. Serotonin levels were measured in serum and plasma from patients with SLE (n=148) and healthy volunteers (n=79) by liquid chromatography and ELISA, as well as intracellularly in platelets by flow cytometry. We found that SLE patients had decreased serotonin levels in serum (p=0.01) and platelets (pserotonin (p=0.0008) as well as increased IDO activity (pserotonin levels in platelets and serum (pserotonin levels were associated with severe SLE with presence of anti-dsDNA antibodies and nephritis. In all, reduced serum serotonin levels in SLE patients were related to severe disease phenotype, including nephritis, suggesting involvement of important immunopathological processes. Further, our data suggest that type I IFNs, present in SLE sera, are able to up-regulate IDO expression, which may lead to decreased serum serotonin levels. PMID:25897671

  11. Protective Role of Toll-like Receptor 3-Induced Type I Interferon in Murine Coronavirus Infection of Macrophages

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    Sonia Navas-Martin

    2012-05-01

    Full Text Available Toll-like Receptors (TLRs sense viral infections and induce production of type I interferons (IFNs, other cytokines, and chemokines. Viral recognition by TLRs and other pattern recognition receptors (PRRs has been proven to be cell-type specific. Triggering of TLRs with selected ligands can be beneficial against some viral infections. Macrophages are antigen-presenting cells that express TLRs and have a key role in the innate and adaptive immunity against viruses. Coronaviruses (CoVs are single-stranded, positive-sense RNA viruses that cause acute and chronic infections and can productively infect macrophages. Investigation of the interplay between CoVs and PRRs is in its infancy. We assessed the effect of triggering TLR2, TLR3, TLR4, and TLR7 with selected ligands on the susceptibility of the J774A.1 macrophage cell line to infection with murine coronavirus (mouse hepatitis virus, [MHV]. Stimulation of TLR2, TLR4, or TLR7 did not affect MHV production. In contrast, pre-stimulation of TLR3 with polyinosinic-polycytidylic acid (poly I:C hindered MHV infection through induction of IFN-β in macrophages. We demonstrate that activation of TLR3 with the synthetic ligand poly I:C mediates antiviral immunity that diminishes (MHV-A59 or suppresses (MHV-JHM, MHV-3 virus production in macrophages.

  12. Ligand-independent interaction of the type I interferon receptor complex is necessary to observe its biological activity.

    Science.gov (United States)

    Krause, Christopher D; Digioia, Gina; Izotova, Lara S; Xie, Junxia; Kim, Youngsun; Schwartz, Barbara J; Mirochnitchenko, Olga V; Pestka, Sidney

    2013-10-01

    Ectopic coexpression of the two chains of the Type I and Type III interferon (IFN) receptor complexes (IFN-αR1 and IFN-αR2c, or IFN-λR1 and IL-10R2) yielded sensitivity to IFN-alpha or IFN-lambda in only some cells. We found that IFN-αR1 and IFN-αR2c exhibit FRET only when expressed at equivalent and low levels. Expanded clonal cell lines expressing both IFN-αR1 and IFN-αR2c were sensitive to IFN-alpha only when IFN-αR1 and IFN-αR2c exhibited FRET in the absence of human IFN-alpha. Coexpression of RACK-1 or Jak1 enhanced the affinity of the interaction between IFN-αR1 and IFN-αR2c. Both IFN-αR1 and IFN-αR2c exhibited FRET with Jak1 and Tyk2. Together with data showing that disruption of the preassociation between the IFN-gamma receptor chains inhibited its biological activity, we propose that biologically active IFN receptors require ligand-independent juxtaposition of IFN receptor chains assisted by their associated cytosolic proteins. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Choline Deficiency Causes Colonic Type II Natural Killer T (NKT) Cell Loss and Alleviates Murine Colitis under Type I NKT Cell Deficiency.

    Science.gov (United States)

    Sagami, Shintaro; Ueno, Yoshitaka; Tanaka, Shinji; Fujita, Akira; Niitsu, Hiroaki; Hayashi, Ryohei; Hyogo, Hideyuki; Hinoi, Takao; Kitadai, Yasuhiko; Chayama, Kazuaki

    2017-01-01

    Serum levels of choline and its derivatives are lower in patients with inflammatory bowel disease (IBD) than in healthy individuals. However, the effect of choline deficiency on the severity of colitis has not been investigated. In the present study, we investigated the role of choline deficiency in dextran sulfate sodium (DSS)-induced colitis in mice. Methionine-choline-deficient (MCD) diet lowered the levels of type II natural killer T (NKT) cells in the colonic lamina propria, peritoneal cavity, and mesenteric lymph nodes, and increased the levels of type II NKT cells in the livers of wild-type B6 mice compared with that in mice fed a control (CTR) diet. The gene expression pattern of the chemokine receptor CXCR6, which promotes NKT cell accumulation, varied between colon and liver in a manner dependent on the changes in the type II NKT cell levels. To examine the role of type II NKT cells in colitis under choline-deficient conditions, we assessed the severity of DSS-induced colitis in type I NKT cell-deficient (Jα18-/-) or type I and type II NKT cell-deficient (CD1d-/-) mice fed the MCD or CTR diets. The MCD diet led to amelioration of inflammation, decreases in interferon (IFN)-γ and interleukin (IL)-4 secretion, and a decrease in the number of IFN-γ and IL-4-producing NKT cells in Jα18-/- mice but not in CD1d-/- mice. Finally, adaptive transfer of lymphocytes with type II NKT cells exacerbated DSS-induced colitis in Jα18-/- mice with MCD diet. These results suggest that choline deficiency causes proinflammatory type II NKT cell loss and alleviates DSS-induced colitis. Thus, inflammation in DSS-induced colitis under choline deficiency is caused by type II NKT cell-dependent mechanisms, including decreased type II NKT cell and proinflammatory cytokine levels.

  14. Type I Interferon Reaction to Viral Infection in Interferon-Competent, Immortalized Cell Lines from the African Fruit Bat Eidolon helvum

    Science.gov (United States)

    Biesold, Susanne E.; Ritz, Daniel; Gloza-Rausch, Florian; Wollny, Robert; Drexler, Jan Felix; Corman, Victor M.; Kalko, Elisabeth K. V.; Oppong, Samuel; Drosten, Christian; Müller, Marcel A.

    2011-01-01

    Bats harbor several highly pathogenic zoonotic viruses including Rabies, Marburg, and henipaviruses, without overt clinical symptoms in the animals. It has been suspected that bats might have evolved particularly effective mechanisms to suppress viral replication. Here, we investigated interferon (IFN) response, -induction, -secretion and -signaling in epithelial-like cells of the relevant and abundant African fruit bat species, Eidolon helvum (E. helvum). Immortalized cell lines were generated; their potential to induce and react on IFN was confirmed, and biological assays were adapted to application in bat cell cultures, enabling comparison of landmark IFN properties with that of common mammalian cell lines. E. helvum cells were fully capable of reacting to viral and artificial IFN stimuli. E. helvum cells showed highest IFN mRNA induction, highly productive IFN protein secretion, and evidence of efficient IFN stimulated gene induction. In an Alphavirus infection model, O'nyong-nyong virus exhibited strong IFN induction but evaded the IFN response by translational rather than transcriptional shutoff, similar to other Alphavirus infections. These novel IFN-competent cell lines will allow comparative research on zoonotic, bat-borne viruses in order to model mechanisms of viral maintenance and emergence in bat reservoirs. PMID:22140523

  15. Nucleosynthesis in Type II Supernova Explosions

    Science.gov (United States)

    Elliott, Carrie; Hix, W. Raphael; Harris, A.; Manneschmidt, A.

    2016-09-01

    Type II are the most common class of the ``core collapse'' supernova, involving the destruction of a high mass star (> 8M⊙). Their death is a result of a self-gravitational force becoming unbalanced as fusion ceases in the stellar core, leading to the collapse of the core to form a neutron star. The propagation of the shock ignites fusion into heavier elements as it progress through the star. This process is the origin of most elements present in the universe. In recent years, the complex nature of the explosion (its hydrodynamics, transport of energy, and the created isotopes) have been studied with increasing physical fidelity. Detailed nucleosynthesis from models of these core collapse supernovae is calculated in a post-processing step, using thermodynamic trajectories. My work on the project has been to develop the tools to visualize the results of post-processing calculations in the 2D grid. National Science Foundation (NSF).

  16. Type I Interferon Induced Epigenetic Regulation of Macrophages Suppresses Innate and Adaptive Immunity in Acute Respiratory Viral Infection.

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    Danielle N Kroetz

    2015-12-01

    Full Text Available Influenza A virus (IAV is an airborne pathogen that causes significant morbidity and mortality each year. Macrophages (Mϕ are the first immune population to encounter IAV virions in the lungs and are required to control infection. In the present study, we explored the mechanism by which cytokine signaling regulates the phenotype and function of Mϕ via epigenetic modification of chromatin. We have found that type I interferon (IFN-I potently upregulates the lysine methyltransferase Setdb2 in murine and human Mϕ, and in turn Setdb2 regulates Mϕ-mediated immunity in response to IAV. The induction of Setdb2 by IFN-I was significantly impaired upon inhibition of the JAK-STAT signaling cascade, and chromatin immunoprecipitation revealed that both STAT1 and interferon regulatory factor 7 bind upstream of the transcription start site to induce expression. The generation of Setdb2LacZ reporter mice revealed that IAV infection results in systemic upregulation of Setdb2 in myeloid cells. In the lungs, alveolar Mϕ expressed the highest level of Setdb2, with greater than 70% lacZ positive on day 4 post-infection. Silencing Setdb2 activity in Mϕ in vivo enhanced survival in lethal IAV infection. Enhanced host protection correlated with an amplified antiviral response and less obstruction to the airways. By tri-methylating H3K9, Setdb2 silenced the transcription of Mx1 and Isg15, antiviral effectors that inhibit IAV replication. Accordingly, a reduced viral load in knockout mice on day 8 post-infection was linked to elevated Isg15 and Mx1 transcript in the lungs. In addition, Setdb2 suppressed the expression of a large number of other genes with proinflammatory or immunomodulatory function. This included Ccl2, a chemokine that signals through CCR2 to regulate monocyte recruitment to infectious sites. Consistently, knockout mice produced more CCL2 upon IAV infection and this correlated with a 2-fold increase in the number of inflammatory monocytes and

  17. Biogenesis of non-structural protein 1 (nsp1) and nsp1-mediated type I interferon modulation in arteriviruses

    Energy Technology Data Exchange (ETDEWEB)

    Han, Mingyuan; Kim, Chi Yong [Department of Pathobiology, University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue, Urbana, IL 61802 (United States); Rowland, Raymond R.R.; Fang, Ying [Department of Diagnostic Medicine and Pathobiology, Kansas State University, Manhattan, KS 66506 (United States); Kim, Daewoo [Department of Pathobiology, University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue, Urbana, IL 61802 (United States); Yoo, Dongwan, E-mail: dyoo@illinois.edu [Department of Pathobiology, University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue, Urbana, IL 61802 (United States)

    2014-06-15

    Type I interferons (IFNs-α/β) play a key role for the antiviral state of host, and the porcine arterivirus; porcine reproductive and respiratory syndrome virus (PRRSV), has been shown to down-regulate the production of IFNs during infection. Non-structural protein (nsp) 1 of PRRSV has been identified as a viral IFN antagonist, and the nsp1α subunit of nsp1 has been shown to degrade the CREB-binding protein (CBP) and to inhibit the formation of enhanceosome thus resulting in the suppression of IFN production. The study was expanded to other member viruses in the family Arteriviridae: equine arteritis virus (EAV), murine lactate dehydrogenase-elevating virus (LDV), and simian hemorrhagic fever virus (SHFV). While PRRSV–nsp1 and LDV–nsp1 were auto-cleaved to produce the nsp1α and nsp1β subunits, EAV–nsp1 remained uncleaved. SHFV–nsp1 was initially predicted to be cleaved to generate three subunits (nsp1α, nsp1β, and nsp1γ), but only two subunits were generated as SHFV–nsp1αβ and SHFV–nsp1γ. The papain-like cysteine protease (PLP) 1α motif in nsp1α remained inactive for SHFV, and only the PLP1β motif of nsp1β was functional to generate SHFV–nsp1γ subunit. All subunits of arterivirus nsp1 were localized in the both nucleus and cytoplasm, but PRRSV–nsp1β, LDV–nsp1β, EAV–nsp1, and SHFV–nsp1γ were predominantly found in the nucleus. All subunits of arterivirus nsp1 contained the IFN suppressive activity and inhibited both interferon regulatory factor 3 (IRF3) and NF-κB mediated IFN promoter activities. Similar to PRRSV–nsp1α, CBP degradation was evident in cells expressing LDV–nsp1α and SHFV–nsp1γ, but no such degradation was observed for EAV–nsp1. Regardless of CBP degradation, all subunits of arterivirus nsp1 suppressed the IFN-sensitive response element (ISRE)-promoter activities. Our data show that the nsp1-mediated IFN modulation is a common strategy for all arteriviruses but their mechanism of action may differ

  18. Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.

    Directory of Open Access Journals (Sweden)

    Juliet Morrison

    2013-03-01

    Full Text Available An estimated 50 million dengue virus (DENV infections occur annually and more than forty percent of the human population is currently at risk of developing dengue fever (DF or dengue hemorrhagic fever (DHF. Despite the prevalence and potential severity of DF and DHF, there are no approved vaccines or antiviral therapeutics available. An improved understanding of DENV immune evasion is pivotal for the rational development of anti-DENV therapeutics. Antagonism of type I interferon (IFN-I signaling is a crucial mechanism of DENV immune evasion. DENV NS5 protein inhibits IFN-I signaling by mediating proteasome-dependent STAT2 degradation. Only proteolytically-processed NS5 can efficiently mediate STAT2 degradation, though both unprocessed and processed NS5 bind STAT2. Here we identify UBR4, a 600-kDa member of the N-recognin family, as an interacting partner of DENV NS5 that preferentially binds to processed NS5. Our results also demonstrate that DENV NS5 bridges STAT2 and UBR4. Furthermore, we show that UBR4 promotes DENV-mediated STAT2 degradation, and most importantly, that UBR4 is necessary for efficient viral replication in IFN-I competent cells. Our data underscore the importance of NS5-mediated STAT2 degradation in DENV replication and identify UBR4 as a host protein that is specifically exploited by DENV to inhibit IFN-I signaling via STAT2 degradation.

  19. Inactivation of the type I interferon pathway reveals long double-stranded RNA-mediated RNA interference in mammalian cells.

    Science.gov (United States)

    Maillard, Pierre V; Van der Veen, Annemarthe G; Deddouche-Grass, Safia; Rogers, Neil C; Merits, Andres; Reis E Sousa, Caetano

    2016-12-01

    RNA interference (RNAi) elicited by long double-stranded (ds) or base-paired viral RNA constitutes the major mechanism of antiviral defence in plants and invertebrates. In contrast, it is controversial whether it acts in chordates. Rather, in vertebrates, viral RNAs induce a distinct defence system known as the interferon (IFN) response. Here, we tested the possibility that the IFN response masks or inhibits antiviral RNAi in mammalian cells. Consistent with that notion, we find that sequence-specific gene silencing can be triggered by long dsRNAs in differentiated mouse cells rendered deficient in components of the IFN pathway. This unveiled response is dependent on the canonical RNAi machinery and is lost upon treatment of IFN-responsive cells with type I IFN Notably, transfection with long dsRNA specifically vaccinates IFN-deficient cells against infection with viruses bearing a homologous sequence. Thus, our data reveal that RNAi constitutes an ancient antiviral strategy conserved from plants to mammals that precedes but has not been superseded by vertebrate evolution of the IFN system. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  20. Type I interferons as stimulators of DC-mediated cross-priming: impact on anti-tumor response

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    Giovanna eSchiavoni

    2013-12-01

    Full Text Available Induction of potent tumor-specific cytotoxic T-cell responses is a fundamental objective in anticancer therapeutic strategies. This event requires that antigen-presenting cells (APC present tumor-associated antigens (Ag on their MHC class-I molecule, in a process termed cross-presentation. Dendritic cells (DC are particularly keen on this task and can induce the cross-priming of CD8+ T cells, when exposed to danger or inflammatory signals that stimulate their activation. Type I interferons (IFN-I, a family of long-known immunostimulatory cytokines, have been proven to produce optimal activation signal for DC-induced cross-priming. Recent in vitro and in vivo evidences have suggested that IFN-I -stimulated cross-priming by DC against tumor-associated Ag is a key mechanism for cancer immunosurveillance and may be usefully exploited to boost anti-tumor CD8+ T-cell responses. Here, we will review the cross-presentation properties of different DC subsets, with special focus on cell-associated and tumor Ag, and discuss how IFN-I can modify this function, with the aim of identifying more specific and effective strategies for improving anticancer responses.

  1. Understanding the role of type 1 interferon in resistance to cancer ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Chemotherapy is the main form of treatment for cancer, but it cannot cure most types of cancer. Another form of treatment is immunotherapy, which aims to stimulate cells of the body's immune system (T cells) to kill cancer cells. Unfortunately, cancers may become resistant to T cells in the same way they learned to resist ...

  2. Elevated sodium chloride drives type I interferon signaling in macrophages and increases antiviral resistance.

    Science.gov (United States)

    Zhang, Wu-Chang; Du, Lin-Juan; Zheng, Xiao-Jun; Chen, Xiao-Qing; Shi, Chaoji; Chen, Bo-Yan; Sun, Xue-Nan; Li, Chao; Zhang, Yu-Yao; Liu, Yan; Xiao, Hui; Leng, Qibin; Jiang, Xinquan; Zhang, Zhiyuan; Sun, Shuyang; Duan, Sheng-Zhong

    2018-01-19

    Type I IFN production and signaling in macrophages play critical roles in innate immune responses. High salt ( i.e. high concentrations of NaCl) has been proposed to be an important environmental factor that influences immune responses in multiple ways. However, it remains unknown whether high salt regulates type I IFN production and signaling in macrophages. Here, we demonstrated that high salt promoted IFNβ production and its signaling in both human and mouse macrophages, and consequentially primed macrophages for strengthened immune sensing and signaling when challenged with viruses or viral nucleic acid analogues. Using both pharmacological inhibitors and RNA interference we showed that these effects of high salt on IFNβ signaling were mediated by the p38 MAPK/ATF2/AP1 signaling pathway. Consistently, high salt increased resistance to vesicle stomatitis virus (VSV) infection in vitro. In vivo data indicated that a high-salt diet protected mice from lethal VSV infection. Taken together, these results identify high salt as a crucial regulator of type I IFN production and signaling, shedding important new light on the regulation of innate immune responses. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Interferon-γ from Brain Leukocytes Enhances Meningitis by Type 4 Streptococcus pneumoniae

    Science.gov (United States)

    Pettini, Elena; Fiorino, Fabio; Cuppone, Anna Maria; Iannelli, Francesco; Medaglini, Donata; Pozzi, Gianni

    2015-01-01

    Streptococcus pneumoniae is the leading cause of bacterial meningitis. Pneumococcal meningitis is a life-threatening disease with high rates of mortality and neurological sequelae. Immune targeting of S. pneumoniae is essential for clearance of infection; however, within the brain, the induced inflammatory response contributes to pathogenesis. In this study we investigate the local inflammatory response and the role of IFN-γ in a murine model of pneumococcal meningitis induced by intracranial injection of type 4 S. pneumoniae. Lymphoid and myeloid cell populations involved in meningitis, as well as cytokine gene expression, were investigated after infection. Animals were treated with a monoclonal antibody specific for murine IFN-γ to evaluate its role in animal survival. Intracranial inoculation of 3 × 104 colony-forming units of type 4 strain TIGR4 caused 75% of mice to develop meningitis within 4 days. The amount of lymphocytes, NK cells, neutrophils, monocytes and macrophages in the brain increased 48 h post infection. IFN-γ mRNA levels were about 240-fold higher in brains of infected mice compared to controls. Pro-inflammatory cytokines such as IL-1β and TNF-α, and TLR2 were also upregulated. In vivo treatment with anti-IFN-γ antibody increased survival of infected mice. This study shows that IFN-γ produced during meningitis by type 4 S. pneumoniae enhances bacterial pathogenesis exerting a negative effect on the disease outcome. PMID:26648922

  4. Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains.

    Directory of Open Access Journals (Sweden)

    Dane Parker

    2014-02-01

    Full Text Available The tremendous success of S. aureus as a human pathogen has been explained primarily by its array of virulence factors that enable the organism to evade host immunity. Perhaps equally important, but less well understood, is the importance of the intensity of the host response in determining the extent of pathology induced by S. aureus infection, particularly in the pathogenesis of pneumonia. We compared the pathogenesis of infection caused by two phylogenetically and epidemiologically distinct strains of S. aureus whose behavior in humans has been well characterized. Induction of the type I IFN cascade by strain 502A, due to a NOD2-IRF5 pathway, was the major factor in causing severe pneumonia and death in a murine model of pneumonia and was associated with autolysis and release of peptidogylcan. In contrast to USA300, 502A was readily eliminated from epithelial surfaces in vitro. Nonetheless, 502A caused significantly increased tissue damage due to the organisms that were able to invade systemically and trigger type I IFN responses, and this was ameliorated in Ifnar⁻/⁻ mice. The success of USA300 to cause invasive infection appears to depend upon its resistance to eradication from epithelial surfaces, but not production of specific toxins. Our studies illustrate the important and highly variable role of type I IFN signaling within a species and suggest that targeted immunomodulation of specific innate immune signaling cascades may be useful to prevent the excessive morbidity associated with S. aureus pneumonia.

  5. Neuropathogenesis of Zika Virus in a Highly Susceptible Immunocompetent Mouse Model after Antibody Blockade of Type I Interferon (Open Access Publisher’s Version)

    Science.gov (United States)

    2017-01-09

    and Zika virus infections—an unprecedented epidemic wave of mosquito-borne viruses in the Pacific 2012–2014. Euro Surveill 19. 13. Campos GS...RESEARCH ARTICLE Neuropathogenesis of Zika Virus in a Highly Susceptible Immunocompetent Mouse Model after Antibody Blockade of Type I Interferon...joseph.w.golden.ctr@mail.mil (JWG) Abstract Animal models are needed to better understand the pathogenic mechanisms of Zika virus (ZIKV) and to

  6. Osteoblasts from osteoarthritis patients show enhanced susceptibility to Ross River virus infection associated with delayed type I interferon responses.

    Science.gov (United States)

    Chen, Weiqiang; Foo, Suan-Sin; Li, Rachel W; Smith, Paul N; Mahalingam, Suresh

    2014-11-19

    Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) have caused widespread outbreaks of chronic polyarthritis. The inflammatory responses in alphavirus-induced arthritis and osteoarthritis (OA) share many similar features, which suggests the possibility of exacerbated alphavirus-induced bone pathology in individuals with pre-existing OA. Here, we investigated the susceptibility of osteoblasts (OBs) from OA patients to RRV infection and dissected the immune mechanisms elicited from infection. Primary hOBs obtained from trabecular bone of healthy donors and OA patients were infected with RRV. Infectivity and viral replication were determined using flow cytometry and plaque assay, respectively. Real-time PCR was performed to determine expression kinetics of type I interferon (IFN)-related immune mediators and osteotropic factors. OA hOBs showed enhanced RRV infectivity and replication during infection, which was associated with delayed induction of IFN-β and RIG-I expression. Enhanced susceptibility of OA hOBs to RRV was associated with a more pronounced increase in RANKL/OPG ratio and expression of osteotropic factors (IL-6, IL-1β, TNF-α and CCL2) in comparison to RRV-infected healthy hOBs. Delayed activation of type I IFN-signalling pathway may have contributed to enhanced susceptibility to RRV infection in hOBs from OA patients. RRV-induced increases in RANKL/OPG ratio and expression of osteotropic factors that favour bone resorption, which may be exacerbated during osteoarthritis. This study provides the novel insight that osteoarthritis may be a risk factor for exacerbated arthritogenic alphaviral infection.

  7. miR-222 isoforms are differentially regulated by type-I interferon.

    OpenAIRE

    Nejad, Charlotte; Pillman, Katherine A; Siddle, Katherine J; Pépin, Geneviève; Änkö, Minna-Liisa; McCoy, Claire E; Beilharz, Traude H; Quintana-Murci, Lluís; Goodall, Gregory J; Bracken, Cameron P; Gantier, Michael P

    2018-01-01

    Endogenous microRNAs (miRNAs) often exist as multiple isoforms (known as "isomiRs") with predominant variation around their 3'-end. Increasing evidence suggests that different isomiRs of the same family can have diverse functional roles, as recently demonstrated with the example of miR-222-3p 3'-end variants. While isomiR levels from a same miRNA family can vary between tissues and cell types, change of templated isomiR stoichiometry to stimulation has not been reported to date. Relying on sm...

  8. Recent Concepts of Ovarian Carcinogenesis: Type I and Type II

    Directory of Open Access Journals (Sweden)

    Masafumi Koshiyama

    2014-01-01

    Full Text Available Type I ovarian tumors, where precursor lesions in the ovary have clearly been described, include endometrioid, clear cell, mucinous, low grade serous, and transitional cell carcinomas, while type II tumors, where such lesions have not been described clearly and tumors may develop de novo from the tubal and/or ovarian surface epithelium, comprise high grade serous carcinomas, undifferentiated carcinomas, and carcinosarcomas. The carcinogenesis of endometrioid and clear cell carcinoma (CCC arising from endometriotic cysts is significantly influenced by the free iron concentration, which is associated with cancer development through the induction of persistent oxidative stress. A subset of mucinous carcinomas develop in association with ovarian teratomas; however, the majority of these tumors do not harbor any teratomatous component. Other theories of their origin include mucinous metaplasia of surface epithelial inclusions, endometriosis, and Brenner tumors. Low grade serous carcinomas are thought to evolve in a stepwise fashion from benign serous cystadenoma to a serous borderline tumor (SBT. With regard to high grade serous carcinoma, the serous tubal intraepithelial carcinomas (STICs of the junction of the fallopian tube epithelium with the mesothelium of the tubal serosa, termed the “tubal peritoneal junction” (TPJ, undergo malignant transformation due to their location, and metastasize to the nearby ovary and surrounding pelvic peritoneum. Other theories of their origin include the ovarian hilum cells.

  9. Nonlocal conductivity in type-II superconductors

    International Nuclear Information System (INIS)

    Mou, C.; Wortis, R.; Dorsey, A.T.; Huse, D.A.

    1995-01-01

    Multiterminal transport measurements on YBa 2 Cu 2 O 7 crystals in the vortex liquid regime have shown nonlocal conductivity on length scales up to 50 microns. Motivated by these results we explore the wave vector (k) dependence of the dc conductivity tensor, σ μν (k), in the Meissner, vortex lattice, and disordered phases of a type-II superconductor. Our results are based on time-dependent Ginzburg-Landau (TDGL) theory and on phenomenological arguments. We find four qualitatively different types of behavior. First, in the Meissner phase, the conductivity is infinite at k=0 and is a continuous function of k, monotonically decreasing with increasing k. Second, in the vortex-lattice phase, in the absence of pinning, the conductivity is finite (due to flux flow) at k=0; it is discontinuous there and remains qualitatively like the Meissner phase for k>0. Third, in the vortex liquid regime in a magnetic field and at low temperature, the conductivity is finite, smooth and nonmonotonic, first increasing with k at small k and then decreasing at larger k. This third behavior is expected to apply at temperatures just above the melting transition of the vortex lattice, where the vortex liquid shows strong short-range order and a large viscosity. Finally, at higher temperatures in the disordered phase, the conductivity is finite, smooth and again monotonically decreasing with k. This last, monotonic behavior applies in zero magnetic field for the entire disordered phase, i.e., at all temperatures above T c , while in a field the nonmonotonic behavior may occur in a low-temperature portion of the disordered phase

  10. Type I interferon is critical for the homeostasis and functional maturation of type 3 γδ T cells

    DEFF Research Database (Denmark)

    Agerholm, Rasmus; Kadekar, Darshana Dattatraya; Rizk, John

    2017-01-01

    Type I IFN (IFN-I) is highly expressed during viral infection and many autoimmune pathologies such as SLE and psoriasis. In addition, IFN-I is important to maintain the homeostasis of a number of different immune populations. Our aim was to identify whether IFN-I regulates type 3 γδ T (γδT3) cells...... behavior. Such γδT3 anergy is characterized by failure to induce skin inflammation and unresponsiveness to cytokine stimuli. Moreover, IFNAR deficient mice display deregulated γδT3homeostasis due to a neonatal maturation defect. In conclusion, our data show that tonic type I IFN signaling during neonatal...

  11. Type-II Symmetry-Protected Topological Dirac Semimetals

    Science.gov (United States)

    Chang, Tay-Rong; Xu, Su-Yang; Sanchez, Daniel S.; Tsai, Wei-Feng; Huang, Shin-Ming; Chang, Guoqing; Hsu, Chuang-Han; Bian, Guang; Belopolski, Ilya; Yu, Zhi-Ming; Yang, Shengyuan A.; Neupert, Titus; Jeng, Horng-Tay; Lin, Hsin; Hasan, M. Zahid

    2017-07-01

    The recent proposal of the type-II Weyl semimetal state has attracted significant interest. In this Letter, we propose the concept of the three-dimensional type-II Dirac fermion and theoretically identify this new symmetry-protected topological state in the large family of transition-metal icosagenides, M A3 (M =V , Nb, Ta; A =Al , Ga, In). We show that the VAl3 family features a pair of strongly Lorentz-violating type-II Dirac nodes and that each Dirac node can be split into four type-II Weyl nodes with chiral charge ±1 via symmetry breaking. Furthermore, we predict that the Landau level spectrum arising from the type-II Dirac fermions in VAl3 is distinct from that of known Dirac or Weyl semimetals. We also demonstrate a topological phase transition from a type-II Dirac semimetal to a quadratic Weyl semimetal or a topological crystalline insulator via crystalline distortions.

  12. Serum levels of the interferon-gamma-inducing cytokine interleukin-18 are increased in individuals at high risk of developing type I diabetes

    DEFF Research Database (Denmark)

    Nicoletti, F; Conget, I; Di Marco, R

    2001-01-01

    Interleukin (IL)-18 is a cytokine primarily produced by macrophages and capable of inducing T lymphocyte synthesis of interferon (IFN)-gamma. An up-regulated synthesis of IFN-gamma with consequential Type I cytokine dominance has been repeatedly shown in Type I (insulin-dependent) diabetes mellitus...... and thought to be involved in its pathogenesis. Because increased production of IFN-gamma could be secondary to a dysregulated synthesis of IL-18, we compared the circulating levels of IL-18 in patients with newly diagnosed Type I diabetes with those of non-diabetic first-degree relatives and healthy control...

  13. A Potent In Vivo Antitumor Efficacy of Novel Recombinant Type I Interferon.

    Science.gov (United States)

    Zhang, Kang-Jian; Yin, Xiao-Fei; Yang, Yuan-Qin; Li, Hui-Ling; Xu, Yan-Ni; Chen, Lie-Yang; Liu, Xi-Jun; Yuan, Su-Jing; Fang, Xian-Long; Xiao, Jing; Wu, Shuai; Xu, Hai-Neng; Chu, Liang; Katlinski, Kanstantsin V; Katlinskaya, Yuliya V; Guo, Rong-Bing; Wei, Guang-Wen; Wang, Da-Cheng; Liu, Xin-Yuan; Fuchs, Serge Y

    2017-04-15

    Purpose: Antiproliferative, antiviral, and immunomodulatory activities of endogenous type I IFNs (IFN1) prompt the design of recombinant IFN1 for therapeutic purposes. However, most of the designed IFNs exhibited suboptimal therapeutic efficacies against solid tumors. Here, we report evaluation of the in vitro and in vivo antitumorigenic activities of a novel recombinant IFN termed sIFN-I. Experimental Design: We compared primary and tertiary structures of sIFN-I with its parental human IFNα-2b, as well as affinities of these ligands for IFN1 receptor chains and pharmacokinetics. These IFN1 species were also compared for their ability to induce JAK-STAT signaling and expression of the IFN1-stimulated genes and to elicit antitumorigenic effects. Effects of sIFN-I on tumor angiogenesis and immune infiltration were also tested in transplanted and genetically engineered immunocompetent mouse models. Results: sIFN-I displayed greater affinity for IFNAR1 (over IFNAR2) chain of the IFN1 receptor and elicited a greater extent of IFN1 signaling and expression of IFN-inducible genes in human cells. Unlike IFNα-2b, sIFN-I induced JAK-STAT signaling in mouse cells and exhibited an extended half-life in mice. Treatment with sIFN-I inhibited intratumoral angiogenesis, increased CD8 + T-cell infiltration, and robustly suppressed growth of transplantable and genetically engineered tumors in immunodeficient and immunocompetent mice. Conclusions: These findings define sIFN-I as a novel recombinant IFN1 with potent preclinical antitumorigenic effects against solid tumor, thereby prompting the assessment of sIFN-I clinical efficacy in humans. Clin Cancer Res; 23(8); 2038-49. ©2016 AACR . ©2016 American Association for Cancer Research.

  14. Evasion of the Innate Immune Type I Interferon System by Monkeypox Virus.

    Science.gov (United States)

    Arndt, William D; Cotsmire, Samantha; Trainor, Kelly; Harrington, Heather; Hauns, Kevin; Kibler, Karen V; Huynh, Trung P; Jacobs, Bertram L

    2015-10-01

    The vaccinia virus (VACV) E3 protein has been shown to be important for blocking activation of the cellular innate immune system and allowing viral replication to occur unhindered. Mutation or deletion of E3L severely affects viral host range and pathogenesis. While the monkeypox virus (MPXV) genome encodes a homologue of the VACV E3 protein, encoded by the F3L gene, the MPXV gene is predicted to encode a protein with a truncation of 37 N-terminal amino acids. VACV with a genome encoding a similarly truncated E3L protein (VACV-E3LΔ37N) has been shown to be attenuated in mouse models, and infection with VACV-E3LΔ37N has been shown to lead to activation of the host antiviral protein kinase R pathway. In this report, we present data demonstrating that, despite containing a truncated E3 homologue, MPXV phenotypically resembles a wild-type (wt) VACV rather than VACV-E3LΔ37N. Thus, MPXV appears to contain a gene or genes that can suppress the phenotypes associated with an N-terminal truncation in E3. The suppression maps to sequences outside F3L, suggesting that the suppression is extragenic in nature. Thus, MPXV appears to have evolved mechanisms to minimize the effects of partial inactivation of its E3 homologue. Poxviruses have evolved to have many mechanisms to evade host antiviral innate immunity; these mechanisms may allow these viruses to cause disease. Within the family of poxviruses, variola virus (which causes smallpox) is the most pathogenic, while monkeypox virus is intermediate in pathogenicity between vaccinia virus and variola virus. Understanding the mechanisms of monkeypox virus innate immune evasion will help us to understand the evolution of poxvirus innate immune evasion capabilities, providing a better understanding of how poxviruses cause disease. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  15. The velocities of type II solar radio bursts

    International Nuclear Information System (INIS)

    Tlamicha, A.; Karlicky, M.

    1976-01-01

    A list is presented of type II radio bursts identified at Ondrejov between January 1973 and December 1974 in the frequency range of the dynamic spectrum 70 to 810 MHz. The velocities of shock waves in the individual cases of type II bursts are given using the fourfold Newkirk model. Some problems associated with type II radio bursts and with the propagation of the shock wave into the interplanetary space and into the region of the Earth are also discussed. (author)

  16. PKMiner: a database for exploring type II polyketide synthases

    OpenAIRE

    Kim Jinki; Yi Gwan-Su

    2012-01-01

    Abstract Background Bacterial aromatic polyketides are a pharmacologically important group of natural products synthesized by type II polyketide synthases (type II PKSs) in actinobacteria. Isolation of novel aromatic polyketides from microbial sources is currently impeded because of the lack of knowledge about prolific taxa for polyketide synthesis and the difficulties in finding and optimizing target microorganisms. Comprehensive analysis of type II PKSs and the prediction of possible polyke...

  17. Inefficient type I interferon-mediated antiviral protection of primary mouse neurons is associated with the lack of apolipoprotein l9 expression.

    Science.gov (United States)

    Kreit, Marguerite; Paul, Sophie; Knoops, Laurent; De Cock, Aurélie; Sorgeloos, Frédéric; Michiels, Thomas

    2014-04-01

    We examined the antiviral response promoted by type I interferons (IFN) in primary mouse neurons. IFN treatment of neuron cultures strongly upregulated the transcription of IFN-stimulated genes but conferred a surprisingly low resistance to infection by neurotropic viruses such as Theiler's murine encephalomyelitis virus (TMEV) or vesicular stomatitis virus (VSV). Response of primary mouse neurons to IFN treatment was heterogeneous, as many neurons failed to express the typical IFN response marker Mx1 after IFN treatment. This heterogeneous response of primary neurons correlated with a low level of basal expression of IFN-stimulated genes, such as Stat1, that are involved in signal transduction of the IFN response. In addition, transcriptomic analysis identified 15 IFN-responsive genes whose expression was low in IFN-treated primary neurons compared to that of primary fibroblasts derived from the same mice (Dhx58, Gvin1, Sp100, Ifi203 isoforms 1 and 2, Irgm2, Lgals3bp, Ifi205, Apol9b, Ifi204, Ifi202b, Tor3a, Slfn2, Ifi35, Lgals9). Among these genes, the gene coding for apolipoprotein L9b (Apol9b) displayed antiviral activity against Theiler's virus when overexpressed in L929 cells or in primary neurons. Accordingly, knocking down Apol9b expression in L929 cells increased viral replication. Therefore, we identified a new antiviral protein induced by interferon, ApoL9b, whose lack of expression in primary neurons likely contributes to the high sensitivity of these cells to viral infection. The type I interferon (IFN) response is an innate immune defense mechanism that is critical to contain viral infection in the host until an adaptive immune response can be mounted. Neurons are a paradigm for postmitotic, highly differentiated cells. Our data show that primary mouse neurons that are exposed to type I interferon remain surprisingly susceptible to viral infection. On one hand, the low level of basal expression of some factors in neurons might prevent a rapid response

  18. Self-dual nonsupersymmetric Type II String Compactifications

    International Nuclear Information System (INIS)

    Kachru, Shamit; Silverstein, Eva

    1998-01-01

    It has recently been proposed that certain nonsupersymmetric type II orbifolds have vanishing perturbative contributions to the cosmological constant. We show that techniques of Sen and Vafa allow one to construct dual type II descriptions of these models (some of which have no weakly coupled heterotic dual). The dual type II models are given by the same orbifolds with the string coupling S and a T 2 volume T exchanged. This allows us to argue that in various strongly coupled limits of the original type II models, there are weakly coupled duals which exhibit the same perturbative cancellations as the original models

  19. The use of monoclonal antibody (Rituximab in the treatment of type II mixed cryoglobulinemia

    Directory of Open Access Journals (Sweden)

    Thiago Carlos Gonçalves Rego

    Full Text Available Anti-CD20 monoclonal antibody has been successfully used to treat several self-immune diseases. The authors report the case of a 71 year-old female patient under the use of pegylated form of interferon á associated with ribavirin for the treatment of hepatitis C, who, after concluding the therapeutic program - negative Polymerase Chain Reaction (PCR - developed a severe cutaneous vasculitis, receiving the diagnostic of type II mixed cryoglobulinemia. Four sessions of plasmapheresis were prescribed along the period of 11 days, with no result. The choice made was to administer anti-CD 20 monoclonal antibody (rituximab, 375 mg/m², per week, during four consecutive weeks. One could observe fast recovery from the purpura, as well as total remission of urticaria.

  20. Type-II Superlattice Avalanche Photodiodes

    Science.gov (United States)

    Huang, Jun

    Type-II superlattice avalanche photodiodes have shown advantages compared to conventional mercury cadmium telluride photodiodes for infrared wavelength detection. However, surface or interface leakage current has been a major issue for superlattice avalanche photodiodes, especially in infrared wavelength region. First, passivation of the superlattice device with ammonium sulfide and thioacetamide was carried out, and its surface quality was studied by X-ray Photoelectron Spectroscopy. The study showed that both ammonium sulfide and thiacetamide passivation can actively remove the native oxide at the surface. Thiacetamide passivation combine more sulfur bonds with III-V elements than that of ammonium sulfide. Another X-ray photoelectron spectra of thiacetamide-treated atomic layer deposited zinc sulfide capped InAs/GaSb superlattice was performed to investigate the interface sulfur bond conditions. Sb--S and As--S bonds disappear while In-S bond gets enhanced, indicating that Indium Sulfide should be the major components at the interface after ZnS deposition. Second, the simulation of electrical characteristics for zinc sulfide, silicon nitride and silicon dioxide passivated superlattice devices was performed by SILVACO software to fit the experimental results and to discover the surface current mechanism. Different surface current mechanism strengths were found. Third, several novel dual-carrier avalanche photodiode structures were designed and simulated. The structures had alternate carrier multiplication regions, placed next to a wider electron multiplication region, creating dual-carrier multiplication feedback systems. Gain and excess noise factor of these structures were simulated and compared based on the dead space multiplication theory under uniform electric field. From the simulation, the applied bias can be greatly lowered or the thickness can be shrunk to achieve the same gain from the conventional device. The width of the thin region was the most

  1. Type II and type III deiodinase activity in human placenta as a function of gestational age

    NARCIS (Netherlands)

    Koopdonk-Kool, J. M.; de Vijlder, J. J.; Veenboer, G. J.; Ris-Stalpers, C.; Kok, J. H.; Vulsma, T.; Boer, K.; Visser, T. J.

    1996-01-01

    Thyroid hormones are essential for fetal development. T4 can be activated by type I (ID-I) and type II (ID-II) iodothyronine deiodinase or inactivated by type III deiodinase (ID-III). The influence of placental ID-II and ID-III on the regulation of fetal thyroid hormone levels was investigated.

  2. Ladder-like amplification of the type I interferon gene cluster in the human osteosarcoma cell line MG63

    Czech Academy of Sciences Publication Activity Database

    Marella, N.V.; Zeitz, M.J.; Malyavantham, K.S.; Pliss, A.; Matsui, S.; Goetze, S.; Bode, J.; Raška, Ivan; Berezney, R.

    2008-01-01

    Roč. 16, č. 8 (2008), s. 1177-1192 ISSN 0967-3849 Grant - others:GA MŠk(CZ) LC535 Program:LC Institutional research plan: CEZ:AV0Z50110509 Keywords : array comparative genomic hybridization * human osteosarcoma cells * interferon gene cluster Subject RIV: EB - Gene tics ; Molecular Biology Impact factor: 3.405, year: 2008

  3. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis.

    NARCIS (Netherlands)

    Axtell, R.C.; Jong, B.A. de; Boniface, K.; Voort, L.F. van der; Bhat, R.; Sarno, P. De; Naves, R.; Han, M.; Zhong, F.; Castellanos, J.G.; Mair, R.; Christakos, A.; Kolkowitz, I.; Katz, L.; Killestein, J.; Polman, C.H.; Waal Malefyt, R. de; Steinman, L.; Raman, C.

    2010-01-01

    Interferon-beta (IFN-beta) is the major treatment for multiple sclerosis. However, this treatment is not always effective. Here we have found congruence in outcome between responses to IFN-beta in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting multiple sclerosis (RRMS).

  4. Neuropathogenesis of Zika Virus in a Highly Susceptible Immunocompetent Mouse Model After Antibody Blockade of Type I Interferon

    Science.gov (United States)

    2016-12-12

    46. Sheehan KC, Lazear HM, Diamond MS, Schreiber RD (2015) Selective Blockade of Interferon-alpha and -beta Reveals Their Non-Redundant Functions ...4: 229-237. 49. Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, et al. (1998) Microglia-specific 750 localisation of a novel calcium binding

  5. The human adenovirus type 5 E1B 55 kDa protein obstructs inhibition of viral replication by type I interferon in normal human cells.

    Directory of Open Access Journals (Sweden)

    Jasdave S Chahal

    Full Text Available Vectors derived from human adenovirus type 5, which typically lack the E1A and E1B genes, induce robust innate immune responses that limit their therapeutic efficacy. We reported previously that the E1B 55 kDa protein inhibits expression of a set of cellular genes that is highly enriched for those associated with anti-viral defense and immune responses, and includes many interferon-sensitive genes. The sensitivity of replication of E1B 55 kDa null-mutants to exogenous interferon (IFN was therefore examined in normal human fibroblasts and respiratory epithelial cells. Yields of the mutants were reduced at least 500-fold, compared to only 5-fold, for wild-type (WT virus replication. To investigate the mechanistic basis of such inhibition, the accumulation of viral early proteins and genomes was compared by immunoblotting and qPCR, respectively, in WT- and mutant-infected cells in the absence or presence of exogenous IFN. Both the concentration of viral genomes detected during the late phase and the numbers of viral replication centers formed were strongly reduced in IFN-treated cells in the absence of the E1B protein, despite production of similar quantities of viral replication proteins. These defects could not be attributed to degradation of entering viral genomes, induction of apoptosis, or failure to reorganize components of PML nuclear bodies. Nor was assembly of the E1B- and E4 Orf6 protein- E3 ubiquitin ligase required to prevent inhibition of viral replication by IFN. However, by using RT-PCR, the E1B 55 kDa protein was demonstrated to be a potent repressor of expression of IFN-inducible genes in IFN-treated cells. We propose that a primary function of the previously described transcriptional repression activity of the E1B 55 kDa protein is to block expression of IFN- inducible genes, and hence to facilitate formation of viral replication centers and genome replication.

  6. Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage.

    Science.gov (United States)

    Qian, Suhong; Fan, Wenchun; Liu, Tingting; Wu, Mengge; Zhang, Huawei; Cui, Xiaofang; Zhou, Yun; Hu, Junjie; Wei, Shaozhong; Chen, Huanchun; Li, Xiangmin; Qian, Ping

    2017-08-15

    Seneca Valley virus (SVV) is an oncolytic RNA virus belonging to the Picornaviridae family. Its nucleotide sequence is highly similar to those of members of the Cardiovirus genus. SVV is also a neuroendocrine cancer-selective oncolytic picornavirus that can be used for anticancer therapy. However, the interaction between SVV and its host is yet to be fully characterized. In this study, SVV inhibited antiviral type I interferon (IFN) responses by targeting different host adaptors, including mitochondrial antiviral signaling (MAVS), Toll/interleukin 1 (IL-1) receptor domain-containing adaptor inducing IFN-β (TRIF), and TRAF family member-associated NF-κB activator (TANK), via viral 3C protease (3C pro ). SVV 3C pro mediated the cleavage of MAVS, TRIF, and TANK at specific sites, which required its protease activity. The cleaved MAVS, TRIF, and TANK lost the ability to regulate pattern recognition receptor (PRR)-mediated IFN production. The cleavage of TANK also facilitated TRAF6-induced NF-κB activation. SVV was also found to be sensitive to IFN-β. Therefore, SVV suppressed antiviral IFN production to escape host antiviral innate immune responses by cleaving host adaptor molecules. IMPORTANCE Host cells have developed various defenses against microbial pathogen infection. The production of IFN is the first line of defense against microbial infection. However, viruses have evolved many strategies to disrupt this host defense. SVV, a member of the Picornavirus genus, is an oncolytic virus that shows potential functions in anticancer therapy. It has been demonstrated that IFN can be used in anticancer therapy for certain tumors. However, the relationship between oncolytic virus and innate immune response in anticancer therapy is still not well known. In this study, we showed that SVV has evolved as an effective mechanism to inhibit host type I IFN production by using its 3C pro to cleave the molecules MAVS, TRIF, and TANK directly. These molecules are crucial for

  7. Vpx rescues HIV-1 transduction of dendritic cells from the antiviral state established by type 1 interferon

    Directory of Open Access Journals (Sweden)

    Reinhard Christian

    2011-06-01

    Full Text Available Abstract Background Vpx is a virion-associated protein encoded by SIVSM, a lentivirus endemic to the West African sooty mangabey (Cercocebus atys. HIV-2 and SIVMAC, zoonoses resulting from SIVSM transmission to humans or Asian rhesus macaques (Macaca mulatta, also encode Vpx. In myeloid cells, Vpx promotes reverse transcription and transduction by these viruses. This activity correlates with Vpx binding to DCAF1 (VPRBP and association with the DDB1/RBX1/CUL4A E3 ubiquitin ligase complex. When delivered experimentally to myeloid cells using VSV G-pseudotyped virus-like particles (VLPs, Vpx promotes reverse transcription of retroviruses that do not normally encode Vpx. Results Here we show that Vpx has the extraordinary ability to completely rescue HIV-1 transduction of human monocyte-derived dendritic cells (MDDCs from the potent antiviral state established by prior treatment with exogenous type 1 interferon (IFN. The magnitude of rescue was up to 1,000-fold, depending on the blood donor, and was also observed after induction of endogenous IFN and IFN-stimulated genes (ISGs by LPS, poly(I:C, or poly(dA:dT. The effect was relatively specific in that Vpx-associated suppression of soluble IFN-β production, of mRNA levels for ISGs, or of cell surface markers for MDDC differentiation, was not detected. Vpx did not rescue HIV-2 or SIVMAC transduction from the antiviral state, even in the presence of SIVMAC or HIV-2 VLPs bearing additional Vpx, or in the presence of HIV-1 VLPs bearing all accessory genes. In contrast to the effect of Vpx on transduction of untreated MDDCs, HIV-1 rescue from the antiviral state was not dependent upon Vpx interaction with DCAF1 or on the presence of DCAF1 within the MDDC target cells. Additionally, although Vpx increased the level of HIV-1 reverse transcripts in MDDCs to the same extent whether or not MDDCs were treated with IFN or LPS, Vpx rescued a block specific to the antiviral state that occurred after HIV-1 c

  8. Biomarkers of Type II Synthetic Pyrethroid Pesticides in Freshwater Fish

    Directory of Open Access Journals (Sweden)

    Anilava Kaviraj

    2014-01-01

    Full Text Available Type II synthetic pyrethroids contain an alpha-cyano group which renders them more neurotoxic than their noncyano type I counterparts. A wide array of biomarkers have been employed to delineate the toxic responses of freshwater fish to various type II synthetic pyrethroids. These include hematological, enzymatic, cytological, genetic, omic and other types of biomarkers. This review puts together the applications of different biomarkers in freshwater fish species in response to the toxicity of the major type II pyrethroid pesticides and assesses their present status, while speculating on the possible future directions.

  9. High interferon type I responses in the lung, plasma and spleen during highly pathogenic H5N1 infection of chicken

    Directory of Open Access Journals (Sweden)

    Moulin Hervé R

    2011-01-01

    Full Text Available Abstract This study shows that high pathogenic H5N1 influenza virus infection of chicken induced high levels of bioactive interferon type I in the lung (4.3 × 105 U/mg tissue, plasma (1.1 × 105 U/mL, and spleen (9.1 × 105 U/mg tissue. In contrast, a low pathogenic attenuated H5N1 vaccine strain only induced approximately 24 times less IFN in the lung, 441 times less in the spleen and 649 less in the plasma. This was in the same range as a reassortant carrying the HA from the vaccine strain and the remaining genes from the high pathogenic virus. On the other hand, a reassortant virus with the HA from the high pathogenic H5N1 with the remaining genes from the vaccine strain had intermediate levels of IFN. The level of interferon responses related to the viral load, and those in the spleen and blood to the spread of virus to lymphoid tissue, as well as disease severity. In vitro, the viruses did not induce interferon in chicken embryonic fibroblasts, but high levels in splenocytes, with not clear relationship to pathogenicity and virulence. This, and the responses also with inactivated viruses imply the presence of plasmacytoid dendritic cell-like leukocytes within the chicken immune system, possibly responsible for the high interferon responses during H5N1 infection. Our data also indicate that the viral load as well as the cleavability of the HA enabling systemic spread of the virus are two major factors controlling systemic IFN responses in chicken.

  10. The prevalence of microalbuminuria among patients with type II ...

    African Journals Online (AJOL)

    This cross-sectional community-based study was carried out to determine the prevalence of microalbuminuria among patients with type II diabetes mellitus in a primary care setting, and to study the association between various risk factors and the presence of microalbuminuria. All patients with type II diabetes mellitus who ...

  11. Sequence diversity of dengue virus type 2 in brain and thymus of infected interferon receptor ko mice: implications for dengue virulence.

    Science.gov (United States)

    Dhole, Priya; Nakayama, Emi E; Saito, Akatsuki; Limkittikul, Kriengsak; Phanthanawiboon, Supranee; Shioda, Tatsuo; Kurosu, Takeshi

    2016-11-30

    We previously reported that a clinical isolate of dengue virus (DENV) is capable of causing acute-phase systemic infection in mice harboring knockouts of the genes encoding type-I and -II interferon IFN receptors (IFN-α/β/γR KO mice); in contrast, other virulent DENV isolates exhibited slow disease progression in this mice, yielding lethal infection around 20 days post-infection (p.i.). In the present study, we sought to clarify the dynamics of slow disease progression by examining disease progression of a type-2 DENV clinical isolate (DV2P04/08) in mice. The tissue distributions of DV2P04/08 in several organs of infeted mice were examined at different time points. Whole genome viral sequences from organs were determined. At day 6 p.i., high levels of viral RNA (vRNA) were detected in non-neuronal organs (including peritoneal exudate cells (PECs), spleen, kidney, liver, lung, and bone marrow) but not in brain. By day 14 p.i, vRNA levels subsequently decreased in most organs, with the exception of thymus and brain. Sequence analysis of the whole genome of the original P04/08 and those of viruses recovered from mouse brain and thymus demonstrated the presence of both synonymous and non-synonymous mutations. Individual mice showed different virus populations in the brain. The vRNA sequence derived from brain of one mouse was nearly identical to the original DV2P04/08 inoculum, suggesting that there was no need for adaptation of DV2P04/08 for growth in the brain. However, quasispecies (that is, mixed populations, detected as apparent nucleotide mixtures during sequencing) were observed in the thymus of another mouse, and interestingly only mutant population invaded the brain at a late stage of infection. These results suggested that the mouse nearly succeeded in eliminating virus from non-neuronal organs but failed to do so from brain. Although the cause of death by DV2P04/08 infection is likely to be the result of virus invasion to brain, its processes to the

  12. Mutation and biochemical analysis in carnitine palmitoyltransferase type II (CPT II) deficiency

    DEFF Research Database (Denmark)

    Olpin, S E; Afifi, A; Clark, S

    2003-01-01

    Carnitine palmitoyltransferase type II (CPT II) deficiency has three basic phenotypes, late-onset muscular (mild), infantile/juvenile hepatic (intermediate) and severe neonatal. We have measured fatty acid oxidation and CPT II activity and performed mutation studies in 24 symptomatic patients rep...

  13. Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes.

    Science.gov (United States)

    Marroqui, Laura; Dos Santos, Reinaldo S; Op de Beeck, Anne; Coomans de Brachène, Alexandra; Marselli, Lorella; Marchetti, Piero; Eizirik, Decio L

    2017-04-01

    Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I, endoplasmic reticulum (ER) stress and beta cell apoptosis. The mediators of these phenomena remain to be defined. The type I interferon IFNα is expressed in human islets from type 1 diabetes patients and mediates HLA class I overexpression. We presently evaluated the mechanisms involved in IFNα-induced HLA class I expression in human beta cells and determined whether this cytokine contributes to ER stress and apoptosis. IFNα-induced inflammation, ER stress and apoptosis were evaluated by RT-PCR, western blot, immunofluorescence and nuclear dyes, and proteins involved in type I interferon signalling were inhibited by small interfering RNAs. All experiments were performed in human islets or human EndoC-βH1 cells. IFNα upregulates HLA class I, inflammation and ER stress markers in human beta cells via activation of the candidate gene TYK2, and the transcription factors signal transducer and activator of transcription 2 and IFN regulatory factor 9. Furthermore, it acts synergistically with IL-1β to induce beta cell apoptosis. The innate immune effects induced by IFNα may induce and amplify the adaptive immune response against human beta cells, indicating that IFNα has a central role in the early phases of diabetes.

  14. CT appearance of liver and gallbladder in type II diabetics

    International Nuclear Information System (INIS)

    Li Jingshan; Li Wei; Zhang Yuzhong; Zhao Xiuyi; Zhang Xuelin

    2005-01-01

    Objective: To evaluate CT findings of liver and gallbladder in type II diabetics and to discuss diabetic, and investigate the correlation between type II diabetics, and investigate the correlation between the diabetes and the lesions found in the liver or gallbladder. Methods: Retrospective analysis was made on the CT findings of hepatic and gallbladder lesions in 586 cases of II diabetes. Results: In total 586 type II diabetics, cholecystitis and/or gallstone were revealed in 33.45% patients; and hepatic alteration was noted in 20.48% cases. Hepatic abnormalities were found in 58.67% cases in the cholecystitis/gallstone group, significantly different from the group with unremarkable gallbladder, in which hepatic lesions were found only in 1.28% cases. Conclusion: The hepatic alteration is secondary to the gallbladder lesions in type II diabetics. (authors)

  15. M27 Expressed by Cytomegalovirus Counteracts Effective Type I Interferon Induction of Myeloid Cells but Not of Plasmacytoid Dendritic Cells

    Science.gov (United States)

    Döring, Marius; Lessin, Irina; Frenz, Theresa; Spanier, Julia; Kessler, Annett; Tegtmeyer, Pia; Dağ, Franziska; Thiel, Nadine; Trilling, Mirko; Lienenklaus, Stefan; Weiss, Siegfried; Scheu, Stefanie; Messerle, Martin; Cicin-Sain, Luka; Hengel, Hartmut

    2014-01-01

    ABSTRACT In healthy individuals, the functional immune system effectively confines human cytomegalovirus (CMV) replication, while viral immune evasion and persistence preclude sterile immunity. Mouse CMV (MCMV) is a well-established model to study the delicate CMV-host balance. Effective control of MCMV infection depends on the induction of protective type I interferon (IFN-I) responses. Nevertheless, it is unclear whether in professional antigen-presenting cell subsets MCMV-encoded evasins inhibit the induction of IFN-I responses. Upon MCMV treatment, enhanced expression of MCMV immediate-early and early proteins was detected in bone marrow cultures of macrophages and myeloid dendritic cells compared with plasmacytoid dendritic cell cultures, whereas plasmacytoid dendritic cells mounted more vigorous IFN-I responses. Experiments with Toll-like receptor (TLR)- and/or RIG-I like helicase (RLH)-deficient cell subsets revealed that upon MCMV treatment of myeloid cells, IFN-I responses were triggered independently of TLR and RLH signaling, whereas in plasmacytoid dendritic cells, IFN-I induction was strictly TLR dependent. Macrophages and myeloid dendritic cells treated with either UV-inactivated MCMV or live MCMV that lacked the STAT2 antagonist M27 mounted significantly higher IFN-I responses than cells treated with live wild-type MCMV. In contrast, plasmacytoid dendritic cells responded similarly to UV-inactivated and live MCMV. These experiments illustrated that M27 not only inhibited IFN-I-mediated receptor signaling, but also evaded the induction of IFN responses in myeloid dendritic cells. Furthermore, we found that additional MCMV-encoded evasins were needed to efficiently shut off IFN-I responses of macrophages, but not of myeloid dendritic cells, thus further elucidating the subtle adjustment of the host-pathogen balance. IMPORTANCE MCMV may induce IFN-I responses in fibroblasts and epithelial cells, as well as in antigen-presenting cell subsets. We focused

  16. Chains of N=2, D=4 heterotic type II duals

    CERN Document Server

    Aldazabal, G; Font, A; Quevedo, Fernando

    1996-01-01

    We report on a search for N=2 heterotic strings that are dual candidates of type II compactifications on Calabi-Yau threefolds described as K3 fibrations. We find many new heterotic duals by using standard orbifold techniques. The associated type II compactifications fall into chains in which the proposed duals are heterotic compactifications related one another by a sequential Higgs mechanism. This breaking in the heterotic side typically involves the sequence SU(4)\\rightarrow SU(3)\\rightarrow SU(2)\\rightarrow 0, while in the type II side the weights of the complex hypersurfaces and the structure of the K3 quotient singularities also follow specific patterns.

  17. Cartilage turnover reflected by metabolic processing of type II collagen

    DEFF Research Database (Denmark)

    Gudmann, Karoline Natasja Stæhr; Wang, Jianxia; Hoielt, Sabine

    2014-01-01

    The aim of this study was to enable measurement of cartilage formation by a novel biomarker of type II collagen formation. The competitive enzyme-linked immunosorbent assay (ELISA) Pro-C2 was developed and characterized for assessment of the beta splice variant of type II procollagen (PIIBNP....... To our knowledge this is the first assay, which is able to specifically evaluate PIIBNP excretion. The Pro-C2 assay seems to provide a promising and novel marker of type II collagen formation....

  18. Serum markers for type II diabetes mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Metz, Thomas O; Qian, Wei-Jun; Jacobs, Jon M; Polpitiya, Ashoka D; Camp, II, David G; Smith, Richard D

    2014-03-18

    A method for identifying persons with increased risk of developing type 2 diabetes mellitus utilizing selected biomarkers described hereafter either alone or in combination. The present invention allows for broad based, reliable, screening of large population bases and provides other advantages, including the formulation of effective strategies for characterizing, archiving, and contrasting data from multiple sample types under varying conditions.

  19. On authomorphisms of extremal type II codes

    Directory of Open Access Journals (Sweden)

    Ismael Gutiérrez García

    2013-01-01

    Full Text Available En el presente artículo se muestran algunas técnicas para obtener tipos de automorfismos de los códigos binarios auto-duales, doblemente pares y extremales, también denominados extremales de tipo II, con parámetros [24, 12, 8], [48, 24, 12] y [120, 60, 24]. El objetivo central es obtener informa- ción sobre el correspondiente grupo de automorfismos a partir de la exclusión de algunos números primos de su orden.

  20. Genetics Home Reference: glutaric acidemia type II

    Science.gov (United States)

    ... electron transfer flavoprotein alpha-subunit deficiency in two Japanese children with different phenotypes of glutaric acidemia type ... of Medicine Lister Hill National Center for Biomedical Communications 8600 Rockville Pike, Bethesda, MD 20894, USA HONCode ...

  1. Intersubband Light Emission Type II Heterostructures

    National Research Council Canada - National Science Library

    Mendez, Emillo

    2003-01-01

    We have studied the physics underlying some of the pending issues in quantum cascade lasers, with an emphasis on electronic transport across InAs/AlSb/GaSb heterojunctions - the building block of type...

  2. Histological Types of Polypoid Cutaneous Melanoma II

    OpenAIRE

    Knežević, Fabijan; Duančić, Vjekoslav; Šitić, Sanda; Horvat-Knežević, Anica; Benković, Vesna; Ramić, Snježana; Kostović, Krešimir; Ramljak, Vesna; Velemir Vrdoljak, Danko; Stanec, Mladen; Božović, Angelina

    2007-01-01

    The aim of this study was to ascertain which histological types of melanoma can clinically and morphologically appear as polypoid melanomas. In 645 cases of primary cutaneous melanoma we have analyzed criteria for diagnosis of polypoid cutaneous melanoma and afterwards we have analyzed growth phase in each polypoid melanoma, histological type of atypical melanocytes, the number of epidermal ridges which are occupied by atypical melanocytes, and distribution according to age, sex a...

  3. Tyrosine Hydroxylase Expression in Type II Cochlear Afferents in Mice.

    Science.gov (United States)

    Vyas, Pankhuri; Wu, Jingjing Sherry; Zimmerman, Amanda; Fuchs, Paul; Glowatzki, Elisabeth

    2017-02-01

    Acoustic information propagates from the ear to the brain via spiral ganglion neurons that innervate hair cells in the cochlea. These afferents include unmyelinated type II fibers that constitute 5 % of the total, the majority being myelinated type I neurons. Lack of specific genetic markers of type II afferents in the cochlea has been a roadblock in studying their functional role. Unexpectedly, type II afferents were visualized by reporter proteins induced by tyrosine hydroxylase (TH)-driven Cre recombinase. The present study was designed to determine whether TH-driven Cre recombinase (TH-2A-CreER) provides a selective and reliable tool for identification and genetic manipulation of type II rather than type I cochlear afferents. The "TH-2A-CreER neurons" radiated from the spiral lamina, crossed the tunnel of Corti, turned towards the base of the cochlea, and traveled beneath the rows of outer hair cells. Neither the processes nor the somata of TH-2A-CreER neurons were labeled by antibodies that specifically labeled type I afferents and medial efferents. TH-2A-CreER-positive processes partially co-labeled with antibodies to peripherin, a known marker of type II afferents. Individual TH-2A-CreER neurons gave off short branches contacting 7-25 outer hair cells (OHCs). Only a fraction of TH-2A-CreER boutons were associated with CtBP2-immunopositive ribbons. These results show that TH-2A-CreER provides a selective marker for type II versus type I afferents and can be used to describe the morphology and arborization pattern of type II cochlear afferents in the mouse cochlea.

  4. NNDSS - Table II. Hepatitis (viral, acute, by type) C

    Data.gov (United States)

    U.S. Department of Health & Human Services — NNDSS - Table II. Hepatitis (viral, acute, by type) C - 2018. In this Table, provisional cases of selected notifiable diseases (≥1,000 cases reported during the...

  5. Genetics Home Reference: distal hereditary motor neuropathy, type II

    Science.gov (United States)

    ... neuropathy, type II change single protein building blocks ( amino acids ) in the protein sequence. If either protein is altered, they may be more likely to cluster together and form clumps (aggregates). Aggregates of heat shock proteins may ...

  6. NNDSS - Table II. Hepatitis (viral, acute, by type) A & B

    Data.gov (United States)

    U.S. Department of Health & Human Services — NNDSS - Table II. Hepatitis (viral, acute, by type) A & B - 2018. In this Table, provisional cases of selected notifiable diseases (≥1,000 cases reported...

  7. NNDSS - Table II. Hepatitis (viral, acute, by type) A & B

    Data.gov (United States)

    U.S. Department of Health & Human Services — NNDSS - Table II. Hepatitis (viral, acute, by type) A & B - 2018. In this Table, provisional cases of selected notifiable diseases (≥1,000 cases reported during...

  8. NNDSS - Table II. Hepatitis (viral, acute, by type) C

    Data.gov (United States)

    U.S. Department of Health & Human Services — NNDSS - Table II. Hepatitis (viral, acute, by type) C - 2018. In this Table, provisional cases of selected notifiable diseases (≥1,000 cases reported during the...

  9. The type I interferon signature in leukocyte subsets from peripheral blood of patients with early arthritis: a major contribution by granulocytes.

    Science.gov (United States)

    de Jong, Tamarah D; Lübbers, Joyce; Turk, Samina; Vosslamber, Saskia; Mantel, Elise; Bontkes, Hetty J; van der Laken, Conny J; Bijlsma, Johannes W; van Schaardenburg, Dirkjan; Verweij, Cornelis L

    2016-07-13

    The type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response. Identification of the cell type(s) contributing to this IFN signature could provide insight into the signature's functional consequences. The aim of this study was to investigate the contribution of peripheral leukocyte subsets to the IFN signature in early arthritis. Blood was collected from 26 patients with early arthritis and lysed directly or separated into peripheral blood mononuclear cells (PBMCs) and polymorphonuclear granulocytes (PMNs). PBMCs were sorted into CD4(+) T cells, CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes by flow cytometry. Messenger RNA expression of three interferon response genes (IRGs RSAD2, IFI44L, and MX1) and type I interferon receptors (IFNAR1 and IFNAR2) was determined in whole blood and blood cell subsets by quantitative polymerase chain reaction. IRG expression was averaged to calculate an IFN score for each sample. Patients were designated "IFN(high)" (n = 8) or "IFN(low)" (n = 18) on the basis of an IFN score cutoff in whole peripheral blood from healthy control subjects. The difference in IFN score between IFN(high) and IFN(low) patients was remarkably large for the PMN fraction (mean 25-fold) compared with the other subsets (mean 6- to 9-fold), indicating that PMNs are the main inducers of IRGs. Moreover, the relative contribution of the PMN fraction to the whole-blood IFN score was threefold higher than expected from its abundance in blood (p = 0.008), whereas it was three- to sixfold lower for the other subsets (p ≤ 0.063), implying that the PMNs are most sensitive to IFN signaling. Concordantly, IFNAR1 and IFNAR2 were upregulated compared with healthy controls selectively in patient PMNs (p ≤ 0.0077) but not in PBMCs. PMNs are the main contributors to the whole-blood type I IFN signature in patients with early arthritis, which seems due to

  10. Type I Interferons Function as Autocrine and Paracrine Factors to Induce Autotaxin in Response to TLR Activation

    Science.gov (United States)

    Song, Jianwen; Guan, Ming; Zhao, Zhenwen; Zhang, Junjie

    2015-01-01

    Lysophosphatidic acid (LPA) is an important phospholipid mediator in inflammation and immunity. However, the mechanism of LPA regulation during inflammatory response is largely unknown. Autotaxin (ATX) is the key enzyme to produce extracellular LPA from lysophosphatidylcholine (LPC). In this study, we found that ATX was induced in monocytic THP-1 cells by TLR4 ligand lipopolysaccharide (LPS), TLR9 ligand CpG oligonucleotide, and TLR3 ligand poly(I:C), respectively. The ATX induction by TLR ligand was abolished by the neutralizing antibody against IFN-β or the knockdown of IFNAR1, indicating that type I IFN autocrine loop is responsible for the ATX induction upon TLR activation. Both IFN-β and IFN-α were able to induce ATX expression via the JAK-STAT and PI3K-AKT pathways but with different time-dependent manners. The ATX induction by IFN-β was dramatically enhanced by IFN-γ, which had no significant effect on ATX expression alone, suggesting a synergy effect between type I and type II IFNs in ATX induction. Extracellular LPA levels were significantly increased when THP-1 cells were treated with IFN-α/β or TLR ligands. In addition, the type I IFN-mediated ATX induction was identified in human monocyte-derived dendritic cells (moDCs) stimulated with LPS or poly(I:C), and IFN-α/β could induce ATX expression in human peripheral blood mononuclear cells (PBMCs) and monocytes isolated form blood samples. These results suggest that, in response to TLR activation, ATX is induced through a type I INF autocrine-paracrine loop to enhance LPA generation. PMID:26313906

  11. Type I Interferons Function as Autocrine and Paracrine Factors to Induce Autotaxin in Response to TLR Activation.

    Directory of Open Access Journals (Sweden)

    Jianwen Song

    Full Text Available Lysophosphatidic acid (LPA is an important phospholipid mediator in inflammation and immunity. However, the mechanism of LPA regulation during inflammatory response is largely unknown. Autotaxin (ATX is the key enzyme to produce extracellular LPA from lysophosphatidylcholine (LPC. In this study, we found that ATX was induced in monocytic THP-1 cells by TLR4 ligand lipopolysaccharide (LPS, TLR9 ligand CpG oligonucleotide, and TLR3 ligand poly(I:C, respectively. The ATX induction by TLR ligand was abolished by the neutralizing antibody against IFN-β or the knockdown of IFNAR1, indicating that type I IFN autocrine loop is responsible for the ATX induction upon TLR activation. Both IFN-β and IFN-α were able to induce ATX expression via the JAK-STAT and PI3K-AKT pathways but with different time-dependent manners. The ATX induction by IFN-β was dramatically enhanced by IFN-γ, which had no significant effect on ATX expression alone, suggesting a synergy effect between type I and type II IFNs in ATX induction. Extracellular LPA levels were significantly increased when THP-1 cells were treated with IFN-α/β or TLR ligands. In addition, the type I IFN-mediated ATX induction was identified in human monocyte-derived dendritic cells (moDCs stimulated with LPS or poly(I:C, and IFN-α/β could induce ATX expression in human peripheral blood mononuclear cells (PBMCs and monocytes isolated form blood samples. These results suggest that, in response to TLR activation, ATX is induced through a type I INF autocrine-paracrine loop to enhance LPA generation.

  12. PKMiner: a database for exploring type II polyketide synthases

    Directory of Open Access Journals (Sweden)

    Kim Jinki

    2012-08-01

    Full Text Available Abstract Background Bacterial aromatic polyketides are a pharmacologically important group of natural products synthesized by type II polyketide synthases (type II PKSs in actinobacteria. Isolation of novel aromatic polyketides from microbial sources is currently impeded because of the lack of knowledge about prolific taxa for polyketide synthesis and the difficulties in finding and optimizing target microorganisms. Comprehensive analysis of type II PKSs and the prediction of possible polyketide chemotypes in various actinobacterial genomes will thus enable the discovery or synthesis of novel polyketides in the most plausible microorganisms. Description We performed a comprehensive computational analysis of type II PKSs and their gene clusters in actinobacterial genomes. By identifying type II PKS subclasses from the sequence analysis of 280 known type II PKSs, we developed highly accurate domain classifiers for these subclasses and derived prediction rules for aromatic polyketide chemotypes generated by different combinations of type II PKS domains. Using 319 available actinobacterial genomes, we predicted 231 type II PKSs from 40 PKS gene clusters in 25 actinobacterial genomes, and polyketide chemotypes corresponding to 22 novel PKS gene clusters in 16 genomes. These results showed that the microorganisms capable of producing aromatic polyketides are specifically distributed within a certain suborder of Actinomycetales such as Catenulisporineae, Frankineae, Micrococcineae, Micromonosporineae, Pseudonocardineae, Streptomycineae, and Streptosporangineae. Conclusions We could identify the novel candidates of type II PKS gene clusters and their polyketide chemotypes in actinobacterial genomes by comprehensive analysis of type II PKSs and prediction of aromatic polyketides. The genome analysis results indicated that the specific suborders in actinomycetes could be used as prolific taxa for polyketide synthesis. The chemotype-prediction rules with

  13. PKMiner: a database for exploring type II polyketide synthases.

    Science.gov (United States)

    Kim, Jinki; Yi, Gwan-Su

    2012-08-08

    Bacterial aromatic polyketides are a pharmacologically important group of natural products synthesized by type II polyketide synthases (type II PKSs) in actinobacteria. Isolation of novel aromatic polyketides from microbial sources is currently impeded because of the lack of knowledge about prolific taxa for polyketide synthesis and the difficulties in finding and optimizing target microorganisms. Comprehensive analysis of type II PKSs and the prediction of possible polyketide chemotypes in various actinobacterial genomes will thus enable the discovery or synthesis of novel polyketides in the most plausible microorganisms. We performed a comprehensive computational analysis of type II PKSs and their gene clusters in actinobacterial genomes. By identifying type II PKS subclasses from the sequence analysis of 280 known type II PKSs, we developed highly accurate domain classifiers for these subclasses and derived prediction rules for aromatic polyketide chemotypes generated by different combinations of type II PKS domains. Using 319 available actinobacterial genomes, we predicted 231 type II PKSs from 40 PKS gene clusters in 25 actinobacterial genomes, and polyketide chemotypes corresponding to 22 novel PKS gene clusters in 16 genomes. These results showed that the microorganisms capable of producing aromatic polyketides are specifically distributed within a certain suborder of Actinomycetales such as Catenulisporineae, Frankineae, Micrococcineae, Micromonosporineae, Pseudonocardineae, Streptomycineae, and Streptosporangineae. We could identify the novel candidates of type II PKS gene clusters and their polyketide chemotypes in actinobacterial genomes by comprehensive analysis of type II PKSs and prediction of aromatic polyketides. The genome analysis results indicated that the specific suborders in actinomycetes could be used as prolific taxa for polyketide synthesis. The chemotype-prediction rules with the suggested type II PKS modules derived using this resource

  14. Effect of recombinant alpha interferon on NK and ADCC function in lung cancer patients: results from a phase II trial

    DEFF Research Database (Denmark)

    Hokland, P; Hokland, M; Olesen, B K

    1985-01-01

    During a phase II trial of recombinant IFN-alpha given in doses of 50 X 10(6) units/m2 three times per week to lung cancer patients, 13 patients were evaluated longitudinally in NK and ADCC assays and in immunofluorescence tests enumerating the number of cells reactive with the new N901 NK....... These data are discussed in relation to other clinical trials using leukocyte or recombinant IFN-alpha. Udgivelsesdato: 1984 Fall...

  15. Significance of type II fiber atrophy in chronic alcoholic myopathy.

    Science.gov (United States)

    Fernández-Solá, J; Sacanella, E; Estruch, R; Nicolás, J M; Grau, J M; Urbano-Márquez, A

    1995-05-01

    To determine the significance of type II fiber atrophy in alcoholic myopathy and its relationship with ethanol-related diseases a prospective study was carried out in 100 chronic alcoholics who showed clinical suspicion of skeletal myopathy. Measurement of muscle strength, laboratory analysis, nutritional assessment and open biopsy of deltoid muscle were performed in each case, as well as electrophysiological testing for peripheral neuropathy. Hepatic ultrasonography and liver biopsy, echocardiography and radionuclide cardiac scanning were carried out in selected subjects. According to histomorphometric analysis, type II fiber atrophy was found in 33 cases (33%), being selective for type II B fiber in 23 (70%). Skeletal myopathy was diagnosed in 61 cases, alcoholic cardiomyopathy in 26, peripheral neuropathy in 23 and cirrhosis in 12. Patients with type II fiber atrophy had a significantly higher total lifetime dose of ethanol, presented a greater incidence of skeletal myopathy and peripheral neuropathy, and exhibited significantly lower values of percentage of ideal body weight and lean body mass than their counterparts. However, the only independent factors for developing type II fiber atrophy were the coexistence of caloric malnutrition (p = 0.004) and the presence of skeletal myopathy (p = 0.043). Selective type II fiber atrophy is a non-specific finding in alcohol-induced muscle damage appearing, overall, in the patients with caloric malnutrition as well as in those with histologic evidence of myopathy.

  16. Anomalous Nernst effect in type-II Weyl semimetals

    Science.gov (United States)

    Saha, Subhodip; Tewari, Sumanta

    2018-01-01

    Topological Weyl semimetals (WSM), a new state of quantum matter with gapless nodal bulk spectrum and open Fermi arc surface states, have recently sparked enormous interest in condensed matter physics. Based on the symmetry and fermiology, it has been proposed that WSMs can be broadly classified into two types, type-I and type-II Weyl semimetals. While the undoped, conventional, type-I WSMs have point like Fermi surface and vanishing density of states (DOS) at the Fermi energy, the type-II Weyl semimetals break Lorentz symmetry explicitly and have tilted conical spectra with electron and hole pockets producing finite DOS at the Fermi level. The tilted conical spectrum and finite DOS at Fermi level in type-II WSMs have recently been shown to produce interesting effects such as a chiral anomaly induced longitudinal magnetoresistance that is strongly anisotropic in direction and a novel anomalous Hall effect. In this work, we consider the anomalous Nernst effect in type-II WSMs in the absence of an external magnetic field using the framework of semi-classical Boltzmann theory. Based on both a linearized model of time-reversal breaking WSM with a higher energy cut-off and a more realistic lattice model, we show that the anomalous Nernst response in these systems is strongly anisotropic in space, and can serve as a reliable signature of type-II Weyl semimetals in a host of magnetic systems with spontaneously broken time reversal symmetry.

  17. Clinical Presentation of Mucopolysaccharidosis Type II (Hunter's ...

    African Journals Online (AJOL)

    hanumantp

    syndrome), treatment has been mainly palliative.[3] However, enzyme replacement therapy (ERT) with .... This is akin to what happens in glycogen storage disease where degeneration of excess glycogen in the liver can .... Danis P, Toussant D. Retinal pigmentary changes in mucopolysacharidoses of hunters type. Bull Soc ...

  18. The effect of serum angiotensin II and angiotensin II type 1 receptor ...

    African Journals Online (AJOL)

    Ehab

    2012-06-18

    Jun 18, 2012 ... The effect of serum angiotensin II and angiotensin II type 1 receptor gene polymorphism on pediatric lupus nephritis. INTRODUCTION. Renin angiotensin system (RAS) has been considered one of the probable pathophysiologic mechanisms involved in SLE progression. However, the contribution of the ...

  19. Enhanced Materials Based on Submonolayer Type-II Quantum Dots

    Energy Technology Data Exchange (ETDEWEB)

    Tamargo, Maria C [City College of New York, NY (United States); Kuskovsky, Igor L. [City Univ. (CUNY), NY (United States) Queens College; Meriles, Carlos [City College of New York, NY (United States); Noyan, Ismail C. [Columbia Univ., New York, NY (United States)

    2017-04-15

    We have investigated a nanostructured material known as sub-monolayer type-II QDs, made from wide bandgap II-VI semiconductors. Our goal is to understand and exploit their tunable optical and electrical properties by taking advantage of the type-II band alignment and quantum confinement effects. Type-II ZnTe quantum dots (QDs) in a ZnSe host are particularly interesting because of their relatively large valence band and conduction band offsets. In the current award we have developed new materials based on sub-monolayer type-II QDs that may be advantageous for photovoltaic and spintronics applications. We have also expanded the structural characterization of these materials by refining the X-ray diffraction methodologies needed to investigate them. In particular, we have 1) demonstrated ZnCdTe/ZnCdSe type-II QDs materials that have ideal properties for the development of novel high efficiency “intermediate band solar cells”, 2) we developed a comprehensive approach to describe and model the growth of these ultra-small type-II QDs, 3) analysis of the evolution of the photoluminescence (PL) emission, combined with other characterization probes allowed us to predict the size and density of the QDs as a function of the growth conditions, 4) we developed and implemented novel sophisticated X-ray diffraction techniques from which accurate size and shape of the buried type-II QDs could be extracted, 5) a correlation of the shape anisotropy with polarization dependent PL was observed, confirming the QDs detailed shape and providing insight about the effects of this shape anisotropy on the physical properties of the type-II QD systems, and 6) a detailed “time-resolved Kerr rotation” investigation has led to the demonstration of enhanced electron spin lifetimes for the samples with large densities of type-II QDs and an understanding of the interplay between the QDs and Te-isoelectroic centers, a defect that forms in the spacer layers that separate the QDs.

  20. Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge.

    Science.gov (United States)

    Holmgren, Alicia M; Miller, Katelyn D; Cavanaugh, Sarah E; Rall, Glenn F

    2015-11-01

    In permissive mouse central nervous system (CNS) neurons, measles virus (MV) spreads in the absence of hallmark viral budding or neuronal death, with transmission occurring efficiently and exclusively via the synapse. MV infection also initiates a robust type I interferon (IFN) response, resulting in the synthesis of a large number of genes, including bone marrow stromal antigen 2 (Bst2)/tetherin/CD317. Bst2 restricts the release of some enveloped viruses, but to date, its role in viral infection of neurons has not been assessed. Consequently, we investigated how Bst2 was induced and what role it played in MV neuronal infection. The magnitude of induction of neuronal Bst2 RNA and protein following IFN exposure and viral infection was notably higher than in similarly treated mouse embryo fibroblasts (MEFs). Bst2 synthesis was both IFN and Stat1 dependent. Although Bst2 prevented MV release from nonneuronal cells, its deletion had no effect on viral pathogenesis in MV-challenged mice. Our findings underscore how cell-type-specific differences impact viral infection and pathogenesis. Viral infections of the central nervous system can lead to debilitating disease and death. Moreover, it is becoming increasingly clear that nonrenewable cells, including most central nervous system neurons, combat neurotropic viral infections in fundamentally different ways than other rapidly dividing and renewable cell populations. Here we identify type I interferon signaling as a key inducer of a known antiviral protein (Bst2) in neurons. Unexpectedly, the gene is dispensable for clearance of neurotropic viral infection despite its well-defined contribution to limiting the spread of enveloped viruses in proliferating cells. A deeper appreciation of the importance of cell type heterogeneity in antiviral immunity will aid in the identification of unique therapeutic targets for life-threatening viral infections. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  1. Towards Optimal Diagnosis of Type II Germ Cell Tumors

    NARCIS (Netherlands)

    J.A. Stoop (Hans)

    2011-01-01

    textabstractThe aim of the work described in this thesis is to improve the understanding of the pathobiology of testicular cancer (type II Germ Cell Tumors) to create possibilities for optimalization of diagnosis for this type of malignancy in routine pathology laboratories. The different studies

  2. Aldosterone synthase C-344T, angiotensin II type 1 receptor ...

    Indian Academy of Sciences (India)

    This study was undertaken to investigate the association of aldosterone synthase C-344T, angiotensin II type I receptor A1166C and 11- hydroxysteroid dehydrogenase type 2 G534A polymorphisms with essential hypertension in the population of Odisha, India. A total of 246 hypertensive subjects (males, 159; females, ...

  3. AGO2 Negatively Regulates Type I Interferon Signaling Pathway by Competition Binding IRF3 with CBP/p300

    Directory of Open Access Journals (Sweden)

    Shengyu Wang

    2017-05-01

    Full Text Available Viral infection triggers a series of signaling cascades and host innate immune responses, including interferon (IFN production, which depends on coordinated activity of multiple transcription factors. IFN regulatory factor 3 (IRF3 and transcriptional coactivator CREB binding protein (CBP and/or p300 are core factors that participate in transcriptional complex formation in the nucleus. In general, cells balance the production of IFNs through suppressive and stimulative mechanisms, but viral infections can disrupt such equilibrium. This study determined that H5N1 viral infection reduced the distribution of human argonaute 2 (AGO2 in A549 cell nucleus. AGO2 did not block phosphorylation, nuclear translocation, and DNA binding ability of IRF3 but inhibited its association with CBP. Therefore, this newly revealed mechanism shows that cellular response leads to transfer of AGO2 from cell nucleus and promotes IFN-β expression to increase host survival during viral infection.

  4. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier

    OpenAIRE

    Lazear, Helen M.; Daniels, Brian P.; Pinto, Amelia K.; Huang, Albert C.; Vick, Sarah C.; Doyle, Sean E.; Gale, Michael; Klein, Robyn S.; Diamond, Michael S.

    2015-01-01

    Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even t...

  5. Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism.

    Science.gov (United States)

    Niu, Congrong; Li, Li; Daffis, Stephane; Lucifora, Julie; Bonnin, Marc; Maadadi, Sarah; Salas, Eduardo; Chu, Ruth; Ramos, Hilario; Livingston, Christine M; Beran, Rudolf K; Garg, Abhishek V; Balsitis, Scott; Durantel, David; Zoulim, Fabien; Delaney, William E; Fletcher, Simon P

    2018-05-01

    GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previously shown to induce prolonged suppression of serum viral DNA and antigens in the woodchuck and chimpanzee models of CHB. Herein, we investigated the molecular mechanisms that contribute to the antiviral response to GS-9620 using in vitro models of hepatitis B virus (HBV) infection. Cryopreserved primary human hepatocytes (PHH) and differentiated HepaRG (dHepaRG) cells were infected with HBV and treated with GS-9620, conditioned media from human peripheral blood mononuclear cells treated with GS-9620 (GS-9620 conditioned media [GS-9620-CM]), or other innate immune stimuli. The antiviral and transcriptional response to these agents was determined. GS-9620 had no antiviral activity in HBV-infected PHH, consistent with low level TLR7 mRNA expression in human hepatocytes. In contrast, GS-9620-CM induced prolonged reduction of HBV DNA, RNA, and antigen levels in PHH and dHepaRG cells via a type I interferon (IFN)-dependent mechanism. GS-9620-CM did not reduce covalently closed circular DNA (cccDNA) levels in either cell type. Transcriptional profiling demonstrated that GS-9620-CM strongly induced various HBV restriction factors - although not APOBEC3A or the Smc5/6 complex - and indicated that established HBV infection does not modulate innate immune sensing or signaling in cryopreserved PHH. GS-9620-CM also induced expression of immunoproteasome subunits and enhanced presentation of an immunodominant viral peptide in HBV-infected PHH. Type I IFN induced by GS-9620 durably suppressed HBV in human hepatocytes without reducing cccDNA levels. Moreover, HBV antigen presentation was enhanced, suggesting additional components of the TLR7-induced immune response played a role in the antiviral response to GS-9620 in animal models of CHB. GS-9620 is a drug currently being tested in clinical trials for the treatment of chronic

  6. Glutathione synthesis and homeostasis in isolated type II alveolar cells

    International Nuclear Information System (INIS)

    Saito, K.; Warshaw, J.B.; Prough, R.A.

    1986-01-01

    After isolation of Type II cells from neonatal rat lung, the glutathione (GSH) levels in these cells were greatly depressed. The total glutathione content could be increased 5-fold within 12-24 h by incubating the cells in media containing sulfur amino acids. Similarly, the activity of γ-glutamyltranspeptidase was low immediately after isolation, but was increased 2-fold during the first 24 h culture. Addition of either GSH or GSSG to the culture media increased the GSH content of Type II cells 2-2.5-fold. Buthionine sulfoximine and NaF prevented this replenishment of GSH during 24 h culture. When the rates of de novo synthesis of GSH and GSSG from 35 S-cysteine were measured, the amounts of newly formed GSH decreased to 80% in the presence of GSH or GSSG. This suggests that exogenous GSH/GSSG can be taken up by the Type II cells to replenish the intracellular pool of GSH. Methionine was not as effective as cysteine in the synthesis of GSH. These results suggest that GSH levels in the isolated Type II cell can be maintained by de novo synthesis or uptake of exogenous GSH. Most of the GSH synthesized from cysteine, however, was excreted into the media of the cultured cells indicative of a potential role for the type II cell in export of the non-protein thiol

  7. A Statistical Study of Interplanetary Type II Bursts: STEREO Observations

    Science.gov (United States)

    Krupar, V.; Eastwood, J. P.; Magdalenic, J.; Gopalswamy, N.; Kruparova, O.; Szabo, A.

    2017-12-01

    Coronal mass ejections (CMEs) are the primary cause of the most severe and disruptive space weather events such as solar energetic particle (SEP) events and geomagnetic storms at Earth. Interplanetary type II bursts are generated via the plasma emission mechanism by energetic electrons accelerated at CME-driven shock waves and hence identify CMEs that potentially cause space weather impact. As CMEs propagate outward from the Sun, radio emissions are generated at progressively at lower frequencies corresponding to a decreasing ambient solar wind plasma density. We have performed a statistical study of 153 interplanetary type II bursts observed by the two STEREO spacecraft between March 2008 and August 2014. These events have been correlated with manually-identified CMEs contained in the Heliospheric Cataloguing, Analysis and Techniques Service (HELCATS) catalogue. Our results confirm that faster CMEs are more likely to produce interplanetary type II radio bursts. We have compared observed frequency drifts with white-light observations to estimate angular deviations of type II burst propagation directions from radial. We have found that interplanetary type II bursts preferably arise from CME flanks. Finally, we discuss a visibility of radio emissions in relation to the CME propagation direction.

  8. Prevalence of Gastroesophageal Reflux Disease in Type II Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Huihui Sun

    2014-01-01

    Full Text Available Background/Aims. Patients with type II diabetes mellitus (DM were known to have higher prevalence of gastroesophageal reflux disease (GERD in the Western countries, but data on the impact of GERD on DM patients in our country are scarce. The aim of this study was to evaluate the prevalence of GERD in type II DM patients in Shanghai, China, and to explore its possible risk factors. Methods. 775 type II DM cases were randomly collected. Reflux Disease Questionnaire (RDQ was used to check the presence of GERD. Patients’ characteristics, laboratory data, face-to-face interview, nerve conduction study, and needle electromyogram (EMG test were analyzed. Results. 16% patients were found with typical GERD symptoms. Pathophysiological factors such as peripheral neuropathy, metabolism syndrome, and obesity were found to have no significant differences between GERD and non-GERD type II DM patients in the present study. Conclusion. The prevalence of GERD in type II DM patients is higher than that in adult inhabitants in Shanghai, China. No difference in pathophysiological factors, such as peripheral neuropathy, and metabolism syndrome was found in DM-GERD patients, suggesting that further study and efforts are needed to explore deeper the potential risk factors for the high prevalence rate of GERD in DM patients.

  9. Signaling through RIG-I and type I interferon receptor: Immune activation by Newcastle disease virus in man versus immune evasion by Ebola virus (Review).

    Science.gov (United States)

    Schirrmacher, Volker

    2015-07-01

    In this review, two types of RNA viruses are compared with regard to the type I interferon (IFN) response in order to obtain a better understanding of the molecular mechanisms of immune activation or evasion. Upon human infection, both viruses exert either beneficial or detrimental effects. The Newcastle disease virus (NDV), is a type strain for avian paramyxoviruses, while the Ebola virus (EBOV), is a virus affecting primates. During evolution, both viruses specifically adapted to their respective hosts, acquiring sophisticated viral escape mechanisms. Two types of receptors play an important role in the life cycle of these two viruses: cytoplasmic retinoic acid‑inducible gene I (RIG‑I) and membrane expressed type I IFN receptor (IFNAR). In mouse and human cells, NDV is a strong inducer of the type I IFN response. The early phase of this is initiated by signaling through RIG‑I and the late response by signaling through IFNAR. EBOV does not induce type I IFN responses in humans as it has viral proteins that specifically and strongly interfere with RIG‑I and IFNAR signaling, as well as immune activation. In this review, we discuss whether the beneficial effects of one virus can be exploited in the fight against the detrimental effects of the other.

  10. Progenitors of low-luminosity Type II-Plateau supernovae

    Science.gov (United States)

    Lisakov, Sergey M.; Dessart, Luc; Hillier, D. John; Waldman, Roni; Livne, Eli

    2018-01-01

    The progenitors of low-luminosity Type II-Plateau supernovae (SNe II-P) are believed to be red supergiant (RSG) stars, but there is much disparity in the literature concerning their mass at core collapse and therefore on the main sequence. Here, we model the SN radiation arising from the low-energy explosion of RSG stars of 12, 25 and 27 M⊙ on the main sequence and formed through single star evolution. Despite the narrow range in ejecta kinetic energy (2.5-4.2 × 1050 erg) in our model set, the SN observables from our three models are significantly distinct, reflecting the differences in progenitor structure (e.g. surface radius, H-rich envelope mass and He-core mass). Our higher mass RSG stars give rise to Type II SNe that tend to have bluer colours at early times, a shorter photospheric phase, and a faster declining V-band light curve (LC) more typical of Type II-linear SNe, in conflict with the LC plateau observed for low-luminosity SNe II. The complete fallback of the CO core in the low-energy explosions of our high-mass RSG stars prevents the ejection of any 56Ni (nor any core O or Si), in contrast to low-luminosity SNe II-P, which eject at least 0.001 M⊙ of 56Ni. In contrast to observations, Type II SN models from higher mass RSGs tend to show an H α absorption that remains broad at late times (due to a larger velocity at the base of the H-rich envelope). In agreement with the analyses of pre-explosion photometry, we conclude that low-luminosity SNe II-P likely arise from low-mass rather than high-mass RSG stars.

  11. Luminescence dynamics in type-II GaAs/AlAs superlattices near the type-I to type-II crossover

    DEFF Research Database (Denmark)

    Langbein, Wolfgang Werner; Kalt, H.; Hvam, Jørn Märcher

    1996-01-01

    We report on a study of the time-resolved luminescence of type-II GaAs/AlAs superlattices near the type-I to type-II crossover. In spite of the slight type-II band alignment, the luminescence is dominated by the type-I transition. This is due to the inhomogeneous broadening of the type-I transition...... and the weak type-II oscillator strength, leading to a dominant luminescence of deeply localized type-I states. The relaxation within these localized states is found to be in agreement with a hopping model. At higher temperatures and excitation densities, the AlAs X minima act as an electron reservoir, leading...

  12. Partial Activation of Natural Killer and γδ T Cells by Classical Swine Fever Viruses Is Associated with Type I Interferon Elicited from Plasmacytoid Dendritic Cells

    Science.gov (United States)

    Franzoni, Giulia; Edwards, Jane C.; Kurkure, Nitin V.; Edgar, Daniel S.; Sanchez-Cordon, Pedro J.; Haines, Felicity J.; Salguero, Francisco J.; Everett, Helen E.; Bodman-Smith, Kikki B.; Crooke, Helen R.

    2014-01-01

    Vaccination with live attenuated classical swine fever virus (CSFV) vaccines can rapidly confer protection in the absence of neutralizing antibodies. With an aim of providing information on the cellular mechanisms that may mediate this protection, we explored the interaction of porcine natural killer (NK) cells and γδ T cells with CSFV. Both NK and γδ T cells were refractory to infection with attenuated or virulent CSFV, and no stimulatory effects, as assessed by the expression of major histocompatibility complex (MHC) class II (MHC-II), perforin, and gamma interferon (IFN-γ), were observed when the cells were cultured in the presence of CSFV. Coculture with CSFV and myeloid dendritic cells (mDCs) or plasmacytoid dendritic cells (pDCs) showed that pDCs led to a partial activation of both NK and γδ T cells, with upregulation of MHC-II being observed. An analysis of cytokine expression by infected DC subsets suggested that this effect was due to IFN-α secreted by infected pDCs. These results were supported by ex vivo analyses of NK and γδ T cells in the tonsils and retropharyngeal lymph nodes from pigs that had been vaccinated with live attenuated CSFV and/or virulent CSFV. At 5 days postchallenge, there was evidence of significant upregulation of MHC-II but not perforin on NK and γδ T cells, which was observed only following a challenge of the unvaccinated pigs and correlated with increased CSFV replication and IFN-α expression in both the tonsils and serum. Together, these data suggest that it is unlikely that NK or γδ T cells contribute to the cellular effector mechanisms induced by live attenuated CSFV. PMID:25080554

  13. Type II see-saw dominance in SO(10)

    CERN Document Server

    Melfo, Alejandra; Senjanovic, Goran

    2010-01-01

    Grand unified theories where the neutrino mass is given by Type II seesaw have the potential to provide interesting connections between the neutrino and charged fermion sectors. We explore the possibility of having a dominant Type II seesaw contribution in supersymmetric SO(10). We show that this can be achieved in the model where symmetry breaking is triggered by 54 and 45-dimensional representations, without the need for additional fields other than those already required to have a realistic charged fermion mass spectrum. Physical consequences, such as the implementation of the BSV mechanism, the possibility of the fields responsible for Type II see-saw dominance being messengers of supersymmetry breaking, and the realization of baryo and leptogenesis in this theories are discussed.

  14. Melatonin inhibits type 1 interferon signaling of toll-like receptor 4 via heme oxygenase-1 induction in hepatic ischemia/reperfusion.

    Science.gov (United States)

    Kang, Jung-Woo; Lee, Sun-Mee

    2012-08-01

    The cytoprotective mechanisms of melatonin in hepatic ischemia/reperfusion (I/R) injury associated with heme oxygenase-1 (HO-1) induction and type 1 interferon (IFN) signaling pathway downstream of toll-like receptor 4 (TLR4) were investigated. Rats were subjected to 60min of ischemia followed by 5-hr reperfusion. Melatonin (10mg/kg) or vehicle (5% ethanol in saline) was administered intraperitoneally 15min prior to ischemia and immediately before reperfusion. Rats were pretreated with zinc protoporphyrin (ZnPP, 10mg/kg, i.p.), a HO-1 inhibitor, at 16 and 3hr prior to ischemia. Melatonin attenuated the I/R-induced increase in serum alanine aminotransferase activity, and ZnPP reversed this attenuation. Melatonin augmented the levels of HO activity and HO-1 protein and mRNA expression, and this enhancement was reversed by ZnPP. Melatonin enhanced the level of NF-E2-related factor-2 (Nrf2) nuclear translocation, and ZnPP reversed this increase. Overexpression of TLR4 and its adaptor proteins, toll-receptor-associated activator of interferon (TRIF), and myeloid differentiation factor 88 (MyD88), induced by I/R, was attenuated by melatonin; ZnPP reversed the effect of melatonin on TLR4 and TRIF expression. Melatonin suppressed the increased interaction between TLR4/TRIF and TLR4/MyD88, which was reversed by ZnPP. Melatonin attenuated the increased levels of JAK2 and STAT1 activation as well as IFN-β, and ZnPP reversed these inhibitory effects of melatonin. Melatonin inhibited the level of chemokine (C-X-C motif) ligand 10 (CXCL-10), and ZnPP reversed this inhibition. Our findings suggest that melatonin protects the liver against I/R injury by HO-1 overexpression, which suppresses the type 1 IFN signaling pathway downstream of TLR4. © 2012 John Wiley & Sons A/S.

  15. Suppression of type I interferon production by porcine epidemic diarrhea virus and degradation of CREB-binding protein by nsp1

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qingzhan; Shi, Kaichuang; Yoo, Dongwan, E-mail: dyoo@illinois.edu

    2016-02-15

    Type I interferons (IFN-α/β) are the major components of the innate immune response of hosts, and in turn many viruses have evolved to modulate the host response during infection. We found that the IFN-β production was significantly suppressed during PEDV infection in cells. To identify viral IFN antagonists and to study their suppressive function, viral coding sequences for the entire structural and nonstructural proteins were cloned and expressed. Of 16 PEDV nonstructural proteins (nsps), nsp1, nsp3, nsp7, nsp14, nsp15 and nsp16 were found to inhibit the IFN-β and IRF3 promoter activities. The sole accessory protein ORF3, structure protein envelope (E), membrane (M), and nucleocapsid (N) protein were also shown to inhibit such activities. PEDV nsp1 did not interfere the IRF3 phosphorylation and nuclear translocation but interrupted the enhanceosome assembly of IRF3 and CREB-binding protein (CBP) by degrading CBP. A further study showed that the CBP degradation by nsp1 was proteasome-dependent. Our data demonstrate that PEDV modulates the host innate immune responses by degrading CBP and suppressing ISGs expression. - Highlights: • PEDV modulates the host innate immune system by suppressing the type I interferon production and ISGs expression. • Ten viral proteins were identified as IFN antagonists, and nsp1 was the most potent viral IFN antagonist. • PEDV nsp1 did not interfere the IRF3 phosphorylation and nuclear translocation but interrupted the enhanceosome assembly of IRF3 and CREB-binding protein (CBP). • PEDV nsp1 caused the CBP degradation in the nucleus, which may be the key mechanism for PEDV-mediated IFN downregulation.

  16. The structure of classical swine fever virus N(pro: a novel cysteine Autoprotease and zinc-binding protein involved in subversion of type I interferon induction.

    Directory of Open Access Journals (Sweden)

    Keerthi Gottipati

    Full Text Available Pestiviruses express their genome as a single polypeptide that is subsequently cleaved into individual proteins by host- and virus-encoded proteases. The pestivirus N-terminal protease (N(pro is a cysteine autoprotease that cleaves between its own C-terminus and the N-terminus of the core protein. Due to its unique sequence and catalytic site, it forms its own cysteine protease family C53. After self-cleavage, N(pro is no longer active as a protease. The released N(pro suppresses the induction of the host's type-I interferon-α/β (IFN-α/β response. N(pro binds interferon regulatory factor-3 (IRF3, the key transcriptional activator of IFN-α/β genes, and promotes degradation of IRF3 by the proteasome, thus preventing induction of the IFN-α/β response to pestivirus infection. Here we report the crystal structures of pestivirus N(pro. N(pro is structurally distinct from other known cysteine proteases and has a novel "clam shell" fold consisting of a protease domain and a zinc-binding domain. The unique fold of N(pro allows auto-catalysis at its C-terminus and subsequently conceals the cleavage site in the active site of the protease. Although many viruses interfere with type I IFN induction by targeting the IRF3 pathway, little information is available regarding structure or mechanism of action of viral proteins that interact with IRF3. The distribution of amino acids on the surface of N(pro involved in targeting IRF3 for proteasomal degradation provides insight into the nature of N(pro's interaction with IRF3. The structures thus establish the mechanism of auto-catalysis and subsequent auto-inhibition of trans-activity of N(pro, and its role in subversion of host immune response.

  17. Expression of microsomal prostaglandin E synthase in bovine endometrium: coexpression with cyclooxygenase type 2 and regulation by interferon-tau.

    Science.gov (United States)

    Parent, Julie; Chapdelaine, Pierre; Sirois, Jean; Fortier, Michel A

    2002-08-01

    Prostaglandins (PGs) are important regulators of reproductive functions. In ruminants, interferon (IFN)-tau is the embryonic signal responsible for recognition of pregnancy. This is effected by a reduction of the production of PGF(2alpha) relative to PGE(2.) This may be accomplished by a decrease in PGF(2alpha) production, but a stimulation of PGE(2) via the PGE synthase might also be involved. The purpose of the present study was to confirm the presence of PGE synthase (PGES) in the bovine endometrium, identify the factors affecting its expression, and compare it with that of cyclooxygenase-2 (COX-2). This was done by Northern blot analysis using primary cultures of bovine epithelial and stromal cells of the endometrium and bovine endometrial cell line. PGES mRNA expression was increased in the presence of lipopolysaccharides, TNF-alpha, and IFN-tau in stromal cells and IFN-tau in epithelial cells. In stromal cells, IFN-tau induced a rapid increase of PGES and COX-2 mRNA expression. In bovine endometrial cells, phorbol 12-myristate 13-actetate increased PGES mRNA, COX-2 mRNA and PGE(2) production. These results suggest that in endometrial cells, the expression of PGE synthase is correlated with that of COX-2 and is an important enzyme for the production of PGE(2). Increasing this production will modulate the PGE(2)/PGF(2alpha) ratio and contribute to establishment of pregnancy.

  18. Mutation and biochemical analysis in carnitine palmitoyltransferase type II (CPT II) deficiency

    DEFF Research Database (Denmark)

    Olpin, S E; Afifi, A; Clark, S

    2003-01-01

    Carnitine palmitoyltransferase type II (CPT II) deficiency has three basic phenotypes, late-onset muscular (mild), infantile/juvenile hepatic (intermediate) and severe neonatal. We have measured fatty acid oxidation and CPT II activity and performed mutation studies in 24 symptomatic patients...... representing the full clinical spectrum of disease. Severe and intermediate phenotypes show a clear correlation with biochemical indices and genetic analysis revealed causative mutations in most patients. Studies of mild phenotypes suggest a more complex interaction, with higher residual fatty acid oxidation...... of symptomatic patients appear to have significant residual CPT II activity (42-60%) The synergistic interaction of partial deficiencies of CPT II, muscle adenosine monophosphate deaminase and possibly other enzymes of muscle energy metabolism in the aetiology of episodic myopathy deserves wider consideration....

  19. Oral-facial-digital syndrome type II: Transitional type between Mohr ...

    African Journals Online (AJOL)

    We report a 2 months old boy, the first in order of birth of non-consanguineous parents, with several typical features of oral-facial-digital syndrome type II (OFDS II) including cleft lip, high arched palate, retromicrognathia, preaxial polysyndactyly of hands and feet, duplication of thumb and hallux. Interestingly, the patient also ...

  20. Can optical afterglows be used to discriminate between Type I and Type II GRBs?

    OpenAIRE

    Kann, D. A.

    2008-01-01

    The precise localization of short/hard (Type I) gamma-ray bursts (GRBs) in recent years has answered many questions but raised even more. I present some results of a systematic study of the optical afterglows of long/soft (Type II) and short/hard (Type I) GRBs, focusing on the optical luminosity as another puzzle piece in the classification of GRBs.

  1. Type I vs type II spiral ganglion neurons exhibit differential survival and neuritogenesis during cochlear development

    Directory of Open Access Journals (Sweden)

    Housley Gary D

    2011-10-01

    Full Text Available Abstract Background The mechanisms that consolidate neural circuitry are a major focus of neuroscience. In the mammalian cochlea, the refinement of spiral ganglion neuron (SGN innervation to the inner hair cells (by type I SGNs and the outer hair cells (by type II SGNs is accompanied by a 25% loss of SGNs. Results We investigated the segregation of neuronal loss in the mouse cochlea using β-tubulin and peripherin antisera to immunolabel all SGNs and selectively type II SGNs, respectively, and discovered that it is the type II SGN population that is predominately lost within the first postnatal week. Developmental neuronal loss has been attributed to the decline in neurotrophin expression by the target hair cells during this period, so we next examined survival of SGN sub-populations using tissue culture of the mid apex-mid turn region of neonatal mouse cochleae. In organotypic culture for 48 hours from postnatal day 1, endogenous trophic support from the organ of Corti proved sufficient to maintain all type II SGNs; however, a large proportion of type I SGNs were lost. Culture of the spiral ganglion as an explant, with removal of the organ of Corti, led to loss of the majority of both SGN sub-types. Brain-derived neurotrophic factor (BDNF added as a supplement to the media rescued a significant proportion of the SGNs, particularly the type II SGNs, which also showed increased neuritogenesis. The known decline in BDNF production by the rodent sensory epithelium after birth is therefore a likely mediator of type II neuron apoptosis. Conclusion Our study thus indicates that BDNF supply from the organ of Corti supports consolidation of type II innervation in the neonatal mouse cochlea. In contrast, type I SGNs likely rely on additional sources for trophic support.

  2. Towards Optimal Diagnosis of Type II Germ Cell Tumors

    OpenAIRE

    Stoop, Hans

    2011-01-01

    textabstractThe aim of the work described in this thesis is to improve the understanding of the pathobiology of testicular cancer (type II Germ Cell Tumors) to create possibilities for optimalization of diagnosis for this type of malignancy in routine pathology laboratories. The different studies presented here show valuable additional information on the microscopic diagnostics in daily practice. This enables proper and complete diagnosis of this relative rare variant of cancer ensuring the b...

  3. Perinatal lethal type II osteogenesis imperfecta: a case report | Ayadi ...

    African Journals Online (AJOL)

    We report a new case of osteogenesis imperfecta (OI) type II which is a perinatal lethal form. First trimester ultrasound didn't identified abnormalities. Second trimester ultrasound showed incurved limbs, narrow chest, with hypomineralization and multiple fractures of ribs and long bones. Parents refused pregnancy ...

  4. A Mobitz type II atrioventricular block in multicentric ischemic stroke ...

    African Journals Online (AJOL)

    Cardiac and cerebrovascular illnesses are major causes of mortality and morbidity. Thromboembolisms, which are the result of cardiac arrhythmia, are important causes of ischemic stroke. In this study, we present a rare case of multicentric ischemic stroke induced by Mobitz type II atrioventricular block. The Pan African ...

  5. Acute type II cryoglobulinaemic vasculitis mimicking atherosclerotic peripheral vascular disease.

    LENUS (Irish Health Repository)

    Saeed, A

    2012-01-31

    Atherosclerotic peripheral vascular disease is a common presenting cause for digital ischaemia in life long smokers. Acute severe Type II Cryoglobulinaemic vasculitis is a rare yet important cause, which may present with similar clinical features and which if undiagnosed may be rapidly fatal. Following the instigation of therapy with intravenous methylprednisolone and cyclophosphamide this patient made an excellent recovery.

  6. Aldosterone synthase C-344T, angiotensin II type 1 receptor ...

    Indian Academy of Sciences (India)

    2014-12-26

    Dec 26, 2014 ... RESEARCH ARTICLE. Aldosterone synthase C-344T, angiotensin II type 1 receptor A1166C and 11-β hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha, India. MANISHA PATNAIK1,5, PALLABI PATI1, SURENDRA N. SWAIN2, MANOJ K.

  7. Bianchi Type-II inflationary models with constant deceleration ...

    Indian Academy of Sciences (India)

    Einstein's field equations are considered for a locally rotationally symmetric Bianchi Type-II space–time in the presence of a massless scalar field with a scalar potential. Exact solutions of scale factors and other physical parameters are obtained by using a special law of variation for Hubble's parameter that yields a constant ...

  8. Conversion of DNA gyrase into a conventional type II topoisomerase

    DEFF Research Database (Denmark)

    Kampranis, S C; Maxwell, A

    1996-01-01

    -dependent manner. Novobiocin, a competitive inhibitor of ATP binding by gyrase, inhibits this reaction. The truncated enzyme, unlike gyrase, does not introduce a right-handed wrap when bound to DNA and stabilizes DNA crossovers; characteristics reminiscent of conventional type II topoisomerases. This new enzyme...

  9. Genetics Home Reference: lattice corneal dystrophy type II

    Science.gov (United States)

    ... network of protein filaments that gives structure to cells (the cytoskeleton). Mutations that cause lattice corneal dystrophy type II change a single protein building block (amino acid) in the gelsolin protein. ... from the cell. These protein fragments clump together and form amyloid ...

  10. Cardiovascular risk markers in type II diabetes and hypertension at ...

    African Journals Online (AJOL)

    Sly

    1. Cardiovascular risk markers in type II diabetes and hypertension at the Battor. Catholic Hospital, Volta Region of Ghana. WILLIAM K.B.A. OWIREDU1,3* .... Table 1: General socio-demographic characteristics of respondents by disease status. Variable. Total, n (%) Control, n (%). Case, n (%). P-value. Sex. Female.

  11. Genetics Home Reference: hereditary sensory and autonomic neuropathy type II

    Science.gov (United States)

    ... is found in the cells of the nervous system, including sensory neurons. The mutations involved in HSAN2A result in ... Samuels M, Rouleau GA. Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II. J Clin Invest. 2008 Jul; ...

  12. Knowledge Is Power: Teaching Children about Type II Diabetes

    Science.gov (United States)

    Feild-Berner, Natalie; Balgopal, Meena

    2011-01-01

    World Diabetes Day (November 14) offers a wonderful opportunity to educate elementary children about the power they have to control their health. First lady Michelle Obama has urged Americans to educate themselves about childhood obesity, which is often associated with the onset of type II diabetes (Rabin 2010). The authors developed activities to…

  13. Hypertension In Type II Diabetes Mellitus In Jos University Teaching ...

    African Journals Online (AJOL)

    Methods: A cross-sectional study of hypertension in type II diabetic patients in Jos University Teaching Hospital, Jos, Nigeria Results: Forty-two of the patients were hypertensive with only 28 (32.9%) previously diagnosed and were on treatment. Age of patient, duration of diabetes and diabetic retinopathy were significantly ...

  14. Left Ventricular Geometry In Nigerians With Type II Diabetes Mellitus ...

    African Journals Online (AJOL)

    Background: Left ventricular hypertrophy is independently associated with increased incidence of cardiovascular disease, cardiovascular and all cause mortality. In a relatively healthy hypertensive adult population, type II diabetes is associated with higher left ventricular mass, concentric left ventricular geometry and lower ...

  15. Evidence for topological type-II Weyl semimetal WTe2

    KAUST Repository

    Li, Peng

    2017-12-11

    Recently, a type-II Weyl fermion was theoretically predicted to appear at the contact of electron and hole Fermi surface pockets. A distinguishing feature of the surfaces of type-II Weyl semimetals is the existence of topological surface states, so-called Fermi arcs. Although WTe2 was the first material suggested as a type-II Weyl semimetal, the direct observation of its tilting Weyl cone and Fermi arc has not yet been successful. Here, we show strong evidence that WTe2 is a type-II Weyl semimetal by observing two unique transport properties simultaneously in one WTe2 nanoribbon. The negative magnetoresistance induced by a chiral anomaly is quite anisotropic in WTe2 nanoribbons, which is present in b-axis ribbon, but is absent in a-axis ribbon. An extra-quantum oscillation, arising from a Weyl orbit formed by the Fermi arc and bulk Landau levels, displays a two dimensional feature and decays as the thickness increases in WTe2 nanoribbon.

  16. Bianchi Type-II inflationary models with constant deceleration ...

    Indian Academy of Sciences (India)

    pp. 707–720. Bianchi Type-II inflationary models with constant deceleration parameter in general relativity. C P SINGH* and S KUMAR. Department of Applied Mathematics, Delhi College of Engineering, Bawana Road,. Delhi 110 042, India. E-mail: cpsphd@rediffmail.com. MS received 24 January 2006; revised 19 January ...

  17. Cardiovascular risk markers in type II diabetes and hypertension at ...

    African Journals Online (AJOL)

    Sly

    Keywords: Type II diabetes, hypertension, Cardiovascular disease, Cardiovascular risk score, Inflammation, ... matched healthy individuals in the study area without a history of diabetes, hypertension or any ... sex, educational background, period of work, dietary salt, sugar, fat as well as alcohol consumption, physical.

  18. Enzymatic Breakdown of Type II Collagen in the Human Vitreous

    NARCIS (Netherlands)

    van Deemter, Marielle; Pas, Hendri H.; Kuijer, Roel; van der Worp, Roelofje J.; Hooymans, Johanna M. M.; Los, Leonoor I.

    2009-01-01

    PURPOSE. To investigate whether enzymatic collagen breakdown is an active process in the human vitreous. METHODS. Human donor eyes were used for immunohistochemistry to detect the possible presence of the matrix metalloproteinase (MMP)-induced type II collagen breakdown product col2-3/4C-short in

  19. Type II restriction endonucleases--a historical perspective and more.

    Science.gov (United States)

    Pingoud, Alfred; Wilson, Geoffrey G; Wende, Wolfgang

    2014-07-01

    This article continues the series of Surveys and Summaries on restriction endonucleases (REases) begun this year in Nucleic Acids Research. Here we discuss 'Type II' REases, the kind used for DNA analysis and cloning. We focus on their biochemistry: what they are, what they do, and how they do it. Type II REases are produced by prokaryotes to combat bacteriophages. With extreme accuracy, each recognizes a particular sequence in double-stranded DNA and cleaves at a fixed position within or nearby. The discoveries of these enzymes in the 1970s, and of the uses to which they could be put, have since impacted every corner of the life sciences. They became the enabling tools of molecular biology, genetics and biotechnology, and made analysis at the most fundamental levels routine. Hundreds of different REases have been discovered and are available commercially. Their genes have been cloned, sequenced and overexpressed. Most have been characterized to some extent, but few have been studied in depth. Here, we describe the original discoveries in this field, and the properties of the first Type II REases investigated. We discuss the mechanisms of sequence recognition and catalysis, and the varied oligomeric modes in which Type II REases act. We describe the surprising heterogeneity revealed by comparisons of their sequences and structures. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  20. Ambitwistor pure spinor string in a type II supergravity background

    Energy Technology Data Exchange (ETDEWEB)

    Chandia, Osvaldo [Departamento de Ciencias, Facultad de Artes Liberales, Universidad Adolfo Ibáñez,Facultad de Ingeniería y Ciencias, Universidad Adolfo Ibáñez,Diagonal Las Torres 2640, Peñalolén, Santiago (Chile); Vallilo, Brenno Carlini [Departamento de Ciencias Físicas, Facultad de Ciencias Exactas, Universidad Andres Bello,República 220, Santiago (Chile)

    2015-06-30

    We construct the ambitwistor pure spinor string in a general type II supergravity background in the semi-classical regime. Almost all supergravity constraints are obtained from nilpotency of the BRST charge and further consistency conditions from additional world-sheet the case of AdS{sub 5}×S{sup 5} background.

  1. The SARS Coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor.

    Directory of Open Access Journals (Sweden)

    Rinki Minakshi

    2009-12-01

    Full Text Available The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV is reported to cause apoptosis of infected cells and several of its proteins including the 3a accessory protein, are pro-apoptotic. Since the 3a protein localizes to the endoplasmic reticulum (ER-Golgi compartment, its role in causing ER stress was investigated in transiently transfected cells. Cells expressing the 3a proteins showed ER stress based on activation of genes for the ER chaperones GRP78 and GRP94. Since ER stress can cause differential modulation of the unfolded protein response (UPR, which includes the inositol-requiring enzyme 1 (IRE-1, activating transcription factor 6 (ATF6 and PKR-like ER kinase (PERK pathways, these were individually tested in 3a-expressing cells. Only the PERK pathway was found to be activated in 3a-expressing cells based on (1 increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2alpha and inhibitory effects of a dominant-negative form of eIF2alpha on GRP78 promoter activity, (2 increased translation of activating transcription factor 4 (ATF4 mRNA, and (3 ATF4-dependent activation of the C/EBP homologous protein (CHOP gene promoter. Activation of PERK affects innate immunity by suppression of type 1 interferon (IFN signaling. The 3a protein was found to induce serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1 degradation motif and to increase IFNAR1 ubiquitination. Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells. These results provide further mechanistic details of the pro-apoptotic effects of the SARS-CoV 3a protein, and suggest a potential role for it in attenuating interferon responses and innate immunity.

  2. Inhibition of CRISPR/Cas9-Mediated Genome Engineering by a Type I Interferon-Induced Reduction in Guide RNA Expression.

    Science.gov (United States)

    Machitani, Mitsuhiro; Sakurai, Fuminori; Wakabayashi, Keisaku; Nakatani, Kosuke; Takayama, Kazuo; Tachibana, Masashi; Mizuguchi, Hiroyuki

    2017-01-01

    Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated genome engineering technology is a powerful tool for generation of cells and animals with engineered mutations in their genomes. In order to introduce the CRISPR/Cas9 system into target cells, nonviral and viral vectors are often used; however, such vectors trigger innate immune responses associated with production of type I interferons (IFNs). We have recently demonstrated that type I IFNs inhibit short-hairpin RNA-mediated gene silencing, which led us to hypothesize that type I IFNs may also inhibit CRISPR/Cas9-mediated genome mutagenesis. Here we investigated this hypothesis. A single-strand annealing assay using a reporter plasmid demonstrated that CRISPR/Cas9-mediated cleavage efficiencies of the target double-stranded DNA were significantly reduced by IFNα. A mismatch recognition nuclease-dependent genotyping assay also demonstrated that IFNα reduced insertion or deletion (indel) mutation levels by approximately half. Treatment with IFNα did not alter Cas9 protein expression levels, whereas the copy numbers of guide RNA (gRNA) were significantly reduced by IFNα stimulation. These results indicate that type I IFNs significantly reduce gRNA expression levels following introduction of the CRISPR/Cas9 system in the cells, leading to a reduction in the efficiencies of CRISPR/Cas9-mediated genome mutagenesis. Our findings provide important clues for the achievement of efficient genome engineering using the CRISPR/Cas9 system.

  3. Comparison of candidate serologic markers for type I and type II ovarian cancer

    DEFF Research Database (Denmark)

    Lu, Dan; Kuhn, Elisabetta; Bristow, Robert E

    2011-01-01

    To examine the value of individual and combinations of ovarian cancer associated blood biomarkers for the discrimination between plasma of patients with type I or II ovarian cancer and disease-free volunteers....

  4. Natural killer cell-mediated cytotoxicity is increased by a type II arabinogalactan from Anoectochilus formosanus.

    Science.gov (United States)

    Yang, Li-Chan; Lai, Ching-Yi; Lin, Wen-Chuan

    2017-01-02

    This study investigated the effects of a type II arabinogalactan from Anoectochilus formosanus (AGAF) on natural killer (NK) cell-mediated cytotoxicity and the possible underlying mechanisms. This study reported that sustained exposure to AGAF increased NK-92MI cell-mediated cytotoxicity in a time- and concentration-dependent manner, as characterized according to the cellular lactic dehydrogenase leakage from K562 leukemia cells. Additionally, antibody neutralization studies have reported that interferon (IFN)-γ, but not perforin or tumor necrosis factor-α, released by NK-92MI NK cells is crucial in enhancing cytotoxicity through an autocrine loop. In this study, AGAF was further demonstrated to induce IFN-γ expression, increasing the susceptibility to NK-92MI cell-mediated cytotoxicity through the toll-like receptor (TLR)-2, TLR4, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-κB pathways. A pharmacological study revealed that Janus kinase 2/signal transducers and activators of the signal transducers and of transcription 3 signaling are involved in IFN-γ-induced NK cell-mediated cytotoxicity. Copyright © 2016. Published by Elsevier Ltd.

  5. Limited trafficking of a neurotropic virus through inefficient retrograde axonal transport and the type I interferon response.

    Directory of Open Access Journals (Sweden)

    Karen Z Lancaster

    2010-03-01

    Full Text Available Poliovirus is an enteric virus that rarely invades the human central nervous system (CNS. To identify barriers limiting poliovirus spread from the periphery to CNS, we monitored trafficking of 10 marked viruses. After oral inoculation of susceptible mice, poliovirus was present in peripheral neurons, including vagus and sciatic nerves. To model viral trafficking in peripheral neurons, we intramuscularly injected mice with poliovirus, which follows a muscle-sciatic nerve-spinal cord-brain route. Only 20% of the poliovirus population successfully moved from muscle to brain, and three barriers limiting viral trafficking were identified. First, using light-sensitive viruses, we found limited viral replication in peripheral neurons. Second, retrograde axonal transport of poliovirus in peripheral neurons was inefficient; however, the efficiency was increased upon muscle damage, which also increased the transport efficiency of a non-viral neural tracer, wheat germ agglutinin. Third, using susceptible interferon (IFN alpha/beta receptor knockout mice, we demonstrated that the IFN response limited viral movement from the periphery to the brain. Surprisingly, the retrograde axonal transport barrier was equivalent in strength to the IFN barrier. Illustrating the importance of barriers created by the IFN response and inefficient axonal transport, IFN alpha/beta receptor knockout mice with muscle damage permitted 80% of the viral population to access the brain, and succumbed to disease three times faster than mice with intact barriers. These results suggest that multiple separate barriers limit poliovirus trafficking from peripheral neurons to the CNS, possibly explaining the rare incidence of paralytic poliomyelitis. This study identifies inefficient axonal transport as a substantial barrier to poliovirus trafficking in peripheral neurons, which may limit CNS access for other viruses.

  6. Effects of type II thyroplasty on adductor spasmodic dysphonia.

    Science.gov (United States)

    Sanuki, Tetsuji; Yumoto, Eiji; Minoda, Ryosei; Kodama, Narihiro

    2010-04-01

    Type II thyroplasty, or laryngeal framework surgery, is based on the hypothesis that the effect of adductor spasmodic dysphonia (AdSD) on the voice is due to excessively tight closure of the glottis, hampering phonation. Most of the previous, partially effective treatments have aimed to relieve this tight closure, including recurrent laryngeal nerve section or avulsion, extirpation of the adductor muscle, and botulinum toxin injection, which is currently the most popular. The aim of this study was to assess the effects of type II thyroplasty on aerodynamic and acoustic findings in patients with AdSD. Case series. University hospital. Ten patients with AdSD underwent type II thyroplasty between August 2006 and December 2008. Aerodynamic and acoustic analyses were performed prior to and six months after surgery. Mean flow rates (MFRs) and voice efficiency were evaluated with a phonation analyzer. Jitter, shimmer, the harmonics-to-noise ratio (HNR), standard deviation of the fundamental frequency (SDF0), and degree of voice breaks (DVB) were measured from each subject's longest sustained phonation sample of the vowel /a/. Voice efficiency improved significantly after surgery. No significant difference was found in the MFRs between before and after surgery. Jitter, shimmer, HNR, SDF0, and DVB improved significantly after surgery. Treatment of AdSD with type II thyroplasty significantly improved aerodynamic and acoustic findings. The results of this study suggest that type II thyroplasty provides relief from voice strangulation in patients with AdSD. Copyright 2010 American Academy of Otolaryngology-Head and Neck Surgery Foundation. Published by Mosby, Inc. All rights reserved.

  7. Repopulation of denuded tracheal grafts with alveolar type II cells

    International Nuclear Information System (INIS)

    Johnson, N.F.

    1988-01-01

    Repopulation of denuded heterotopic tracheal grafts with populations of specific epithelial cell types is one approach to study the differentiation potential of various cell types. This technique has been adopted to delineate the differentiation pathways of alveolar type II cells isolated from rat lungs. Under the conditions of this experiment, the reestablished epithelial lining was alveolar-like, however, ultrastructural analysis of the cells showed them to be like Clara cells. These preliminary results suggest that the secretary cells of the lung parenchyma and terminal airways may share a common ancestry. (author)

  8. Covalent ISG15 conjugation to CHIP promotes its ubiquitin E3 ligase activity and inhibits lung cancer cell growth in response to type I interferon.

    Science.gov (United States)

    Yoo, Lang; Yoon, A-Rum; Yun, Chae-Ok; Chung, Kwang Chul

    2018-01-24

    The carboxyl terminus of Hsp70-interacting protein (CHIP) acts as a ubiquitin E3 ligase and a link between the chaperones Hsp70/90 and the proteasome system, playing a vital role in maintaining protein homeostasis. CHIP regulates a number of proteins involved in a myriad of physiological and pathological processes, but the underlying mechanism of action via posttranslational modification has not been extensively explored. In this study, we investigated a novel modulatory mode of CHIP and its effect on CHIP enzymatic activity. ISG15, an ubiquitin-like modifier, is induced by type I interferon (IFN) stimulation and can be conjugated to target proteins (ISGylation). Here we demonstrated that CHIP may be a novel target of ISGylation in HEK293 cells stimulated with type I IFN. We also found that Lys143/144/145 and Lys287 residues in CHIP are important for and target residues of ISGylation. Moreover, ISGylation promotes the E3 ubiquitin ligase activity of CHIP, subsequently causing a decrease in levels of oncogenic c-Myc, one of its many ubiquitination targets, in A549 lung cancer cells and inhibiting A549 cell and tumor growth. In conclusion, the present study demonstrates that covalent ISG15 conjugation produces a novel CHIP regulatory mode that enhances the tumor-suppressive activity of CHIP, thereby contributing to the antitumor effect of type I IFN.

  9. Intrafibrillar Mineral May be Absent in Dentinogenesis Imperfecta Type II (DI-II)

    Energy Technology Data Exchange (ETDEWEB)

    Pople, John A

    2001-03-29

    High-resolution synchrotron radiation computed tomography (SRCT) and small angle x-ray scattering (SAXS) were performed on normal and dentinogenesis imperfecta type II (DI-II) teeth. Three normal and three DI-II human third molars were used in this study. The normal molars were unerupted and had intact enamel; donors were female and ranged in age from 18-21y. The DI-II specimens, which were also unerupted with intact enamel, came from a single female donor age 20y. SRCT showed that the mineral concentration was 33% lower on average in the DI-II dentin with respect to normal dentin. The SAXS spectra from normal dentin exhibited low-angle diffraction peaks at harmonics of 67.6 nm, consistent with nucleation and growth of the apatite phase within gaps in the collagen fibrils (intrafibrillar mineralization). In contrast, the low-angle peaks were almost nonexistent in the DI-II dentin. Crystallite thickness was independent of location in both DI-II and normal dentin, although the crystallites were significantly thicker in DI-II dentin (6.8 nm (s.d. = 0.5) vs 5.1 nm (s.d. = 0.6)). The shape factor of the crystallites, as determined by SAXS, showed a continuous progression in normal dentin from roughly one-dimensional (needle-like) near the pulp to two-dimensional (plate-like) near the dentin-enamel junction. The crystallites in DI-II dentin, on the other hand, remained needle-like throughout. The above observations are consistent with an absence of intrafibrillar mineral in DI-II dentin.

  10. Hybrid type I-type II superconducting behavior in magnesium diboride

    International Nuclear Information System (INIS)

    Kunchur, M.N.; Saracila, G.; Arcos, D.A.; Cui, Y.; Pogrebnyakov, A.; Orgiani, P.; Xi, X.X.

    2006-01-01

    In traditional type-II superconductors, an applied magnetic field depresses the transition temperature and introduces magnetic flux vortices that cause resistive losses accompanied by a broadening of the transition. High-field high-pulsed-current measurements have revealed a new hybrid behavior in disordered magnesium diboride films: The superconductivity survives high magnetic fields by entering a mixed state with vortices (like a type II superconductor) but holds its vortices nearly motionless and avoids dissipation (like a type I superconductor). A study of this phenomenon in magnesium diboride films with varying degrees of scattering indicate that the hybrid type I-type II behavior arises from the two-band nature of the superconductivity and the different degrees of influence that disorder exerts on its different bands. (author)

  11. General Hypochondriasis in Diabetes Mellitus Type-II (DM-II: Implications for Clinicians

    Directory of Open Access Journals (Sweden)

    Mohd. Fazil

    2013-01-01

    Full Text Available Background Relatively little is known about the epidemiology of hypochondriasis, especially in Diabetes Mellitus Type-II (DM-II patients, though hypochondriasis is considered to be of high relevance in the healthcare sector, especially in chronic diseases. The aims of this study were to study the prevalence of general hypochondriasis in DM-II patients and to explore some of the possible aggravating factors. Methods Thedatawascollectedbyinterviewandobservationmethodwith Illness Behaviour Questionnaire and Temperament Assessment Format. Results Hypochondriasiswasfoundtobemostprevalentinsubjectshaving Saudavi temperament (75.55% followed by those having Balghami temperament (56.81%. The patients having elevated blood sugar and those on injectable hypoglycemics also demonstrated a higher prevalence of hypochondriasis. Conclusion The results indicate that hypochondriasis is quite prevalent in DM-II patients; and, in addition to the severity of disease, it may also be influenced by the medication and patient’s temperament.

  12. Type II restriction endonucleases—a historical perspective and more

    Science.gov (United States)

    Pingoud, Alfred; Wilson, Geoffrey G.; Wende, Wolfgang

    2014-01-01

    This article continues the series of Surveys and Summaries on restriction endonucleases (REases) begun this year in Nucleic Acids Research. Here we discuss ‘Type II’ REases, the kind used for DNA analysis and cloning. We focus on their biochemistry: what they are, what they do, and how they do it. Type II REases are produced by prokaryotes to combat bacteriophages. With extreme accuracy, each recognizes a particular sequence in double-stranded DNA and cleaves at a fixed position within or nearby. The discoveries of these enzymes in the 1970s, and of the uses to which they could be put, have since impacted every corner of the life sciences. They became the enabling tools of molecular biology, genetics and biotechnology, and made analysis at the most fundamental levels routine. Hundreds of different REases have been discovered and are available commercially. Their genes have been cloned, sequenced and overexpressed. Most have been characterized to some extent, but few have been studied in depth. Here, we describe the original discoveries in this field, and the properties of the first Type II REases investigated. We discuss the mechanisms of sequence recognition and catalysis, and the varied oligomeric modes in which Type II REases act. We describe the surprising heterogeneity revealed by comparisons of their sequences and structures. PMID:24878924

  13. Type 1 Diabetes Mellitus Associated with Pegylated Interferon-α Plus Ribavirin Treatment for Chronic Hepatitis C: Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Reiko Oka

    2011-01-01

    Full Text Available Combined pegylated interferon (PEG-IFN+ribavirin (RBV therapy has been used as a primary treatment for chronic hepatitis C. However, IFN-induced autoimmune disease, including type 1 diabetes mellitus, has been highlighted as one of the problems with this therapy. Here we report the case of a patient who developed type 1 diabetes mellitus during combined PEG-IFN+RBV therapy for hepatitis C but who showed no exacerbation of diabetes despite continued use of IFN. A 63-year-old man with chronic hepatitis C and a nonresponder to previous IFNα treatments, was admitted to our hospital because of excessive thirst, polydipsia, and polyuria 24 weeks after the start of PEG-IFNα+RBV therapy. High levels of blood glucose and glycosylated hemoglobin and low levels of C-peptide and immunoreactive insulin were observed. The serum antiglutamic acid decarboxylase antibody titer was 27,700 U/mL. We diagnosed IFN-induced type 1 diabetes mellitus; however PEG-IFNα+RBV therapy was continued for 48 weeks. Serum HCV remains negative five years after this treatment. Intensive insulin therapy was started immediately after the diagnosis of type 1 diabetes. Although the patient initially required 22 U/day of insulin, the dosage could be gradually reduced after completion of PEG-IFNα+RBV therapy and blood glucose remained well controlled. Prediction of onset of type 1 diabetes mellitus on the basis of baseline measurement of pancreas-associated autoantibodies is difficult. Therefore, it would be advisable to consider the possibility of onset of type 1 diabetes mellitus in all patients receiving IFN+RBV therapy.

  14. Inhibition of Zn(II binding type IA topoisomerases by organomercury compounds and Hg(II.

    Directory of Open Access Journals (Sweden)

    Bokun Cheng

    Full Text Available Type IA topoisomerase activities are essential for resolving DNA topological barriers via an enzyme-mediated transient single strand DNA break. Accumulation of topoisomerase DNA cleavage product can lead to cell death or genomic rearrangement. Many antibacterial and anticancer drugs act as topoisomerase poison inhibitors that form stabilized ternary complexes with the topoisomerase covalent intermediate, so it is desirable to identify such inhibitors for type IA topoisomerases. Here we report that organomercury compounds were identified during a fluorescence based screening of the NIH diversity set of small molecules for topoisomerase inhibitors that can increase the DNA cleavage product of Yersinia pestis topoisomerase I. Inhibition of relaxation activity and accumulation of DNA cleavage product were confirmed for these organomercury compounds in gel based assays of Escherichia coli topoisomerase I. Hg(II, but not As(III, could also target the cysteines that form the multiple Zn(II binding tetra-cysteine motifs found in the C-terminal domains of these bacterial topoisomerase I for relaxation activity inhibition. Mycobacterium tuberculosis topoisomerase I activity is not sensitive to Hg(II or the organomercury compounds due to the absence of the Zn(II binding cysteines. It is significant that the type IA topoisomerases with Zn(II binding domains can still cleave DNA when interfered by Hg(II or organomercury compounds. The Zn(II binding domains found in human Top3α and Top3β may be potential targets of toxic metals and organometallic complexes, with potential consequence on genomic stability and development.

  15. Performance evaluation type II and type IIA box beam end terminals--volume II : appendices.

    Science.gov (United States)

    2010-01-10

    Two types of guide rail end terminals were constructed and evaluated according to the American Association of State Highway : and Transportation Officials (AASHTOs) Manual for Assessing Safety Hardware (MASH). The guide rail end terminals are u...

  16. Type I interferon production during herpes simplex virus infection is controlled by cell-type-specific viral recognition through Toll-like receptor 9, the mitochondrial antiviral signaling protein pathway, and novel recognition systems

    DEFF Research Database (Denmark)

    Rasmussen, Simon Brandtoft; Sørensen, Louise Nørgaard; Malmgaard, Lene

    2007-01-01

    Recognition of viruses by germ line-encoded pattern recognition receptors of the innate immune system is essential for rapid production of type I interferon (IFN) and early antiviral defense. We investigated the mechanisms of viral recognition governing production of type I IFN during herpes...... simplex virus (HSV) infection. We show that early production of IFN in vivo is mediated through Toll-like receptor 9 (TLR9) and plasmacytoid dendritic cells, whereas the subsequent alpha/beta IFN (IFN-alpha/beta) response is derived from several cell types and induced independently of TLR9...... and fibroblasts, where the virus was able to replicate, HSV-induced IFN-alpha/beta production was dependent on both viral entry and replication, and ablated in cells unable to signal through the mitochondrial antiviral signaling protein pathway. Thus, during an HSV infection in vivo, multiple mechanisms...

  17. Ceramide content is higher in type I compared to type II fibers in obesity and type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Kristensen, Ditte Bech; Prats Gavalda, Clara; Larsen, Steen

    2012-01-01

    This study investigated fiber-type-specific muscle ceramide content in obese subjects and type 2 diabetes patients. Two substudies, one which compared type 2 diabetes patients to both lean- and obese BMI-matched subjects and the other study which compared lean body-matched post-obese, obese...... index was higher in lean compared to type 2 diabetes patients and obese controls. Also in control and post-obese subjects, a higher insulin sensitivity was observed compared to obese subjects. Ceramide content was consistently higher in type I than in type II muscle fibers and higher in deltoideus than...... vastus lateralis across all groups. No significant differences between groups were observed in ceramide content in either of the two substudies. In human skeletal muscle, ceramide content was higher in type I than in type II fibers in patients with type 2 diabetes and in obese subjects, but overall...

  18. Instability in the magnetic field penetration in type II superconductors

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, Isaías G. de, E-mail: isaias@ufrrj.br

    2015-07-17

    Under the view of the time-dependent Ginzburg–Landau theory we have investigated the penetration of the magnetic field in the type II superconductors. We show that the single vortices, situated along the borderline, between the normal region channel and the superconducting region, can escape to regions still empty of vortices. We show that the origin of this process is the repulsive nature of vortex–vortex interaction, in addition to the non-homogeneous distribution of the vortices along the normal region channel. Using London theory we explain the extra gain of kinetic energy by the vortices situated along this borderline. - Highlights: • TDGL is used to study the magnetic field penetration in type II superconductors. • Instability process is found during the magnetic field penetration. • Vortices along the front of the normal region escape to superconducting region. • We explain the extra-gain of kinetic energy by vortices along the borderline.

  19. Subclinical onychomycosis in patients with type II diabetes

    Directory of Open Access Journals (Sweden)

    Amira Elbendary

    2015-12-01

    Full Text Available Fungal organisms could be present in the nail without any clinical manifestations. As onychomycosis in diabetics has more serious complications, early detection of such infection could be helpful to prevent them. We aim in this study to assess the possibility of detecting subclinical onychomycosis in type II diabetic patients and addressing possible associated neuropathy. A cross sectional, observational study included patients with type II diabetes with normal big toe nail. All were subjected to nail clipping of the big toe nail, followed by staining with Hematoxylin and Eosin and Periodic-Acid-Schiff (PAS stains and examined microscopically. A total of 106 patients were included, fungal infection was identified in eight specimens, all were uncontrolled diabetes, and six had neuropathy. Using the nail clipping and microscopic examination with PAS stain to detect such subclinical infection could be an applicable screening test for diabetic patients, for early detection and management of onychomycosis.

  20. UBVRIz LIGHT CURVES OF 51 TYPE II SUPERNOVAE

    International Nuclear Information System (INIS)

    Galbany, Lluis; Hamuy, Mario; Jaeger, Thomas de; Moraga, Tania; González-Gaitán, Santiago; Gutiérrez, Claudia P.; Phillips, Mark M.; Morrell, Nidia I.; Thomas-Osip, Joanna; Suntzeff, Nicholas B.; Maza, José; González, Luis; Antezana, Roberto; Wishnjewski, Marina; Krisciunas, Kevin; Krzeminski, Wojtek; McCarthy, Patrick; Anderson, Joseph P.; Stritzinger, Maximilian; Folatelli, Gastón

    2016-01-01

    We present a compilation of UBVRIz light curves of 51 type II supernovae discovered during the course of four different surveys during 1986–2003: the Cerro Tololo Supernova Survey, the Calán/Tololo Supernova Program (C and T), the Supernova Optical and Infrared Survey (SOIRS), and the Carnegie Type II Supernova Survey (CATS). The photometry is based on template-subtracted images to eliminate any potential host galaxy light contamination, and calibrated from foreground stars. This work presents these photometric data, studies the color evolution using different bands, and explores the relation between the magnitude at maximum brightness and the brightness decline parameter (s) from maximum light through the end of the recombination phase. This parameter is found to be shallower for redder bands and appears to have the best correlation in the B band. In addition, it also correlates with the plateau duration, being shorter (longer) for larger (smaller) s values

  1. Unification of type-II strings and T duality.

    Science.gov (United States)

    Hohm, Olaf; Kwak, Seung Ki; Zwiebach, Barton

    2011-10-21

    We present a unified description of the low-energy limits of type-II string theories. This is achieved by a formulation that doubles the space-time coordinates in order to realize the T-duality group O(10,10) geometrically. The Ramond-Ramond fields are described by a spinor of O(10,10), which couples to the gravitational fields via the Spin(10,10) representative of the so-called generalized metric. This theory, which is supplemented by a T-duality covariant self-duality constraint, unifies the type-II theories in that each of them is obtained for a particular subspace of the doubled space. © 2011 American Physical Society

  2. UBVRIz LIGHT CURVES OF 51 TYPE II SUPERNOVAE

    Energy Technology Data Exchange (ETDEWEB)

    Galbany, Lluis; Hamuy, Mario; Jaeger, Thomas de; Moraga, Tania; González-Gaitán, Santiago; Gutiérrez, Claudia P. [Millennium Institute of Astrophysics, Universidad de Chile (Chile); Phillips, Mark M.; Morrell, Nidia I.; Thomas-Osip, Joanna [Carnegie Observatories, Las Campanas Observatory, Casilla 60, La Serena (Chile); Suntzeff, Nicholas B. [Department of Physics and Astronomy, Texas A and M University, College Station, TX 77843 (United States); Maza, José; González, Luis; Antezana, Roberto; Wishnjewski, Marina [Departamento de Astronomía, Universidad de Chile, Camino El Observatorio 1515, Las Condes, Santiago (Chile); Krisciunas, Kevin [George P. and Cynthia Woods Mitchell Institute for Fundamental Physics and Astronomy, Texas A. and M. University, Department of Physics and Astronomy, 4242 TAMU, College Station, TX 77843 (United States); Krzeminski, Wojtek [N. Copernicus Astronomical Center, ul. Bartycka 18, 00-716 Warszawa (Poland); McCarthy, Patrick [The Observatories of the Carnegie Institution for Science, 813 Santa Barbara Street, Pasadena, CA 91101 (United States); Anderson, Joseph P. [European Southern Observatory, Alonso de Cordova 3107, Vitacura, Casilla 19001, Santiago (Chile); Stritzinger, Maximilian [Department of Physics and Astronomy, Aarhus University (Denmark); Folatelli, Gastón, E-mail: lgalbany@das.uchile.cl [Instituto de Astrofísica de La Plata (IALP, CONICET) (Argentina); and others

    2016-02-15

    We present a compilation of UBVRIz light curves of 51 type II supernovae discovered during the course of four different surveys during 1986–2003: the Cerro Tololo Supernova Survey, the Calán/Tololo Supernova Program (C and T), the Supernova Optical and Infrared Survey (SOIRS), and the Carnegie Type II Supernova Survey (CATS). The photometry is based on template-subtracted images to eliminate any potential host galaxy light contamination, and calibrated from foreground stars. This work presents these photometric data, studies the color evolution using different bands, and explores the relation between the magnitude at maximum brightness and the brightness decline parameter (s) from maximum light through the end of the recombination phase. This parameter is found to be shallower for redder bands and appears to have the best correlation in the B band. In addition, it also correlates with the plateau duration, being shorter (longer) for larger (smaller) s values.

  3. Type I Interferon Supports Inducible Nitric Oxide Synthase in Murine Hepatoma Cells and Hepatocytes and during Experimental Acetaminophen-Induced Liver Damage

    Directory of Open Access Journals (Sweden)

    Malte Bachmann

    2017-07-01

    Full Text Available Cytokine regulation of high-output nitric oxide (NO derived from inducible NO synthase (iNOS is critically involved in inflammation biology and host defense. Herein, we set out to characterize the role of type I interferon (IFN as potential regulator of hepatic iNOS in vitro and in vivo. In this regard, we identified in murine Hepa1-6 hepatoma cells a potent synergism between pro-inflammatory interleukin-β/tumor necrosis factor-α and immunoregulatory IFNβ as detected by analysis of iNOS expression and nitrite release. Upregulation of iNOS by IFNβ coincided with enhanced binding of signal transducer and activator of transcription-1 to a regulatory region at the murine iNOS promoter known to support target gene expression in response to this signaling pathway. Synergistic iNOS induction under the influence of IFNβ was confirmed in alternate murine Hepa56.1D hepatoma cells and primary hepatocytes. To assess iNOS regulation by type I IFN in vivo, murine acetaminophen (APAP-induced sterile liver inflammation was investigated. In this model of acute liver injury, excessive necroinflammation drives iNOS expression in diverse liver cell types, among others hepatocytes. Herein, we demonstrate impaired iNOS expression in type I IFN receptor-deficient mice which associated with diminished APAP-induced liver damage. Data presented indicate a vital role of type I IFN within the inflamed liver for fine-tuning pathological processes such as overt iNOS expression.

  4. Interaction of Ultrasound with Vortices in Type-II Superconductors

    OpenAIRE

    Sonin, E. B.

    1996-01-01

    The theory of the ultrasound propagation in the mixed state of type-II superconductors is suggested which takes into account the Magnus force on vortices, the anti-Magnus force on ions, and diamagnetism of the mixed state. The acoustic Faraday effect (rotation of polarization of the transverse ultrasonic wave propagating along vortices) is shown to be linear in the Magnus force in any regime of the flux flow for wavelengths used in the ultrasound experiments now. Therefore, in contrast to pre...

  5. Flavour-symmetric type-II Dirac neutrino seesaw mechanism

    Science.gov (United States)

    Bonilla, Cesar; Lamprea, J. M.; Peinado, Eduardo; Valle, Jose W. F.

    2018-04-01

    We propose a Standard Model extension with underlying A4 flavour symmetry where small Dirac neutrino masses arise from a Type-II seesaw mechanism. The model predicts the "golden" flavour-dependent bottom-tau mass relation, requires an inverted neutrino mass ordering and non-maximal atmospheric mixing angle. Using the latest neutrino oscillation global fit [1] we derive restrictions on the oscillation parameters, such as a correlation between δCP and mνlightest.

  6. Evaluation of Oral Health in Type II Diabetes Mellitus Patients

    OpenAIRE

    Rathy Ravindran; M.G. Deepa; A.K. Sruthi; Cherian Kuruvila; S Priya; S Sunil; Joseph Edward; G Roopesh

    2015-01-01

    Background: Oral cav ity re flects the general health status of a person and diagnosing and treating oral manifestations of systemic disease pose a greater challenge. Even though there is strong evidence that supports the relationship between oral health and diabetes mellitus, oral health awareness is lacking among diabetic patients and health professionals. The present study was undertaken to determine the oral health status in type II diabetic patients and also...

  7. [A pancreas suture-less type II binding pancreaticogastrostomy].

    Science.gov (United States)

    Peng, Shu-you; Hong, De-fei; Liu, Ying-bin; Li, Jiang-tao; Tao, Feng; Tan, Zhi-jian

    2009-12-01

    To explore the feasibility and safety of type II binding pancreaticogastrostomy (BPG) in pancreaticoduodenectomy and mid-segmentectomy of pancreas. From November 2008 to May 2009, 26 patients underwent pancreaticoduodenectomy and mid-segmentectomy of pancreas with type II BPG reconstruction, including 13 cases of pancreatic head cancer, 3 cases of duodenal adenocarcinoma, 2 cases of ampullary carcinoma, 4 cases of cholangiocarcinoma, 1 case of bile duct cell severe atypical hyperplasia, and 1 case of stomach cancer. The process of type II BPG was described as the following: after pancreas remnant was mobilized for 2-3 cm, a piece of sero-muscular layer at the posterior gastric wall was excised and then a sero-muscular depth purse-suturing with 3-0 prolene was pre-placed (outer purse-string). Incising anterior gastric wall or opening part of the closed distal gastric stump, the mucosa layer at the sero-muscular defect was incised and then purse-suture at the mucosal tube was pre-placed (inner purse-string). Through the two pre-placed purse-strings, the pancreas remnant was pulled into the gastric lumen and then posterior gastric wall was pushed backward to keep it closely in contact with the retro-peritoneal wall. Thereafter, the outer purse-string was tied (outer binding) and then the inner purse-string was tied (inner binding). All cases underwent BPG of type II. The operative time ranged from 3 to 5.5 hours. The postoperative hospital stay ranged from 6 to 48 days. Postoperative complications included 1 case of ascites, 2 cases of delayed gastric emptying and 1 case of intra-abdominal bleeding. All cases with complications were cured after nonsurgical treatment. No mortality or pancreatic leakage occurred. Pancreaticogastrostomy is good for accommodating a large pancreas stump. Binding technique is very helpful in minimizing the leak rate of pancreaticogastrostomy. While type I BPG is safe and easy to perform, type II is even safer and easier to be done.

  8. Type I-II laryngeal cleft: clinical course and outcome.

    Science.gov (United States)

    Slonimsky, Guy; Carmel, Eldar; Drendel, Michael; Lipschitz, Noga; Wolf, Michael

    2015-04-01

    Laryngeal cleft (LC) is a rare congenital anomaly manifesting in a variety of symptoms, including swallowing disorders and aspirations, dyspnea, stridor and hoarseness. The mild forms (types I-II) may be underdiagnosed, leading to protracted symptomatology and morbidity. To evaluate the diagnostic process, clinical course, management and outcome in children with type I-II laryngeal clefts. We conducted a retrospective case analysis for the years 2005-2012 in a tertiary referral center. Seven children were reviewed: five boys and two girls ranging in age from birth to 5 years. The most common presenting symptoms were cough, aspirations and pneumonia. Evaluation procedures included fiber-optic laryngoscopy (FOL), direct laryngoscopy (DL) and videofluoroscopy. Other pathologies were seen in three children. Six children underwent successful endoscopic surgery and one child was treated conservatively. The postoperative clinical course was uneventful in most of the cases. Types I-II LC should be considered in the differential diagnosis of children presenting with protracted cough and aspirations. DL is crucial for establishing the diagnosis. Endoscopic surgery is safe and should be applied promptly when conservative measures fail.

  9. Perinatal lethal type II osteogenesis imperfecta: a case report.

    Science.gov (United States)

    Ayadi, Imene Dahmane; Hamida, Emira Ben; Rebeh, Rania Ben; Chaouachi, Sihem; Marrakchi, Zahra

    2015-01-01

    We report a new case of osteogenesis imperfecta (OI) type II which is a perinatal lethal form. First trimester ultrasound didn't identified abnormalities. Second trimester ultrasound showed incurved limbs, narrow chest, with hypomineralization and multiple fractures of ribs and long bones. Parents refused pregnancy termination; they felt that the diagnosis was late. At birth, the newborn presented immediate respiratory distress. Postnatal examination and bone radiography confirmed the diagnosis of OI type IIA. Death occurred on day 25 of life related to respiratory failure.

  10. Type II restriction endonucleases : a historical perspective and more

    OpenAIRE

    Pingoud, Alfred; Wilson, Geoffrey G.; Wende, Wolfgang

    2014-01-01

    This article continues the series of Surveys and Summaries on restriction endonucleases (REases) begun this year in Nucleic Acids Research. Here we discuss ‘Type II’ REases, the kind used for DNA analysis and cloning. We focus on their biochemistry: what they are, what they do, and how they do it. Type II REases are produced by prokaryotes to combat bacteriophages. With extreme accuracy, each recognizes a particular sequence in double-stranded DNA and cleaves at a fixed position within or nea...

  11. Obstetric ultrasonographic findings of Chiari type II: Case report

    Directory of Open Access Journals (Sweden)

    Alptekin Tosun

    2009-01-01

    Full Text Available Chiari malformations divided into 3 groups. Chiari type I malformation is caudal protrusion of cerebellar tonsils. Type II malformation is the most common and associate with meningomyelocele. Type III is a high cervical men-ingoencephalocele and uncommon.Spina bifida, has classified into open and closed forms as skin covered spine lesions. Cranial signs are not ac-companiment on closed type. Open type usually diag-nosed on prenatal period. Typical findings are ventricu-lomegaly, lemon sign (bifrontal indentation, banana sign (Chiari II malformation, obliteration of cisterna magna and small BPD and body measurements according to gestation age. Occipital horns are higher than 10 mm in ventriculomegaly. Choroid plexus are small and looking like tear. Limon sign defines biconcave frontal bones as looking like a lemon. Banana sign and obliteration of cis-terna magna resulted cause of hypoplasia of posterior fossa. Compression of cerebellum causing abnormal lo-calization, although cerebellar tonsils and vermis herni-ated to foramen magnum. Hemispheres are wrapping brain stem and looking like ‘‘C’’ (banana sign. Spinal longitudinal sonogram reveals open spine and skin de-fect, although dilatation on spine canal and increased in-terpedincular distance.

  12. Increased incidence of neonatal respiratory distress in infants with mucopolysaccharidosis type II (MPS II, Hunter syndrome).

    Science.gov (United States)

    Dodsworth, Charlotte; Burton, Barbara K

    2014-02-01

    Records were reviewed on all patients with mucopolysaccharidosis type II (Hunter syndrome) seen at a single institution from 1999 to 2013 to identify those with a history of neonatal intensive care. Eleven of 34 patients were in a neonatal intensive care unit and all had respiratory distress with 8 diagnoses of respiratory distress syndrome and 3 of transient tachypnea of the newborn. None of the infants were premature; four were delivered by cesarean section. These findings suggest that respiratory distress is more commonly observed in neonates with MPS II than in the general population. This may reflect airway disease already present in this disorder at the time of birth. © 2013.

  13. Rapid single step subcloning procedure by combined action of type II and type IIs endonucleases with ligase

    Directory of Open Access Journals (Sweden)

    Klingenspor Martin

    2007-11-01

    Full Text Available Abstract Background The subcloning of a DNA fragment from an entry vector into a destination vector is a routinely performed task in molecular biology labs. Results We here present a novel benchtop procedure to achieve rapid recombination into any destination vector of choice with the sole requirement of an endonuclease recognition site. The method relies on a specifically designed entry vector and the combined action of type II and type IIs endonucleases with ligase. The formulation leads to accumulation of a single stable cloning product representing the desired insert carrying destination vector. Conclusion The described method provides a fast single step procedure for routine subcloning from an entry vector into a series of destination vectors with the same restriction enzyme recognition site.

  14. Rapid single step subcloning procedure by combined action of type II and type IIs endonucleases with ligase.

    Science.gov (United States)

    Fromme, Tobias; Klingenspor, Martin

    2007-11-26

    The subcloning of a DNA fragment from an entry vector into a destination vector is a routinely performed task in molecular biology labs. We here present a novel benchtop procedure to achieve rapid recombination into any destination vector of choice with the sole requirement of an endonuclease recognition site. The method relies on a specifically designed entry vector and the combined action of type II and type IIs endonucleases with ligase. The formulation leads to accumulation of a single stable cloning product representing the desired insert carrying destination vector. The described method provides a fast single step procedure for routine subcloning from an entry vector into a series of destination vectors with the same restriction enzyme recognition site.

  15. Evidence for a pathophysiological role of keratinocyte-derived type III interferon (IFNλ) in cutaneous lupus erythematosus.

    Science.gov (United States)

    Zahn, Sabine; Rehkämper, Claudia; Kümmerer, Beate M; Ferring-Schmidt, Sandra; Bieber, Thomas; Tüting, Thomas; Wenzel, Jörg

    2011-01-01

    Type I IFNs (IFNα/β) have been shown to have a central role in the pathophysiology of lupus erythematosus (LE). The recently discovered type III IFNs (IFNλ1/IL29, IFNλ2/IL28a, IFNλ3/IL28b) share several functional similarities with type I IFNs, particularly in antiviral immunity. As IFNλs act primarily on epithelial cells, we investigated whether type III IFNs might also have a role in the pathogenesis of cutaneous LE (CLE). Our investigations demonstrate that IFNλ and the IFNλ receptor were strongly expressed in the epidermis of CLE skin lesions and related autoimmune diseases (lichen planus and dermatomyositis). Significantly enhanced IFNλ1 could be measured in the serum of CLE patients with active skin lesions. Functional analyses revealed that human keratinocytes are able to produce high levels of IFNλ1 but only low amounts of IFNα/β/γ in response to immunostimulatory nuclear acids, suggesting that IFNλ is a major IFN produced by these cells. Exposure of human keratinocytes to IFNλ1 induced the expression of several proinflammatory cytokines, including CXCL9 (CXC-motiv ligand 9), which drive the recruitment of immune cells and are associated with the formation of CLE skin lesions. Our results provide evidence for a role of type III IFNs in not only antiviral immunity but also autoimmune diseases of the skin.

  16. Bruton’s Tyrosine Kinase Phosphorylates DDX41 and Activates Its Binding of dsDNA and STING to Initiate Type 1 Interferon Response

    Directory of Open Access Journals (Sweden)

    Koon-Guan Lee

    2015-02-01

    Full Text Available The innate immune system senses cytosolic dsDNA and bacterial cyclic dinucleotides and initiates signaling via the adaptor STING to induce type 1 interferon (IFN response. We demonstrate here that BTK-deficient cells have impaired IFN-β production and TBK1/IRF3 activation when stimulated with agonists or infected with pathogens that activate STING signaling. BTK interacts with STING and DDX41 helicase. The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site. Modeling studies further indicate that phospho-Tyr414 strengthens DDX41’s interaction with STING. Hence, BTK plays a critical role in the activation of DDX41 helicase and STING signaling.

  17. Microparticles released from Mycobacterium tuberculosis-infected human macrophages contain increased levels of the type I interferon inducible proteins including ISG15.

    Science.gov (United States)

    Hare, Nathan J; Chan, Brian; Chan, Edwina; Kaufman, Kimberley L; Britton, Warwick J; Saunders, Bernadette M

    2015-09-01

    Microparticles (MPs) are small membranous particles (100-1000 nm) released under normal steady-state conditions and are thought to provide a communication network between host cells. Previous studies demonstrated that Mycobacterium tuberculosis (M. tb) infection of macrophages increased the release of MPs, and these MPs induced a proinflammatory response from uninfected macrophages in vitro and in vivo following their transfer into uninfected mice. To determine how M. tb infection modulates the protein composition of the MPs, and if this contributes to their proinflammatory properties, we compared the proteomes of MPs derived from M. tb-infected (TBinf-MP) and uninfected human THP-1 monocytic cells. MP proteins were analyzed by GeLC-MS/MS with spectral counting revealing 68 proteins with statistically significant differential abundances. The 42 proteins increased in abundance in TBinf-MPs included proteins associated with immune function (7), lysosomal/endosomal maturation (4), vesicular formation (12), nucleosome proteins (4), and antigen processing (9). Prominent among these were the type I interferon inducible proteins, ISG15, IFIT1, IFIT2, and IFIT3. Exposure of uninfected THP-1 cells to TBinf-MPs induced increased gene expression of isg15, ifit1, ifit2, and ifit3 and the release of proinflammatory cytokines. These proteins may regulate the proinflammatory potential of the MPs and provide candidate biomarkers for M. tb infection. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. TRIM32 protein modulates type I interferon induction and cellular antiviral response by targeting MITA/STING protein for K63-linked ubiquitination.

    Science.gov (United States)

    Zhang, Jing; Hu, Ming-Ming; Wang, Yan-Yi; Shu, Hong-Bing

    2012-08-17

    Viral infection activates several transcription factors including NF-κB and IRF3, which collaborate to induce type I interferons (IFNs) and innate antiviral response. MITA (also called STING) is a critical adaptor protein that links virus-sensing receptors to IRF3 activation upon infection by both RNA and DNA pathogens. Here we show that the E3 ubiquitin ligase tripartite motif protein 32 (TRIM32) ubiquitinated MITA and dramatically enhanced MITA-mediated induction of IFN-β. Overexpression of TRIM32 potentiated virus-triggered IFNB1 expression and cellular antiviral response. Consistently, knockdown of TRIM32 had opposite effects. TRIM32 interacted with MITA, and was located at the mitochondria and endoplasmic reticulum. TRIM32 targeted MITA for K63-linked ubiquitination at K20/150/224/236 through its E3 ubiquitin ligase activity, which promoted the interaction of MITA with TBK1. These findings suggest that TRIM32 is an important regulatory protein for innate immunity against both RNA and DNA viruses by targeting MITA for K63-linked ubiquitination and downstream activation.

  19. Preferential type II muscle fiber damage from plyometric exercise.

    Science.gov (United States)

    Macaluso, Filippo; Isaacs, Ashwin W; Myburgh, Kathryn H

    2012-01-01

    Plyometric training has been successfully used in different sporting contexts. Studies that investigated the effect of plyometric training on muscle morphology are limited, and results are controversial with regard to which muscle fiber type is mainly affected. To analyze the skeletal muscle structural and ultrastructural change induced by an acute bout of plyometric exercise to determine which type of muscle fibers is predominantly damaged. Descriptive laboratory study. Research laboratory. Eight healthy, untrained individuals (age = 22 ± 1 years, height = 179.2 ± 6.4 cm, weight = 78.9 ± 5.9 kg). Participants completed an acute bout of plyometric exercise (10 sets of 10 squat-jumps with a 1-minute rest between sets). Blood samples were collected 9 days and immediately before and 6 hours and 1, 2, and 3 days after the acute intervention. Muscle samples were collected 9 days before and 3 days after the exercise intervention. Blood samples were analyzed for creatine kinase activity. Muscle biopsies were analyzed for damage using fluorescent and electron transmission microscopy. Creatine kinase activity peaked 1 day after the exercise bout (529.0 ± 317.8 U/L). Immunofluorescence revealed sarcolemmal damage in 155 of 1616 fibers analyzed. Mainly fast-twitch fibers were damaged. Within subgroups, 7.6% of type I fibers, 10.3% of type IIa fibers, and 14.3% of type IIx fibers were damaged as assessed by losses in dystrophin staining. Similar damage was prevalent in IIx and IIa fibers. Electron microscopy revealed clearly distinguishable moderate and severe sarcomere damage, with damage quantifiably predominant in type II muscle fibers of both the glycolytic and oxidative subtypes (86% and 84%, respectively, versus only 27% of slow-twitch fibers). We provide direct evidence that a single bout of plyometric exercise affected mainly type II muscle fibers.

  20. A temporal role of type I interferon signaling in CD8+ T cell maturation during acute West Nile virus infection.

    Directory of Open Access Journals (Sweden)

    Amelia K Pinto

    2011-12-01

    Full Text Available A genetic absence of the common IFN-α/β signaling receptor (IFNAR in mice is associated with enhanced viral replication and altered adaptive immune responses. However, analysis of IFNAR(-/- mice is limited for studying the functions of type I IFN at discrete stages of viral infection. To define the temporal functions of type I IFN signaling in the context of infection by West Nile virus (WNV, we treated mice with MAR1-5A3, a neutralizing, non cell-depleting anti-IFNAR antibody. Inhibition of type I IFN signaling at or before day 2 after infection was associated with markedly enhanced viral burden, whereas treatment at day 4 had substantially less effect on WNV dissemination. While antibody treatment prior to infection resulted in massive expansion of virus-specific CD8(+ T cells, blockade of type I IFN signaling starting at day 4 induced dysfunctional CD8(+ T cells with depressed cytokine responses and expression of phenotypic markers suggesting exhaustion. Thus, only the later maturation phase of anti-WNV CD8(+ T cell development requires type I IFN signaling. WNV infection experiments in BATF3(-/- mice, which lack CD8-α dendritic cells and have impaired priming due to inefficient antigen cross-presentation, revealed a similar effect of blocking IFN signaling on CD8(+ T cell maturation. Collectively, our results suggest that cell non-autonomous type I IFN signaling shapes maturation of antiviral CD8(+ T cell response at a stage distinct from the initial priming event.

  1. Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.

    Science.gov (United States)

    Li, He; Reksten, Tove Ragna; Ice, John A; Kelly, Jennifer A; Adrianto, Indra; Rasmussen, Astrid; Wang, Shaofeng; He, Bo; Grundahl, Kiely M; Glenn, Stuart B; Miceli-Richard, Corinne; Bowman, Simon; Lester, Sue; Eriksson, Per; Eloranta, Maija-Leena; Brun, Johan G; Gøransson, Lasse G; Harboe, Erna; Guthridge, Joel M; Kaufman, Kenneth M; Kvarnström, Marika; Cunninghame Graham, Deborah S; Patel, Ketan; Adler, Adam J; Farris, A Darise; Brennan, Michael T; Chodosh, James; Gopalakrishnan, Rajaram; Weisman, Michael H; Venuturupalli, Swamy; Wallace, Daniel J; Hefner, Kimberly S; Houston, Glen D; Huang, Andrew J W; Hughes, Pamela J; Lewis, David M; Radfar, Lida; Vista, Evan S; Edgar, Contessa E; Rohrer, Michael D; Stone, Donald U; Vyse, Timothy J; Harley, John B; Gaffney, Patrick M; James, Judith A; Turner, Sean; Alevizos, Ilias; Anaya, Juan-Manuel; Rhodus, Nelson L; Segal, Barbara M; Montgomery, Courtney G; Scofield, R Hal; Kovats, Susan; Mariette, Xavier; Rönnblom, Lars; Witte, Torsten; Rischmueller, Maureen; Wahren-Herlenius, Marie; Omdal, Roald; Jonsson, Roland; Ng, Wan-Fai; Nordmark, Gunnel; Lessard, Christopher J; Sivils, Kathy L

    2017-06-01

    Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

  2. Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.

    Directory of Open Access Journals (Sweden)

    He Li

    2017-06-01

    Full Text Available Sjögren's syndrome (SS is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1 peaking at rs10774671 (PeQTL = 6.05 × 10-14. Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86. The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

  3. Mouse embryonic stem cells are deficient in type I interferon expression in response to viral infections and double-stranded RNA.

    Science.gov (United States)

    Wang, Ruoxing; Wang, Jundi; Paul, Amber M; Acharya, Dhiraj; Bai, Fengwei; Huang, Faqing; Guo, Yan-Lin

    2013-05-31

    Embryonic stem cells (ESCs) are considered to be a promising cell source for regenerative medicine because of their unlimited capacity for self-renewal and differentiation. However, little is known about the innate immunity in ESCs and ESC-derived cells. We investigated the responses of mouse (m)ESCs to three types of live viruses as follows: La Crosse virus, West Nile virus, and Sendai virus. Our results demonstrated mESCs were susceptible to viral infection, but they were unable to express type I interferons (IFNα and IFNβ, IFNα/β), which differ from fibroblasts (10T1/2 cells) that robustly express IFNα/β upon viral infections. The failure of mESCs to express IFNα/β was further demonstrated by treatment with polyIC, a synthetic viral dsRNA analog that strongly induced IFNα/β in 10T1/2 cells. Although polyIC transiently inhibited the transcription of pluripotency markers, the stem cell morphology was not significantly affected. However, polyIC can induce dsRNA-activated protein kinase in mESCs, and this activation resulted in a strong inhibition of cell proliferation. We conclude that the cytosolic receptor dsRNA-activated protein kinase is functional, but the mechanisms that mediate type I IFN expression are deficient in mESCs. This conclusion is further supported by the findings that the major viral RNA receptors are either expressed at very low levels (TLR3 and MDA5) or may not be active (retinoic acid-inducible gene I) in mESCs.

  4. Antiviral effects of bovine interferons on bovine respiratory tract viruses.

    OpenAIRE

    Fulton, R W; Downing, M M; Cummins, J M

    1984-01-01

    The antiviral effects of bovine interferons on the replication of bovine respiratory tract viruses were studied. Bovine turbinate monolayer cultures were treated with bovine interferons and challenged with several bovine herpesvirus 1 strains, bovine viral diarrhea virus, parainfluenza type 3 virus, goat respiratory syncytial virus, bovine respiratory syncytial virus, bovine adenovirus type 7, or vesicular stomatitis virus. Treatment with bovine interferons reduced viral yield for each of the...

  5. Vacuum stability and naturalness in type-II seesaw

    Energy Technology Data Exchange (ETDEWEB)

    Haba, Naoyuki; Ishida, Hiroyuki [Shimane University, Graduate School of Science and Engineering, Matsue (Japan); Okada, Nobuchika [University of Alabama, Department of Physics and Astronomy, Tuscaloosa, AL (United States); Yamaguchi, Yuya [Shimane University, Graduate School of Science and Engineering, Matsue (Japan); Hokkaido University, Department of Physics, Faculty of Science, Sapporo (Japan)

    2016-06-15

    We study the vacuum stability and perturbativity conditions in the minimal type-II seesaw model. These conditions give characteristic constraints to the model parameters. In the model, there is a SU(2){sub L} triplet scalar field, which could cause a large Higgs mass correction. From the naturalness point of view, heavy Higgs masses should be lower than 350 GeV, which may be testable by the LHC Run-II results. Due to the effects of the triplet scalar field, the branching ratios of the Higgs decay (h → γγ, Zγ) deviate from the standard model, and a large parameter region is excluded by the recent ATLAS and CMS combined analysis of h → γγ. Our result of the signal strength for h → γγ is R{sub γγ}

  6. Specific detection of type II human chorionic gonadotropin beta subunit produced by trophoblastic and neoplastic cells.

    Science.gov (United States)

    Aldaz-Carroll, L; Richon, S; Dangles-Marie, V; Cocquebert, M; Fournier, T; Troalen, F; Stevens, D; Guery, B; Hersant, A-M; Guibourdenche, J; Nordor, A; Pecking, A; Bellet, D

    2015-04-15

    The sequence of the beta-subunit of human chorionic gonadotropin (hCGβ) varies depending on whether hCGβ is encoded by type I or type II genes. Type II genes are upregulated in trophoblast and cancer but hCGβ can be detected in the serum of nonpregnant women and healthy individuals. We aimed to determine whether monoclonal antibody (mAb) FBT11-II specifically detects hCGβ encoded by type II genes (type II hCGβ). Competitive inhibition assays with synthetic peptides, immunocytochemical and immunohistochemical studies, type II hCGβ dosing immunoassays and sequencing of CGB genes were performed. Competitive inhibition assays determined that mAb FBT11-II recognizes the type II hCGβ derived peptide. CGB mRNA sequencing of JEG-3 (trophoblastic) and T24 (bladder) cell lines confirmed that JEG-3 expresses type II genes while T24 expresses exclusively type I. FBT11-II only recognizes JEG-expressed hCGβ. Placenta immunohistochemical studies confirmed that type II hCGβ expression is restricted to the syncytiotrophoblast. Immunoassays detected type II hCGβ in serum of patients with either nontrophoblastic cancers or fetal Down syndrome. Type II gene expression can be detected using FBT11-II. This specific recognition could improve the clinical usefulness of assays aimed at either managing aggressive tumors or screening for Down syndrome. Copyright © 2015. Published by Elsevier B.V.

  7. The role of alveolar type II cells in swine leptospirosis

    Directory of Open Access Journals (Sweden)

    Ângela P. Campos

    2015-07-01

    Full Text Available Abstract: This study aimed to investigate a possible relationship between alveolar type II cells and the inflammatory response to infection with Leptospira spp., and thus comprise a further element that can be involved in the pathogenesis of lung injury in naturally infected pigs. The study group consisted of 73 adult pigs that were extensively reared and slaughtered in Teresina, Piauí state, and Timon, Maranhão state, Brazil. The diagnosis of leptospirosis was made using the microscopic agglutination test (MAT aided by immunohistochemistry and polymerase chain reaction. The MAT registered the occurrence of anti-Leptospira antibodies in 10.96% (8/73 of the pigs. Immunohistochemistry allowed for the visualization of the Leptospira spp. antigen in the lungs of 87.67% (64/73 of the pigs. There was hyperplasia of bronchus-associated lymphoid tissue and circulatory changes, such as congestion of alveolar septa, parenchymal hemorrhage and edema within the alveoli. Lung inflammation was more intense (p = 0.0312 in infected animals, which also showed increased thickening of the alveolar septa (p = 0.0006. Evaluation of alveolar type II (ATII cells using an anti-TTF-1 (Thyroid Transcription Factor-1 antibody showed that there were more immunostained cells in the non-infected pigs (53.8% than in the infected animals (46.2% and that there was an inverse correlation between TTF-1 positive cells and the inflammatory infiltrate. There was no amplification of Leptospira DNA in the lung samples, but leptospiral DNA amplification was observed in the kidneys. The results of this study showed that a relationship exists between a decrease in alveolar type II cells and a leptospire infection. Thus, this work points to the importance of studying the ATII cells as a potential marker of the level of lung innate immune response during leptospirosis in pigs.

  8. Type II diabetes mellitus and menopause: a multinational study.

    Science.gov (United States)

    Monterrosa-Castro, A; Blümel, J E; Portela-Buelvas, K; Mezones-Holguín, E; Barón, G; Bencosme, A; Benítez, Z; Bravo, L M; Calle, A; Chedraui, P; Flores, D; Espinoza, M T; Gómez, G; Hernández-Bueno, J A; Laribezcoa, F; Lima, S; Martino, M; Mostajo, D; Ojeda, E; Onatra, W; Sánchez, H; Navarro, D; Tserotas, K; Vallejo, M S; Witis, S; Zuñiga, M C

    2013-12-01

    Type II diabetes mellitus causes metabolic changes that may lead to early menopause and worsen climacteric symptoms. To determine the risk factors for type II diabetes mellitus and assess the impact of this disease on the age of menopause and on climacteric symptoms. A total of 6079 women aged between 40 and 59 years from 11 Latin American countries were requested to answer the Menopause Rating Scale and Goldberg Anxiety-Depression Scale. The prevalence of diabetes was 6.7%. Diabetes mellitus was associated with arterial hypertension (odds ratio (OR) 4.49; 95% confidence interval (CI) 3.47-5.31), the use of psychotropic drugs (OR 1.54; 95% CI 1.22-1.94), hormonal therapy (OR 1.46; 95% CI 1.11-1.92), ≥ 50 years of age (OR 1.48; 95% CI 1.17-1.86), overweight or obese (OR 1.47; 95% CI 1.15-1.89), and waist circumference ≥ 88 cm (OR 1.32; 95% CI 1.06-1.65). Factors associated with lower risk of diabetes were the use of hormonal contraceptives (OR 0.55; 95% CI 0.35-0.87), alcohol (OR 0.73; 95% CI 0.54-0.98) and living in cities > 2500 meters above sea level (OR 0.70; 95% CI 0.53-0.91) or with high temperatures (OR 0.67; 95% CI 0.51-0.88). In turn, diabetes tripled the risk of menopause in women under 45 years of age. Diabetes did not increase the risk of deterioration of quality of life due to climacteric symptoms. Menopause does not increase the risk of type II diabetes mellitus. Diabetes is associated with early menopause in women under 45 years of age.

  9. Biotechnology: interferon patent contested.

    Science.gov (United States)

    Earl, C; Beardsley, T

    Biogen, a biotechnology company based in Cambridge, Mass., and Geneva, Switzerland, has been notified by the European Patent Office that it will receive a product patent for its alpha interferon synthesized by recombinant DNA technology. Genentech, a San Francisco company which claims priority for producing mature interferon, is planning a vigorous appeal of the decision.

  10. Dendritic cell maturation, but not type I interferon exposure, restricts infection by HTLV-1, and viral transmission to T-cells.

    Directory of Open Access Journals (Sweden)

    Gergès Rizkallah

    2017-04-01

    Full Text Available Human T lymphotropic Virus type 1 (HTLV-1 is the etiological agent of Adult T cell Leukemia/Lymphoma (ATLL and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP. Both CD4+ T-cells and dendritic cells (DCs infected with HTLV-1 are found in peripheral blood from HTLV-1 carriers. We previously demonstrated that monocyte-derived IL-4 DCs are more susceptible to HTLV-1 infection than autologous primary T-cells, suggesting that DC infection precedes T-cell infection. However, during blood transmission, breast-feeding or sexual transmission, HTLV-1 may encounter different DC subsets present in the blood, the intestinal or genital mucosa respectively. These different contacts may impact HTLV-1 ability to infect DCs and its subsequent transfer to T-cells. Using in vitro monocyte-derived IL-4 DCs, TGF-β DCs and IFN-α DCs that mimic DCs contacting HTLV-1 in vivo, we show here that despite their increased ability to capture HTLV-1 virions, IFN-α DCs restrict HTLV-1 productive infection. Surprisingly, we then demonstrate that it is not due to the antiviral activity of type-I interferon produced by IFN-α DCs, but that it is likely to be linked to a distinct trafficking route of HTLV-1 in IL-4 DCs vs. IFN-α DCs. Finally, we demonstrate that, in contrast to IL-4 DCs, IFN-α DCs are impaired in their capacity to transfer HTLV-1 to CD4 T-cells, both after viral capture and trans-infection and after their productive infection. In conclusion, the nature of the DCs encountered by HTLV-1 upon primo-infection and the viral trafficking route through the vesicular pathway of these cells determine the efficiency of viral transmission to T-cells, which may condition the fate of infection.

  11. Type II Superstring Field Theory: Geometric Approach and Operadic Description

    CERN Document Server

    Jurco, Branislav

    2013-01-01

    We outline the construction of type II superstring field theory leading to a geometric and algebraic BV master equation, analogous to Zwiebach's construction for the bosonic string. The construction uses the small Hilbert space. Elementary vertices of the non-polynomial action are described with the help of a properly formulated minimal area problem. They give rise to an infinite tower of superstring field products defining a $\\mathcal{N}=1$ generalization of a loop homotopy Lie algebra, the genus zero part generalizing a homotopy Lie algebra. Finally, we give an operadic interpretation of the construction.

  12. Predicted continuum spectra of type II supernovae - LTE results

    Science.gov (United States)

    Shaviv, G.; Wehrse, R.; Wagoner, R. V.

    1985-01-01

    The continuum spectral energy distribution of the flux emerging from type II supernovae is calculated from quasi-static radiative transfer through a power-law density gradient, assuming radiative equilibrium and LTE. It is found that the Balmer jump disappears at high effective temperatures and low densities, while the spectrum resembles that of a dilute blackbody but is flatter with a sharper cutoff at the short-wavelength end. A significant UV excess is found in all models calculated. The calculation should be considered exploratory because of significant effects which are anticipated to arise from departure from LTE.

  13. Vitamin D - Dependent Rickets, Type II Case Report

    OpenAIRE

    Azemi, Mehmedali; Berisha, Majlinda; Ismaili-Jaha, Vlora; Kolgeci, Selim; Hoxha, Rina; Grajçevci-Uka, Violeta; Hoxha-Kamberi, Teuta

    2014-01-01

    Aim: The aim of this work the report of one case with vitamin D-dependent rickets, type II. Methods: Diagnosis has been established based on anamnesis, physical examination, laboratory findings and radiological examination. Results: A female child (age 25 months) has been hospitalized due to bone deformity, bone pain, alopecia and walking difficulties. The laboratory findings have revealed that the calcium values was low (1.20 mmol/L), phosphates in the reference value (1.30 mmol/L) the alkal...

  14. Nonsurgical endodontic treatment of type II dens invaginatus

    Science.gov (United States)

    MA, Rajini; Kaiwar, Anjali; N, Meena; Kumari R, Anitha; Shetty, Ashish; DN, Naveen; N, Shubhashini

    2009-01-01

    The endodontic treatment of teeth with dens invaginatus, characterized by an infolding of enamel and dentin, extending deep into the pulp cavity near the root apex, may be complicated and challenging. The complexity of the internal anatomy may create challenges for the complete removal of diseased pulpal tissue and the subsequent sealing of the canal system. Because of the bizarre root canal anatomy and widely open apex, a combination of nonsurgical and surgical endodontic treatment or extraction is the most common choice of therapy. This article describes case reports of nonsurgical endodontic treatment of Type II dens invaginatus associated with periradicular lesion. PMID:20617071

  15. Deficiency in plasmacytoid dendritic cells and type I interferon signalling prevents diet-induced obesity and insulin resistance in mice

    DEFF Research Database (Denmark)

    Hannibal, Tine D.; Schmidt-Christensen, Anja; Nilsson, Julia

    2017-01-01

    with a high fat content or normal chow. The mice were analysed in vivo and in vitro using cellular, biochemical and molecular approaches. Results We found that the development of obesity was inhibited by an inability to respond to type I IFNs. Furthermore, the development of obesity and insulin resistance...... in this model was associated with pDC recruitment to the fatty tissues and liver of obese mice (a 4.3-fold and 2.7-fold increase, respectively). Finally, we demonstrated that the depletion of pDCs protects mice from DIO and from developing obesity-associated metabolic complications. Conclusions...

  16. Successful management of transfusion-dependent congenital dyserythropoietic anemia type 1b with interferon alfa-2a

    DEFF Research Database (Denmark)

    Rathe, Mathias; Møller, Michael Boe; Greisen, Pernille Wied

    2018-01-01

    The congenital dyserythropoietic anemias (CDAs) are a group of rare inherited blood disorders characterized by ineffective erythropoiesis as the principal cause of anemia. We present a child with CDA 1b-the rarest and least well-described type-due to a mutation in the C15orf41 gene. The patient...... presented with severe in utero and neonatal manifestations, typical peripheral limb anomalies as well as rarely reported cardiac manifestations, visual impairment, short stature, and hip dysplasia. Anemia was complicated by iron overload and pronounced extra medullary erythropoiesis leading to skull...

  17. CA-125 level as a prognostic indicator in type I and type II epithelial ovarian cancer.

    Science.gov (United States)

    Chen, Xiaoxiang; Zhang, Jing; Cheng, Wenjun; Chang, Doo Young; Huang, Jianfei; Wang, Xuan; Jia, Lizhou; Rosen, Daniel G; Zhang, Wei; Yang, Da; Gershenson, David M; Sood, Anil K; Bast, Robert C; Liu, Jinsong

    2013-06-01

    Most patients with epithelial ovarian cancer achieve a complete clinical remission (CCR) with normal CA-125 but will still relapse and die from their disease. The present study was designed to determine whether CA-125 levels before, during, and after primary treatment provide prognostic information for both type I and type II ovarian cancer. In this retrospective study, we identified 410 patients with epithelial ovarian cancer who had achieved a CCR between 1984 and 2011. A Cox proportional hazards model and log-rank test were used to assess associations between the nadir CA-125, histotype, and prognosis. The baseline serum CA-125 concentration was higher in patients with type II ovarian cancer than in those with type I ovarian cancer (P CA-125 was an independent predictor of progression-free survival (PFS; P CA-125 of 10 U/mL or less and 13.6 and 64.6 months in those with CA-125 of 11 to 35 U/mL, respectively (P = 0.01 and P = 0.002, respectively). Histotype was an independent predictor of PFS (P = 0.041): the PFS and OS durations of the patients with type I ovarian cancer were longer than those of the patients with type II ovarian cancer (P CA-125 and histotype are predictive of PFS and OS durations in patients with ovarian cancers who experienced a CCR. Progression-free survival and OS durations were shorter in the patients with CA-125 levels of 11 to 35 U/mL and type II disease than in those with CA-125 levels of 10 U/mL or less and type I ovarian cancer.

  18. The type II collagen fragments Helix-II and CTX-II reveal different enzymatic pathways of human cartilage collagen degradation

    DEFF Research Database (Denmark)

    Charni-Ben Tabassi, N; Desmarais, S; Jensen, Anne-Christine Bay

    2008-01-01

    OBJECTIVE: Cartilage degradation in osteoarthritis (OA) generates the type II collagen fragments, Helix-II and CTX-II that can be used as clinical biological markers. Helix-II and C-telopeptide of type II collagen (CTX-II) levels are associated independently with progression of OA suggesting...... that they may be generated through different collagenolytic pathways. In this study we analyzed the release of Helix-II and CTX-II from human cartilage collagen by the proteinases reported to play a role in cartilage degradation. METHODS: In vitro, human articular cartilage extract was incubated with activated...... pathways. Helix-II and CTX-II alone reflect only partially overall cartilage collagen degradation. These findings may explain why these two biological markers could provide complementary information on disease progression in OA....

  19. Effect of Collagen Type I or Type II on Chondrogenesis by Cultured Human Articular Chondrocytes

    NARCIS (Netherlands)

    Rutgers, M.; Saris, Daniël B.F.; Vonk, L.A.; van Rijen, M.H.P.; Akrum, V.; Langeveld, D.; van Boxtel, A.; Dhert, W.J.A.; Creemers, L.B.

    2013-01-01

    Introduction: Current cartilage repair procedures using autologous chondrocytes rely on a variety of carriers for implantation. Collagen types I and II are frequently used and valuable properties of both were shown earlier in vitro, although a preference for either was not demonstrated. Recently,

  20. Cognitive Dysfunction Is Worse among Pediatric Patients with Bipolar Disorder Type I than Type II

    Science.gov (United States)

    Schenkel, Lindsay S.; West, Amy E.; Jacobs, Rachel; Sweeney, John A.; Pavuluri, Mani N.

    2012-01-01

    Background: Impaired profiles of neurocognitive function have been consistently demonstrated among pediatric patients with bipolar disorder (BD), and may aid in the identification of endophenotypes across subtypes of the disorder. This study aims to determine phenotypic cognitive profiles of patients with BD Type I and II. Methods: Subjects (N =…

  1. Synthesis and characterization of heterobimetallic complexes of the type [Cu(pn2][MCl4] where M = Co(II, Ni(II, Cu(II, Zn(II, Cd(II, and Hg(II

    Directory of Open Access Journals (Sweden)

    Seema Yadav

    2016-11-01

    Full Text Available A series of new bimetallic transition metal complexes of the type [Cu(pn2] [MCl4] have been synthesized (where M = Co(II, Ni(II, Cu(II, Zn(II, Cd(II and Hg(II, pn = 1,3-diaminopropane and characterized by elemental analysis, molar conductance, TGA, IR and electronic spectra. All the compounds are 1:1 electrolyte in DMF. The Cu(II ion is square-planar while metal ions in the anionic moiety acquire their usual tetrahedral arrangement. On the basis of these studies it is concluded that anionic moiety is electrically stabilized by its cationic counterpart.

  2. Alveolar epithelial type II cells induce T cell tolerance to specific antigen

    DEFF Research Database (Denmark)

    Lo, Bernice; Hansen, Søren; Evans, Kathy

    2008-01-01

    The lungs face the immunologic challenge of rapidly eliminating inhaled pathogens while maintaining tolerance to innocuous Ags. A break in this immune homeostasis may result in pulmonary inflammatory diseases, such as allergies or asthma. The observation that alveolar epithelial type II cells (Type...... II) constitutively express the class II MHC led us to hypothesize that Type II cells play a role in the adaptive immune response. Because Type II cells do not express detectable levels of the costimulatory molecules CD80 and CD86, we propose that Type II cells suppress activation of naive T cells...

  3. Collagen type II enhances chondrogenesis in adipose tissue-derived stem cells by affecting cell shape

    NARCIS (Netherlands)

    Lu, Z.; Doulabi, B.Z.; Huang, C.; Bank, R.A.; Helder, M.N.

    2010-01-01

    Ideally, biomaterials have inductive properties, favoring specific lineage differentiation. For chondrogenic induction, these properties have been attributed to collagen type II. However, the underlying mechanisms are largely unknown. This study aimed to investigate whether collagen type II favors

  4. Collagen Type II Enhances Chondrogenesis in Adipose Tissue-Derived Stem Cells by Affecting Cell Shape

    NARCIS (Netherlands)

    Lu, ZuFu; Doulabi, Behrouz Zandieh; Huang, ChunLing; Bank, Ruud A.; Helder, Marco N.

    Ideally, biomaterials have inductive properties, favoring specific lineage differentiation. For chondrogenic induction, these properties have been attributed to collagen type II. However, the underlying mechanisms are largely unknown. This study aimed to investigate whether collagen type II favors

  5. Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.

    Directory of Open Access Journals (Sweden)

    Silvia A Fuertes Marraco

    Full Text Available BACKGROUND: DC are activated by pathogen-associated molecular patterns (PAMPs, and this is pivotal for the induction of adaptive immune responses. Thereafter, the clearance of activated DC is crucial to prevent immune pathology. While PAMPs are of major interest for vaccine science due to their adjuvant potential, it is unclear whether and how PAMPs may affect DC viability. We aimed to elucidate the possible apoptotic mechanisms that control activated DC lifespan in response to PAMPs, particularly in vivo. METHODOLOGY/PRINCIPAL FINDINGS: We report that polyinosinic:polycytidylic acid (PolyIC, synthetic analogue of dsRNA induces dramatic apoptosis of mouse splenic conventional DC (cDC in vivo, predominantly affecting the CD8α subset, as shown by flow cytometry-based analysis of splenic DC subsets. Importantly, while Bim deficiency conferred only minor protection, cDC depletion was prevented in mice lacking Bim plus one of three other BH3-only proteins, either Puma, Noxa or Bid. Furthermore, we show that Type I Interferon (IFN is necessary and sufficient for DC death both in vitro and in vivo, and that TLR3 and MAVS co-operate in IFNß production in vivo to induce DC death in response to PolyIC. CONCLUSIONS/SIGNIFICANCE: These results demonstrate for the first time in vivo that apoptosis restricts DC lifespan following activation by PolyIC, particularly affecting the CD8α cDC subset. Such DC apoptosis is mediated by the overlapping action of pro-apoptotic BH3-only proteins, including but not solely involving Bim, and is driven by Type I IFN. While Type I IFNs are important anti-viral factors, CD8α cDC are major cross-presenting cells and critical inducers of CTL. We discuss such paradoxical finding on DC death with PolyIC/Type I IFN. These results could contribute to understand immunosuppression associated with chronic infection, and to the optimization of DC-based therapies and the clinical use of PAMPs and Type I IFNs.

  6. Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.

    Science.gov (United States)

    Fuertes Marraco, Silvia A; Scott, Clare L; Bouillet, Philippe; Ives, Annette; Masina, Slavica; Vremec, David; Jansen, Elisa S; O'Reilly, Lorraine A; Schneider, Pascal; Fasel, Nicolas; Shortman, Ken; Strasser, Andreas; Acha-Orbea, Hans

    2011-01-01

    DC are activated by pathogen-associated molecular patterns (PAMPs), and this is pivotal for the induction of adaptive immune responses. Thereafter, the clearance of activated DC is crucial to prevent immune pathology. While PAMPs are of major interest for vaccine science due to their adjuvant potential, it is unclear whether and how PAMPs may affect DC viability. We aimed to elucidate the possible apoptotic mechanisms that control activated DC lifespan in response to PAMPs, particularly in vivo. We report that polyinosinic:polycytidylic acid (PolyIC, synthetic analogue of dsRNA) induces dramatic apoptosis of mouse splenic conventional DC (cDC) in vivo, predominantly affecting the CD8α subset, as shown by flow cytometry-based analysis of splenic DC subsets. Importantly, while Bim deficiency conferred only minor protection, cDC depletion was prevented in mice lacking Bim plus one of three other BH3-only proteins, either Puma, Noxa or Bid. Furthermore, we show that Type I Interferon (IFN) is necessary and sufficient for DC death both in vitro and in vivo, and that TLR3 and MAVS co-operate in IFNß production in vivo to induce DC death in response to PolyIC. These results demonstrate for the first time in vivo that apoptosis restricts DC lifespan following activation by PolyIC, particularly affecting the CD8α cDC subset. Such DC apoptosis is mediated by the overlapping action of pro-apoptotic BH3-only proteins, including but not solely involving Bim, and is driven by Type I IFN. While Type I IFNs are important anti-viral factors, CD8α cDC are major cross-presenting cells and critical inducers of CTL. We discuss such paradoxical finding on DC death with PolyIC/Type I IFN. These results could contribute to understand immunosuppression associated with chronic infection, and to the optimization of DC-based therapies and the clinical use of PAMPs and Type I IFNs.

  7. Activation of type I and III interferon signalling pathways occurs in lung epithelial cells infected with low pathogenic avian influenza viruses.

    Directory of Open Access Journals (Sweden)

    Richard Sutejo

    Full Text Available The host response to the low pathogenic avian influenza (LPAI H5N2, H5N3 and H9N2 viruses were examined in A549, MDCK, and CEF cells using a systems-based approach. The H5N2 and H5N3 viruses replicated efficiently in A549 and MDCK cells, while the H9N2 virus replicated least efficiently in these cell types. However, all LPAI viruses exhibited similar and higher replication efficiencies in CEF cells. A comparison of the host responses of these viruses and the H1N1/WSN virus and low passage pH1N1 clinical isolates was performed in A549 cells. The H9N2 and H5N2 virus subtypes exhibited a robust induction of Type I and Type III interferon (IFN expression, sustained STAT1 activation from between 3 and 6 hpi, which correlated with large increases in IFN-stimulated gene (ISG expression by 10 hpi. In contrast, cells infected with the pH1N1 or H1N1/WSN virus showed only small increases in Type III IFN signalling, low levels of ISG expression, and down-regulated expression of the IFN type I receptor. JNK activation and increased expression of the pro-apoptotic XAF1 protein was observed in A549 cells infected with all viruses except the H1N1/WSN virus, while MAPK p38 activation was only observed in cells infected with the pH1N1 and the H5 virus subtypes. No IFN expression and low ISG expression levels were generally observed in CEF cells infected with either AIV, while increased IFN and ISG expression was observed in response to the H1N1/WSN infection. These data suggest differences in the replication characteristics and antivirus signalling responses both among the different LPAI viruses, and between these viruses and the H1N1 viruses examined. These virus-specific differences in host cell signalling highlight the importance of examining the host response to avian influenza viruses that have not been extensively adapted to mammalian tissue culture.

  8. Primary Biliary Cirrhosis and Type II Autoimmune Polyglandular Syndrome

    Directory of Open Access Journals (Sweden)

    Mark Ram Borgaonkar

    1999-01-01

    Full Text Available A 45-year-old female was diagnosed with Hashimoto’s thyroiditis in 1976 and Addison’s disease in 1979. At that time, her antimitochondrial antibody (AMA level was elevated at 1:32. She subsequently developed premature ovarian failure and type I diabetes mellitus. In 1996, she became jaundiced with a cholestatic enzyme pattern. AMA was positive at a titre of 1:256. A liver biopsy confirmed the diagnosis of primary biliary cirrhosis (PBC. She underwent a liver transplantation in January 1998. This is the first report of PBC in association with type II autoimmune polyglandular syndrome. The association of PBC with other organ-specific autoimmune diseases supports an immune-mediated pathogenesis and may have implications in further studies of PBC.

  9. Flux-flow noise in type II superconductors

    International Nuclear Information System (INIS)

    Choe, H.M.; Ziel, A. van der

    1976-01-01

    This paper discusses flux-flow noise in type II superconductors. A theoretical expression is given for flux-flow noise in a rectangular sample with two probes, and compared with earlier models; the differences are not very large. Experiments give no flicker noise below 20 μW/mm 2 dissipation at 4.2 K, whereas much larger dissipations can be tolerated below the lambda temperature before flicker noise sets in. The shape of the spectrum at elevated frequencies is of the 1/f type, as predicted by the theory, followed by a probe size effect at still higher frequencies. The noise is much larger than would be expected from single fluxoids; this is caused by the flux bundle effect which, in turn, is due to pinning and fluxoid interaction. The size of the flux bundles can be determined from the data, it decreases with increasing current. (Auth.)

  10. Exotic dual of type II double field theory

    Directory of Open Access Journals (Sweden)

    Eric A. Bergshoeff

    2017-04-01

    Full Text Available We perform an exotic dualization of the Ramond–Ramond fields in type II double field theory, in which they are encoded in a Majorana–Weyl spinor of O(D,D. Starting from a first-order master action, the dual theory in terms of a tensor–spinor of O(D,D is determined. This tensor–spinor is subject to an exotic version of the (self-duality constraint needed for a democratic formulation. We show that in components, reducing O(D,D to GL(D, one obtains the expected exotically dual theory in terms of mixed Young tableaux fields. To this end, we generalize exotic dualizations to self-dual fields, such as the 4-form in type IIB string theory.

  11. Gravitational Field Shielding by Scalar Field and Type II Superconductors

    Directory of Open Access Journals (Sweden)

    Zhang B. J.

    2013-01-01

    Full Text Available The gravitational field shielding by scalar field and type II superconductors are theoret- ically investigated. In accord with the well-developed five-dimensional fully covariant Kaluza-Klein theory with a scalar field, which unifies the Einsteinian general relativity and Maxwellian electromagnetic theory, the scalar field cannot only polarize the space as shown previously, but also flatten the space as indicated recently. The polariza- tion of space decreases the electromagnetic field by increasing the equivalent vacuum permittivity constant, while the flattening of space decreases the gravitational field by decreasing the equivalent gravitational constant. In other words, the scalar field can be also employed to shield the gravitational field. A strong scalar field significantly shield the gravitational field by largely decreasing the equivalent gravitational constant. According to the theory of gravitational field shielding by scalar field, the weight loss experimentally detected for a sample near a rotating ceramic disk at very low tempera- ture can be explained as the shielding of the Earth gravitational field by the Ginzburg- Landau scalar field, which is produced by the type II superconductors. The significant shielding of gravitational field by scalar field produced by superconductors may lead to a new spaceflight technology in future.

  12. The black hole interior and the type II Weyl fermions

    Science.gov (United States)

    Zubkov, M. A.

    2018-03-01

    It was proposed recently that the black hole may undergo a transition to the state, where inside the horizon the Fermi surface is formed that reveals an analogy with the recently discovered type II Weyl semimetals. In this scenario, the low energy effective theory outside of the horizon is the Standard Model, which describes excitations that reside near a certain point P(0) in momentum space of the hypothetical unified theory. Inside the horizon the low energy physics is due to the excitations that reside at the points in momentum space close to the Fermi surface. We argue that those points may be essentially distant from P(0) and, therefore, inside the black hole the quantum states are involved in the low energy dynamics that are not described by the Standard Model. We analyze the consequences of this observation for the physics of the black holes and present the model based on the direct analogy with the type II Weyl semimetals, which illustrates this pattern.

  13. Vitamin D - Dependent Rickets, Type II Case Report

    Science.gov (United States)

    Azemi, Mehmedali; Berisha, Majlinda; Ismaili-Jaha, Vlora; Kolgeci, Selim; Hoxha, Rina; Grajçevci-Uka, Violeta; Hoxha-Kamberi, Teuta

    2014-01-01

    Aim: The aim of this work the report of one case with vitamin D-dependent rickets, type II. Methods: Diagnosis has been established based on anamnesis, physical examination, laboratory findings and radiological examination. Results: A female child (age 25 months) has been hospitalized due to bone deformity, bone pain, alopecia and walking difficulties. The laboratory findings have revealed that the calcium values was low (1.20 mmol/L), phosphates in the reference value (1.30 mmol/L) the alkaline phosphatase value was quite high (852 IU/L), high value of parathyroid hormone (9.21 pmol/L), normal value of 25- hydroxyvitamin D, whereas the values of 1,25-dihydroxyvitamin D was high (185 μmol/L). Radiographic changes were evident and typical in the distal metaphysis of radius and ulna as well as in the bones of lower limbs (distal metaphysis of femur and proximal metaphysis of tibia and fibula). After treatment with calcium and calcitriol, the above mentioned clinical manifestations, laboratory test values and the radiographic changes in bones withdrew. Conclusions: Vitamin D-dependent rickets, type II is a rare genetic recessive disease, and its treatment includes a constant use of calcium and calcitriol. PMID:24757409

  14. Characterization of hearing loss in aged type II diabetics

    Science.gov (United States)

    Frisina, Susan T.; Mapes, Frances; Kim, SungHee; Frisina, D. Robert; Frisina, Robert D.

    2009-01-01

    Presbycusis – age-related hearing loss – is the number one communicative disorder and a significant chronic medical condition of the aged. Little is known about how type II diabetes, another prevalent age-related medical condition, and presbycusis interact. The present investigation aimed to comprehensively characterize the nature of hearing impairment in aged type II diabetics. Hearing tests measuring both peripheral (cochlea) and central (brainstem and cortex) auditory processing were utilized. The majority of differences between the hearing abilities of the aged diabetics and their age-matched controls were found in measures of inner ear function. For example, large differences were found in pure-tone audiograms, wideband noise and speech reception thresholds, and otoacoustic emissions. The greatest deficits tended to be at low frequencies. In addition, there was a strong tendency for diabetes to affect the right ear more than the left. One possible interpretation is that as one develops presbycusis, the right ear advantage is lost, and this decline is accelerated by diabetes. In contrast, auditory processing tests that measure both peripheral and central processing showed fewer declines between the elderly diabetics and the control group. Consequences of elevated blood sugar levels as possible underlying physiological mechanisms for the hearing loss are discussed. PMID:16309862

  15. Hijacking of the pleiotropic cytokine interferon-γ by the type III secretion system of Yersinia pestis.

    Directory of Open Access Journals (Sweden)

    Claire Gendrin

    Full Text Available Yersinia pestis, the causative agent of bubonic plague, employs its type III secretion system to inject toxins into target cells, a crucial step in infection establishment. LcrV is an essential component of the T3SS of Yersinia spp, and is able to associate at the tip of the secretion needle and take part in the translocation of anti-host effector proteins into the eukaryotic cell cytoplasm. Upon cell contact, LcrV is also released into the surrounding medium where it has been shown to block the normal inflammatory response, although details of this mechanism have remained elusive. In this work, we reveal a key aspect of the immunomodulatory function of LcrV by showing that it interacts directly and with nanomolar affinity with the inflammatory cytokine IFNγ. In addition, we generate specific IFNγ mutants that show decreased interaction capabilities towards LcrV, enabling us to map the interaction region to two basic C-terminal clusters of IFNγ. Lastly, we show that the LcrV-IFNγ interaction can be disrupted by a number of inhibitors, some of which display nanomolar affinity. This study thus not only identifies novel potential inhibitors that could be developed for the control of Yersinia-induced infection, but also highlights the diversity of the strategies used by Y. pestis to evade the immune system, with the hijacking of pleiotropic cytokines being a long-range mechanism that potentially plays a key role in the severity of plague.

  16. Isolation and molecular characterization of type I and type II feline coronavirus in Malaysia.

    Science.gov (United States)

    Amer, Alazawy; Siti Suri, Arshad; Abdul Rahman, Omar; Mohd, Hair Bejo; Faruku, Bande; Saeed, Sharif; Tengku Azmi, Tengku Ibrahim

    2012-11-21

    Feline infectious peritonitis virus (FIPV) and feline enteric coronavirus (FECV) are two important coronaviruses of domestic cat worldwide. Although FCoV is prevalent among cats; the fastidious nature of type I FCoV to grow on cell culture has limited further studies on tissue tropism and pathogenesis of FCoV. While several studies reported serological evidence for FCoV in Malaysia, neither the circulating FCoV isolated nor its biotypes determined. This study for the first time, describes the isolation and biotypes determination of type I and type II FCoV from naturally infected cats in Malaysia. Of the total number of cats sampled, 95% (40/42) were RT-PCR positive for FCoV. Inoculation of clinical samples into Crandell feline kidney cells (CrFK), and Feline catus whole fetus-4 cells (Fcwf-4), show cytopathic effect (CPE) characterized by syncytial cells formation and later cell detachment. Differentiation of FCoV biotypes using RT-PCR assay revealed that, 97.5% and 2.5% of local isolates were type I and type II FCoV, respectively. These isolates had high sequence homology and phylogenetic similarity with several FCoV isolates from Europe, South East Asia and USA. This study reported the successful isolation of local type I and type II FCoV evident with formation of cytopathic effects in two types of cell cultures namely the CrFK and Fcwf-4 , where the later cells being more permissive. However, the RT-PCR assay is more sensitive in detecting the antigen in suspected samples as compared to virus isolation in cell culture. The present study indicated that type I FCoV is more prevalent among cats in Malaysia.

  17. Isolation and molecular characterization of type I and type II feline coronavirus in Malaysia

    Directory of Open Access Journals (Sweden)

    Amer Alazawy

    2012-11-01

    Full Text Available Abstract Background Feline infectious peritonitis virus (FIPV and feline enteric coronavirus (FECV are two important coronaviruses of domestic cat worldwide. Although FCoV is prevalent among cats; the fastidious nature of type I FCoV to grow on cell culture has limited further studies on tissue tropism and pathogenesis of FCoV. While several studies reported serological evidence for FCoV in Malaysia, neither the circulating FCoV isolated nor its biotypes determined. This study for the first time, describes the isolation and biotypes determination of type I and type II FCoV from naturally infected cats in Malaysia. Findings Of the total number of cats sampled, 95% (40/42 were RT-PCR positive for FCoV. Inoculation of clinical samples into Crandell feline kidney cells (CrFK, and Feline catus whole fetus-4 cells (Fcwf-4, show cytopathic effect (CPE characterized by syncytial cells formation and later cell detachment. Differentiation of FCoV biotypes using RT-PCR assay revealed that, 97.5% and 2.5% of local isolates were type I and type II FCoV, respectively. These isolates had high sequence homology and phylogenetic similarity with several FCoV isolates from Europe, South East Asia and USA. Conclusions This study reported the successful isolation of local type I and type II FCoV evident with formation of cytopathic effects in two types of cell cultures namely the CrFK and Fcwf-4 , where the later cells being more permissive. However, the RT-PCR assay is more sensitive in detecting the antigen in suspected samples as compared to virus isolation in cell culture. The present study indicated that type I FCoV is more prevalent among cats in Malaysia.

  18. Type I and type II residual stress in iron meteorites determined by neutron diffraction measurements

    Science.gov (United States)

    Caporali, Stefano; Pratesi, Giovanni; Kabra, Saurabh; Grazzi, Francesco

    2018-04-01

    In this work we present a preliminary investigation by means of neutron diffraction experiment to determine the residual stress state in three different iron meteorites (Chinga, Sikhote Alin and Nantan). Because of the very peculiar microstructural characteristic of this class of samples, all the systematic effects related to the measuring procedure - such as crystallite size and composition - were taken into account and a clear differentiation in the statistical distribution of residual stress in coarse and fine grained meteorites were highlighted. Moreover, the residual stress state was statistically analysed in three orthogonal directions finding evidence of the existence of both type I and type II residual stress components. Finally, the application of von Mises approach allowed to determine the distribution of type II stress.

  19. Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA.

    Science.gov (United States)

    Lanford, Robert E; Feng, Zongdi; Chavez, Deborah; Guerra, Bernadette; Brasky, Kathleen M; Zhou, Yan; Yamane, Daisuke; Perelson, Alan S; Walker, Christopher M; Lemon, Stanley M

    2011-07-05

    Hepatitis A virus (HAV) is an hepatotropic human picornavirus that is associated only with acute infection. Its pathogenesis is not well understood because there are few studies in animal models using modern methodologies. We characterized HAV infections in three chimpanzees, quantifying viral RNA by quantitative RT-PCR and examining critical aspects of the innate immune response including intrahepatic IFN-stimulated gene expression. We compared these infection profiles with similar studies of chimpanzees infected with hepatitis C virus (HCV), an hepatotropic flavivirus that frequently causes persistent infection. Surprisingly, HAV-infected animals exhibited very limited induction of type I IFN-stimulated genes in the liver compared with chimpanzees with acute resolving HCV infection, despite similar levels of viremia and 100-fold greater quantities of viral RNA in the liver. Minimal IFN-stimulated gene 15 and IFIT1 responses peaked 1-2 wk after HAV challenge and then subsided despite continuing high hepatic viral RNA. An acute inflammatory response at 3-4 wk correlated with the appearance of virus-specific antibodies and apoptosis and proliferation of hepatocytes. Despite this, HAV RNA persisted in the liver for months, remaining present long after clearance from serum and feces and revealing dramatic differences in the kinetics of clearance in the three compartments. Viral RNA was detected in the liver for significantly longer (35 to >48 wk) than HCV RNA in animals with acute resolving HCV infection (10-20 wk). Collectively, these findings indicate that HAV is far stealthier than HCV early in the course of acute resolving infection. HAV infections represent a distinctly different paradigm in virus-host interactions within the liver.

  20. A Sample of Light Curves of Type II-n and other Unclassified Supernova

    Science.gov (United States)

    Mock, Justin; Martin, J. C.; Hambsch, F.; Strickland, W.; Cason, A.

    2014-01-01

    It has long been speculated that there is a connection between supernova impostors and Type II-n supernovae. The modern Type II-n spectroscopic classification overlaps a great deal with Zwicky’s “Type V” supernovae, which includes several impostors. In late 2012, SN 2009ip, a known impostor, may have exploded as a Type II-n supernova. The decline from that event exhibited unusual fluctuations in brightness that are not evident in other Type II-n light curves. We present the light curves of several more recent Type II-n supernova and compare them with other published samples.

  1. Interferon-α is the primary plasma type-I IFN in HIV-1 infection and correlates with immune activation and disease markers.

    Directory of Open Access Journals (Sweden)

    Gareth A D Hardy

    Full Text Available Type-I interferon (IFN-I has been increasingly implicated in HIV-1 pathogenesis. Various studies have shown elevated IFN-I and an IFN-I-induced gene and protein expression signature in HIV-1 infection, yet the elevated IFN-I species has not been conclusively identified, its source remains obscure and its role in driving HIV-1 pathogenesis is controversial. We assessed IFN-I species in plasma by ELISAs and bioassay, and we investigated potential sources of IFN-I in blood and lymph node tissue by qRT-PCR. Furthermore, we measured the effect of therapeutic administration of IFNα in HCV-infected subjects to model the effect of IFNα on chronic immune activation. IFN-I bioactivity was significantly increased in plasma of untreated HIV-1-infected subjects relative to uninfected subjects (p = 0.012, and IFNα was the predominant IFN-I subtype correlating with IFN-I bioactivity (r = 0.658, p<0.001. IFNα was not detectable in plasma of subjects receiving anti-retroviral therapy. Elevated expression of IFNα mRNA was limited to lymph node tissue cells, suggesting that peripheral blood leukocytes are not a major source of IFNα in untreated chronic HIV-1 infection. Plasma IFN-I levels correlated inversely with CD4 T cell count (p = 0.003 and positively with levels of plasma HIV-1 RNA and CD38 expression on CD8 T cells (p = 0.009. In hepatitis C virus-infected subjects, treatment with IFN-I and ribavirin increased expression of CD38 on CD8 T cells (p = 0.003. These studies identify IFNα derived from lymph nodes, rather than blood leukocytes, as a possible source of the IFN-I signature that contributes to immune activation in HIV-1 infection.

  2. Interferon-alpha mediates restriction of human immunodeficiency virus type-1 replication in primary human macrophages at an early stage of replication.

    Directory of Open Access Journals (Sweden)

    Kelly M Cheney

    2010-10-01

    Full Text Available Type I interferons (IFNα and β are induced directly in response to viral infection, resulting in an antiviral state for the cell. In vitro studies have shown that IFNα is a potent inhibitor of viral replication; however, its role in HIV-1 infection is incompletely understood. In this study we describe the ability of IFNα to restrict HIV-1 infection in primary human macrophages in contrast to peripheral blood mononuclear cells and monocyte-derived dendritic cells. Inhibition to HIV-1 replication in cells pretreated with IFNα occurred at an early stage in the virus life cycle. Late viral events such as budding and subsequent rounds of infection were not affected by IFNα treatment. Analysis of early and late HIV-1 reverse transcripts and integrated proviral DNA confirmed an early post entry role for IFNα. First strand cDNA synthesis was slightly reduced but late and integrated products were severely depleted, suggesting that initiation or the nucleic acid intermediates of reverse transcription are targeted. The depletion of integrated provirus is disproportionally greater than that of viral cDNA synthesis suggesting the possibility of a least an additional later target. A role for either cellular protein APOBEC3G or tetherin in this IFNα mediated restriction has been excluded. Vpu, previously shown by others to rescue a viral budding restriction by tetherin, could not overcome this IFNα induced effect. Determining both the viral determinants and cellular proteins involved may lead to novel therapeutic approaches. Our results add to the understanding of HIV-1 restriction by IFNα.

  3. Suppression of the toll-like receptor 7-dependent type I interferon production pathway by autophagy resulting from enterovirus 71 and coxsackievirus A16 infections facilitates their replication.

    Science.gov (United States)

    Song, Jie; Hu, Yajie; Li, Jiaqi; Zheng, Huiwen; Wang, Jingjing; Guo, Lei; Shi, Haijng; Liu, Longding

    2018-01-01

    Toll-like receptors (TLRs) act as molecular sentinels, detecting invading viral pathogens and triggering host innate immune responses, including autophagy. However, many viruses have evolved a series of strategies to manipulate autophagy for their own benefit. Enterovirus 71 (EV71) and coxsackievirus A16 (CA16), as the primary agents causing hand, foot and mouth disease (HFMD), can induce autophagy leading to their replication. Therefore, the objective of this study was to investigate whether enhanced viral replication caused by autophagy in EV71 and CA16 infections was associated with a TLR-related signaling pathway. Our results demonstrate that complete autophagy and incomplete autophagy were observed in human bronchial epithelial (16HBE) cells infected with EV71 and CA16. Moreover, suppression of autophagy by the pharmacological modulator 3-MA significantly and clearly decreased the survival rates and viral replication of EV71 and CA16 in 16HBE cells. Inhibition of autophagy also enhanced the expression of molecules related to the TLR7-dependent type I interferon (IFN-I) production pathway, such as TLR7, MyD88, IRF7 and IFN-α/β. Finally, immunofluorescence staining demonstrated that TLR7 endosome marker M6PR levels were clearly reduced in EV71- and CA16-infected cells, while they were markedly elevated in infected cells treated with 3-MA. These findings suggest that increased EV71 and CA16 replication meditated by autophagy in 16HBE cells might promote degradation of the endosome, leading to suppression of the TLR7-mediated IFN-I signaling pathway.

  4. Metallicity from Type II supernovae from the (i)PTF

    International Nuclear Information System (INIS)

    Taddia, F.; Moquist, P.; Sollerman, J.; Rubin, A.; Leloudas, G.

    2016-01-01

    Type IIP supernovae (SNe IIP) have recently been proposed as metallicity (Z) probes. The spectral models of Dessart et al. (2014, MNRAS, 440, 1856) showed that the pseudo-equivalent width of Fe ii λ5018 (pEW 5018 ) during the plateau phase depends on the primordial Z, but there was a paucity of SNe IIP exhibiting pEW 5018 that were compatible with Z < 0.4 Z ⊙ . This lack might be due to some physical property of the SN II population or to the fact that those SNe have been discovered in luminous, metal-rich targeted galaxies. In this paper, we use SN II observations from the untargeted (intermediate) Palomar Transient Factory [(i)PTF] survey, aiming to investigate the pEW 5018 distribution of this SN population and, in particular, to look for the presence of SNe II at lower Z. We perform pEW 5018 measurements on the spectra of a sample of 39 (i)PTF SNe II, selected to have well-constrained explosion epochs and light-curve properties. Based on the comparison with the pEW 5018 spectral models, we subgrouped our SNe into four Z bins from Z ≈ 0.1 Z ⊙ up to Z ≈ 2 Z ⊙ . We also independently investigated the Z of the hosts by using their absolute magnitudes and colors and, in a few cases, using strong-line diagnostics from spectra. We searched for possible correlations between SN observables, such as their peak magnitudes and the Z inferred from pEW 5018 . We found 11 events with pEW 5018 that were small enough to indicate Z ≈ 0.1 Z ⊙ . The trend of pEW 5018 with Z matches the Z estimates obtained from the host-galaxy photometry, although the significance of the correlation is weak. Finally, we also found that SNe with brighter peak magnitudes have smaller pEW 5018 and occur at lower Z.

  5. Multicentre, open, noncomparative Phase II trial to evaluate the efficacy and tolerability of fotemustine, cisplatin, alpha-interferon and interleukin-2 in advanced melanoma patients.

    Science.gov (United States)

    Ridolfi, Laura; Fiorentini, Giammaria; Guida, Michele; Michiara, Maria; Freschi, Andrea; Aitini, Enrico; Ballardini, Michela; Bichisao, Ettore; Ridolfi, Ruggero

    2009-04-01

    The efficacy and tolerability of fotemustine, cisplatin, alpha-interferon and interleukin-2 biochemotherapy were evaluated in advanced melanoma patients. The schedule consisted of fotemustine (100 mg/m) and cisplatin (75 mg/m) intravenous on day 1, followed by subcutaneous interleukin-2 at a dose of 4.5 MIU on days 3-5 and 8-12 and alpha-interferon at a dose of 3 MU three times/week, every 3 weeks for six cycles. Sixty patients were evaluated for tumour response, 12 of whom had brain metastases (BM). One patient (1.7%) with BM achieved a complete response and partial responses were observed in 10 patients (16.7%), including one BM patient. Overall response rate was 18.4 and 16.6% in BM patients (median response duration 8.2 months). Disease control, defined as overall response and stable disease, was 58.4% in all patients and 75% in patients with BM. Median time to progression was 3.2 months (4.2 months in BM patients). Median overall survival was 8.9 months (7.6 months in BM patients). Toxic events were mild to moderate. This combination was well tolerated and showed acceptable clinical activity, especially in BM patients.

  6. Magnetoexcitons in type-II semiconductor quantum dots

    Science.gov (United States)

    Fuster, Gonzalo; Barticevic, Zdenka; Pacheco, Monica; Oliveira, Luiz E.

    2004-03-01

    We present a theoretical investigation of excitons in type-II semiconductor quantum dots (QD). In these systems the confinement of electrons inside the QD and the hole outside the QD produces a ring-like structure [1-2]. Recently, Ribeiro et al [3], in a magnetophotoluminescence study of type-II InP/GaAs self-assembled quantum dots, observed Aharonov-Bohm-type oscillations characteristic of the ring topology for neutral excitons. Using a simple model they have derived the groundstate hole energy as a function of the magnetic field, and obtained values for the ring parameters which are in good agreement with the measured values. However, some of the features observed experimentally, in the photoluminescence intensity, can not be well explained under that approach. In this work we present a more realistic model which considers the finite width of the ring and the electron-hole interaction included via a perturbative approach. The calculations are performed within the oneparticle formalism using the effective mass approximation. The confinement potential for electrons is modelled as the superposition of a quantum well potential along the axial direction, and a parabolic lateral confinement potential. The energies for the hole in the ring plane are calculated using the method of reference [4]. Theoretical calculations are in good agreement with the experimental results of reference [3] provided that excitonic effects are properly taken into account. References 1. A.O. Govorov et al., Physica E 13 , 297 (2002). 2. K. L. Janssens et al. Phys. Rev B64, 155324 (2001), and Phys. Rev. B66, 075314 (2002). 3. E. Ribeiro, G. Medeiros-Ribeiro, and W.Carvalho Jr., and A.O. Govorov, condmat/0304092 (2003). 4. Z. Barticevic, G. Fuster, and M. Pacheco,Phys. Rev. B 65, 193307 (2002).

  7. MicroRNA-Attenuated Clone of Virulent Semliki Forest Virus Overcomes Antiviral Type I Interferon in Resistant Mouse CT-2A Glioma.

    Science.gov (United States)

    Martikainen, Miika; Niittykoski, Minna; von und zu Fraunberg, Mikael; Immonen, Arto; Koponen, Susanna; van Geenen, Maartje; Vähä-Koskela, Markus; Ylösmäki, Erkko; Jääskeläinen, Juha E; Saksela, Kalle; Hinkkanen, Ari

    2015-10-01

    Glioblastoma is a terminal disease with no effective treatment currently available. Among the new therapy candidates are oncolytic viruses capable of selectively replicating in cancer cells, causing tumor lysis and inducing adaptive immune responses against the tumor. However, tumor antiviral responses, primarily mediated by type I interferon (IFN-I), remain a key problem that severely restricts viral replication and oncolysis. We show here that the Semliki Forest virus (SFV) strain SFV4, which causes lethal encephalitis in mice, is able to infect and replicate independent of the IFN-I defense in mouse glioblastoma cells and cell lines originating from primary human glioblastoma patient samples. The ability to tolerate IFN-I was retained in SFV4-miRT124 cells, a derivative cell line of strain SFV4 with a restricted capacity to replicate in neurons due to insertion of target sites for neuronal microRNA 124. The IFN-I tolerance was associated with the viral nsp3-nsp4 gene region and distinct from the genetic loci responsible for SFV neurovirulence. In contrast to the naturally attenuated strain SFV A7(74) and its derivatives, SFV4-miRT124 displayed increased oncolytic potency in CT-2A murine astrocytoma cells and in the human glioblastoma cell lines pretreated with IFN-I. Following a single intraperitoneal injection of SFV4-miRT124 into C57BL/6 mice bearing CT-2A orthotopic gliomas, the virus homed to the brain and was amplified in the tumor, resulting in significant tumor growth inhibition and improved survival. Although progress has been made in development of replicative oncolytic viruses, information regarding their overall therapeutic potency in a clinical setting is still lacking. This could be at least partially dependent on the IFN-I sensitivity of the viruses used. Here, we show that the conditionally replicating SFV4-miRT124 virus shares the IFN-I tolerance of the pathogenic wild-type SFV, thereby allowing efficient targeting of a glioma that is refractory

  8. PACT- and RIG-I-Dependent Activation of Type I Interferon Production by a Defective Interfering RNA Derived from Measles Virus Vaccine

    Science.gov (United States)

    Ho, Ting-Hin; Kew, Chun; Lui, Pak-Yin; Chan, Chi-Ping; Satoh, Takashi; Akira, Shizuo

    2015-01-01

    ABSTRACT The live attenuated measles virus vaccine is highly immunostimulatory. Identification and characterization of its components that activate the innate immune response might provide new strategies and agents for the rational design and development of chemically defined adjuvants. In this study, we report on the activation of type I interferon (IFN) production by a defective interfering (DI) RNA isolated from the Hu-191 vaccine strain of measles virus. We found that the Hu-191 virus induced IFN-β much more potently than the Edmonston strain. In the search for IFN-inducing species in Hu-191, we identified a DI RNA specifically expressed by this strain. This DI RNA, which was of the copy-back type, was predicted to fold into a hairpin structure with a long double-stranded stem region of 206 bp, and it potently induced the expression of IFN-β. Its IFN-β-inducing activity was further enhanced when both cytoplasmic RNA sensor RIG-I and its partner, PACT, were overexpressed. On the contrary, this activity was abrogated in cells deficient in PACT or RIG-I. The DI RNA was found to be associated with PACT in infected cells. In addition, both the 5′-di/triphosphate end and the double-stranded stem region on the DI RNA were essential for its activation of PACT and RIG-I. Taken together, our findings support a model in which a viral DI RNA is sensed by PACT and RIG-I to initiate an innate antiviral response. Our work might also provide a foundation for identifying physiological PACT ligands and developing novel adjuvants or antivirals. IMPORTANCE The live attenuated measles virus vaccine is one of the most successful human vaccines and has largely contained the devastating impact of a highly contagious virus. Identifying the components in this vaccine that stimulate the host immune response and understanding their mechanism of action might help to design and develop better adjuvants, vaccines, antivirals, and immunotherapeutic agents. We identified and characterized

  9. Herpes simplex virus infection is sensed by both Toll-like receptors and retinoic acid-inducible gene- like receptors, which synergize to induce type I interferon production

    DEFF Research Database (Denmark)

    Rasmussen, Simon Brandtoft; Jensen, Søren B; Nielsen, C

    2009-01-01

    interferons (IFNs) after infection with herpes simplex virus (HSV). Our work also identified RNase L as a critical component in IFN induction. Moreover, we found that TLR9 and RLRs activate distinct, as well as overlapping, intracellular signalling pathways. Thus, RLRs are important for recognition of HSV...

  10. Successful Pregnancy Outcome In Maternal Crigler Najjar Syndrome Type II

    Directory of Open Access Journals (Sweden)

    Shakuntala PN

    2012-10-01

    Full Text Available Estimated incidence of Crigler-Najjar syndrome(CNS is 1 case per 1,000,000 births(1 million. The overall prevalence of CN syndrome is unknown, with only several hundred people reported to have this disease. It is interestingly very rare to encounter a pregnant adult women with congenital jaundice. Pregnancy in CN type II patients is a diagnostic and a therapeutic challenge because of the high risk of bilirubin encephalopathy with serious neurological damage as life-threatening complications for the fetus. To date 8 pregnancy outcome have been reported from 5 women and we report the6 woman with a successful 9 th pregnancy outcome. We have discussed detail history, presentation and management during pregnancy and care of the new born.

  11. Distribution of magnetic field in type II superconductors

    International Nuclear Information System (INIS)

    Castro, J.L. de.

    1986-09-01

    The magnetie field penetration profile, in type II superconductor, has studied in specially designed cylindrical samples. The samples consist of alternated thick layers ( > 30 μm ) of niobium and copper deposited, by electron-beam evaporation or electro-chemical deposition, on cylindric core of either niobium or copper. The magnetization curves, the magnetic susceptibility and the differential susceptibility for small hysteresis loop ( H c1 c2 ) were measured for all the samples between 4. 2 and 9.5 K. These measurements, done with flux pinned and without, show some peculiar descontinuities and inflections which seems to resemble the samples shape. A simple phenonenological extension of Bean's critical state model was applied to these results, giving a resonable qualitative agreement. Also, a more elaborated theoretical model was improve which could give more quantitative fitting. (author) [pt

  12. Neutrinos from Choked Jets Accompanied by Type-II Supernovae

    Science.gov (United States)

    He, Hao-Ning; Kusenko, Alexander; Nagataki, Shigehiro; Fan, Yi-Zhong; Wei, Da-Ming

    2018-04-01

    The origin of the IceCube neutrinos is still an open question. Upper limits from diffuse gamma-ray observations suggest that the neutrino sources are either distant or hidden from gamma-ray observations. It is possible that the neutrinos are produced in jets that are formed in core-collapsing massive stars and fail to break out, the so-called choked jets. We study neutrinos from the jets choked in the hydrogen envelopes of red supergiant stars. Fast photo-meson cooling softens the neutrino spectrum, making it hard to explain the PeV neutrinos observed by IceCube in a one-component scenario, but a two-component model can explain the spectrum. Furthermore, we predict that a newly born jet-driven type-II supernova may be observed to be associated with a neutrino burst detected by IceCube.

  13. Glycogen storage disease type II (Pompe disease in children

    Directory of Open Access Journals (Sweden)

    A. N. Semyachkina

    2014-01-01

    Full Text Available The paper gives the data available in the literature, which reflect the manifestations, diagnosis, and current treatments of the rare (orphan inherited disease glycogen storage disease type II or Pomp disease in children, as well as its classification. The infant form is shown to be most severe, resulting in death from cardiovascular or pulmonary failure generally within the first year of a child’s life. Emphasis is laid on major difficulties in the differential and true diagnosis of this severe disease. Much attention is given to the new pathogenetic treatment — genetically engineered enzyme replacement drug Myozyme®. The authors describe their clinical case of a child with the juvenile form of glycogen storage disease type II (late-onset Pompe disease. Particular emphasis is laid on the clinical symptoms of the disease and its diagnostic methods, among which the morphological analysis of a muscle biopsy specimen by light and electron microscopies, and enzyme and DNA diagnoses are of most importance. The proband was found to have significant lysosomal glycogen accumulation in the muscle biopsy specimen, reduced lymphocyte acid α-1,4-glucosidase activity to 4,2 nM/mg/h (normal value, 13,0—53,6 nM/mg/h, described in the HGMD missense mutation database from 1000 G>A p.Gly334er of the GAA in homozygous state, which verified the diagnosis of Pompe disease. 

  14. Functional assessment of feet of patients with type II diabetes

    Directory of Open Access Journals (Sweden)

    Vinicius Saura Cardoso

    2014-09-01

    Full Text Available Objective: To evaluate the incidence of functional changes and risk of developing ulcers in type II diabetic patients seen in Primary Healthcare Units (Unidades Básicas de Saúde- UBS. Methods: A cross-sectional, quantitative and descriptive study comprising 80patients with type II diabetes mellitus (DM aged between 41 to 85 years and attended inthe UBS in the city of Parnaíba-PI. Volunteers responded to the identification form and theMichigan Neuropathy Screening Instrument (MNSI, followed by an evaluation of the lowerlimbs, as follows: achilles and patellar reflex, palpation of arterial pulses (dorsalis pedis and posterior tibial, tactile sensitivity (Monofilament 10g and vibration sensitivity (128Hz tuning fork; identification of the presence of changes such as ingrown toenails, calluses,claw toes and hair loss. Finally, using the information acquired from the assessment, subjects were classified according to the risk of developing wounds. Results: The sample consisted of 76 diabetic patients, with average age of 63.8 ± 10.4 years, 63 (82.8% were female, mean diagnostic time 8.8 ± 7.2 years, average body mass index (BMI 28.2 ± 5.4 kg/m2, with 15.7% of the sample being smokers. The myotatic reflexes and arterial pulses were reduced. Tactile sensitivity was identified in 81.5% and 13.1% did not feel the vibration of the tuning fork. The most dominant changes identified were calluses, 76.3% (n = 58. Risk level 2 of developing ulcers stood out, 52.6% (n = 40. Conclusion: Functional changes were detected in the sample and a classification of risk 2 for developing wounds was found in more than 50% of the assessed patients. doi:http://dx.doi.org/10.5020/18061230.2013.p563

  15. Axonal interferon responses and alphaherpesvirus neuroinvasion

    Science.gov (United States)

    Song, Ren

    Infection by alphaherpesviruses, including herpes simplex virus (HSV) and pseudorabies virus (PRV), typically begins at a peripheral epithelial surface and continues into the peripheral nervous system (PNS) that innervates this tissue. Inflammatory responses are induced at the infected peripheral site prior to viral invasion of the PNS. PNS neurons are highly polarized cells with long axonal processes that connect to distant targets. When the peripheral tissue is first infected, only the innervating axons are exposed to this inflammatory milieu, which include type I interferon (e.g. IFNbeta) and type II interferon (i.e. IFNgamma). IFNbeta can be produced by all types of cells, while IFNgamma is secreted by some specific types of immune cells. And both types of IFN induce antiviral responses in surrounding cells that express the IFN receptors. The fundamental question is how do PNS neurons respond to the inflammatory milieu experienced only by their axons. Axons must act as potential front-line barriers to prevent PNS infection and damage. Using compartmented cultures that physically separate neuron axons from cell bodies, I found that pretreating isolated axons with IFNbeta or IFNgamma significantly diminished the number of HSV-1 and PRV particles moving from axons to the cell bodies in an IFN receptor-dependent manner. Furthermore, I found the responses in axons are activated differentially by the two types of IFNs. The response to IFNbeta is a rapid, axon-only response, while the response to IFNgamma involves long distance signaling to the PNS cell body. For example, exposing axons to IFNbeta induced STAT1 phosphorylation (p-STAT1) only in axons, while exposure of axons to IFNgamma induced p-STAT1 accumulation in distant cell body nuclei. Blocking transcription in cell bodies eliminated IFNgamma-, but not IFNbeta-mediated antiviral effects. Proteomic analysis of IFNbeta- or IFNgamma-treated axons identified several differentially regulated proteins. Therefore

  16. Inhibition of dengue and chikungunya virus infections by RIG-I-mediated type I interferon-independent stimulation of the innate antiviral response.

    Science.gov (United States)

    Olagnier, David; Scholte, Florine E M; Chiang, Cindy; Albulescu, Irina C; Nichols, Carmen; He, Zhong; Lin, Rongtuan; Snijder, Eric J; van Hemert, Martijn J; Hiscott, John

    2014-04-01

    RIG-I is a cytosolic sensor critically involved in the activation of the innate immune response to RNA virus infection. In the present study, we evaluated the inhibitory effect of a RIG-I agonist on the replication of two emerging arthropod-borne viral pathogens, dengue virus (DENV) and chikungunya virus (CHIKV), for which no therapeutic options currently exist. We demonstrate that when a low, noncytotoxic dose of an optimized 5'triphosphorylated RNA (5'pppRNA) molecule was administered, RIG-I stimulation generated a robust antiviral response against these two viruses. Strikingly, 5'pppRNA treatment before or after challenge with DENV or CHIKV provided protection against infection. In primary human monocytes and monocyte-derived dendritic cells, the RIG-I agonist blocked both primary infection and antibody-dependent enhancement of DENV infection. The protective response against DENV and CHIKV induced by 5'pppRNA was dependent on an intact RIG-I/MAVS/TBK1/IRF3 axis and was largely independent of the type I IFN response. Altogether, this in vitro analysis of the antiviral efficacy of 5'pppRNA highlights the therapeutic potential of RIG-I agonists against emerging viruses such as DENV and CHIKV. DENV and CHIKV are two reemerging mosquito-borne viruses for which no therapeutic options currently exist. Both viruses overlap geographically in tropical regions of the world, produce similar fever-like symptoms, and are difficult to diagnose. This study investigated the inhibitory effect of a RIG-I agonist on the replication of these two viruses. RIG-I stimulation using 5'pppRNA before or after DENV or CHIKV infection generated a protective antiviral response against both pathogens in immune and nonimmune cells; interestingly, the protective response against the viruses was largely independent of the classical type I interferon response. The antiviral efficacy of 5'pppRNA highlights the therapeutic potential of RIG-I agonists against emerging viruses such as DENV and CHIKV.

  17. The immunoregulatory role of type I and type II NKT cells in cancer and other diseases

    Science.gov (United States)

    Terabe, Masaki; Berzofsky, Jay A.

    2014-01-01

    NKT cells are CD1d-restricted T cells that recognize lipid antigens. They also have been shown to play critical roles in the regulation of immune responses. In the immune responses against tumors, two subsets of NKT cells, type I and type II, play opposing roles and cross-regulate each other. As members of both the innate and adaptive immune systems, which form a network of multiple components, they also interact with other immune components. Here we discuss the function of NKT cells in tumor immunity and their interaction with other regulatory cells, especially CD4+CD25+Foxp3+ regulatory T cells. PMID:24384834

  18. Overexpression of interleukin-1β and interferon-γ in type I thoracic aortic dissections and ascending thoracic aortic aneurysms: possible correlation with matrix metalloproteinase-9 expression and apoptosis of aortic media cells.

    Science.gov (United States)

    Zhang, Lei; Liao, Ming-fang; Tian, Lei; Zou, Si-li; Lu, Qing-sheng; Bao, Jun-min; Pei, Yi-fei; Jing, Zai-ping

    2011-07-01

    To examine the expression of interleukin-1β and interferon-γ and their possible roles in aortic dissections and aneurysms. Aortic specimens were obtained from patients with type I thoracic aortic dissection, ascending thoracic aortic aneurysms, and control organ donors. The expression of interleukin-1β, interferon-γ, matrix metalloproteinase-9, and signal transduction factors phospho-p38 and phosphorylated c-jun N-terminal kinase (phospho-JNK) were detected by real time reverse transcription-polymerase chain reaction (real time RT-PCR), Western blot, and immunohistochemistry, respectively. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining was performed to detect apoptosis of media cells. The correlation of these factors and apoptosis was also studied. Apoptosis in the media of thoracic aortic dissection and in ascending thoracic aortic aneurysms was dramatically higher than in the control group. The expression of interleukin-1β gradually increased from the control group, thoracic aortic dissection to ascending thoracic aortic aneurysms (p matrix metalloproteinase-9 was significantly increased in the media of thoracic aortic dissection and ascending thoracic aortic aneurysms compared with the control group (p correlations between interleukin-1β versus matrix metalloproteinase-9, interleukin-1β versus phospho-p38 in thoracic aortic dissection (p matrix metalloproteinase-9, interferon-γ versus phospho-JNK, interferon-γ versus apoptosis, and interleukin-1β versus apoptosis in ascending thoracic aortic aneurysms (p = 0.02, 0.02, p matrix metalloproteinase-9 and the apoptosis of media cells in humans. Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

  19. The prognostic value of dividing epithelial ovarian cancer into type I and type II tumors based on pathologic characteristics

    DEFF Research Database (Denmark)

    Prahm, Kira Philipsen; Karlsen, Mona Aarenstrup; Høgdall, Estrid

    2015-01-01

    OBJECTIVE: To investigate the prognostic significance of dividing epithelial ovarian cancer (EOC) in type I and type II tumors based on pathologic variables. METHODS: We used the Danish Gynecologic Cancer Database to identify all patients diagnosed with EOC from 2005 to 2012. Information...... on histologic type and grade were used to classify tumors as either type I or type II. Death, and several prognostic factors were used in the multivariate Cox regression, and Landmark analysis was used to estimate hazard ratios of all-cause mortality. RESULTS: Among 2660 patients diagnosed with EOC, 735 were...... categorized as type I tumors, and 1925 as type II tumors. Patients with type II EOC were more frequently diagnosed in late FIGO stages (stages III-IV) than patients with type I EOC (78.1% vs. 32.1% respectively; P

  20. Molecular determinants on the insect sodium channel for the specific action of type II pyrethroid insecticides

    Science.gov (United States)

    Du, Yuzhe; Nomura, Yoshiko; Luo, Ningguang; Liu, Zhiqi; Lee, Jung-Eun; Khambay, Bhupinder; Dong, Ke

    2011-01-01

    Pyrethroid insecticides are classified as type I or type II based on their distinct symptomology and effects on sodium channel gating. Structurally, type II pyrethroids possess an α-cyano group at the phenylbenzyl alcohol position, which is lacking in type I pyrethroids. Both type I and type II pyrethroids inhibit deactivation consequently prolonging the opening of sodium channels. However, type II pyrethroids inhibit the deactivation of sodium channels to a greater extent than type I pyrethroids inducing much slower decaying of tail currents upon repolarization. The molecular basis of type II-specific action, however, is not known. Here we report the identification of a residue G1111 and two positively charged lysines immediately downstream of G1111 in the intracellular linker connecting domains II and III of the cockroach sodium channel that are specifically involved in the action of type II pyrethroids, but not in the action of type I pyrethroids. Deletion of G1111, a consequence of alternative splicing, reduced the sodium channel sensitivity to type II pyrethroids, but had no effect on channel sensitivity to type I pyrethroids. Interestingly, charge neutralization or charge reversal of two positively charged lysines (Ks) downstream of G1111 had a similar effect. These results provide the molecular insight into the type II-specific interaction of pyrethroids with the sodium channel at the molecular level. PMID:19022275

  1. Increased Levels of Type 1 Interferon in a Type 1 Diabetic Mouse Model Induce the Elimination of B Cells from the Periphery by Apoptosis and Increase their Retention in the Spleen

    Directory of Open Access Journals (Sweden)

    Badr Mohamed Badr

    2015-01-01

    Full Text Available Background: The autoimmune disease type 1 diabetes mellitus (T1D is associated with a defect in the immune response, which increases susceptibility to infection. We recently demonstrated that prolonged elevated levels of type 1 interferon (IFN induce lymphocyte exhaustion during T1D. Aims: In the present study, we further investigated the effect of blocking the type I IFN receptor signaling pathway on diabetic dyslipidemia, in which an abnormal lipid profile leads to the exhaustion of B cells and alteration of their distribution and functions. Methods: T1D was induced in a mouse model by an intraperitoneal injection of a single dose (60 mg/kg of streptozotocin (STZ. Three groups of mice were examined: a non-diabetic control group, a diabetic group and a diabetic group treated with an anti-IFN (alpha, beta and omega receptor 1 (IFNAR1 blocking antibody to block type I IFN signaling. Results: We observed that induction of T1D was accompanied by a marked destruction of β cells and a reduction in the insulin levels in the diabetic group. Diabetic mice exhibited many changes, including alterations in their lipid profiles, expansion of splenic B cells, increased caspase-3, -8 and -9 activity, and apoptosis in peripheral B cells. Blocking type 1 IFN signaling in diabetic mice significantly returned the insulin and lipid profiles to normal levels, subsequently restored the B cell distribution, and rescued the peripheral B cells from apoptosis. Conclusion: Our data suggest the potential role of type I IFN in mediating diabetic dyslipidemia and an exhausted state of B cells during T1D.

  2. Relative potencies of Type I and Type II pyrethroids for inhibition of spontaneous firing in neuronal networks.

    Science.gov (United States)

    Pyrethroids insecticides commonly used in pest control disrupt the normal function of voltage-sensitive sodium channels. We have previously demonstrated that permethrin (a Type I pyrethroid) and deltamethrin (a Type II pyrethroid) inhibit sodium channel-dependent spontaneous netw...

  3. Type-I and type-II topological nodal superconductors with s -wave interaction

    Science.gov (United States)

    Huang, Beibing; Yang, Xiaosen; Xu, Ning; Gong, Ming

    2018-01-01

    Topological nodal superconductors with protected gapless points in momentum space are generally realized based on unconventional pairings. In this work we propose a minimal model to realize these topological nodal phases with only s -wave interaction. In our model the linear and quadratic spin-orbit couplings along the two orthogonal directions introduce anisotropic effective unconventional pairings in momentum space. This model may support different nodal superconducting phases characterized by either an integer winding number in BDI class or a Z2 index in D class at the particle-hole invariant axes. In the vicinity of the nodal points the effective Hamiltonian can be described by either type-I or type-II Dirac equations, and the Lifshitz transition from type-I nodal phases to type-II nodal phases can be driven by external in-plane magnetic fields. We show that these nodal phases are robust against weak impurities, which only slightly renormalizes the momentum-independent parameters in the impurity-averaged Hamiltonian, thus these phases are possible to be realized in experiments with real semi-Dirac materials. The smoking-gun evidences to verify these phases based on scanning tunneling spectroscopy method are also briefly discussed.

  4. Higgs potential in the type II seesaw model

    International Nuclear Information System (INIS)

    Arhrib, A.; Benbrik, R.; Chabab, M.; Rahili, L.; Ramadan, J.; Moultaka, G.; Peyranere, M. C.

    2011-01-01

    The standard model Higgs sector, extended by one weak gauge triplet of scalar fields with a very small vacuum expectation value, is a very promising setting to account for neutrino masses through the so-called type II seesaw mechanism. In this paper we consider the general renormalizable doublet/triplet Higgs potential of this model. We perform a detailed study of its main dynamical features that depend on five dimensionless couplings and two mass parameters after spontaneous symmetry breaking, and highlight the implications for the Higgs phenomenology. In particular, we determine (i) the complete set of tree-level unitarity constraints on the couplings of the potential and (ii) the exact tree-level boundedness from below constraints on these couplings, valid for all directions. When combined, these constraints delineate precisely the theoretically allowed parameter space domain within our perturbative approximation. Among the seven physical Higgs states of this model, the mass of the lighter (heavier) CP even state h 0 (H 0 ) will always satisfy a theoretical upper (lower) bound that is reached for a critical value μ c of μ (the mass parameter controlling triple couplings among the doublet/triplet Higgses). Saturating the unitarity bounds, we find an upper bound m h 0 or approx. μ c and μ c . In the first regime the Higgs sector is typically very heavy, and only h 0 that becomes SM-like could be accessible to the LHC. In contrast, in the second regime, somewhat overlooked in the literature, most of the Higgs sector is light. In particular, the heaviest state H 0 becomes SM-like, the lighter states being the CP odd Higgs, the (doubly) charged Higgses, and a decoupled h 0 , possibly leading to a distinctive phenomenology at the colliders.

  5. Insulin gene polymorphisms in type 1 diabetes, Addison's disease and the polyglandular autoimmune syndrome type II

    Directory of Open Access Journals (Sweden)

    Hahner Stefanie

    2008-07-01

    Full Text Available Abstract Background Polymorphisms within the insulin gene can influence insulin expression in the pancreas and especially in the thymus, where self-antigens are processed, shaping the T cell repertoire into selftolerance, a process that protects from β-cell autoimmunity. Methods We investigated the role of the -2221Msp(C/T and -23HphI(A/T polymorphisms within the insulin gene in patients with a monoglandular autoimmune endocrine disease [patients with isolated type 1 diabetes (T1D, n = 317, Addison's disease (AD, n = 107 or Hashimoto's thyroiditis (HT, n = 61], those with a polyglandular autoimmune syndrome type II (combination of T1D and/or AD with HT or GD, n = 62 as well as in healthy controls (HC, n = 275. Results T1D patients carried significantly more often the homozygous genotype "CC" -2221Msp(C/T and "AA" -23HphI(A/T polymorphisms than the HC (78.5% vs. 66.2%, p = 0.0027 and 75.4% vs. 52.4%, p = 3.7 × 10-8, respectively. The distribution of insulin gene polymorphisms did not show significant differences between patients with AD, HT, or APS-II and HC. Conclusion We demonstrate that the allele "C" of the -2221Msp(C/T and "A" -23HphI(A/T insulin gene polymorphisms confer susceptibility to T1D but not to isolated AD, HT or as a part of the APS-II.

  6. High Quantum Efficiency Type II SLS FPAs for Space-Based Applications Project

    Data.gov (United States)

    National Aeronautics and Space Administration — This Phase II SBIR proposes to develop high quantum efficiency (QE) and low dark current infrared epitaxy materials based on Type II Strained Layer Superlattice...

  7. FimH adhesin of type 1 fimbriae is a potent inducer of innate antimicrobial responses which requires TLR4 and type 1 interferon signalling.

    Directory of Open Access Journals (Sweden)

    Ali A Ashkar

    2008-12-01

    Full Text Available Components of bacteria have been shown to induce innate antiviral immunity via Toll-like receptors (TLRs. We have recently shown that FimH, the adhesin portion of type 1 fimbria, can induce the innate immune system via TLR4. Here we report that FimH induces potent in vitro and in vivo innate antimicrobial responses. FimH induced an innate antiviral state in murine macrophage and primary MEFs which was correlated with IFN-beta production. Moreover, FimH induced the innate antiviral responses in cells from wild type, but not from MyD88(-/-, Trif(-/-, IFN-alpha/betaR(-/- or IRF3(-/- mice. Vaginal delivery of FimH, but not LPS, completely protected wild type, but not MyD88(-/-, IFN-alpha/betaR(-/-, IRF3(-/- or TLR4(-/- mice from subsequent genital HSV-2 challenge. The FimH-induced innate antiviral immunity correlated with the production of IFN-beta, but not IFN-alpha or IFN-gamma. To examine whether FimH plays a role in innate immune induction in the context of a natural infection, the innate immune responses to wild type uropathogenic E. coli (UPEC and a FimH null mutant were examined in the urinary tract of C57Bl/6 (B6 mice and TLR4-deficient mice. While UPEC expressing FimH induced a robust polymorphonuclear response in B6, but not TLR4(-/- mice, mutant bacteria lacking FimH did not. In addition, the presence of TLR4 was essential for innate control of and protection against UPEC. Our results demonstrate that FimH is a potent inducer of innate antimicrobial responses and signals differently, from that of LPS, via TLR4 at mucosal surfaces. Our studies suggest that FimH can potentially be used as an innate microbicide against mucosal pathogens.

  8. Effects of angiotensin II and angiotensin II type 1 receptor blockade on neointimal formation after stent implantation

    NARCIS (Netherlands)

    Groenewegen, Hendrik C.; van der Harst, Pim; Roks, Anton J. M.; Buikema, Hendrik; Zijlstra, Felix; van Gilst, Wiek H.; de Smet, Bart J. G. L.

    2008-01-01

    Background: To evaluate the effect of supraphysiological levels of angiotensin II and selective angiotensin II type 1 receptor ( AT1-receptor) blockade on neointimal formation and systemic endothelial function after stent implantation in the rat abdominal aorta. Methods: Male Wistar rats were

  9. Changes in the molecular structure of a type II-S kerogen (Monterey Formation, USA) during sequential chemical degradation

    NARCIS (Netherlands)

    Sinninghe Damsté, J.S.; Hold, I.M.; Brussee, N.J.; Schouten, S.

    1998-01-01

    Flash pyrolysis and sequential chemical degradation were combined to study the molecular composition of an immature Type II-S kerogen from the Miocene Monterey Formation. Firstly, base hydrolysis was performed in order to hydrolyse ester bonds, in the second step aliphatic ethers were cleaved and in

  10. Phase II study of photodynamic therapy (PDT) with Photofrin II for Hilar type early lung cancer

    International Nuclear Information System (INIS)

    Furuse, K.

    1992-01-01

    Recently, an increase in lung cancer incidence has been recognized internationally, and more early stage cases of lung cancer are being detected as a result of improvements in survey and diagnostic techniques, including flexible bronchofiberscope. However, some early stage cases that are inoperable due to age, poor pulmonary function, etc. are generally treated with conventional modalities, such as radiation therapy and/or chemotherapy. Modality to curatively treat such inoperable early stage lung cancers has still not been established. PhotoDynamic Therapy is a newly developed local therapeutic modality which has been shown to be able to obtain complete response and cure in those early stage lung cancers with carcinoma in situ. The objective of this study is, first, to evaluate the activity and toxicity of PDT with Photofrin II in hilar type of early lung cancer, and second, to determine the complete response rate as primary end-point. (author). 5 tabs

  11. Zika Virus Infection in Dexamethasone-immunosuppressed Mice Demonstrating Disseminated Infection with Multi-organ Involvement Including Orchitis Effectively Treated by Recombinant Type I Interferons.

    Science.gov (United States)

    Chan, Jasper Fuk-Woo; Zhang, Anna Jinxia; Chan, Chris Chung-Sing; Yip, Cyril Chik-Yan; Mak, Winger Wing-Nga; Zhu, Houshun; Poon, Vincent Kwok-Man; Tee, Kah-Meng; Zhu, Zheng; Cai, Jian-Piao; Tsang, Jessica Oi-Ling; Chik, Kenn Ka-Heng; Yin, Feifei; Chan, Kwok-Hung; Kok, Kin-Hang; Jin, Dong-Yan; Au-Yeung, Rex Kwok-Him; Yuen, Kwok-Yung

    2016-12-01

    Disseminated or fatal Zika virus (ZIKV) infections were reported in immunosuppressed patients. Existing interferon-signaling/receptor-deficient mouse models may not be suitable for evaluating treatment effects of recombinant interferons. We developed a novel mouse model for ZIKV infection by immunosuppressing BALB/c mice with dexamethasone. Dexamethasone-immunosuppressed male mice (6-8weeks) developed disseminated infection as evidenced by the detection of ZIKV-NS1 protein expression and high viral loads in multiple organs. They had ≥10% weight loss and high clinical scores soon after dexamethasone withdrawal (10dpi), which warranted euthanasia at 12dpi. Viral loads in blood and most tissues at 5dpi were significantly higher than those at 12dpi (Pvirus dissemination, inflammation of various tissues, especially orchitis, may be potential complications of ZIKV infection with significant implications on disease transmission and male fertility. Interferon treatment should be considered in patients at high risks for ZIKV-associated complications when the potential benefits outweigh the side effects of treatment. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  12. Radioprotective effect of interferon

    Energy Technology Data Exchange (ETDEWEB)

    Zasukhina, G.

    1984-12-18

    A cycle of experiments performed jointly with associations of the Moscow Engineering Physics Institute reportedly demonstrated that interferons protect human cells cultivated in a test tube against the action of fast neutrons and gamma radiation. Cells treated in advance with interferon not only survived irradiation but were almost totally protected against harmful effects of fast neutrons on the structure of chromosomes, according to the author. She mentions that the laboratory has also been studying effects produced on cells by compounds of heavy metals and other chemical compounds, including ones which cause breaks in the DNA molecule. Interferon's ability to protect cells against effects of chemical compounds has been studied in this connection. Another direction of the laboratory's work is research on interferon's effects on blood cells of persons suffering from certain hereditary diseases in which restorative processes of cells are impaired. The purpose of this is to develop courses of treatment which will not cause irreversible damages to chromosomes, the author explains. Interferon has been found to stimulate the reparation systems of cells in cases of Marfan's syndrome, for example.

  13. Ca(2+) currents and voltage responses in Type I and Type II hair cells of the chick embryo semicircular canal.

    Science.gov (United States)

    Masetto, Sergio; Zampini, Valeria; Zucca, Giampiero; Valli, Paolo

    2005-11-01

    Type I and Type II hair cells, and Type II hair cells located in different zones of the semicircular canal crista, express different patterns of voltage-dependent K channels, each one specifically shaping the hair cell receptor potential. We report here that, close to hatching, chicken embryo semicircular canal Type I and Type II hair cells express a similar voltage-dependent L-type calcium current (I(Ca)), whose main features are: activation above -60 mV, fast activation kinetics, and scarce inactivation. I(Ca) should be already active at rest in Zone 1 Type II hair cells, whose resting membrane potential was on average slightly less negative than -60 mV. Conversely, I(Ca) would not be active at rest in Type II hair cells from Zone 2 and 3, nor in Type I hair cells, since their resting membrane potential was significantly more negative than -60 mV. However, even small depolarising currents would activate I(Ca) steadily in Zone 2 and 3 Type II hair cells, but not in Type I hair cells because of the robust repolarising action of their specific array of K(+) currents. The implications of the present findings in the afferent discharge are discussed.

  14. Active locking and entanglement in type II optical parametric oscillators

    Science.gov (United States)

    Ruiz-Rivas, Joaquín; de Valcárcel, Germán J.; Navarrete-Benlloch, Carlos

    2018-02-01

    Type II optical parametric oscillators are amongst the highest-quality sources of quantum-correlated light. In particular, when pumped above threshold, such devices generate a pair of bright orthogonally-polarized beams with strong continuous-variable entanglement. However, these sources are of limited practical use, because the entangled beams emerge with different frequencies and a diffusing phase difference. It has been proven that the use of an internal wave-plate coupling the modes with orthogonal polarization is capable of locking the frequencies of the emerging beams to half the pump frequency, as well as reducing the phase-difference diffusion, at the expense of reducing the entanglement levels. In this work we characterize theoretically an alternative locking mechanism: the injection of a laser at half the pump frequency. Apart from being less invasive, this method should allow for an easier real-time experimental control. We show that such an injection is capable of generating the desired phase locking between the emerging beams, while still allowing for large levels of entanglement. Moreover, we find an additional region of the parameter space (at relatively large injections) where a mode with well defined polarization is in a highly amplitude-squeezed state.

  15. Sexual dysfunction in type II diabetic females: a comparative study.

    Science.gov (United States)

    Erol, Bulent; Tefekli, Ahmet; Ozbey, Isa; Salman, Fatih; Dincag, Nevin; Kadioglu, Ates; Tellaloglu, Sedat

    2002-01-01

    Diabetes Mellitus (DM) is considered to play a principle role in the etiopathogenesis of sexual dysfunction both in men and women. The aim of this study is to evaluate sexual function in Type II diabetic women. A total of 72 young diabetic women (mean age: 38.8 years) with no other systemic diseases and 60 age-matched healthy women were enrolled in our study. We sought from them a detailed medical and sexual history and used the Index of Female Sexual function (IFSF) questionnaire (Kaplan et al., 1999). The mean IFSF score of diabetic women was 29.3 +/- 6.4 and was 37.7 +/- 3.5 in normal cases (p diabetics and was observed in 77% of the women. Diminished clitoral sensation was observed in 62.5% of the women, 37.5% complained of vaginal dryness and 41.6% had vaginal discomfort. Orgasmic dysfunction was found in 49% of the women. The incidence of all these related symptoms were significantly higher when compared to controls. We concluded that significant percentage of diabetic women that we observed experience sexual dysfunction of varying degrees that diminishes their quality of life.

  16. [Cochlear implantation in patients with Waardenburg syndrome type II].

    Science.gov (United States)

    Wan, Liangcai; Guo, Menghe; Chen, Shuaijun; Liu, Shuangriu; Chen, Hao; Gong, Jian

    2010-05-01

    To describe the multi-channel cochlear implantation in patients with Waardenburg syndrome including surgeries, pre and postoperative hearing assessments as well as outcomes of speech recognition. Multi-channel cochlear implantation surgeries have been performed in 12 cases with Waardenburg syndrome type II in our department from 2000 to 2008. All the patients received multi-channel cochlear implantation through transmastoid facial recess approach. The postoperative outcomes of 12 cases were compared with 12 cases with no inner ear malformation as a control group. The electrodes were totally inserted into the cochlear successfully, there was no facial paralysis and cerebrospinal fluid leakage occurred after operation. The hearing threshold in this series were similar to that of the normal cochlear implantation. After more than half a year of speech rehabilitation, the abilities of speech discrimination and spoken language of all the patients were improved compared with that of preoperation. Multi-channel cochlear implantation could be performed in the cases with Waardenburg syndrome, preoperative hearing and images assessments should be done.

  17. Dentinogenesis imperfecta type II: approach for dental treatment

    Directory of Open Access Journals (Sweden)

    Raquel Mantuaneli Scarel-Caminaga

    Full Text Available INTRODUCTION: Dentinogenesis imperfecta (DI is a hereditary dentin development disorder that affects both primary and permanent dentitions. The DI characteristics are discolored and translucent teeth ranging from gray to brownish-blue or amber. The enamel may split readily from the dentin when subjected to occlusal stress. Radiographically there are evident of cervical constrictions, short root and pulp chambers, and the root canals are smaller than normal or completely obliterated. The dental treatment choice can be decided on a case-by case‑basis, considering the degree of dental tissue loss, and child age and cooperation. OBJECTIVE: The aim of this case report was to describe the early dental treatment performed in a child affected by DI type II. CASE REPORT: The treatment involved basic preventive procedures. Primary molars were worn to such an extent that the remained tooth structure was covered with composite resin to protect the exposed dentin. Resin-based sealant was applied in all first permanent molars. Posterior cross bite was treated with the expansion of the upper arch. CONCLUSION: The early treatment restored the patient´s vertical dimension resulting in acceptable esthetics and function for the permanent teeth to complete their eruption.

  18. Impact of Type II Spicules into the Corona

    Science.gov (United States)

    Martinez-Sykora, Juan; De Pontieu, Bart; Carlsson, Mats; Hansteen, Viggo H.; Pereira, Tiago M. D.

    2017-08-01

    In the lower solar atmosphere, the chromosphere is permeated by jets, in which plasma is propelled at speeds of 50-150 km/s into the Sun’s atmosphere or corona. Although these spicules may play a role in heating the million-degree corona and are associated with Alfvén waves that help drive the solar wind, their generation remains mysterious. We implemented in the radiative MHD Bifrost code the effects of partial ionization using the generalized Ohm’s law. This code also solves the full MHD equations with non-grey and non-LTE radiative transfer and thermal conduction along magnetic field lines. The ion-neutral collision frequency is computed using recent studies that improved the estimation of the cross sections under chromospheric conditions (Vranjes & Krstic 2013). Self-consistently driven jets (spicules type II) in magnetohydrodynamic simulations occur ubiquitously when magnetic tension is confined and transported upwards through interactions between ions and neutrals, and impulsively released to drive flows, heat plasma, generate Alfvén waves, and may play an important role in maintaining the substructure of loop fans. This mechanism explains how spicular plasma can be heated to millions of degrees and how Alfvén waves are generated in the chromosphere.

  19. Flux-line-cutting losses in type-II superconductors

    International Nuclear Information System (INIS)

    Clem, J.R.

    1982-01-01

    Energy dissipation associated with flux-line cutting (intersection and cross-joining of adjacent nonparallel vortices) is considered theoretically. The flux-line-cutting contribution to the dissipation per unit volume, arising from mutual annihilation of transverse magnetic flux, is identified as J/sub parallel/xE/sub parallel/, where J/sub parallel/ and E/sub parallel/ are the components of the current density and the electric field parallel to the magnetic induction. The dynamical behavior of the magnetic structure at the flux-line-cutting threshold is shown to be governed by a special critical-state model similar to that proposed by previous authors. The resulting flux-line-cutting critical-state model, characterized in planar geometry by a parallel critical current density J/sub c/parallel or a critical angle gradient k/sub c/, is used to calculate predicted hysteretic ac flux-line-cutting losses in type-II superconductors in which the flux pinning is weak. The relation of the theory to previous experiments is discussed

  20. Redesigning the type II' β-turn in green fluorescent protein to type I': implications for folding kinetics and stability.

    Science.gov (United States)

    Madan, Bharat; Sokalingam, Sriram; Raghunathan, Govindan; Lee, Sun-Gu

    2014-10-01

    Both Type I' and Type II' β-turns have the same sense of the β-turn twist that is compatible with the β-sheet twist. They occur predominantly in two residue β-hairpins, but the occurrence of Type I' β-turns is two times higher than Type II' β-turns. This suggests that Type I' β-turns may be more stable than Type II' β-turns, and Type I' β-turn sequence and structure can be more favorable for protein folding than Type II' β-turns. Here, we redesigned the native Type II' β-turn in GFP to Type I' β-turn, and investigated its effect on protein folding and stability. The Type I' β-turns were designed based on the statistical analysis of residues in natural Type I' β-turns. The substitution of the native "GD" sequence of i+1 and i+2 residues with Type I' preferred "(N/D)G" sequence motif increased the folding rate by 50% and slightly improved the thermodynamic stability. Despite the enhancement of in vitro refolding kinetics and stability of the redesigned mutants, they showed poor soluble expression level compared to wild type. To overcome this problem, i and i + 3 residues of the designed Type I' β-turn were further engineered. The mutation of Thr to Lys at i + 3 could restore the in vivo soluble expression of the Type I' mutant. This study indicates that Type II' β-turns in natural β-hairpins can be further optimized by converting the sequence to Type I'. © 2014 Wiley Periodicals, Inc.

  1. Regulated gene expression in cultured type II cells of adult human lung

    OpenAIRE

    Ballard, Philip L.; Lee, Jae W.; Fang, Xiaohui; Chapin, Cheryl; Allen, Lennell; Segal, Mark R.; Fischer, Horst; Illek, Beate; Gonzales, Linda W.; Kolla, Venkatadri; Matthay, Michael A.

    2010-01-01

    Alveolar type II cells have multiple functions, including surfactant production and fluid clearance, which are critical for lung function. Differentiation of type II cells occurs in cultured fetal lung epithelial cells treated with dexamethasone plus cAMP and isobutylmethylxanthine (DCI) and involves increased expression of 388 genes. In this study, type II cells of human adult lung were isolated at ∼95% purity, and gene expression was determined (Affymetrix) before and after culturing 5 days...

  2. Interferon Beta-1b Injection

    Science.gov (United States)

    Interferon beta-1b injection is used to reduce episodes of symptoms in patients with relapsing-remitting (course of disease ... problems with vision, speech, and bladder control). Interferon beta-1b is in a class of medications called ...

  3. Resveratrol: A novel type of topoisomerase II inhibitor.

    Science.gov (United States)

    Lee, Joyce H; Wendorff, Timothy J; Berger, James M

    2017-12-22

    Resveratrol, a polyphenol found in various plant sources, has gained attention as a possible agent responsible for the purported health benefits of certain foods, such as red wine. Despite annual multi-million dollar market sales as a nutriceutical, there is little consensus about the physiological roles of resveratrol. One suggested molecular target of resveratrol is eukaryotic topoisomerase II (topo II), an enzyme essential for chromosome segregation and DNA supercoiling homeostasis. Interestingly, resveratrol is chemically similar to ICRF-187, a clinically approved chemotherapeutic that stabilizes an ATP-dependent dimerization interface in topo II to block enzyme activity. Based on this similarity, we hypothesized that resveratrol may antagonize topo II by a similar mechanism. Using a variety of biochemical assays, we find that resveratrol indeed acts through the ICRF-187 binding locus, but that it inhibits topo II by preventing ATPase domain dimerization rather than stabilizing it. This work presents the first comprehensive analysis of the biochemical effects of both ICRF-187 and resveratrol on the human isoforms of topo II, and reveals a new mode for the allosteric regulation of topo II through modulation of ATPase status. Natural polyphenols related to resveratrol that have been shown to impact topo II function may operate in a similar manner. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Association of Sleep Apnea and Type II Diabetes

    Science.gov (United States)

    Reichmuth, Kevin J.; Austin, Diane; Skatrud, James B.; Young, Terry

    2005-01-01

    Rationale: Cross-sectional association has been reported between sleep-disordered breathing (SDB) and insulin resistance, but no prospective studies have been performed to determine whether SDB is causal in the development of diabetes. Objectives: The purpose of our study was to investigate the prevalence and incidence of type II diabetes in subjects with SDB and whether an independent relationship exists between them. Methods: A cross-sectional and longitudinal analysis was performed in 1,387 participants of the Wisconsin Sleep Cohort. Full polysomnography was used to characterize SDB. Diabetes was defined in two ways: (1) physician-diagnosis alone or (2) for those with glucose measurements, either fasting glucose ⩾ 126 mg/dl or physician diagnosis. Measurements and Main Results: There was a greater prevalence of diabetes in subjects with increasing levels of SDB. A total of 14.7% of subjects with an apnea–hypopnea index (AHI) of 15 or more had a diagnosis of diabetes compared with 2.8% of subjects with an AHI of less than 5. The odds ratio for having a physician diagnoses of diabetes mellitus with an AHI of 15 or greater versus an AHI of less than 5 was 2.30 (95% confidence interval, 1.28–4.11; p = 0.005) after adjustment for age, sex, and body habitus. The odds ratio for developing diabetes mellitus within 4 yr with an AHI of 15 or more compared with an AHI of less than 5 was 1.62 (95% confidence interval, 0.67–3.65; p = 0.24) when adjusting for age, sex, and body habitus. Conclusions: Diabetes is more prevalent in SDB and this relationship is independent of other risk factors. However, it is not clear that SDB is causal in the development of diabetes. PMID:16192452

  5. Effects of policosanol on postmenopausal women with type II hypercholesterolemia.

    Science.gov (United States)

    Castaño, G; Más, R; Fernández, L; Fernández, J C; Illnait, J; López, L E; Alvarez, E

    2000-06-01

    This randomized, double-blind, placebo-controlled study was conducted to investigate the efficacy, safety and tolerability of policosanol, a cholesterol-lowering drug purified from sugar-cane wax, in postmenopausal women with type II hypercholesterolemia. A total of 244 women who had experienced the menopause and showed elevated serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels despite 6 weeks on a standard lipid-lowering diet were randomized to receive placebo or policosanol 5 mg/day for 12 weeks, after which the dose was doubled to 10 mg/day for the next 12 weeks. Policosanol (5 and 10 mg/day) significantly lowered LDL-C levels (17.7% and 25.2%, respectively) and total cholesterol (12.6% and 16.7%, respectively), as well as the ratios of LDL-C to high-density lipoprotein cholesterol (HDL-C) (17.0% and 29.3%, respectively) and total cholesterol to HDL-C (16.7% and 27.2%, respectively), compared to the baseline and placebo; at the same time, policosanol significantly raised HDL-C levels by 16.5% and 29.3%, respectively. The drug was safe and well tolerated. No drug-related adverse events were observed, and even the extent of adverse events was less in the policosanol group than in the placebo group. Four serious adverse events occurred in the placebo group (one myocardial infarction, two cases of hypertensive status and one surgical intervention) compared to none in the policosanol group. In conclusion, policosanol is effective, safe and well tolerated in hypercholesterolemic postmenopausal women.

  6. The Three-Dimensional Structural Basis of Type II Hyperprolinemia

    Energy Technology Data Exchange (ETDEWEB)

    Srivastava, Dhiraj; Singh, Ranjan K.; Moxley, Michael A.; Henzl, Michael T.; Becker, Donald F.; Tanner, John J. (UNL); (UMC)

    2012-08-31

    Type II hyperprolinemia is an autosomal recessive disorder caused by a deficiency in {Delta}{sup 1}-pyrroline-5-carboxylate dehydrogenase (P5CDH; also known as ALDH4A1), the aldehyde dehydrogenase that catalyzes the oxidation of glutamate semialdehyde to glutamate. Here, we report the first structure of human P5CDH (HsP5CDH) and investigate the impact of the hyperprolinemia-associated mutation of Ser352 to Leu on the structure and catalytic properties of the enzyme. The 2. 5-{angstrom}-resolution crystal structure of HsP5CDH was determined using experimental phasing. Structures of the mutant enzymes S352A (2.4 {angstrom}) and S352L (2.85 {angstrom}) were determined to elucidate the structural consequences of altering Ser352. Structures of the 93% identical mouse P5CDH complexed with sulfate ion (1.3 {angstrom} resolution), glutamate (1.5 {angstrom}), and NAD{sup +} (1.5 {angstrom}) were determined to obtain high-resolution views of the active site. Together, the structures show that Ser352 occupies a hydrophilic pocket and is connected via water-mediated hydrogen bonds to catalytic Cys348. Mutation of Ser352 to Leu is shown to abolish catalytic activity and eliminate NAD{sup +} binding. Analysis of the S352A mutant shows that these functional defects are caused by the introduction of the nonpolar Leu352 side chain rather than the removal of the Ser352 hydroxyl. The S352L structure shows that the mutation induces a dramatic 8-{angstrom} rearrangement of the catalytic loop. Because of this conformational change, Ser349 is not positioned to interact with the aldehyde substrate, conserved Glu447 is no longer poised to bind NAD{sup +}, and Cys348 faces the wrong direction for nucleophilic attack. These structural alterations render the enzyme inactive.

  7. Behavioral effects of type II pyrethroid cyhalothrin in rats

    International Nuclear Information System (INIS)

    Righi, D. Abbud; Palermo-Neto, J.

    2003-01-01

    Synthetic pyrethroids such as cyhalothrin are extensively used in agriculture for the control of a broad range of ectoparasites in farm animals. It has been suggested that type II pyrethroids might induce anxiogenic-like effects in laboratory animals. The present study was undertaken to investigate a possible anxiogenic-like outcome of cyhalothrin in rats. Adult male rats were orally dosed for 7 days with 1.0, 3.0, or 7.0 mg/kg/day of cyhalothrin, present in a commercial formulation (Grenade Coopers do Brazil S.A.). The neurobehavioral changes induced by cyhalothrin as well as those produced on corticosterone serum levels were measured 24 h after the last treatment. Picrotoxin (1.0 mg/kg) was also acutely used as a positive control for anxiety. Results showed that cyhalothrin: (1) induced some signs and symptoms of intoxication that included salivation, tremors, and liquid feces; (2) reduced total locomotor activity in the open-field; (3) reduced the percentage of time spent in open-field central zones; (4) increased immobility time in the open-field; (5) reduced the percentage of time spent in plus-maze open arms exploration; (6) reduced the time spent in social interactions, and (7) increased the levels of serum corticosterone. The behavioral changes reported for cyhalothrin (3.0 mg/kg/day) were similar of those induced by picrotoxin. The no effect level dose obtained for cyhalothrin in this study was 1.0 mg/kg/day. These results provide experimental evidence that cyhalothrin induces anxiety-like symptoms, with this effect being dose-related. Thus, anxiety must be included among the several signs and symptoms of pesticide intoxication

  8. Costing of diabetes mellitus type II in Cambodia.

    Science.gov (United States)

    Flessa, Steffen; Zembok, Anika

    2014-12-01

    Diabetes Mellitus Type II (T2DM) is a major and growing medical, social and economic burden in the East-Asian country of Cambodia. However, no economic modelling has been done to predict the number of cases and the budget impact. This paper forecasts the epidemiological and economic consequences of T2DM in Cambodia. The Ministry of Health and related donor agencies are supported to select the most cost-effective interventions against the disease. At the same time this paper demonstrates the relevance and potential of health economic modelling for least developed countries. We developed a Markov-Model for the specific situation of Cambodia. Data was taken from the scientific literature, grey literature in Cambodia and key-informant interviews. The number of people living with T2DM is steadily increasing from 145,000 in the year 2008 to 264,000 in the year 2028 (+82 %). In the year 2008 the diagnosed T2DM patients would incur costs of some 2 million US$ to cover all of diabetes treatment. 57 % of this amount would have to be spent for OAD-therapy, the rest for insulin therapy. In the year 2028 this amount will have grown to some 4 million US$. If all patients (incl. non-diagnosed) had to be paid-for the respective figure would be 5.5 million and 11 million US$. Screening for T2DM is only cost-effective if the sensitivity of the test is high while the unit price is low. The results of this simulation call for targeting the high-risk groups. However, an increased availability of Oral Anti-Diabetic and Insulin Therapy is highly cost-effective. Type 2 Diabetes Mellitus is a major public health challenge in Cambodia. The simulations clearly indicate that prevention and treatment of this disease is highly cost-effective. However, not everything that is cost-effective might be affordable in Cambodia. This country will require external support to ease the growing burden of T2DM.

  9. Innate Interferons Regulate CNS Inflammation

    DEFF Research Database (Denmark)

    Dieu, Ruthe; Khorooshi, Reza M. H.; Mariboe, Anne

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) whose pathology is characterised by demyelination and axonal damage. This results from interplay between CNS-resident glia, infiltrating leukocytes and a plethora of cytokines and chemokines. Currently......, there is no cure for MS, however a standard first-line therapy is recombinant interferon (IFN)-beta. IFN-beta belongs to the family of type I IFNs, which also include IFN-alpha. These engage to one common receptor, IFNAR. Type I IFNs can be induced by several innate immune receptors, including toll-like receptors...... mass homeostasis. Whether RANK-signaling is capable of inducing type I IFNs within the CNS has not yet been studied. Preliminary data from IFN-beta-luciferase reporter mice already show that RANK-signaling by intrathecally applied RANKL can induce CNS-endogenous IFN-beta. Experiments in IFN...

  10. Intake of coffee, caffeine and other methylxanthines and risk of Type I vs Type II endometrial cancer.

    Science.gov (United States)

    Uccella, S; Mariani, A; Wang, A H; Vierkant, R A; Cliby, W A; Robien, K; Anderson, K E; Cerhan, J R

    2013-10-01

    Coffee and other sources of methylxanthines and risk of Type I vs Type II endometrial cancer (EC) have not been evaluated previously. Prospective cohort of 23,356 postmenopausal women with 471 Type I and 71 Type II EC cases. Type I EC was statistically significantly associated with caffeinated (relative risk (RR)=0.65 for 4+ cups per day vs ≤1 cup per month: 95% confidence interval (CI): 0.47-0.89) but not decaffeinated (RR=0.76; 95% CI: 0.50-1.15) coffee intake; there were no associations with tea, cola or chocolate, or for Type II EC. The inverse association with caffeinated coffee intake was specific to women with a body mass index 30+ kg m(-2) (RR=0.56; 95% CI: 0.36-0.89). Coffee may protect against Type I EC in obese postmenopausal women.

  11. Evaluation of Serum HDL and LDL levels in Type II Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    K R Joshi

    2013-06-01

    Full Text Available   Introduction: Diabetes mellitus is a type of metabolic disorder characterized by hyperglycemia resulting from defect in insulin secretion, insulin action or both. This study intended to compare High Density Lipoprotein Cholesterol (HDL and Low Density Lipoprotein Cholesterol (LDL profile between type II diabetic and non-diabetic subjects and also find the correlation between HDL and LDL cholesterol in type II diabetic.   Methods: The study was conducted on 100 total subjects out of which experimental group with 50 subjects of known Type II Diabetes mellitus and control group with 50 subjects.   Results: The result of the present study suggests that fasting blood sugar and LDL cholesterol levels were increased but HDL cholesterol level was reduced in type II diabetic subjects when compared to controls.   Conclusion: The estimation of HDL cholesterol and LDL cholesterol in type II diabetes mellitus is very useful as it may serve as a useful parameter to monitor the prognosis of the patient.

  12. Effects of low-dose rate irradiation on two types of type II diabetes model mice

    International Nuclear Information System (INIS)

    Nomura, Takaji; Sakai, Kazuo

    2004-01-01

    The effects of low-dose rate gamma-irradiation were investigated in two mouse strains - C57BL/KsJ-db/db (db mouse) and AKITA (AKITA mouse)-for type II diabetes mellitus. Both strains develop the developed type II diabetes by about 8 weeks of age due to dysfunction of the insulin/insulin receptor. The db Mouse' shows obese and exhibits hyperinsulinism, and the onset of Type II diabetes like resembles that for Westerners. On the other hand, the AKITA mouse has exhibits disordered insulin secretion, and the diabetes such as resembles that of Asians. Ten-week old female mice, in groups of 8 or 12, were irradiated at 0.65 mGy/hr in the low-dose rate irradiation facility in the Low Dose Radiation Research Center. The level of urine glucose was measured with test slips. The urine glucose levels of all of the mice were highly elevated the beginning of the irradiation. In the irradiated group of db mice, three mice showed decrease in glucose level compare to the level of non-irradiated diabetes mice after 35, 52 or 80 weeks of irradiation. All had maintained a normal level thereafter. No such improvement in diabetes was ever observed in the 12 mice of in the non-irradiated control group. The AKITA mice, however, did not decrease the glucose level regardless of the irradiation. Both the db mice and AKITA mice had their lives prolonged their life by the irradiation. The survival rate of db mice at the age of 90 weeks was 75% in the irradiated group, but 50% in the non-irradiated group. The average life span was 104 weeks in the irradiated group and 87 weeks in the control group. Furthermore, a marked difference was furthermore observed in the appearance of the coat hair, skin, and tail; appearances were well preserved in the irradiated group. The average life span in the irradiated AKITA mice was also longer than that for the non-irradiated mice, 51 weeks and 41 weeks in the irradiated and non-irradiated group respectively. These results suggest that the low-dose irradiation

  13. Rules for distinguishing toxicants that cause type I and type II narcosis syndromes.

    Science.gov (United States)

    Veith, G D; Broderius, S J

    1990-01-01

    Narcosis is a nonspecific reversible state of arrested activity of protoplasmic structures caused by a wide variety of organic chemicals. The vast majority of industrial organic chemicals can be characterized by a baseline structure-toxicity relationship as developed for diverse aquatic organisms, using only the n-octanol/water partition coefficient as a descriptor. There are, however, many apparent narcotic chemicals that are more toxic than baseline narcosis predicts. Some of these chemicals have been distinguished as polar narcotics. Joint toxic theory and isobole diagrams were used to show that chemicals strictly additive with phenol were generally more toxic than predicted by narcosis I models and characterized by a different mode of action called narcosis II syndrome. This type of toxicity is exemplified by certain amides, amines, phenols, and nitrogen heterocycles. Evidence is provided that suggests that narcosis II syndrome may result from the presence of a strong hydrogen bonding group on the molecule, and narcosis I syndrome results from hydrophobic bonding of the chemical to enzymes and/or membranes. This shift in toxic action is apparently indistinguishable for narcotic chemicals with log P greater than about 2.7. General rules for selecting the appropriate models are proposed. PMID:2269227

  14. Discriminating neutrino mass models using Type-II see-saw formula

    Indian Academy of Sciences (India)

    the sum of the two terms and 'pure Type-II see-saw formula' to represent only the first term. Type-II ... the vacuum expectation value (VEV) of the Higgs fields imparting mass to the right-handed neutrinos and fR is the Yukawa coupling matrix. The second term. mII. LL in eq. .... We thus express MRR in the most general form ...

  15. Symptoms and well-being in relation to glycemic control in type II diabetes

    NARCIS (Netherlands)

    Van Der Does, Ferdinand E.E.; De Neeling, J. Nico D.; Snoek, Frank J.; Kostense, Pieter J.; Grootenhuis, Peter A.; Bouter, Lex M.; Heine, Robert J.

    1996-01-01

    OBJECTIVE - To describe the cross-sectional relation between glycemic control and physical symptoms, emotional well-being, and general well-being in patients with type II diabetes. RESEARCH DESIGN AND METHODS - The study population consisted of 188 patients with type II diabetes between 40 and 75

  16. Stimulation of DNA synthesis in cultured rat alveolar type II cells

    International Nuclear Information System (INIS)

    Leslie, C.C.; McCormick-Shannon, K.; Robinson, P.C.; Mason, R.J.

    1985-01-01

    Restoration of the alveolar epithelium after injury is thought to be dependent on the proliferation of alveolar type II cells. To understand the factors that may be involved in promoting type II cell proliferation in vivo, we determined the effect of potential mitogens and culture substrata on DNA synthesis in rat alveolar type II cells in primary culture. Type II cells cultured in basal medium containing 10% fetal bovine serum (FBS) exhibited essentially no DNA synthesis. Factors that stimulated 3 H-thymidine incorporation included cholera toxin, epidermal growth factor, and rat serum. The greatest degree of stimulation was achieved by plating type II cells on an extracellular matrix prepared from bovine corneal endothelial cells and then by culturing the pneumocytes in medium containing rat serum, cholera toxin, insulin, and epidermal growth factor. Under conditions of stimulation of 3 H-thymidine incorporation there was an increased DNA content per culture dish but no increase in cell number. The ability of various culture conditions to promote DNA synthesis in type II cells was verified by autoradiography. Type II cells were identified by the presence of cytoplasmic inclusions, which were visualized by tannic acid staining before autoradiography. These results demonstrate the importance of soluble factors and culture substratum in stimulating DNA synthesis in rat alveolar type II cells in primary culture

  17. Type II Estrogen Receptor in the Development and Progression of Breast Cancer

    National Research Council Canada - National Science Library

    Biswas, Subhasis

    1996-01-01

    .... The antibody was able to detect the type II EBS in Western Blot. In order to identify the gene encoding the type II EBS, a cDNA library was created in lambdagt11 using cDNA prepared from pregnant rat uterine tissue...

  18. Characterization of cloned cells from an immortalized fetal pulmonary type II cell line

    Energy Technology Data Exchange (ETDEWEB)

    Henderson, R.F.; Waide, J.J.; Lechner, J.F.

    1995-12-01

    A cultured cell line that maintained expression of pulmonary type II cell markers of differentiation would be advantageous to generate a large number of homogenous cells in which to study the biochemical functions of type II cells. Type II epithelial cells are the source of pulmonary surfactant and a cell of origin for pulmonary adenomas. Last year our laboratory reported the induction of expression of two phenotypic markers of pulmonary type II cells (alkaline phosphatase activity and surfactant lipid synthesis) in cultured fetal rat lung epithelial (FRLE) cells, a spontaneously immortalized cell line of fetal rat lung type II cell origin. Subsequently, the induction of the ability to synthesize surfactant lipid became difficult to repeat. We hypothesized that the cell line was heterogenuous and some cells were more like type II cells than others. The purpose of this study was to test this hypothesis and to obtain a cultured cell line with type II cell phenotypic markers by cloning several FRLE cells and characterizing them for phenotypic markers of type II cells (alkaline phosphatase activity and presence of surfactant lipids). Thirty cloned cell lines were analyzed for induced alkaline phosphatase activity (on x-axis) and for percent of phospholipids that were disaturated (i.e., surfactant).

  19. Oxidative Metabolites of Curcumin Poison Human Type II Topoisomerases†

    Science.gov (United States)

    Ketron, Adam C.; Gordon, Odaine N.; Schneider, Claus; Osheroff, Neil

    2013-01-01

    The polyphenol curcumin is the principal flavor and color component of the spice turmeric. Beyond its culinary uses, curcumin is believed to positively impact human health and displays antioxidant, anti-inflammatory, antibacterial, and chemopreventive properties. It also is in clinical trials as an anticancer agent. In aqueous solution at physiological pH, curcumin undergoes spontaneous autoxidation that is enhanced by oxidizing agents. The reaction proceeds through a series of quinone methide and other reactive intermediates to form a final dioxygenated bicyclopentadione product. Several naturally occurring polyphenols that can form quinones have been shown to act as topoisomerase II poisons (i.e., increase levels of topoisomerase II-mediated DNA cleavage). Because several of these compounds have chemopreventive properties, we determined the effects of curcumin, its oxidative metabolites, and structurally related degradation products (vanillin, ferulic acid, and feruloylmethane), on the DNA cleavage activities of human topoisomerase IIα and IIβ. Intermediates in the curcumin oxidation pathway increased DNA scission mediated by both enzymes ~4-5–fold. In contrast, curcumin and the bicyclopentadione, as well as vanillin, ferulic acid, and feruloylmethane, had no effect on DNA cleavage. As found for other quinone-based compounds, curcumin oxidation intermediates acted as redox-dependent (as opposed to interfacial) topoisomerase II poisons. Finally, under conditions that promote oxidation, the dietary spice turmeric enhanced topoisomerase II-mediated DNA cleavage. Thus, even within the more complex spice formulation, oxidized curcumin intermediates appear to function as topoisomerase II poisons. PMID:23253398

  20. Flux tubes and the type-I/type-II transition in a superconductor coupled to a superfluid

    International Nuclear Information System (INIS)

    Alford, Mark G.; Good, Gerald

    2008-01-01

    We analyze magnetic-flux tubes at zero temperature in a superconductor that is coupled to a superfluid via both density and gradient ('entrainment') interactions. The example we have in mind is high-density nuclear matter, which is a proton superconductor and a neutron superfluid, but our treatment is general and simple, modeling the interactions as a Ginzburg-Landau effective theory with four-fermion couplings, including only s-wave pairing. We numerically solve the field equations for flux tubes with an arbitrary number of flux quanta and compare their energies. This allows us to map the type-I/type-II transition in the superconductor, which occurs at the conventional κ≡λ/ξ=1/√(2) if the condensates are uncoupled. We find that a density coupling between the condensates raises the critical κ and, for a sufficiently high neutron density, resolves the type-I/type-II transition line into an infinite number of bands corresponding to 'type-II(n)' phases, in which n, the number of quanta in the favored flux tube, steps from 1 to infinity. For lower neutron density, the coupling creates spinodal regions around the type-I/type-II boundary, in which metastable flux configurations are possible. We find that a gradient coupling between the condensates lowers the critical κ and creates spinodal regions. These exotic phenomena may not occur in nuclear matter, which is thought to be deep in the type-II region but might be observed in condensed-matter systems

  1. Expression Profiles of Cellular Retinol-binding Protein, Type II (CRBP II in Erlang Mountainous Chickens

    Directory of Open Access Journals (Sweden)

    H. D. Yin

    2014-03-01

    Full Text Available Cellular retinol-binding protein II (CRBP II belongs to the family of cellular retinol-binding proteins and plays a major role in absorption, transport, and metabolism of vitamin A. In addition, because vitamin A is correlated with reproductive performance, we measured CRBP II mRNA abundance in erlang mountainous chickens by real-time PCR using the relative quantification method. The expression of CRBP II showed a tissue-specific pattern and egg production rate-dependent changes. The expression was very high (p<0.05 in jejunum and liver, intermediate in kidney, ovary, and oviduct, and lowest (p<0.05 in heart, hypothalamus, and pituitary. In the hypothalamus, oviduct, ovary, and pituitary, CRBP II mRNA abundance were correlated to egg production rate, which increased from 12 wk to 32 wk, peaked at 32 wk relative to the other time points, and then decreased from 32 wk to 45 wk. In contrast, the expression of CRBP II mRNA in heart, jejunum, kidney, and liver was not different at any of the ages evaluated in this study. These data may help to understand the genetic basis of vitamin A metabolism, and suggest that CRBP II may be a candidate gene to affect egg production traits in chickens.

  2. A putative Type IIS restriction endonuclease GeoICI

    Indian Academy of Sciences (India)

    As opposed to the unstable prototype, which cleaves DNA at 30°C, GeoICI is highly active at elevated temperatures, up to 73°C and over a very wide salt concentration range. Recognition/cleavage sites were determined by: (i) digestion of plasmid and bacteriophage lambda DNA (λ); (ii) cleavage of custom PCR substrates, ...

  3. Molecular determinants of angiotensin II type 1 receptor functional selectivity

    DEFF Research Database (Denmark)

    Aplin, Mark; Bonde, Marie Mi; Hansen, Jakob Lerche

    2008-01-01

    probing with analogues of angiotensin II. These studies also provide clues about the conformational changes that underlie different functional outcomes. In this review, we evaluate current knowledge of the molecular determinants of AT(1) receptor activation, which may distinguish G protein...... of molecular mechanisms that govern disparate signalling events....

  4. Interplay of type I and type II seesaw contributions to neutrino mass

    International Nuclear Information System (INIS)

    Akhmedov, Evgeny Kh.; Frigerio, Michele

    2007-01-01

    Type I and type II seesaw contributions to the mass matrix of light neutrinos are inherently related if left-right symmetry is realized at high energy scales. We investigate implications of such a relation for the interpretation of neutrino data. We proved recently that the left-right symmetric seesaw equation has eight solutions, related by a duality property, for the mass matrix of right-handed neutrinos M R . In this paper the eight allowed structures of M R are reconstructed analytically and analyzed numerically in a bottom-up approach. We study the dependence of right-handed neutrino masses on the mass spectrum of light neutrinos, mixing angle θ 13 , leptonic CP violation, scale of left-right symmetry breaking and on the hierarchy in neutrino Yukawa couplings. The structure of the seesaw formula in several specific SO(10) models is explored in the light of the duality. The outcome of leptogenesis may depend crucially on the choice among the allowed structures of M R and on the level crossing between right-handed neutrino masses

  5. Type II NKT cells: a distinct CD1d-restricted immune regulatory NKT cell subset.

    Science.gov (United States)

    Dasgupta, Suryasarathi; Kumar, Vipin

    2016-08-01

    Type II natural killer T cells (NKT) are a subset of the innate-like CD1d-restricted lymphocytes that are reactive to lipid antigens. Unlike the type I NKT cells, which express a semi-invariant TCR, type II NKT cells express a broader TCR repertoire. Additionally, other features, such as their predominance over type I cells in humans versus mice, the nature of their ligands, CD1d/lipid/TCR binding, and modulation of immune responses, distinguish type II NKT cells from type I NKT cells. Interestingly, it is the self-lipid-reactivity of type II NKT cells that has helped define their physiological role in health and in disease. The discovery of sulfatide as one of the major antigens for CD1d-restricted type II NKT cells in mice has been instrumental in the characterization of these cells, including the TCR repertoire, the crystal structure of the CD1d/lipid/TCR complex, and their function. Subsequently, several other glycolipids and phospholipids from both endogenous and microbial sources have been shown to activate type II NKT cells. The activation of a specific subset of type II NKT cells following administration with sulfatide or lysophosphatidylcholine (LPC) leads to engagement of a dominant immunoregulatory pathway associated with the inactivation of type I NKT cells, conventional dendritic cells, and inhibition of the proinflammatory Th1/Th17 cells. Thus, type II NKT cells have been shown to be immunosuppressive in autoimmune diseases, inflammatory liver diseases, and in cancer. Knowing their relatively higher prevalence in human than type I NKT cells, understanding their biology is imperative for health and disease.

  6. Vitamin D Potentiates the Inhibitory Effect of MicroRNA-130a in Hepatitis C Virus Replication Independent of Type I Interferon Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Xiaoqiong Duan

    2015-01-01

    Full Text Available Calcitriol, the bioactive metabolite of vitamin D, was reported to inhibit HCV production in a synergistic fashion with interferon, a treatment in vitro. Our previous study established that miR-130a inhibits HCV replication by restoring the host innate immune response. We aimed to determine whether there is additive inhibitory effect of calcitriol and miR-130a on HCV replication. Here we showed that calcitriol potentiates the anti-HCV effect of miR-130a in both Con1b replicon and J6/JFH1 culture systems. Intriguingly, this potentiating effect of calcitriol on miR-130a was not through upregulating the expression of cellular miR-130a or through increasing the miR-130a-mediated IFNα/β production. All these findings may contribute to the development of novel anti-HCV therapeutic strategies although the antiviral mechanism needs to be further investigated.

  7. Npro of classical swine fever virus contributes to pathogenicity in pigs by preventing type I interferon induction at local replication sites.

    Science.gov (United States)

    Tamura, Tomokazu; Nagashima, Naofumi; Ruggli, Nicolas; Summerfield, Artur; Kida, Hiroshi; Sakoda, Yoshihiro

    2014-04-17

    Classical swine fever (CSF) caused by CSF virus (CSFV) is a highly contagious disease of pigs. The viral protein Npro of CSFV interferes with alpha- and beta-interferon (IFN-α/β) induction by promoting the degradation of interferon regulatory factor 3 (IRF3). During the establishment of the live attenuated CSF vaccine strain GPE-, Npro acquired a mutation that abolished its capacity to bind and degrade IRF3, rendering it unable to prevent IFN-α/β induction. In a previous study, we showed that the GPE- vaccine virus became pathogenic after forced serial passages in pigs, which was attributed to the amino acid substitutions T830A in the viral proteins E2 and V2475A and A2563V in NS4B. Interestingly, during the re-adaptation of the GPE- vaccine virus in pigs, the IRF3-degrading function of Npro was not recovered. Therefore, we examined whether restoring the ability of Npro to block IFN-α/β induction of both the avirulent and moderately virulent GPE--derived virus would enhance pathogenicity in pigs. Viruses carrying the N136D substitution in Npro regained the ability to degrade IRF3 and suppress IFN-α/β induction in vitro. In pigs, functional Npro significantly reduced the local IFN-α mRNA expression in lymphoid organs while it increased quantities of IFN-α/β in the circulation, and enhanced pathogenicity of the moderately virulent virus. In conclusion, the present study demonstrates that functional Npro influences the innate immune response at local sites of virus replication in pigs and contributes to pathogenicity of CSFV in synergy with viral replication.

  8. Antitumoral action of interferons and interleukins in combination with radiotherapy. Pt. II. Radiobiological and immunologic strategies; Antitumorale Wirkung von Interferonen und Interleukinen in Kombination mit Strahlentherapie. Teil II. Strahlenbiologische und immunologische Strategien

    Energy Technology Data Exchange (ETDEWEB)

    Herskind, C. [Dept. of Experimental Clinical Oncology, Aarhus Univ. Hospital, Aarhus (Denmark); Inst. fuer Klinische Radiologie, Sektion Strahlentherapie, Mannheim (Germany); Fleckenstein, K.; Wenz, F.; Lohr, F. [Inst. fuer Klinische Radiologie, Sektion Strahlentherapie, Mannheim (Germany); Lohr, J. [Dept. of Pathology, Univ. of California San Francisco School of Medicine, San Francisco, CA (United States); Li Chuan-Yuan [Dept. of Radiation Oncology, Duke Univ. Medical Center, Durham, NC (United States)

    2004-06-01

    Methods: based on published clinical studies, the results of treatment with interferons in combination with radiotherapy are reviewed. New strategies for antitumoral application of cytokines, illustrated by interleukin-(IL-)2 and IL-12 in preclinical and clinical studies, are presented. Results: the initially high expectations regarding the antitumoral action of IFN-{alpha}, IFN-{beta} and IFN-{gamma} in combination with radiotherapy have, with few exceptions, not been fulfilled. In particular, toxicity has been a problem after systemic application. Recent advances in immunology, however, have emphasized the importance of local interactions between antigen-presenting cells and effector cells such as natural killer (NK) cells and cytotoxic T-lymphocytes in the immune reaction against tumors. Preclinical studies with IL-2 und IL-12 have shown efficacy mainly against early metastases, but immune reactions against primary tumors have also been observed. Furthermore, the method and timing of the application have proven to be critical. (orig.)

  9. Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome.

    Science.gov (United States)

    Qin, Xian-Yun; Zhang, Yun-Long; Chi, Ya-Fei; Yan, Bo; Zeng, Xiang-Jun; Li, Hui-Hua; Liu, Ying

    2018-01-01

    Naive CD4+ T cells differentiate into T helper cells (Th1 and Th2) that play an essential role in the cardiovascular diseases. However, the molecular mechanism by which angiotensin II (Ang II) promotes Th1 differentiation remains unclear. The aim of this study was to determine whether the Ang II-induced Th1 differentiation regulated by ubiquitin-proteasome system (UPS). Jurkat cells were treated with Ang II (100 nM) in the presence or absence of different inhibitors. The gene mRNA levels were detected by real-time quantitative PCR analysis. The protein levels were measured by ELISA assay or Western blot analysis, respectively. Ang II treatment significantly induced a shift from Th0 to Th1 cell differentiation, which was markedly blocked by angiotensin II type 1 receptor (AT1R) inhibitor Losartan (LST). Moreover, Ang II significantly increased the activities and the expression of proteasome catalytic subunits (β1, β1i, β2i and β5i) in a dose- and time-dependent manner. However, Ang II-induced proteasome activities were remarkably abrogated by LST and PKA inhibitor H-89. Mechanistically, Ang II-induced Th1 differentiation was at least in part through proteasome-mediated degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB. This study for the first time demonstrates that Ang II activates AT1R-PKA-proteasome pathway, which promotes degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB thereby leading to Th1 differentiation. Thus, inhibition of proteasome activation might be a potential therapeutic target for Th1-mediated diseases. © 2018 The Author(s). Published by S. Karger AG, Basel.

  10. Interferon Response and Viral Evasion by Members of the Family Rhabdoviridae

    OpenAIRE

    Faul, Elizabeth J.; Lyles, Douglas S.; Schnell, Matthias J.

    2009-01-01

    Like many animal viruses, those of the Rhabdoviridae family, are able to antagonize the type I interferon response and cause disease in mammalian hosts. Though these negative-stranded RNA viruses are very simple and code for as few as five proteins, they have been seen to completely abrogate the type I interferon response early in infection. In this review, we will discuss the viral organization and type I interferon evasion of rhabdoviruses, focusing on vesicular stomatitis virus (VSV) and r...

  11. Mutations of the interferon sensitivity-determining region (ISDR) correlate with the complexity of hypervariable region (HVR)-1 in the Japanese variant of hepatitis C virus (HCV) type 1b.

    Science.gov (United States)

    Nakano, Isao; Fukuda, Yoshihide; Katano, Yoshiaki; Toyoda, Hidenori; Hayashi, Kazuhiko; Kumada, Takashi; Nakano, Satoshi

    2004-09-01

    Hepatitis C virus (HCV) genotype 1b comprises mainly two subtypes in Japan, each named for its geographic prevalence (Japan-specific, J type; worldwide, W type). Because the newly identified subtypes have not been fully characterized, the present study directed this issue from virological viewpoints such as hypervariable region (HVR)-1 as well as interferon (IFN) sensitivity-determining region (ISDR). Fifty chronic hepatitis patients with HCV 1b (31 men and 19 women; mean age 50.5 years) were enrolled, and J/W type was determined according to envelope 1 (E1) sequence as described previously (23 J type and 27 W type). Correlations between age, number of HVR-1 clones, HVR-1 diversity, and ISDR mutations were analyzed in J and W type patients independently. In addition, the sequences of the three HCV regions obtained for the determination of the above genetic factors were studied phylogenetically. The number of HVR-1 clones was significantly higher for J type in comparison with W type (P = 0.044). In the J type-infected patients, the ISDR mutation number was correlated inversely with HVR-1 clone number (P = 0.0001, r = -0.734) and HVR-1 diversity (P = 0.0001, r = -0.722). However, this correlation was not observed in the W type patients. W type patients showed a significant correlation between age and HVR-1 clone number (P = 0.015, r = 0.462). Phylogenetic study revealed that the nonstructural (NS) 5A sequence, which is obtained for ISDR type determination, can distinguish between J and W types. The inverse correlation in J type patients between ISDR mutations and HVR-1 complexity may explain the usefulness of the ISDR for prediction of IFN response only in Japanese patients. This suggests that the ISDR is not directly related to IFN responsiveness, but the degree of HVR-1 complexity may be more important.

  12. Mapping the brain in type II diabetes: Voxel-based morphometry using DARTEL

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Zhiye [Department of Radiology, PLA General Hospital, 28 Fuxing Road, Beijing 100853 (China); Li, Lin [Department of Geriatric Endocrinology, PLA General Hospital, Beijing 100853 (China); Sun, Jie [Department of Endocrinology, PLA General Hospital, Beijing 100853 (China); Ma, Lin, E-mail: cjr.malin@vip.163.com [Department of Radiology, PLA General Hospital, 28 Fuxing Road, Beijing 100853 (China)

    2012-08-15

    Purpose: To investigate the pattern of brain volume changes of the brain in patients with type II diabetes mellitus using voxel-based morphometry. Material and methods: Institutional ethics approval and informed consent were obtained. VBM based on the high resolution three-dimensional T1-weighted fast spoiled gradient recalled echo MRI images was obtained from 16 type II diabetes patients (mean age 61.2 years) and 16 normal controls (mean age 59.6 years). All images were spatially preprocessed using Diffeomorphic Anatomical Registration using Exponentiated Lie algebra (DARTEL) algorithm, and the DARTEL templates were made from 100 normal subjects. Statistical parametric mapping was generated using analysis of covariance (ANCOVA). Results: An atrophy pattern of gray matter was seen in type II diabetes patients compared with controls that involved the right superior, middle, and inferior temporal gyri, right precentral gyrus, and left rolandic operculum region. The loss of white matter volume in type II diabetes mellitus was observed in right temporal lobe and left inferior frontal triangle region. ROI analysis revealed that the gray and white matter volume of right temporal lobe were significant lower in type II diabetes mellitus than that in controls (P < 0.05). Conclusion: This work demonstrated that type II diabetes mellitus patients mainly exhibited gray and white matter atrophy in right temporal lobe, and this finding supported that type II diabetes mellitus could lead to subtle diabetic brain structural changes in patients without dementia or macrovascular complications.

  13. Mapping the brain in type II diabetes: Voxel-based morphometry using DARTEL

    International Nuclear Information System (INIS)

    Chen, Zhiye; Li, Lin; Sun, Jie; Ma, Lin

    2012-01-01

    Purpose: To investigate the pattern of brain volume changes of the brain in patients with type II diabetes mellitus using voxel-based morphometry. Material and methods: Institutional ethics approval and informed consent were obtained. VBM based on the high resolution three-dimensional T1-weighted fast spoiled gradient recalled echo MRI images was obtained from 16 type II diabetes patients (mean age 61.2 years) and 16 normal controls (mean age 59.6 years). All images were spatially preprocessed using Diffeomorphic Anatomical Registration using Exponentiated Lie algebra (DARTEL) algorithm, and the DARTEL templates were made from 100 normal subjects. Statistical parametric mapping was generated using analysis of covariance (ANCOVA). Results: An atrophy pattern of gray matter was seen in type II diabetes patients compared with controls that involved the right superior, middle, and inferior temporal gyri, right precentral gyrus, and left rolandic operculum region. The loss of white matter volume in type II diabetes mellitus was observed in right temporal lobe and left inferior frontal triangle region. ROI analysis revealed that the gray and white matter volume of right temporal lobe were significant lower in type II diabetes mellitus than that in controls (P < 0.05). Conclusion: This work demonstrated that type II diabetes mellitus patients mainly exhibited gray and white matter atrophy in right temporal lobe, and this finding supported that type II diabetes mellitus could lead to subtle diabetic brain structural changes in patients without dementia or macrovascular complications.

  14. Type II1 factors satisfying the spatial isomorphism conjecture

    DEFF Research Database (Denmark)

    Cameron, Jan; Christensen, Erik; Sinclair, Allan M.

    2012-01-01

    Det vises at hvis et par af von Neumann algebraer er tilstrækkeligt tæt på hinanden i Hausdorff-metrikken, og den ene er en II1 faktor, som er et krydset produkt af en abelsk von Neumann algebra med en gruuppvirkning af en gruppe men triviel begrænset kohomologi, så er de to algebraer unitært...

  15. Evaluation of Cladribine treatment in refractory celiac disease type II

    Science.gov (United States)

    Tack, Greetje J; Verbeek, Wieke HM; Al-Toma, Abdul; Kuik, Dirk J; Schreurs, Marco WJ; Visser, Otto; Mulder, Chris JJ

    2011-01-01

    AIM: To evaluate cladribine [2-chlorodeoxyadenosine (2-CdA)] therapy in refractory celiac disease (RCD) II. METHODS: An open-label cohort-study of RCD II patients treated with 2-CdA was performed between 2000 and 2010. Survival rate, enteropathy associated T-cell lymphoma (EATL) occurrence, clinical course, and histological and immunological response rates were evaluated. RESULTS: Overall, 32 patients were included with a median follow-up of 31 mo. Eighteen patients responded well to 2-CdA. Patients responsive to 2-CdA had a statistically significant increased survival compared to those who were unresponsive. The overall 3- and 5-year survival was 83% in the responder and 63% and 22% in the non-responder group, respectively. The overall 2-year clinical, histological and immunological response rates were 81%, 47% and 41%, respectively. Progression into EATL was reported in 16%, all of these patients died. CONCLUSION: Treatment of RCD II with 2-CdA holds promise, showing excellent clinical and histological response rates, and probably less frequent transition into EATL. PMID:21274381

  16. Direct Angiotensin II Type 2 Receptor Stimulation Ameliorates Insulin Resistance in Type 2 Diabetes Mice with PPARγ Activation

    DEFF Research Database (Denmark)

    Ohshima, Kousei; Mogi, Masaki; Jing, Fei

    2012-01-01

    The role of angiotensin II type 2 (AT(2)) receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) might contribute to possible insulin-sensitizing/anti-diabetic effects in type...... 2 diabetes (T2DM) with PPARγ activation, mainly focusing on adipose tissue....

  17. Bronchoalveolar lavage fluid from normal rats stimulates DNA synthesis in rat alveolar type II cells

    International Nuclear Information System (INIS)

    Leslie, C.C.; McCormick-Shannon, K.; Mason, R.J.

    1989-01-01

    Proliferation of alveolar type II cells after lung injury is important for the restoration of the alveolar epithelium. Bronchoalveolar lavage fluid (BALF) may represent an important source of growth factors for alveolar type II cells. To test this possibility, BALF fluid was collected from normal rats, concentrated 10-fold by Amicon filtration, and tested for its ability to stimulate DNA synthesis in rat alveolar type II cells in primary culture. BALF induced a dose-dependent increase in type II cell DNA synthesis resulting in a 6-fold increase in [3H]thymidine incorporation. Similar doses also stimulated [3H]thymidine incorporation into rat lung fibroblasts by 6- to 8-fold. Removal of pulmonary surface active material by centrifugation did not significantly reduce the stimulatory activity of BALF for type II cells. The stimulation of type II cell DNA synthesis by BALF was reduced by 100% after heating at 100 degrees C for 10 min, and by approximately 80% after reduction with dithiothreitol, and after trypsin treatment. Dialysis of BALF against 1 N acetic acid resulted in a 27% reduction in stimulatory activity. The effect of BALF in promoting type II cell DNA synthesis was more pronounced when tested in the presence of serum, although serum itself has very little effect on type II cell DNA synthesis. When BALF was tested in combination with other substances that stimulate type II cell DNA synthesis (cholera toxin, insulin, epidermal growth factor, and acidic fibroblast growth factor), additive effects or greater were observed. When BALF was chromatographed over Sephadex G150, the activity eluted with an apparent molecular weight of 100 kDa

  18. THE CONNECTIONS BETWEEN THE UV AND OPTICAL Fe ii EMISSION LINES IN TYPE 1 AGNs

    Energy Technology Data Exchange (ETDEWEB)

    Kovacević-Dojcinović, Jelena; Popović, Luka Č., E-mail: jkovacevic@aob.bg.ac.rs, E-mail: lpopovic@aob.bg.ac.rs [Astronomical Observatory, Volgina 7, 11060 Belgrade (Serbia)

    2015-12-15

    We investigate the spectral properties of the UV (λλ2650–3050 Å) and optical (λλ4000–5500 Å) Fe ii emission features in a sample of 293 Type 1 active galactic nuclei (AGNs) from the Sloan Digital Sky Survey database. We explore different correlations between their emission line properties, as well as the correlations with other emission lines from the spectral range. We find several interesting correlations and outline the most interesting results as follows. (i) There is a kinematical connection between the UV and optical Fe ii lines, indicating that the UV and optical Fe ii lines originate from the outer part of the broad line region, the so-called intermediate line region. (ii) The unexplained anticorrelations of the optical Fe ii equivalent width (EW Fe ii{sub opt}) versus EW [O iii] 5007 Å and EW Fe ii{sub opt} versus FWHM Hβ have not been detected for the UV Fe ii lines. (iii) The significant averaged redshift in the UV Fe ii lines, which is not present in optical Fe ii, indicates an inflow in the UV Fe ii emitting clouds, and probably their asymmetric distribution. (iv) Also, we confirm the anticorrelation between the intensity ratio of the optical and UV Fe ii lines and the FWHM of Hβ, and we find the anticorrelations of this ratio with the widths of Mg ii 2800 Å, optical Fe ii, and UV Fe ii. This indicates a very important role for the column density and microturbulence in the emitting gas. We discuss the starburst activity in high-density regions of young AGNs as a possible explanation of the detected optical Fe ii correlations and intensity line ratios of the UV and optical Fe ii lines.

  19. Drusen-like beneath retinal deposits in type II mesangiocapillary glomerulonephritis: a review

    Directory of Open Access Journals (Sweden)

    Miguel Hage Amaro

    2015-02-01

    Full Text Available The aim of this paper is to do a review of Drusen-like beneath retinal deposits in type II mesangiocapillary glomerulonephritis. Drusenlike beneath retinal deposits in type II mesangiocapillary glomerulonephritis appear to develop at an early age, often second decade of life different of drusen from age-related macular degeneration (AMD.Long term follow-up of the cases in this disease shows in the most of them, no progression of the of drusen-like beneath retinal deposits in type II mesangiocapillary glomerulonefritis, the most of subjects retain good visual acuity and no specific treatment is indicated.

  20. Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes

    Science.gov (United States)

    Link, Maire; Wolff, Anette S. B.; Meager, Anthony; Tserel, Liina; Org, Tõnis; Murumägi, Astrid; Uibo, Raivo; Willcox, Nick; Trebušak Podkrajšek, Katarina; Battelino, Tadej; Lobell, Anna; Kämpe, Olle; Lima, Kari; Meloni, Antonella; Ergun-Longmire, Berrin; Maclaren, Noel K.; Perheentupa, Jaakko; Krohn, Kai J. E.; Scott, Hamish S.; Husebye, Eystein S.; Peterson, Pärt

    2008-01-01

    Neutralizing autoantibodies to type I, but not type II, interferons (IFNs) are found at high titers in almost every patient with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease caused by AIRE gene mutations that lead to defects in thymic T-cell selection. Combining genome-wide expression array with real time RT-PCR assays, we here demonstrate that antibodies against IFN-α cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This down-regulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies. Most interestingly, a rare APECED patient with autoantibodies to IFN-ω but not IFN-α showed a marked increase in expression of the same interferon-stimulated genes. We also report unexpected increases in serum CXCL10 levels in APECED. Our results argue that the breakdown of tolerance to IFNs in AIRE deficiency is associated with impaired responses to them in thymus, and highlight APECED as another autoimmune disease with associated dysregulation of IFN activity. PMID:18606876

  1. Recognition of lysophosphatidylcholine by type II NKT cells and protection from an inflammatory liver disease.

    Science.gov (United States)

    Maricic, Igor; Girardi, Enrico; Zajonc, Dirk M; Kumar, Vipin

    2014-11-01

    Lipids presented by the MHC class I-like molecule, CD1d, are recognized by NK T (NKT) cells, which can be broadly categorized into two subsets. The well-characterized type I NKT cells express a semi-invariant TCR and can recognize both α- and β-linked glycolipids, whereas type II NKT cells are less well studied, express a relatively diverse TCR repertoire, and recognize β-linked lipids. Recent structural studies have shown a distinct mode of recognition of a self-glycolipid sulfatide bound to CD1d by a type II NKT TCR. To further characterize Ag recognition by these cells, we have used the structural data and screened other small molecules able to bind to CD1d and activate type II NKT cells. Using plate-bound CD1d and APC-based Ag presentation assay, we found that phospholipids such as lysophosphatidylcholine (LPC) can stimulate the sulfatide-reactive type II NKT hybridoma Hy19.3 in a CD1d-dependent manner. Using plasmon resonance studies, we found that this type II NKT TCR binds with CD1d-bound LPC with micromolar affinities similar to that for sulfatide. Furthermore, LPC-mediated activation of type II NKT cells leads to anergy induction in type I NKT cells and affords protection from Con A-induced hepatitis. These data indicate that, in addition to self-glycolipids, self-lysophospholipids are also recognized by type II NKT cells. Because lysophospholipids are involved during inflammation, our findings have implications for not only understanding activation of type II NKT cells in physiological settings, but also for the development of immune intervention in inflammatory diseases. Copyright © 2014 by The American Association of Immunologists, Inc.

  2. Design of coke ovens. Part II. Types of coke ovens

    Energy Technology Data Exchange (ETDEWEB)

    Sroka, E.; Haratyk, J.

    1983-08-01

    Design of 4 coke oven types is discussed: H. Koppers ovens, PWR ovens (developed by Giprokoks in the USSR), Koppers-Becker ovens and Nittetsu ovens. Design of each coke oven type is shown in a scheme. Distribution of heat and heat control in the heating walls of coke ovens are analyzed: burners, distribution of flue channels in heating walls, systems for temperature control of gases in flue channels. Gas flow in flue channels of 4 coke oven types is evaluated. Effects of coke oven design on its performance and on coke quality are also discussed.

  3. An Angiotensin II type 1 receptor activation switch patch revealed through Evolutionary Trace analysis

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Yao, Rong; Ma, Jian-Nong

    2010-01-01

    in the cytoplasmic parts of TM2, TM3, and TM6 to form an activation switch that is common to all family A 7TM receptors. We tested this hypothesis in the rat Angiotensin II (Ang II) type 1a (AT1a) receptor. The receptor has important roles in the cardiovascular system, but has also frequently been applied as a model...

  4. Design and synthesis of ruthenium(II) OCO pincer type NHC ...

    Indian Academy of Sciences (India)

    well-defined, air and moisture-stable tridentate type bis- phenolate ruthenium(II) N−heterocyclic carbene com- plexes. Herein, we report a full account on our studies of ruthenium(II) N-heterocyclic carbene catalysts in the dehydrogenative amide synthesis from alcohols with amines. 2. Experimental. 2.1 General comments.

  5. A case of osteogenesis imperfecta type II, a diagnosis made almost ...

    African Journals Online (AJOL)

    Background: Osteogenesis imperfecta (OI) is a rare autosomal dominant disorder of type I collagen (COL I), characterised by excessive bone fragility with low bone mineral density (BMD). Type II is associated with extreme bone fragility leading to intrauterine or early infant death. Objective: To highlight a case of OI type II ...

  6. CD1d-Restricted Type II NKT Cells Reactive With Endogenous Hydrophobic Peptides.

    Science.gov (United States)

    Nishioka, Yusuke; Masuda, Sakiko; Tomaru, Utano; Ishizu, Akihiro

    2018-01-01

    NKT cells belong to a distinct subset of T cells that recognize hydrophobic antigens presented by major histocompatibility complex class I-like molecules, such as CD1d. Because NKT cells stimulated by antigens can activate or suppress other immunocompetent cells through an immediate production of a large amount of cytokines, they are regarded as immunological modulators. CD1d-restricted NKT cells are classified into two subsets, namely, type I and type II. CD1d-restricted type I NKT cells express invariant T cell receptors (TCRs) and react with lipid antigens, including the marine sponge-derived glycolipid α-galactosylceramide. On the contrary, CD1d-restricted type II NKT cells recognize a wide variety of antigens, including glycolipids, phospholipids, and hydrophobic peptides, by their diverse TCRs. In this review, we focus particularly on CD1d-restricted type II NKT cells that recognize endogenous hydrophobic peptides presented by CD1d. Previous studies have demonstrated that CD1d-restricted type I NKT cells usually act as pro-inflammatory cells but sometimes behave as anti-inflammatory cells. It has been also demonstrated that CD1d-restricted type II NKT cells play opposite roles to CD1d-restricted type I NKT cells; thus, they function as anti-inflammatory or pro-inflammatory cells depending on the situation. In line with this, CD1d-restricted type II NKT cells that recognize type II collagen peptide have been demonstrated to act as anti-inflammatory cells in diverse inflammation-induction models in mice, whereas pro-inflammatory CD1d-restricted type II NKT cells reactive with sterol carrier protein 2 peptide have been demonstrated to be involved in the development of small vessel vasculitis in rats.

  7. Binge eating and other psychopathology in patients with type II diabetes mellitus.

    Science.gov (United States)

    Crow, S; Kendall, D; Praus, B; Thuras, P

    2001-09-01

    Type II diabetes mellitus (DM), a common disease with many potential complications, is strongly associated with obesity. Alterations in food consumption can dramatically alter glucose control in individuals with Type II DM. Binge eating disorder (BED) is also closely associated with obesity. The nature of the relationship, if any, between Type II DM and BED is unclear. Forty-three individuals (23 females, 20 males) with Type II DM were assessed using the Structured Clinical Interview for DSM-IV (SCID-I), the Three-Factor Eating Questionnaire (TFEQ), and the Impact of Weight Scale. The most recent hemoglobin A1c level was recorded. Height and weight were also measured. Eleven subjects (25.6%) were diagnosed with BED. Individuals with BED had higher body mass index (BMI) scores, higher TFEQ Disinhibition and Hunger scores, and higher scores on all Impact of Weight subscales (except eating) compared with those without BED. Glycosylated hemoglobin levels did not differ between the two groups (8.1% vs. 8.4%; p = 0.553). Rates of BED in subjects with Type II DM were substantial. Other types of psychopathology were also common. Although glycosylated hemoglobin levels were similar in patients with and without BED, the presence of BED was associated with greater obesity. Assessment for BED is an important aspect of the management of patients with Type II DM. Copyright 2001 by John Wiley & Sons, Inc.

  8. Resveratrol treatment reveals a novel role for HMGB1 in regulation of the type 1 interferon response in dengue virus infection.

    Science.gov (United States)

    Zainal, Nurhafiza; Chang, Chih-Peng; Cheng, Yi-Lin; Wu, Yan-Wei; Anderson, Robert; Wan, Shu-Wen; Chen, Chia-Ling; Ho, Tzong-Shiann; AbuBakar, Sazaly; Lin, Yee-Shin

    2017-02-20

    Dengue is one of the most significant mosquito-borne virus diseases worldwide, particularly in tropical and subtropical regions. This study sought to examine the antiviral activity of resveratrol (RESV), a phytoalexin secreted naturally by plants, against dengue virus (DENV) infection. Our data showed that RESV inhibits the translocation of high mobility group box 1 (HMGB1), a DNA binding protein that normally resides in the nucleus, into the cytoplasm and extracellular milieu. HMGB1 migrates out of the nucleus during DENV infection. This migration is inhibited by RESV treatment and is mediated by induction of Sirt1 which leads to the retention of HMGB1 in the nucleus and consequently helps in the increased production of interferon-stimulated genes (ISGs). Nuclear HMGB1 was found to bind to the promoter region of the ISG and positively regulated the expression of ISG. The enhanced transcription of ISGs by nuclear HMGB1 thus contributes to the antiviral activity of RESV against DENV. To the best of our knowledge, this is the first report to demonstrate that RESV antagonizes DENV replication and that nuclear HMGB1 plays a role in regulating ISG production.

  9. High-Detectivity Type-II Superlattice Detectors for 6-14 um Infrared Applications Project

    Data.gov (United States)

    National Aeronautics and Space Administration — SVT Associates proposes an novel type II superlattice structure to extend the cutoff wavelength and CBIRD SL photo diode structure with unipolar barriers to suppress...

  10. Plasmonic Enhanced Type-II Superlattice Focal Plane Arrays, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — SVT Associates proposes an novel type II superlattice structure to extend the cutoff wavelength and CBIRD SL photo diode structure with unipolar barriers to suppress...

  11. Hydrogenation of Very Long Wavelength Infrared Focal Plane Arrays Based on Type II Superlattices, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — We propose to advance the Ga-free InAs/InAsSb type II superlattice (T2SL) materials technology for very long wavelength infrared (VLWIR) focal plane arrays (FPAs) by...

  12. Long-term use of metformin and colorectal cancer risk in type II diabetics

    DEFF Research Database (Denmark)

    Cardel, Majken; Jensen, S. M.; Pottegård, Anton

    2014-01-01

    In vitro and animal studies indicate that metformin prevents colorectal cancer (CRC). Epidemiological studies, however, have been equivocal. We undertook this study to assess whether metformin prevents CRC in individuals with type II diabetes. We performed a nested case-control study restricted...... to Danish citizens with type II diabetes. Data were collected from four Danish nationwide registries. Cases were type II diabetics with a primary CRC between 2000 and 2009, and controls were sampled among subjects with type II diabetes. Longterm exposure to metformin was defined by the redeeming...... of prescriptions for a cumulative dose of 2000 g within 5 years prior to the index date. To control for potential confounders, we used unconditional logistic regression. We generated adjusted odds ratios (OR) for the association between metformin and CRC and performed subanalyses for selected subgroups...

  13. Large Format LW Type-II SLS FPAs for Space Applications, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — This Phase I SBIR proposes to develop high performance (low dark current, high quantum efficiency, and low NEdT) infrared epitaxy materials based on Type II Strained...

  14. Study of Statewide Type II Noise Abatement Program for the Texas Department of Transportation

    Science.gov (United States)

    2000-02-01

    This project will provide sufficient information to the Texas Department of Transportation and the Texas Transportation Commission to make an informed decision regarding the development and implementation of a statewide Type II Noise Abatement Progra...

  15. High Quantum Efficiency Type II SLS FPAs for Space-Based Applications Project

    Data.gov (United States)

    National Aeronautics and Space Administration — This Phase I SBIR proposes to develop high quantum efficiency (QE) and low dark current infrared epitaxy materials based on Type II Strained Layer Superlattice (SLS)...

  16. The imaging manifestations of caseous pulmonary tuberculosis with type-II diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Mingyue Wang

    2015-11-01

    Conclusion: Type-II diabetic patients with caseous tuberculosis mainly showed consolidation and atypical lung field lesions on chest radiographs. Becoming familiar with these features will be helpful to imaging diagnosis of DMTB.

  17. Allograft Inflammatory Factor-1 Links T-Cell Activation, Interferon Response, and Macrophage Activation in Chronic Kawasaki Disease Arteritis.

    Science.gov (United States)

    Rowley, Anne H; Baker, Susan C; Kim, Kwang-Youn A; Shulman, Stanford T; Yang, Amy; Arrollo, David; DeBerge, Matthew; Han, Shuling; Sibinga, Nicholas E S; Pink, Adam J; Thorp, Edward B

    2017-09-01

    Kawasaki disease (KD) is widely viewed as an acute arteritis. However, our pathologic studies show that chronic coronary arteritis can persist long after disease onset and is closely linked with arterial stenosis. Transcriptome profiling of acute KD arteritis tissues revealed upregulation of T lymphocyte, type I interferon, and allograft inflammatory factor-1 (AIF1) genes. We determined whether these immune responses persist in chronic KD arteritis, and we investigated the role of AIF1 in these responses. Gene expression in chronic KD and childhood control arteries was determined by real-time reverse-transcriptase polymerase chain reaction, and arterial protein expression was determined by immunohistochemistry and immunofluorescence. Allograft inflammatory factor-1 small-interfering ribonucleic acid macrophage treatment was performed to investigate the role of AIF1 in macrophage and T lymphocyte activation. Allograft inflammatory factor-1 protein was highly expressed in stenotic KD arteries and colocalized with the macrophage marker CD68. T lymphocyte and interferon pathway genes were significantly upregulated in chronic KD coronary artery tissues. Alpha interferon-induced macrophage expression of CD80 and major histocompatibility complex class II was dependent on AIF1, and macrophage expression of AIF1 was required for antigen-specific T lymphocyte activation. Allograft inflammatory factor-1, originally identified in posttransplant arterial stenosis, is markedly upregulated in KD stenotic arterial tissues. T lymphocyte and type I interferon responses persist in chronic KD arteritis. Allograft inflammatory factor-1 may play multiple roles linking type I interferon response, macrophage activation, and antigen-specific T lymphocyte activation. These results suggest the likely importance of lymphocyte-myeloid cell cross-talk in the pathogenesis of KD arteritis and can inform selection of new immunotherapies for clinical trials in high-risk KD children.

  18. The Nickel Mass Distribution of Normal Type II Supernovae

    Science.gov (United States)

    Müller, Tomás; Prieto, José L.; Pejcha, Ondřej; Clocchiatti, Alejandro

    2017-06-01

    Core-collapse supernova (SN) explosions expose the structure and environment of massive stars at the moment of their death. We use the global fitting technique of Pejcha & Prieto to estimate a set of physical parameters of 19 normal SNe II, such as their distance moduli, reddenings, 56Ni masses {M}{Ni}, and explosion energies {E}\\exp from multicolor light curves and photospheric velocity curves. We confirm and characterize known correlations between {M}{Ni} and bolometric luminosity at 50 days after the explosion, and between {M}{Ni} and {E}\\exp . We pay special attention to the observed distribution of {M}{Ni} coming from a joint sample of 38 SNe II, which can be described as a skewed-Gaussian-like distribution between 0.005 {M}⊙ and 0.280 {M}⊙ , with a median of 0.031 {M}⊙ , mean of 0.046 {M}⊙ , standard deviation of 0.048 {M}⊙ , and skewness of 3.050. We use a two-sample Kolmogorov-Smirnov test and two-sample Anderson-Darling test to compare the observed distribution of {M}{Ni} to results from theoretical hydrodynamical codes of core-collapse explosions with the neutrino mechanism presented in the literature. Our results show that the theoretical distributions obtained from the codes tested in this work, KEPLER and Prometheus Hot Bubble, are compatible with the observations irrespective of different pre-SN calibrations and different maximum mass of the progenitors.

  19. Design and Fabrication of High-Performance LWIR Photodetectors Based on Type-II Superlattices

    Science.gov (United States)

    2017-08-11

    and strain-balanced InAs1-xSbx/InAs Type- II superlattices for LWIR detection and imaging . After this study, it is expected to achieve a superlattice...persistent surveillance applications. Improvement in material quality and processing technique, as well as evolutionary modifications in device... imaging . 15. SUBJECT TERMS Focal plane array, improved minority carrier lifetime, type II superlattice and infrared 16. SECURITY CLASSIFICATION OF: 17

  20. Throughput of Type II HARQ-OFDM/TDM Using MMSE-FDE in a Multipath Channel

    Directory of Open Access Journals (Sweden)

    Haris Gacanin

    2009-01-01

    Full Text Available In type II hybrid ARQ (HARQ schemes, the uncoded information bits are transmitted first, while the error correction parity bits are sent upon request. Consequently, frequency diversity cannot be exploited during the first transmission. In this paper, we present the use of OFDM/TDM with MMSE-FDE and type II HARQ to increase throughput of OFDM due to frequency diversity gain.

  1. Carbon black nanoparticles induce type II epithelial cells to release chemotaxins for alveolar macrophages

    Directory of Open Access Journals (Sweden)

    Donaldson Ken

    2005-12-01

    Full Text Available Abstract Background Alveolar macrophages are a key cell in dealing with particles deposited in the lungs and in determining the subsequent response to that particle exposure. Nanoparticles are considered a potential threat to the lungs and the mechanism of pulmonary response to nanoparticles is currently under intense scrutiny. The type II alveolar epithelial cell has previously been shown to release chemoattractants which can recruit alveolar macrophages to sites of particle deposition. The aim of this study was to assess the responses of a type II epithelial cell line (L-2 to both fine and nanoparticle exposure in terms of secretion of chemotactic substances capable of inducing macrophage migration. Results Exposure of type II cells to carbon black nanoparticles resulted in significant release of macrophage chemoattractant compared to the negative control and to other dusts tested (fine carbon black and TiO2 and nanoparticle TiO2 as measured by macrophage migration towards type II cell conditioned medium. SDS-PAGE analysis of the conditioned medium from particle treated type II cells revealed that a higher number of protein bands were present in the conditioned medium obtained from type II cells treated with nanoparticle carbon black compared to other dusts tested. Size-fractionation of the chemotaxin-rich supernatant determined that the chemoattractants released from the epithelial cells were between 5 and 30 kDa in size. Conclusion The highly toxic nature and reactive surface chemistry of the carbon black nanoparticles has very likely induced the type II cell line to release pro-inflammatory mediators that can potentially induce migration of macrophages. This could aid in the rapid recruitment of inflammatory cells to sites of particle deposition and the subsequent removal of the particles by phagocytic cells such as macrophages and neutrophils. Future studies in this area could focus on the exact identity of the substance(s released by the

  2. Type-II Quantum Dot Nanowire Structures with Large Oscillator Strengths for Optical Quantum Gating Applications

    DEFF Research Database (Denmark)

    Taherkhani, Masoomeh; Gregersen, Niels; Willatzen, Morten

    2017-01-01

    The exciton oscillator strength (OS) in type-II quantum dot (QD) nanowires is calculated by using a fast and efficient method. We propose a new structure in Double-Well QD (DWQD) nanowire that considerably increases OS of type-II QDs which is a key parameter in optical quantum gating in the stimu...... in the stimulated Raman adiabatic passage (STIRAP) process [1] for implementing quantum gates....

  3. Treatment of Hepatitis C Infections with Interferon: A Historical Perspective

    Science.gov (United States)

    2010-01-01

    Treatment of Hepatitis C Infections with Interferon: A Historical Perspective Robert M. Friedman and Sara Contente Department of Pathology, Uniformed...sufficient quantities of it were available for treatment of hepatitis C virus (HCV) infections, Clinicians now have an excellent understanding of the basis...02 JUL 2010 2. REPORT TYPE 3. DATES COVERED 00-00-2010 to 00-00-2010 4. TITLE AND SUBTITLE Treatment of Hepatitis C Infections with Interferon

  4. Discovery and development of the N-terminal procollagen type II (NPII) biomarker: a tool for measuring collagen type II synthesis.

    Science.gov (United States)

    Nemirovskiy, O V; Sunyer, T; Aggarwal, P; Abrams, M; Hellio Le Graverand, M P; Mathews, W R

    2008-12-01

    Progression of joint damage in osteoarthritis (OA) is likely to result from an imbalance between cartilage degradation and synthesis processes. Markers reflecting these two components appear to be promising in predicting the rate of OA progression. Both N- and C-terminal propeptides of type II collagen reflect the rates of collagen type II synthesis. The ability to quantify the procollagen peptides in biological fluids would enable a better understanding of OA disease pathology and provide means for assessing the proof of mechanism of anabolic disease modifying OA drugs (DMOADs). A polyclonal antibody that recognizes the sequence GPKGQKGEPGDIKDI in the propeptide region of rat, dog, and human type II collagen was raised in chicken and peptide-affinity purified. The immunoaffinity liquid chromatography mass spectrometry (LC-MS/MS) was used to extensively characterize N-terminal procollagen type II (NPII) peptides found in biological fluids. The novel competition enzyme-linked immunosorbent assay (ELISA) assay was developed to quantitatively measure the NPII peptides. Several peptides ranging from 17 to 41 amino acids with various modifications including hydroxylations on proline and lysine residues, oxidation of lysines to allysines, and attachments of glucose and galactose moieties to hydroxylysines were identified in a simple system such as ex vivo cultures of human articular cartilage (HAC) explants as well as in more complex biological fluids such as human urine and plasma. A competitive ELISA assay has been developed and applied to urine, plasma, and synovial fluid matrices in human, rat and dog samples. A novel NPII assay has been developed and applied to OA and normal human subjects to understand the changes in collagen type II synthesis related to the pathology of OA.

  5. Structural and biochemical characterization of the type-II LOG protein from Streptomyces coelicolor A3.

    Science.gov (United States)

    Seo, Hogyun; Kim, Kyung-Jin

    2018-03-29

    Streptomyces coelicolor A3 contains Sc5140, a gene coding for poorly understood bacterial LOG-like protein. In this study, we determined the crystal structure of Sc5140 and found it resembles the overall structure of other type-II LOGs. In addition, Sc5140 exhibited phosphoribohydrolase activity against adenosine monophosphate (AMP), indicating that it had the same function as known type-II LOGs. Based on these results, we designated Sc5140 as ScLOGII. We performed docking calculations of AMP into the ScLOGII structure, which suggested the mode of binding for type-II LOG with their AMP substrate. The ScLOGII structure uniquely exhibited a long tail-like structure at the N-terminus that was involved in hexamerization of the protein; the disordered N-terminal region (DNR). Truncation of DNR in ScLOGII negatively affected both the phosphoribohydrolase activity and the oligomerization of the protein, suggesting that this region functioned in enzyme stabilization. However, results from truncation experiments using ScLOGII and CgLOGII, a type-II LOG homologue from Corynebacterium glutamicum, were quite different, leaving uncertainty regarding the general functions of DNR in type-II LOGs. Overall, the current structural work may help in understand the significance of type-II LOG protein at the molecular level. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Alveolar type II cell transplantation restores pulmonary surfactant protein levels in lung fibrosis.

    Science.gov (United States)

    Guillamat-Prats, Raquel; Gay-Jordi, Gemma; Xaubet, Antoni; Peinado, Victor I; Serrano-Mollar, Anna

    2014-07-01

    Alveolar Type II cell transplantation has been proposed as a cell therapy for the treatment of idiopathic pulmonary fibrosis. Its long-term benefits include repair of lung fibrosis, but its success partly depends on the restoration of lung homeostasis. Our aim was to evaluate surfactant protein restoration after alveolar Type II cell transplantation in an experimental model of bleomycin-induced lung fibrosis in rats. Lung fibrosis was induced by intratracheal instillation of bleomycin. Alveolar Type II cells were obtained from healthy animals and transplanted 14 days after bleomycin was administered. Furthermore, one group transplanted with alveolar macrophages and another group treated with surfactant were established to evaluate the specificity of the alveolar Type II cell transplantation. The animals were euthanized at 21 days after bleomycin instillation. Lung fibrosis was confirmed by a histologic study and an evaluation of the hydroxyproline content. Changes in surfactant proteins were evaluated by mRNA expression, Western blot and immunofluorescence studies. The group with alveolar Type II cell transplantation was the only one to show a reduction in the degree of lung fibrosis and a complete recovery to normal levels of surfactant proteins. One of the mechanisms involved in the beneficial effect of alveolar Type II cell transplantation is restoration of lung surfactant protein levels, which is required for proper respiratory function. Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  7. Creation of a type IIS restriction endonuclease with a long recognition sequence.

    Science.gov (United States)

    Lippow, Shaun M; Aha, Patti M; Parker, Matthew H; Blake, William J; Baynes, Brian M; Lipovsek, Dasa

    2009-05-01

    Type IIS restriction endonucleases cleave DNA outside their recognition sequences, and are therefore particularly useful in the assembly of DNA from smaller fragments. A limitation of type IIS restriction endonucleases in assembly of long DNA sequences is the relative abundance of their target sites. To facilitate ligation-based assembly of extremely long pieces of DNA, we have engineered a new type IIS restriction endonuclease that combines the specificity of the homing endonuclease I-SceI with the type IIS cleavage pattern of FokI. We linked a non-cleaving mutant of I-SceI, which conveys to the chimeric enzyme its specificity for an 18-bp DNA sequence, to the catalytic domain of FokI, which cuts DNA at a defined site outside the target site. Whereas previously described chimeric endonucleases do not produce type IIS-like precise DNA overhangs suitable for ligation, our chimeric endonuclease cleaves double-stranded DNA exactly 2 and 6 nt from the target site to generate homogeneous, 5', four-base overhangs, which can be ligated with 90% fidelity. We anticipate that these enzymes will be particularly useful in manipulation of DNA fragments larger than a thousand bases, which are very likely to contain target sites for all natural type IIS restriction endonucleases.

  8. Cardiovascular risk markers in type II diabetes and hypertension at ...

    African Journals Online (AJOL)

    Background:Inflammation has been suugested to be associated with hypertension and type 2 diabetes; inflammation either precedes or is a consequence of the development of these diseases. This study sought to evaluate the role of inflammatory markers as cardiovascular risk factors and also determine their association ...

  9. Numerical simulation for i - ii type of distribution header throttle

    International Nuclear Information System (INIS)

    Yuheng, Feng; Wenjun, Hu; Xuedong, Qiao; Zhifeng, Hou

    2009-01-01

    In the simulation of distribution header throttle structure, using the computational fluid dynamic code-CFX, compared with experiment, the reasons of error is discussed and the reliability of this simulation is proved. Authors have checked same types of calculations, particularly introduced the relationship between CFD and experiment. The results will be theoretic base and reference

  10. NO EVIDENCE FOR A SYSTEMATIC Fe II EMISSION LINE REDSHIFT IN TYPE 1 ACTIVE GALACTIC NUCLEI

    International Nuclear Information System (INIS)

    Sulentic, Jack W.; Marziani, Paola; Zamfir, Sebastian; Meadows, Zachary A.

    2012-01-01

    We test the recent claim by Hu et al. that Fe II emission in type 1 active galactic nuclei shows a systematic redshift relative to the local source rest frame and broad-line Hβ. We compile high signal-to-noise median composites using Sloan Digital Sky Survey spectra from both the Hu et al. sample and our own sample of the 469 brightest DR5 spectra. Our composites are generated in bins of FWHM Hβ and Fe II strength as defined in our 4D Eigenvector 1 formalism. We find no evidence for a systematic Fe II redshift and consistency with previous assumptions that Fe II shift and width (FWHM) follow Hβ shift and FWHM in virtually all sources. This result is consistent with the hypothesis that Fe II emission (quasi-ubiquitous in type 1 sources) arises from a broad-line region with geometry and kinematics the same as that producing the Balmer lines.

  11. Ca II H and K emission from late-type stars

    International Nuclear Information System (INIS)

    Middlekoop, F.

    1982-01-01

    This thesis is based on a study of the Ca II H and K emission features of late main-sequence stars. In Chapter II it is shown that rotation periods can be determined from a modulation in the Ca II H and K signal for many stars in a broad range of spectral types. In Chapter III it is shown that a clear correlation exists between Ca II H and K emission and rotational velocity in active main-sequence stars. There is an indication for a (probably colour-dependent) critical velocity at which the Ca II H and K emission suddenly drops. Chapter IV discusses the dependence of Ca II H and K emission on the rotation rate for evolved stars. (Auth./C.F.)

  12. Supersymmetric RG flows and Janus from type II orbifold compactification

    Energy Technology Data Exchange (ETDEWEB)

    Karndumri, Parinya; Upathambhakul, Khem [Chulalongkorn University, String Theory and Supergravity Group, Department of Physics, Faculty of Science, Bangkok (Thailand)

    2017-07-15

    We study holographic RG flow solutions within four-dimensional N = 4 gauged supergravity obtained from type IIA and IIB string theories compactified on T{sup 6}/Z{sub 2} x Z{sub 2} orbifold with gauge, geometric and non-geometric fluxes. In type IIB non-geometric compactifications, the resulting gauged supergravity has ISO(3) x ISO(3) gauge group and admits an N = 4 AdS{sub 4} vacuum dual to an N = 4 superconformal field theory (SCFT) in three dimensions. We study various supersymmetric RG flows from this N = 4 SCFT to N = 4 and N = 1 non-conformal field theories in the IR. The flows preserving N = 4 supersymmetry are driven by relevant operators of dimensions Δ = 1, 2 or alternatively by one of these relevant operators, dual to the dilaton, and irrelevant operators of dimensions Δ = 4 while the N = 1 flows in addition involve marginal deformations. Most of the flows can be obtained analytically. We also give examples of supersymmetric Janus solutions preserving N = 4 and N = 1 supersymmetries. These solutions should describe two-dimensional conformal defects within the dual N = 4 SCFT. Geometric compactifications of type IIA theory give rise to N = 4 gauged supergravity with ISO(3) x U(1){sup 6} gauge group. In this case, the resulting gauged supergravity admits an N = 1 AdS{sub 4} vacuum. We also numerically study possible N = 1 RG flows to non-conformal field theories in this case. (orig.)

  13. The Functions of Type I and Type II Natural Killer T (NKT) Cells in Inflammatory Bowel Diseases

    Science.gov (United States)

    Liao, Chia-Min; Zimmer, Michael I.; Wang, Chyung-Ru

    2013-01-01

    CD1d-restricted natural killer T (NKT) cells are a distinct subset of T cells that rapidly produce an array of cytokines upon activation and play a critical role in regulating various immune responses. NKT cells are classified into two groups based on differences in T cell receptor (TCR) usage. Type I NKT cells have an invariant TCRα-chain and are readily detectable by α-galactosylceramide (α-GalCer)-loaded CD1d tetramers. Type II NKT cells have a more diverse TCR repertoire and cannot be directly identified. Both types of NKT cells as well as multiple CD1d-expressing cell types are present in the intestine and their interactions are likely to be modulated by pathogenic and commensal microbes, which in turn contribute to the intestinal immune responses in health and disease. Indeed, in several animal models of inflammatory bowel disease (IBD), Type I NKT cells have been shown to make both protective and pathogenic contributions to disease. In contrast, in human patients suffering from ulcerative colitis (UC), and a mouse model in which both CD1d expression and the frequency of Type II NKT cells are increased, Type II NKT cells appear to promote intestinal inflammation. In this review, we summarize present knowledge on the antigen recognition, activation and function of NKT cells with a particular focus on their role in IBD, and discuss factors that may influence the functional outcome of NKT cell responses in intestinal inflammation. PMID:23518808

  14. Natural transformation of an engineered Helicobacter pylori strain deficient in type II restriction endonucleases.

    Science.gov (United States)

    Zhang, Xue-Song; Blaser, Martin J

    2012-07-01

    Restriction-modification (RM) systems are important for bacteria to limit foreign DNA invasion. The naturally competent bacterium Helicobacter pylori has highly diverse strain-specific type II systems. To evaluate the roles of strain-specific restriction in H. pylori natural transformation, a markerless type II restriction endonuclease-deficient (REd) mutant was constructed. We deleted the genes encoding all four active type II restriction endonucleases in H. pylori strain 26695 using sacB-mediated counterselection. Transformation by donor DNA with exogenous cassettes methylated by Escherichia coli was substantially (1.7 and 2.0 log(10) for cat and aphA, respectively) increased in the REd strain. There also was significantly increased transformation of the REd strain by donor DNA from other H. pylori strains, to an extent corresponding to their shared type II R-M system strain specificity with 26695. Comparison of the REd and wild-type strains indicates that restriction did not affect the length of DNA fragment integration during natural transformation. There also were no differentials in cell growth or susceptibility to DNA damage. In total, the data indicate that the type II REd mutant has enhanced competence with no loss of growth or repair facility compared to the wild type, facilitating H. pylori mutant construction and other genetic engineering.

  15. Type II NKT Cells in Inflammation, Autoimmunity, Microbial Immunity, and Cancer.

    Science.gov (United States)

    Marrero, Idania; Ware, Randle; Kumar, Vipin

    2015-01-01

    Natural killer T cells (NKT) recognize self and microbial lipid antigens presented by non-polymorphic CD1d molecules. Two major NKT cell subsets, type I and II, express different types of antigen receptors (TCR) with distinct mode of CD1d/lipid recognition. Though type II NKT cells are less frequent in mice and difficult to study, they are predominant in human. One of the major subsets of type II NKT cells reactive to the self-glycolipid sulfatide is the best characterized and has been shown to induce a dominant immune regulatory mechanism that controls inflammation in autoimmunity and in anti-cancer immunity. Recently, type II NKT cells reactive to other self-glycolipids and phospholipids have been identified suggesting both promiscuous and specific TCR recognition in microbial immunity as well. Since the CD1d pathway is highly conserved, a detailed understanding of the biology and function of type II NKT cells as well as their interplay with type I NKT cells or other innate and adaptive T cells will have major implications for potential novel interventions in inflammatory and autoimmune diseases, microbial immunity, and cancer.

  16. ACh-induced hyperpolarization and decreased resistance in mammalian type II vestibular hair cells.

    Science.gov (United States)

    Poppi, Lauren A; Tabatabaee, Hessam; Drury, Hannah R; Jobling, Phillip; Callister, Robert J; Migliaccio, Americo A; Jordan, Paivi M; Holt, Joseph C; Rabbitt, Richard D; Lim, Rebecca; Brichta, Alan M

    2018-01-01

    In the mammalian vestibular periphery, electrical activation of the efferent vestibular system (EVS) has two effects on afferent activity: 1) it increases background afferent discharge and 2) decreases afferent sensitivity to rotational stimuli. Although the cellular mechanisms underlying these two contrasting afferent responses remain obscure, we postulated that the reduction in afferent sensitivity was attributed, in part, to the activation of α9- containing nicotinic acetylcholine (ACh) receptors (α9*nAChRs) and small-conductance potassium channels (SK) in vestibular type II hair cells, as demonstrated in the peripheral vestibular system of other vertebrates. To test this hypothesis, we examined the effects of the predominant EVS neurotransmitter ACh on vestibular type II hair cells from wild-type (wt) and α9-subunit nAChR knockout (α9 -/- ) mice. Immunostaining for choline acetyltransferase revealed there were no obvious gross morphological differences in the peripheral EVS innervation among any of these strains. ACh application onto wt type II hair cells, at resting potentials, produced a fast inward current followed by a slower outward current, resulting in membrane hyperpolarization and decreased membrane resistance. Hyperpolarization and decreased resistance were due to gating of SK channels. Consistent with activation of α9*nAChRs and SK channels, these ACh-sensitive currents were antagonized by the α9*nAChR blocker strychnine and SK blockers apamin and tamapin. Type II hair cells from α9 -/- mice, however, failed to respond to ACh at all. These results confirm the critical importance of α9nAChRs in efferent modulation of mammalian type II vestibular hair cells. Application of exogenous ACh reduces electrical impedance, thereby decreasing type II hair cell sensitivity. NEW & NOTEWORTHY Expression of α9 nicotinic subunit was crucial for fast cholinergic modulation of mammalian vestibular type II hair cells. These findings show a multifaceted

  17. Type-II second-harmonic-generation properties of YCOB and GdCOB single crystals.

    Science.gov (United States)

    Liu, Yanqing; Qi, Hongwei; Lu, Qingming; Yu, Fapeng; Wang, Zhengping; Xu, Xinguang; Zhao, Xian

    2015-02-09

    As excellent nonlinear optical (NLO) crystals, YCa(4)O(BO(3))(3) (YCOB) and GdCa(4)O(BO(3))(3) (GdCOB) have been paid much attention since their first appearance in 1990's. From that time to now, almost all of related researches and applications have focused on their type-I phase-matching (PM) configurations which possess large effective NLO coefficient (d(eff)). In this paper, type-II second-harmonic-generation (SHG) properties of these two crystals are reported, including PM curve, d(eff), angular acceptance and walk-off angle. Both of the type-II SHG experiments for 1064 and 1320 nm have indicated that the optimum directions which have maximum d(eff) locate in the second octant, i.e. (90° crystal, the largest type-II SHG conversion efficiency of a 1064 nm Nd:YAG pico-second laser is 55%, which reaches the same level of the optimum type-I sample. To our knowledge this is the first time that type-II SHG performance of YCOB and GdCOB crystals is investigated intensively. Our research has shown that the smaller d(eff) of type-II PM can be compensated by its larger angular acceptance and less beam walk-off. The same level SHG conversion efficiency implies for such type crystals the type-II components have the potential to replace type-I ones and obtain important NLO applications in the future.

  18. Prevalence of human T-lymphotropic virus type I and type II antibody among blood donors in Eastern Saudi Arabia.

    Science.gov (United States)

    Ul-Hassan, Zahoor; Al-Bahrani, Ahmad T; Panhotra, Bodh R

    2004-10-01

    Human T-cell leukemia/lymphoma virus type I and type II (HTLV-I/II) infections can be transfusion associated, leading to tropical paraparesis, myelopathy and other neurological disorders. The aim of this study is to circumvent the risk of transmission through blood transfusion and to describe the prevalence of HTLV-I/II antibody among blood donors of Al-Hasa region and the cost effectiveness of screening blood donors. The study was conducted at the Department of Laboratory and Blood Bank, King Fahad Hospital, Al-Hofuf, Al-Hasa, Kingdom of Saudi Arabia during the period of 1997 to 2003. A total of 47426 blood donors were screened for HTLV-I/II antibody by enzyme-linked immunosorbent assay test, during the 7 years of study period. The positive samples were confirmed by western blot analysis. Overall, HTLV-I antibody positivity (confirmed by western blot) was 3/47426 (0.006%). Out of 3 donors positive for HTLV-I antibody during 1997 to 1998, 2 were expatriates (Indian) and one was native Saudi donor. Human T-cell leukemia/lymphoma virus type I antibody positivity among the native Saudi donors was 1/47426 (0.002%) (2/100000 blood donors). None of the donor were positive for HTLV-II antibody. During the last 5 consecutive years of the study period (1999-2003), none of the donor was positive for HTLV-I/II antibody. Al-Hasa region is non-endemic for HTLV-I/II virus infections. Screening of native Saudi blood donors for these viruses does not appear to be cost effective.

  19. Optogenetic Stimulation Shifts the Excitability of Cerebral Cortex from Type I to Type II: Oscillation Onset and Wave Propagation.

    Directory of Open Access Journals (Sweden)

    Stewart Heitmann

    2017-01-01

    Full Text Available Constant optogenetic stimulation targeting both pyramidal cells and inhibitory interneurons has recently been shown to elicit propagating waves of gamma-band (40-80 Hz oscillations in the local field potential of non-human primate motor cortex. The oscillations emerge with non-zero frequency and small amplitude-the hallmark of a type II excitable medium-yet they also propagate far beyond the stimulation site in the manner of a type I excitable medium. How can neural tissue exhibit both type I and type II excitability? We investigated the apparent contradiction by modeling the cortex as a Wilson-Cowan neural field in which optogenetic stimulation was represented by an external current source. In the absence of any external current, the model operated as a type I excitable medium that supported propagating waves of gamma oscillations similar to those observed in vivo. Applying an external current to the population of inhibitory neurons transformed the model into a type II excitable medium. The findings suggest that cortical tissue normally operates as a type I excitable medium but it is locally transformed into a type II medium by optogenetic stimulation which predominantly targets inhibitory neurons. The proposed mechanism accounts for the graded emergence of gamma oscillations at the stimulation site while retaining propagating waves of gamma oscillations in the non-stimulated tissue. It also predicts that gamma waves can be emitted on every second cycle of a 100 Hz oscillation. That prediction was subsequently confirmed by re-analysis of the neurophysiological data. The model thus offers a theoretical account of how optogenetic stimulation alters the excitability of cortical neural fields.

  20. Interferon Alpha in Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Timothy B. Niewold

    2010-01-01

    Full Text Available The pleiotropic cytokine interferon alpha is involved in multiple aspects of lupus etiology and pathogenesis. Interferon alpha is important under normal circumstances for antiviral responses and immune activation. However, heightened levels of serum interferon alpha and expression of interferon response genes are common in lupus patients. Lupus-associated autoantibodies can drive the production of interferon alpha and heightened levels of interferon interfere with immune regulation. Several genes in the pathways leading to interferon production or signaling are associated with risk for lupus. Clinical and cellular manifestations of excess interferon alpha in lupus combined with the genetic risk factors associated with interferon make this cytokine a rare bridge between genetic risk and phenotypic effects. Interferon alpha influences the clinical picture of lupus and may represent a therapeutic target. This paper provides an overview of the cellular, genetic, and clinical aspects of interferon alpha in lupus.

  1. The association of type II diabetes with gut microbiota composition.

    Science.gov (United States)

    Navab-Moghadam, Fatemeh; Sedighi, Mansour; Khamseh, Mohammad E; Alaei-Shahmiri, Fariba; Talebi, Malihe; Razavi, Shabnam; Amirmozafari, Nour

    2017-09-01

    It is known that type 2 diabetes (T2D) in humans could be linked to the composition of gut microbiota. The aim of this study was to evaluate three faecal bacterial species, including Bacteroides fragilis, Bifidobacterium longum and Faecalibacterium prausnitzii in patients with T2D. This case control study included 18 patients with T2D and 18 matched persons without diabetes. The concentrations of B. fragilis, B. longum and F. prausnitzii were determined by quantitative Real-Time PCR. Quantitative PCR analysis revealed that the gut bacterial composition in patients with T2D was partially different from that in the healthy individuals. Faecalibacterium prausnitzii was significantly lower in patients with T2D (P-value = 0.038). Bacteroides fragilis was under-represented in the microbiota of the group with diabetes, but its difference between two groups was not significant (P-value = 0.38). No difference was observed for B. longum community between the both groups (P-value = 0.99). Characterization of specific species of intestinal microbiota shows some compositional changes in patients with T2D. The results may be valuable for developing strategies to control type 2 diabetes by modifying the intestinal microbiota. Long-term studies with emphasis on other bacterial groups are suggested to clarify the association of T2D with gut microbiota. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Type IIB flux vacua from G-theory II

    Energy Technology Data Exchange (ETDEWEB)

    Candelas, Philip [Mathematical Institute, University of Oxford,Andrew Wiles Building, Radcliffe Observatory Quarter,Woodstock Road, Oxford, OX2 6GG (United Kingdom); Constantin, Andrei [Department of Physics and Astronomy, Uppsala University,SE-751 20, Uppsala (Sweden); Damian, Cesar [Departamento de Fisica, DCI, Campus Leon, Universidad de Guanajuato,C.P. 37150, Leon, Guanajuato (Mexico); Larfors, Magdalena [Department of Physics and Astronomy, Uppsala University,SE-751 20, Uppsala (Sweden); Morales, Jose Francisco [INFN - Sezione di Roma “TorVergata”,Dipartimento di Fisica, Universita di Roma “TorVergata”, Via della Ricerca Scientica, 00133 Roma (Italy)

    2015-02-27

    We find analytic solutions of type IIB supergravity on geometries that locally take the form Mink×M{sub 4}×ℂ with M{sub 4} a generalised complex manifold. The solutions involve the metric, the dilaton, NSNS and RR flux potentials (oriented along the M{sub 4}) parametrised by functions varying only over ℂ. Under this assumption, the supersymmetry equations are solved using the formalism of pure spinors in terms of a finite number of holomorphic functions. Alternatively, the solutions can be viewed as vacua of maximally supersymmetric supergravity in six dimensions with a set of scalar fields varying holomorphically over ℂ. For a class of solutions characterised by up to five holomorphic functions, we outline how the local solutions can be completed to four-dimensional flux vacua of type IIB theory. A detailed study of this global completion for solutions with two holomorphic functions has been carried out in the companion paper http://arxiv.org/abs/1411.4785. The fluxes of the global solutions are, as in F-theory, entirely codified in the geometry of an auxiliary K3 fibration over ℂℙ{sup 1}. The results provide a geometric construction of fluxes in F-theory.

  3. Heights of Coronal Mass Ejections and Shocks Inferred from Metric and DH Type II Radio Bursts

    Science.gov (United States)

    Shanmugaraju, A.; Bendict Lawrance, M.; Moon, Y. J.; Lee, Jae-Ok; Suresh, K.

    2017-09-01

    A set of 27 continuous events that showed extension of metric Type-II radio bursts (m-Type IIs) into the deca-hectometric (DH) domain is considered. The coronal mass ejections (CMEs) associated with this type of continuous event supply more energy to produce space-weather effects than the CMEs that produce Type-II bursts in any one region. Since the heights of shock formation at the start of m-Type IIs were not available from observations, they were estimated using kinematic modeling in previous studies. In the present study, the heights of shock formation during metric and DH Type-II bursts are determined using two methods: i) the CME leading-edge method and ii) a method employing known electron-density models and start/end frequencies. In the first method, assuming that the shocks are generated by the associated CMEs at the leading edge, the height of the CME leading edge (LE) is calculated at the onset and end of m-Type IIs using the kinematic equation with constant acceleration or constant speed. The LE heights of CMEs that are assumed to be the heights of shock formation/end of nearly 79% of m-Type IIs are found to be within the acceptable range of 1 - 3 R_{⊙}. For other events, the heights are beyond this range, for which the shocks might either have been generated at the CME flanks/flare-blast waves, or the initial CME height might have been different. The CME/shock height at the onset and end of 17 DH Type IIs are found to be in the range of 2 - 6 R_{⊙} and within 30 R_{⊙}, respectively. In addition, the CME LE heights from observations at the onset and end of metric/DH Type IIs are compared with the heights corresponding to the observed frequency that is determined using the known electron-density models, and they are in agreement with the model results. The heights are also estimated using the space speed available for 15 halo CMEs, and it is found that the difference is smaller at the m-Type II start/end (0.02 to 0.66 R_{⊙}) and slightly greater

  4. Beta-interferon inhibits cell infection by Trypanosoma cruzi

    Science.gov (United States)

    Kierszenbaum, F.; Sonnenfeld, G.

    1984-01-01

    Beta interferon has been shown to inhibit the capacity of bloodstream forms of the flagellate Trypanosoma cruzi, the causative agent of Chagas' disease, to associate with and infect mouse peritoneal macrophages and rat heart myoblasts. The inhibitory effect was abrogated in the presence of specific antibodies to the interferon. Pretreatment of the parasites with interferon reduced their infectivity for untreated host cells, whereas pretreament of either type of host cell did not affect the interaction. The effect of interferon on the trypanosomes was reversible; the extent of the inhibitory effect was significantly reduced afer 20 min, and was undetectable after 60 min when macrophages were used as host cells. For the myoblasts, 60 min elapsed before the inhibitory effect began to subside and 120 min elapsed before it became insignificant or undetectable.

  5. An attenuated EIAV strain and its molecular clone strain differentially induce the expression of Toll-like receptors and type-I interferons in equine monocyte-derived macrophages.

    Science.gov (United States)

    Ma, Jian; Wang, Shan-Shan; Lin, Yue-Zhi; Liu, Hai-Fang; Wei, Hua-Mian; Du, Cheng; Wang, Xue-Feng; Zhou, Jian-Hua

    2013-09-27

    Activations of endosomal TLRs include TLR3, TLR7/8, and TLR9 stimulates the production of cytokines, such as type I interferons (IFNs), and therefore involves in virus-host interactions. In the present study, two equine anemia virus (EIAV) strains EIAVFDDV13 and EIAVFDDV3-8, which showed different induction on protective immunity, were compared regarding their ability to regulate the expression of endosomal TLRs, as well as type I IFNs, after infection of equine monocyte-derived macrophages (eMDMs). Our results showed that EIAVFDDV13 dramatically up-regulated the expression of TLR3 and IFNβ and less robustly up-regulated the expression of TRL9 and IFNα1, whereas EIAVFDDV3-8 induced significantly lower expression of type I IFN mRNA and protein and more strongly down-regulated the expression of TLR7 and TLR8. In addition, no significant differences in cell apoptosis were observed between these two strains. Given that the genomic variation of EIAVFDDV13 is considerably higher than that of molecular clone EIAVFDDV3-8, our results suggest that stronger TLR3 activation and increased INFβ production induced by the multi-species strain are associated with an effective vaccine-elicited protective immune response. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Contribution of double-stranded RNA and CPSF30 binding domains of influenza virus NS1 to the inhibition of type I interferon production and activation of human dendritic cells.

    Science.gov (United States)

    Ramos, Irene; Carnero, Elena; Bernal-Rubio, Dabeiba; Seibert, Christopher W; Westera, Liset; García-Sastre, Adolfo; Fernandez-Sesma, Ana

    2013-03-01

    The influenza virus nonstructural protein 1 (NS1) inhibits innate immunity by multiple mechanisms. We previously reported that NS1 is able to inhibit the production of type I interferon (IFN) and proinflammatory cytokines in human primary dendritic cells (DCs). Here, we used recombinant viruses expressing mutant NS1 from the A/Texas/36/91 and A/Puerto Rico/08/34 strains in order to analyze the contribution of different NS1 domains to its antagonist functions. We show that the polyadenylation stimulating factor 30 (CPSF30) binding function of the NS1 protein from A/Texas/36/91 influenza virus, which is absent in the A/Puerto Rico/08/34 strain, is essential for counteracting these innate immune events in DCs. However, the double-stranded RNA (dsRNA) binding domain, present in both strains, specifically inhibits the induction of type I IFN genes in infected DCs, while it is essential only for inhibition of type I IFN proteins and proinflammatory cytokine production in cells infected with influenza viruses lacking a functional CPSF30 binding domain, such as A/Puerto Rico/08/34.

  7. Intrathoracic drainage of a perforated prepyloric gastric ulcer with a type II paraoesophageal hernia

    Directory of Open Access Journals (Sweden)

    Zonneveld Bas JGL

    2008-12-01

    Full Text Available Abstract Background With an incidence of less than 5%, type II paraesophageal hernias are one of the less common types of hiatal hernias. We report a case of a perforated prepyloric gastric ulcer which, due to a type II hiatus hernia, drained into the mediastinum. Case presentation A 61-year old Caucasian man presented with acute abdominal pain. On a conventional x-ray of the chest a large mediastinal air-fluid collection and free intra-abdominal air was seen. Additional computed tomography revealed a large intra-thoracic air-fluid collection with a type II paraesophageal hernia. An emergency upper midline laparotomy was performed and a perforated pre-pyloric gastric ulcer was treated with an omental patch repair. The patient fully recovered after 10 days and continues to do well. Conclusion Type II paraesophageal hernia is an uncommon diagnosis. The main risk is gastric volvulus and possible gastric torsion. Intrathoracic perforation of gastric ulcers due to a type II hiatus hernia is extremely rare and can be a diagnostic and treatment challenge.

  8. Interferon-γ regulates the proliferation and differentiation of mesenchymal stem cells via activation of indoleamine 2,3 dioxygenase (IDO.

    Directory of Open Access Journals (Sweden)

    Juliana Croitoru-Lamoury

    Full Text Available The kynurenine pathway (KP of tryptophan metabolism is linked to antimicrobial activity and modulation of immune responses but its role in stem cell biology is unknown. We show that human and mouse mesenchymal and neural stem cells (MSCs and NSCs express the complete KP, including indoleamine 2,3 dioxygenase 1 (IDO and IDO2, that it is highly regulated by type I (IFN-β and II interferons (IFN-γ, and that its transcriptional modulation depends on the type of interferon, cell type and species. IFN-γ inhibited proliferation and altered human and mouse MSC neural, adipocytic and osteocytic differentiation via the activation of IDO. A functional KP present in MSCs, NSCs and perhaps other stem cell types offers novel therapeutic opportunities for optimisation of stem cell proliferation and differentiation.

  9. Dental pulp stem cell-derived chondrogenic cells demonstrate differential cell motility in type I and type II collagen hydrogels.

    Science.gov (United States)

    Yao, Li; Flynn, Nikol

    2018-02-13

    Advances in the development of biomaterials and stem cell therapy provide a promising approach to regenerating degenerated discs. The normal nucleus pulposus (NP) cells exhibit the similar phenotype as chondrocytes. Because dental pulp stem cells (DPSCs) can be differentiated into chondrogenic cells, the DPSCs and DPSCs-derived chondrogenic cells encapsulated in type I and type II collagen hydrogels can potentially be transplanted into degenerated nucleus pulposus (NP) to repair damaged tissue. The motility of transplanted cells is critical because the cells need to migrate away from the hydrogels containing the cells of high density and disperse into the NP tissue after implantation. The purpose of this study was to determine the motility of DPSC and DPSC-derived chondrogenic cells in type I and type II collagen hydrogels. The time lapse imaging that recorded cell migration was analyzed to quantify the cell migration velocity and distance. The cell viability of DPSCs in native or 4S-StarPEG - crosslinked type I and type II collagen hydrogels was determined using LIVE/DEAD ® cell viability assay and AlamarBlue® assay. DPSCs were differentiated into chondrogenic cells. The migration of DPSCs and DPSC-derived chondrogenic cells in these hydrogels was recorded using a time lapse imaging system. This study was funded by Regional Institute on Aging and Wichita Medical Research and Education Foundation and the authors declare no competing interest. DPSCs showed high cell viability in non-crosslinked and crosslinked collagen hydrogels. DPSCs migrated in collagen hydrogels, and the cell migration speed was not significantly different in either type I collagen or type II collagen hydrogels. The migration speed of DPSC-derived chondrogenic cells was higher in type I collagen hydrogel than in type II collagen hydrogel. Crosslinking of type I collagen with 4S-StarPEG significantly reduced the cell migration speed of DPSC-derived chondrogenic cells. After implantation of

  10. The influence of hormone therapies on type I and II endometrial cancer

    DEFF Research Database (Denmark)

    Mørch, Lina S.; Kjær, Susanne K.; Keiding, Niels

    2016-01-01

    identified from the National Cancer Registry: 4,972 Type I tumors and 500 Type II tumors. Incidence rate ratios (RRs) and 95% confidence intervals (Cls) were estimated by Poisson regression. Compared with women never on HT, the RR of endometrial cancer was increased with conjugated estrogen: 4.27 (1...

  11. Crosstalk between type II NKT cells and T cells leads to spontaneous chronic inflammatory liver disease.

    Science.gov (United States)

    Weng, Xiufang; He, Ying; Visvabharathy, Lavanya; Liao, Chia-Min; Tan, Xiaosheng; Balakumar, Arjun; Wang, Chyung-Ru

    2017-10-01

    Natural killer T (NKT) cells are CD1d-restricted innate-like T cells that modulate innate and adaptive immune responses. Unlike the well-characterized invariant/type I NKT cells, type II NKT cells with a diverse T cell receptor repertoire are poorly understood. This study defines the pathogenic role of type II NKT cells in the etiology of chronic liver inflammation. Transgenic mice with the Lck promoter directing CD1d overexpression on T cells in Jα18 wild-type (Lck-CD1dTgJα18 + ; type I NKT cell sufficient) and Jα18-deficient (Lck-CD1dTgJα18 o , type I NKT cell deficient) mice were analyzed for liver pathology and crosstalk between type II NKT cells and conventional T cells. CD1d expression on T cells in peripheral blood samples and liver sections from autoimmune hepatitis patients and healthy individuals were also examined. Lck-CD1dTgJα18 o and Lck-CD1dTgJα18 + mice developed similar degrees of liver pathology resembling chronic autoimmune hepatitis in humans. Increased CD1d expression on T cells promoted the activation of type II NKT cells and other T cells. This resulted in T h 1-skewing and impaired T h 2 cytokine production in type II NKT cells. Dysfunction of type II NKT cells was accompanied by conventional T cell activation and pro-inflammatory cytokine production, leading to a hepatic T/B lymphocyte infiltration, elevated autoantibodies and hepatic injury in Lck-CD1dTg mice. A similar mechanism could be extended to humans as CD1d expression is upregulated on activated human T cells and increased presence of CD1d-expressing T cells was observed in autoimmune hepatitis patients. Our data reveals enhanced crosstalk between type II NKT cells and conventional T cells, leading to a T h 1-skewed inflammatory milieu, and consequently, to the development of chronic autoimmune liver disease. Lay summary: CD1d overexpression on T cells enhances crosstalk between type II NKT cells and T cells, resulting in their aberrant activation and leading to the

  12. Toll-like receptor 3 stimulation promotes Ro52/TRIM21 synthesis and nuclear redistribution in salivary gland epithelial cells, partially via type I interferon pathway

    Science.gov (United States)

    Kyriakidis, N C; Kapsogeorgou, E K; Gourzi, V C; Konsta, O D; Baltatzis, G E; Tzioufas, A G

    2014-01-01

    Up-regulated expression of Ro52/tripartite motif-containing protein 21 (TRIM21), Ro60/TROVE domain family, member 2 (TROVE2) and lupus LA protein/Sjögren's syndrome antigen B (La/SSB) autoantigens has been described in the salivary gland epithelial cells (SGEC) of patients with Sjögren's syndrome (SS). SGECs, the key regulators of autoimmune SS responses, express high levels of surface functional Toll-like receptor (TLR)-3, whereas Ro52/TRIM21 negatively regulates TLR-3-mediated inflammation. Herein, we investigated the effect of TLR-3-signalling on the expression of Ro52/TRIM21, as well as Ro60/TROVE2 and La/SSB autoantigens, by SGECs. The effect of TLR-3 or TLR-4 stimulation on autoantigen expression was evaluated by polyI:C or lipopolysaccharide (LPS) treatment, respectively, of SGEC lines (10 from SS patients, 12 from non-SS controls) or HeLa cells, followed by analysis of mRNA and protein expression. PolyI:C, but not LPS, resulted in a two-step induction of Ro52/TRIM21 mRNA expression by SGECs, a 12-fold increment at 6 h followed by a 2·5-fold increment at 24–48 h, whereas it induced a late two-fold up-regulation of Ro60/TROVE2 and La/SSB mRNAs at 48 h. Although protein expression levels were not affected significantly, the late up-regulation of Ro52/TRIM21 mRNA was accompanied by protein redistribution, from nucleolar-like pattern to multiple coarse dots spanning throughout the nucleus. These late phenomena were mediated significantly by interferon (IFN)-β production, as attested by cognate secretion and specific inhibition experiments and associated with IFN regulatory factor (IRF)3 degradation. TLR-3-signalling had similar effects on SGECs obtained from SS patients and controls, whereas it did not affect the expression of these autoantigens in HeLa cells. TLR-3 signalling regulates the expression of autoantigens by SGECs, implicating innate immunity pathways in their over-expression in inflamed tissues and possibly in their exposure to the immune

  13. Signature of type-II Weyl semimetal phase in MoTe2

    Science.gov (United States)

    Jiang, J.; Liu, Z. K.; Sun, Y.; Yang, H. F.; Rajamathi, C. R.; Qi, Y. P.; Yang, L. X.; Chen, C.; Peng, H.; Hwang, C.-C.; Sun, S. Z.; Mo, S.-K.; Vobornik, I.; Fujii, J.; Parkin, S. S. P.; Felser, C.; Yan, B. H.; Chen, Y. L.

    2017-01-01

    Topological Weyl semimetal (TWS), a new state of quantum matter, has sparked enormous research interest recently. Possessing unique Weyl fermions in the bulk and Fermi arcs on the surface, TWSs offer a rare platform for realizing many exotic physical phenomena. TWSs can be classified into type-I that respect Lorentz symmetry and type-II that do not. Here, we directly visualize the electronic structure of MoTe2, a recently proposed type-II TWS. Using angle-resolved photoemission spectroscopy (ARPES), we unravel the unique surface Fermi arcs, in good agreement with our ab initio calculations that have nontrivial topological nature. Our work not only leads to new understandings of the unusual properties discovered in this family of compounds, but also allows for the further exploration of exotic properties and practical applications of type-II TWSs, as well as the interplay between superconductivity (MoTe2 was discovered to be superconducting recently) and their topological order.

  14. Na+ currents in vestibular type I and type II hair cells of the embryo and adult chicken.

    Science.gov (United States)

    Masetto, S; Bosica, M; Correia, M J; Ottersen, O P; Zucca, G; Perin, P; Valli, P

    2003-08-01

    In birds, type I and type II hair cells differentiate before birth. Here we describe that chick hair cells, from the semicircular canals, begin expressing a voltage-dependent Na current (INa) from embryonic day 14 (E14) and continue to express the current up to hatching (E21). During this period, INa was present in most (31/43) type I hair cells irrespective of their position in the crista, in most type II hair cells located far from the planum semilunatum (48/63), but only occasionally in type II hair cells close to the planum semilunatum (2/35). INa activated close to -60 mV, showed fast time- and voltage-dependent activation and inactivation, and was completely, and reversibly, blocked by submicromolar concentrations of tetrodotoxin (Kd = 17 nM). One peculiar property of INa concerns its steady-state inactivation, which is complete at -60 mV (half-inactivating voltage = -96 mV). INa was found in type I and type II hair cells from the adult chicken as well, where it had similar, although possibly not identical, properties and regional distribution. Current-clamp experiments showed that INa could contribute to the voltage response provided that the cell membrane was depolarized from holding potentials more negative than -80 mV. When recruited, INa produced a significant acceleration of the cell membrane depolarization, which occasionally elicited a large rapid depolarization followed by a rapid repolarization (action-potential-like response). Possible physiological roles for INa in the embryo and adult chicken are discussed.

  15. GREEN DIPLOMACY-A NEW TYPE OF INTERNATIONAL COOPERATION (II

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    Elena IFTIME

    2014-07-01

    Full Text Available We mention our attempt in a broader context reserved to a generous theme, of a great complexity and of a strict actuality that aims the planet’s health, of human and of other forms of living and nonliving forms of life. Particularly insisting on legal international coordinates of environmental protection and conservation, through which are being accomplished the valences of human’s right to a prosperous, healthy and ecologically balanced environment. This right occupies a central place among human rights, one of those essential gifts of nature to which no one should be detrimental to. It is considered to be a law of human solidarity consecrated by international and internal regulations, which involves in its content: the right to live in an unpolluted environment, which is not degraded by activities that can affect the environment, health, human welfare, sustainable development of society; the right to the highest medical care, unaffected by environmental degradation; right to a healthy working environment; right to benefit of durable usage of nature and its resources, the right to adequate water resources and food. This valences exercise of this right in the context of each state’s internal affairs, but especially in the life of international community, involves a new type of international cooperation suggestively called green diplomacy. It is a special form of the classical diplomacy, adapted to the specific and universality of environmental problems, particularly in the second half of the second century onwards. A diplomacy that seeks to harmonize the interests of a state and other’s interests along with the interests of every human being on the Planet, concerning the conservation and development of natural conditions of life. The major objective of this modern type of diplomacy is highlighted to empower the human beings, the micro and macro human community towards protecting, conserving and sustainable development of the Earth

  16. Lifshitz Transitions, Type-II Dirac and Weyl Fermions, Event Horizon and All That

    Science.gov (United States)

    Volovik, G. E.; Zhang, K.

    2017-12-01

    The type-II Weyl and type-II Dirac points emerge in semimetals and also in relativistic systems. In particular, the type-II Weyl fermions may emerge behind the event horizon of black holes. In this case the horizon with Painlevé-Gullstrand metric serves as the surface of the Lifshitz transition. This relativistic analogy allows us to simulate the black hole horizon and Hawking radiation using the fermionic superfluid with supercritical velocity, and the Dirac and Weyl semimetals with the interface separating the type-I and type-II states. The difference between such type of the artificial event horizon and that which arises in acoustic metric is discussed. At the Lifshitz transition between type-I and type-II fermions the Dirac lines may also emerge, which are supported by the combined action of topology and symmetry. The type-II Weyl and Dirac points also emerge as the intermediate states of the topological Lifshitz transitions. Different configurations of the Fermi surfaces, involved in such Lifshitz transition, are discussed. In one case the type-II Weyl point connects the Fermi pockets and the Lifshitz transition corresponds to the transfer of the Berry flux between the Fermi pockets. In the other case the type-II Weyl point connects the outer and inner Fermi surfaces. At the Lifshitz transition the Weyl point is released from both Fermi surfaces. They loose their Berry flux, which guarantees the global stability, and without the topological support the inner surface disappears after shrinking to a point at the second Lifshitz transition. These examples reveal the complexity and universality of topological Lifshitz transitions, which originate from the ubiquitous interplay of a variety of topological characters of the momentum-space manifolds. For the interacting electrons, the Lifshitz transitions may lead to the formation of the dispersionless (flat) band with zero energy and singular density of states, which opens the route to room

  17. Analysis of predisposing factors in elderly people with type II odontoid fracture.

    Science.gov (United States)

    Watanabe, Masahiko; Sakai, Daisuke; Yamamoto, Yukihiro; Nagai, Toshihiro; Sato, Masato; Mochida, Joji

    2014-06-01

    Type II odontoid fracture is the most frequent individual fracture in elderly people. An older person usually sustains a Type II odontoid fracture in a fall from standing or a seated height. A relationship between osteoarthritis in the upper cervical spine and Type II odontoid fracture has been reported. However, to our knowledge, few reports have investigated statistically whether disproportionate degeneration between joints influences the susceptibility to fracture. The purpose of this study was to assess predisposition to Type II odontoid fracture in the elderly. Retrospective review of elderly patients sustained Type II odontoid fracture and other axis fractures. Thirty-eight patients aged 65 years and older with axis fractures. Evaluation of computed tomography findings by focusing on osteoporosis and the disproportion in degeneration between each of the upper cervical joints (atlantooccipital, atlantoodontoid, and lateral atlantoaxial joints). Seventeen patients had a Type II odontoid fracture, and 21 patients had other axis fractures. Using the computed tomography findings, we classified osteoporosis at the dens-body junction and the severity of degenerative changes in the atlantoodontoid, atlantooccipital, and lateral atlantoaxial joints as none, mild, moderate, or severe. The proportion of patients with moderate or severe osteoporosis and degenerative changes in each joint and that of patients with disproportionate degenerative changes between joints (difference in grade of ≥2 levels between joints) were compared statistically. The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this article. Patients with osteoporosis and with disproportionate degenerative changes between the atlantoodontoid and lateral atlantoaxial joints were significantly more likely to have a Type II odontoid fracture than other axis fractures. These two factors were also assessed in multivariate logistic

  18. Structural and Molecular Properties of Insect Type II Motor Axon Terminals

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    Bettina Stocker

    2018-03-01

    Full Text Available A comparison between the axon terminals of octopaminergic efferent dorsal or ventral unpaired median neurons in either desert locusts (Schistocerca gregaria or fruit flies (Drosophila melanogaster across skeletal muscles reveals many similarities. In both species the octopaminergic axon forms beaded fibers where the boutons or varicosities form type II terminals in contrast to the neuromuscular junction (NMJ or type I terminals. These type II terminals are immunopositive for both tyramine and octopamine and, in contrast to the type I terminals, which possess clear synaptic vesicles, only contain dense core vesicles. These dense core vesicles contain octopamine as shown by immunogold methods. With respect to the cytomatrix and active zone peptides the type II terminals exhibit active zone-like accumulations of the scaffold protein Bruchpilot (BRP only sparsely in contrast to the many accumulations of BRP identifying active zones of NMJ type I terminals. In the fruit fly larva marked dynamic changes of octopaminergic fibers have been reported after short starvation which not only affects the formation of new branches (“synaptopods” but also affects the type I terminals or NMJs via octopamine-signaling (Koon et al., 2011. Our starvation experiments of Drosophila-larvae revealed a time-dependency of the formation of additional branches. Whereas after 2 h of starvation we find a decrease in “synaptopods”, the increase is significant after 6 h of starvation. In addition, we provide evidence that the release of octopamine from dendritic and/or axonal type II terminals uses a similar synaptic machinery to glutamate release from type I terminals of excitatory motor neurons. Indeed, blocking this canonical synaptic release machinery via RNAi induced downregulation of BRP in neurons with type II terminals leads to flight performance deficits similar to those observed for octopamine mutants or flies lacking this class of neurons (Brembs et al., 2007.

  19. Apparent diffusion coefficient vale of the brain in patients with Gaucher's disease type II and type III

    International Nuclear Information System (INIS)

    Abdel Razek, Ahmed Abdel Khalek; Abd El-Gaber, Nahed; Abdalla, Ahmed; Fathy, Abeer; Azab, Ahmed; Rahman, Ashraf Abdel

    2009-01-01

    The aim of this work is to assess the usefulness of apparent diffusion coefficient (ADC) value of the brain for diagnosis of patients with Gaucher's disease type II and type III. Prospective study was conducted upon 13 patients (nine boys and four girls aged 8 months-14 years: mean 6.1 years) with Gaucher's disease type II and III and for age-matched control group (n = 13). Diffusion-weighted magnetic resonance imaging using a single-shot echo-planar imaging with a diffusion-weighted factor b of 0, 500, and 1,000 s/mm 2 was done for all patients and volunteers. The ADC value was calculated in ten regions of the brain parenchyma and correlated with genotyping. There was significantly lower ADC value of the cortical frontal (P = 0.003), cortical temporal (P = 0.04), frontal subcortical white matter (P = 0.02), corticospinal tract (P = 0.001), cerebellum (P = 0.001), medulla (P = 0.002), and midbrain (P = 0.02) between patients and volunteers. There was significant difference in the ADC value of the frontal and temporal gray matter (P = 0.04 and 0.05, respectively) between patients with heterozygous and homozygous gene mutation. We concluded that ADC value is a new promising quantitative imaging parameter that can be used for the detection of brain abnormalities in patients with Gaucher's disease type II and type III and has a correlation with genotyping. (orig.)

  20. Type Ia supernova rate studies from the SDSS-II Supernova Study

    Energy Technology Data Exchange (ETDEWEB)

    Dilday, Benjamin [Univ. of Chicago, IL (United States)

    2008-08-01

    The author presents new measurements of the type Ia SN rate from the SDSS-II Supernova Survey. The SDSS-II Supernova Survey was carried out during the Fall months (Sept.-Nov.) of 2005-2007 and discovered ~ 500 spectroscopically confirmed SNe Ia with densely sampled (once every ~ 4 days), multi-color light curves. Additionally, the SDSS-II Supernova Survey has discovered several hundred SNe Ia candidates with well-measured light curves, but without spectroscopic confirmation of type. This total, achieved in 9 months of observing, represents ~ 15-20% of the total SNe Ia discovered worldwide since 1885. The author describes some technical details of the SN Survey observations and SN search algorithms that contributed to the extremely high-yield of discovered SNe and that are important as context for the SDSS-II Supernova Survey SN Ia rate measurements.

  1. Semiclassical theory of anomalous transport in type-II topological Weyl semimetals

    Science.gov (United States)

    McCormick, Timothy M.; McKay, Robert C.; Trivedi, Nandini

    2017-12-01

    Weyl semimetals possess low-energy excitations which act as monopoles of Berry curvature in momentum space. These emergent monopoles are at the heart of the many novel transport properties that Weyl semimetals exhibit. The singular nature of the Berry curvature around the nodal points in Weyl semimetals allows for the possibility of large anomalous transport coefficients in zero applied magnetic field. Recently, a new class, termed type-II Weyl semimetals, has been demonstrated in a variety of materials, where the Weyl nodes are tilted. We present here a theoretical study of anomalous transport in this new class of Weyl semimetals. We find that the parameter governing the tilt of these type-II Weyl points is intimately related to the zero-field transverse transport properties. We also find that the temperature dependence of the chemical potential plays an important role in determining how the transport coefficients can effectively probe the Berry curvature of the type-II Weyl points. In particular, we find that the transverse thermoelectric transport coefficient Lxy E T is strongly enhanced with the tilt of the type-II Weyl nodes and with increasing temperature. We also discuss the experimental implications of our work for time-reversal breaking type-II Weyl semimetals.

  2. OUTCOME OF GARTLAND TYPEII SUPRACONDYLAR FRACTURES OF HUMERUS TREATED BY CONSERVATIVE METHOD

    Directory of Open Access Journals (Sweden)

    Dinesh Mitra

    2015-08-01

    Full Text Available BACKGROUND: The current literatures recommend operative method (closed reduction and pinning for type II supracondylar fractures of humerus. But some surgeons still prefer conservative method for type II supracondylar fractures of humerus. We pr esent results of 14 cases of type II supracondylar fractures treated with CR and AE POP immobilization . The purpose of this study is to evaluate the outcome of conservative treatment in management of type II supracondylar fracture of humerus. MATERIALS AND METHODS: Fourteen children treated by conservative methods (CR & AE POP between January 2013 and December 2014 is included in this study. The mean age group is 6.8 years (3 years - 11 years. The patient follow up is done for a minimum of 10 - 12 weeks. Treatment outcome is based on final clinical and radiological assessments and grading of results was done using Flynn’s criteria. RESULTS: Gartland type II fracture gives 82% excellent results and 28 % good results as per Flynn’s criteria. Of the 14 patien ts only two cases required re manipulation. Surgical intervention was not needed for any of the patients. No patients in this study developed compartment syndrome / cubitus varus deformity. CONCLUSION: Satisfactory results can be obtained with conservative treatment (closed reduction and above elbow POP if proper selection of the patient and careful clinical and radiological follow up is done

  3. Erythrocyte Membrane Antigen Frequencies in Patients with Type II Congenital Smell Loss

    Science.gov (United States)

    Stateman, William A.; Henkin, Robert I.; Knöppel, Alexandra; Flegel, Willy A.

    2014-01-01

    OBJECTIVE The objective of this study was to determine whether there are genetic factors associated with Type II congenital smell loss. STUDY DESIGN The expression frequencies of 16 erythrocyte antigens among patients with Type II congenital smell loss were determined and compared to those of a large control group. METHODS Blood samples were obtained from 99 patients with Type II congenital smell loss. Presence of the erythrocyte surface antigens A, B, M, N, S, s, Fya, Fyb, D, C, c, E, e, K, Jka, and Jkb was analyzed by blood group serology. Comparisons of expression frequencies of these antigens were made between the patients and a large control group. RESULTS Patients tested for the Duffy b antigen (Fyb haplotype) exhibited a statistically significant 11% decrease in expression frequency compared to the controls. There were no significant differences between patients and controls in the expression frequencies for all other erythrocyte antigens (A, B, M, N, S, s, Fya, D, C, c, E, e, K, Jka, or Jkb). CONCLUSIONS These findings describe the presence of a previously unrevealed genetic tendency among patients with Type II congenital smell loss related to erythrocyte surface antigen expression. The deviation in expression rate of Duffy b suggests a target gene and chromosome region in which future research into this form of congenital smell loss may reveal a more specific genetic basis for Type II congenital smell loss. PMID:25456515

  4. In vivo metabolism of pulmonary alveolar epithelial type II pneumonocytes and macrophages from Syrian hamsters

    International Nuclear Information System (INIS)

    Pfleger, R.C.; Waide, J.J.

    1976-01-01

    Young adult Syrian hamsters were injected intraperitoneally with 14 C-glycerol and 3 H-palmitate 17 hr before they were sacrificed and pulmonary alveolar epithelial type II cells and pulmonary alveolar macrophages (PAM) were isolated. Incorporation of the two labeled components into the cellular lipids showed that the 3 H-specific activity of the phospholipids from the type II cells was three times that of the PAM and the utilization of 14 C-glycerol into phosphatidyl choline (PC) was 50% greater than incorporation into the PC from PAMs. The PC from type II cells showed that 30% was disaturated and from PAMs 21% was disaturated. Another phosphatide, phosphatidyl glycerol contained about one-third of the molecules in disaturated form. These data are consistent with the view that both type II cells and PAMs can synthesize surface-active phospholipids but it is generally accepted that only the pulmonary alveolar epithelial type II cells excrete the disaturated phospholipids which comprise the surface-active components of pulmonary surfactant

  5. Formation of a DNA Mini-Dumbbell with a Quasi-Type II Loop.

    Science.gov (United States)

    Liu, Yuan; Guo, Pei; Lam, Sik Lok

    2017-03-30

    Quasi-loops, wherein the backbone has a discontinuous site in the loop, have been found to provide structural flexibility in the formation of DNA three-way junctions. Recently, a highly compact mini-dumbbell (MDB) structure composed of two adjacent CCTG or TTTA type II loops has been reported. Yet, it remains elusive if the presence of a quasi-loop will also facilitate the formation of an MDB. In this study, the possibility of whether an MDB can be formed containing a quasi-type II loop has been investigated. We first demonstrate that two adjacent CTTG type II loops can also form an MDB, which is thermodynamically more stable than those formed by CCTG and TTTA loops. Then, we systematically introduce quasi-type II loops with their discontinuous sites at different backbone positions in the CTTG MDB. Our results show that an MDB can be formed with a quasi-type II loop, in which there is a discontinuous site between the third thymine and the fourth guanine loop residues. The possible inclusion of a quasi-loop in MDBs expands the sequence criteria for the formation of MDBs by natural DNA sequences.

  6. Silver nanowire interactions with primary human alveolar type-II epithelial cell secretions: contrasting bioreactivity with human alveolar type-I and type-II epithelial cells

    Science.gov (United States)

    Sweeney, Sinbad; Theodorou, Ioannis G.; Zambianchi, Marta; Chen, Shu; Gow, Andrew; Schwander, Stephan; Zhang, Junfeng (Jim); Chung, Kian Fan; Shaffer, Milo S. P.; Ryan, Mary P.; Porter, Alexandra E.; Tetley, Teresa D.

    2015-06-01

    Inhaled nanoparticles have a high deposition rate in the alveolar units of the deep lung. The alveolar epithelium is composed of type-I and type-II epithelial cells (ATI and ATII respectively) and is bathed in pulmonary surfactant. The effect of native human ATII cell secretions on nanoparticle toxicity is not known. We investigated the cellular uptake and toxicity of silver nanowires (AgNWs; 70 nm diameter, 1.5 μm length) with human ATI-like cells (TT1), in the absence or presence of Curosurf® (a natural porcine pulmonary surfactant with a low amount of protein) or harvested primary human ATII cell secretions (HAS; containing both the complete lipid as well as the full protein complement of human pulmonary surfactant i.e. SP-A, SP-B, SP-C and SP-D). We hypothesised that Curosurf® or HAS would confer improved protection for TT1 cells, limiting the toxicity of AgNWs. In agreement with our hypothesis, HAS reduced the inflammatory and reactive oxygen species (ROS)-generating potential of AgNWs with exposed TT1 cells. For example, IL-8 release and ROS generation was reduced by 38% and 29%, respectively, resulting in similar levels to that of the non-treated controls. However in contrast to our hypothesis, Curosurf® had no effect. We found a significant reduction in AgNW uptake by TT1 cells in the presence of HAS but not Curosurf. Furthermore, we show that the SP-A and SP-D are likely to be involved in this process as they were found to be specifically bound to the AgNWs. While ATI cells appear to be protected by HAS, evidence suggested that ATII cells, despite no uptake, were vulnerable to AgNW exposure (indicated by increased IL-8 release and ROS generation and decreased intracellular SP-A levels one day post-exposure). This study provides unique findings that may be important for the study of lung epithelial-endothelial translocation of nanoparticles in general and associated toxicity within the alveolar unit.Inhaled nanoparticles have a high deposition rate in

  7. Macrophage-to-sensory neuron crosstalk mediated by Angiotensin II type-2 receptor elicits neuropathic pain

    OpenAIRE

    Krause, Eric; Shepherd, Andrew; Mickle, Aaron; Copits, Bryan; Karlsson, Pall; Kadunganattil, Suraj; Golden, Judith; Tadinada, Satya; Mack, Madison; Haroutounian, Simon; De Kloet, Annette; Samineni, Vijay; Valtcheva, Manouela; Mcilvried, Lisa; Sheahan, Tayler

    2017-01-01

    Peripheral nerve damage initiates a complex series of cellular and structural processes that culminate in chronic neuropathic pain. Our study defines local angiotensin signaling via activation of the Angiotensin II (Ang II) type-2 receptor (AT2R) on macrophages as the critical trigger of neuropathic pain. An AT2R-selective antagonist attenuates neuropathic, but not inflammatory pain hypersensitivity in mice, and requires the cell damage-sensing ion channel transient receptor potential family-...

  8. Interferon Induced Focal Segmental Glomerulosclerosis

    Directory of Open Access Journals (Sweden)

    Yusuf Kayar

    2016-01-01

    Full Text Available Behçet’s disease is an inflammatory disease of unknown etiology which involves recurring oral and genital aphthous ulcers and ocular lesions as well as articular, vascular, and nervous system involvement. Focal segmental glomerulosclerosis (FSGS is usually seen in viral infections, immune deficiency syndrome, sickle cell anemia, and hyperfiltration and secondary to interferon therapy. Here, we present a case of FSGS identified with kidney biopsy in a patient who had been diagnosed with Behçet’s disease and received interferon-alpha treatment for uveitis and presented with acute renal failure and nephrotic syndrome associated with interferon.

  9. Endoplasmic Reticulum Stress-Associated Lipid Droplet Formation and Type II Diabetes

    OpenAIRE

    Zhang, Xuebao; Zhang, Kezhong

    2012-01-01

    Diabetes mellitus (DM), a metabolic disorder characterized by hyperglycemia, is caused by insufficient insulin production due to excessive loss of pancreatic β cells (type I diabetes) or impaired insulin signaling due to peripheral insulin resistance (type II diabetes). Pancreatic β cell is the only insulin-secreting cell type that has highly developed endoplasmic reticulum (ER) to cope with high demands of insulin synthesis and secretion. Therefore, ER homeostasis is crucial to the proper fu...

  10. Identification and characterization of the human type II collagen gene (COL2A1).

    OpenAIRE

    Cheah, Kathryn; Stoker, N.G.; Griffin, J.R.; Grosveld, Frank; Solomon, E.

    1985-01-01

    textabstractThe gene contained in the human cosmid clone CosHcol1, previously designated an alpha 1(I) collagen-like gene, has now been identified. CosHcol1 hybridizes strongly to a single 5.9-kilobase mRNA species present only in tissue in which type II collagen is expressed. DNA sequence analysis shows that this clone is highly homologous to the chicken alpha 1(II) collagen gene. These data together suggest that CosHcol1 contains the human alpha 1(II) collagen gene COL2A1. The clone appears...

  11. Ribavirin plus interferon versus interferon for chronic hepatitis C

    DEFF Research Database (Denmark)

    Brok, Jesper; Gluud, Lise Lotte; Gluud, Christian

    2010-01-01

    Hepatitis C is a major cause of liver-related morbidity and mortality. Standard therapy is ribavirin plus pegylated interferon to achieve undetectable level of virus in the blood, but the effect on clinical outcomes is controversial.......Hepatitis C is a major cause of liver-related morbidity and mortality. Standard therapy is ribavirin plus pegylated interferon to achieve undetectable level of virus in the blood, but the effect on clinical outcomes is controversial....

  12. The application and evaluation of insulin release test and quantitative parameter in diabetic type II

    International Nuclear Information System (INIS)

    Huang Chenggang; Chen Xiaoyan; Guan Xiaofeng

    2002-01-01

    Objective: To analyse the curve of Insulin Release Test (IRT) about the patients whit type II diabetes, to evaluate β-cell function and the sensitivity of body to Insulin using Insulin Release Index (IRI) and Insulin Sensitivity Index (ISI), and to probe the value for clinical therapy. Methods: 1) Have a IRT of 396 cases with type II diabetes and 17 normal bodies and acquire the IRT curve, 2) Design the count methods about IRI and ISI, IRI = Ins max/Ins FBI x Δ Ins max/T max (minute), ISI=(Ins max-Ins FBI)/(Ins 180'-Ins FBI), 3) Compare IRI Changes of before and after treatment for 12 cases with no insulin release and 9 cases with less insulin release. Results: IRT curve type (No release type 21.0%, less release type 33.3%, peak delay type 36.9%, high insulin type 6.0%, release delay type 2.8%); respective IRI, ISI compared to normal, P<0.01; IRI of before and after treatment with insulin P<0.01. Conclusions: IRT Curve combining IRI and ISI can reflect accurately β-cell function with type II diabetes and the sensitivity of body to insulin, Also it has some reference value for clinical therapy

  13. Syntheses, Crystal Structures and Thermal Behaviors of Two Supramolecular Salamo-Type Cobalt(II and Zinc(II Complexes

    Directory of Open Access Journals (Sweden)

    Gang Li

    2017-07-01

    Full Text Available This paper reports the syntheses of two new complexes, [Co(L1(H2O2] (1 and [{Zn(L2(μ-OAcZn(n-PrOH}2] (2, from asymmetric halogen-substituted Salamo-type ligands H2L1 and H3L2, respectively. Investigation of the crystal structure of complex 1 reveals that the complex includes one Co(II ion, one (L12− unit and two coordinated water molecules. Complex 1 shows slightly distorted octahedral coordination geometry, forming an infinite 2D supramolecular structure by intermolecular hydrogen bond and π–π stacking interactions. Complex 2 contains four Zn(IIions, two completely deprotonated (L23− moieties, two coordinated μ-OAc− ions and n-propanol molecules. The Zn(II ions in complex 2 display slightly distorted trigonal bipyramidal or square pyramidal geometries.

  14. Successful management of acute thromboembolic disease complicated with heparin induced thrombocytopenia type II (HIT II: a case series

    Directory of Open Access Journals (Sweden)

    Trellopoulos George

    2008-07-01

    Full Text Available Abstract Heparin-induced thrombocytopenia type II (HIT II is a rare immune-mediated complication of heparin. The diagnosis of HIT is considered in patients exposed to heparin, presenting with thrombocytopenia and thrombosis. We present two cases with massive pulmonary embolism and HIT, successfully treated with the administration of fondaparinux, an alternative anticoagulant, combined with the insertion of an inferior vena cava filter for the prevention of new thromboembolic events. The two cases supplement the available data of the use of fondaparinux in patients with HIT and pulmonary embolism, before further large studies establish its efficacy and safety in this group of patients. Moreover, the management of these patients reveals the need for future evaluation of the combined therapy of alternative anticoagulant agents with the placement of vena cava filters.

  15. Adipokines: Potential Therapeutic Targets for Vascular Dysfunction in Type II Diabetes Mellitus and Obesity

    Directory of Open Access Journals (Sweden)

    Mostafa Wanees Ahmed El husseny

    2017-01-01

    Full Text Available Adipokines are bioactive molecules that regulate several physiological functions such as energy balance, insulin sensitization, appetite regulation, inflammatory response, and vascular homeostasis. They include proinflammatory cytokines such as adipocyte fatty acid binding protein (A-FABP and anti-inflammatory cytokines such as adiponectin, as well as vasodilator and vasoconstrictor molecules. In obesity and type II diabetes mellitus (DM, insulin resistance causes impairment of the endocrine function of the perivascular adipose tissue, an imbalance in the secretion of vasoconstrictor and vasodilator molecules, and an increased production of reactive oxygen species. Recent studies have shown that targeting plasma levels of adipokines or the expression of their receptors can increase insulin sensitivity, improve vascular function, and reduce the risk of cardiovascular morbidity and mortality. Several reviews have discussed the potential of adipokines as therapeutic targets for type II DM and obesity; however, this review is the first to focus on their therapeutic potential for vascular dysfunction in type II DM and obesity.

  16. Plasma exchange in the treatment of thyroid storm secondary to type II amiodarone-induced thyrotoxicosis

    Directory of Open Access Journals (Sweden)

    Ling Zhu

    2016-07-01

    Full Text Available Type II amiodarone-induced thyrotoxicosis (AIT is an uncommon cause of thyroid storm. Due to the rarity of the condition, little is known about the role of plasma exchange in the treatment of severe AIT. A 56-year-old male presented with thyroid storm 2months following cessation of amiodarone. Despite conventional treatment, his condition deteriorated. He underwent two cycles of plasma exchange, which successfully controlled the severe hyperthyroidism. The thyroid hormone levels continued to fall up to 10h following plasma exchange. He subsequently underwent emergency total thyroidectomy and the histology of thyroid gland confirmed type II AIT. Management of thyroid storm secondary to type II AIT can be challenging as patients may not respond to conventional treatments, and thyroid storm may be more harmful in AIT patients owing to the underlying cardiac disease. If used appropriately, plasma exchange can effectively reduce circulating hormones, to allow stabilisation of patients in preparation for emergency thyroidectomy.

  17. Multiple long bone cysts revealed by MRI in trichorhinophalangeal syndrome type II predisposing to pathological fractures

    Energy Technology Data Exchange (ETDEWEB)

    Konala, Praveen; Cassar-Pullicino, Victor N. [The Robert Jones and Agnes Hunt Orthopaedic Hospital, Department of Radiology, Oswestry (United Kingdom); Kiely, Nigel [The Robert Jones and Agnes Hunt Orthopaedic Hospital, Department of Orthopaedic Surgery, Oswestry (United Kingdom); Noakes, Charlotte [Oxford University Hospital, The Oxford Genetics Laboratories, Oxford (United Kingdom); Blair, Edward [Oxford University Hospital, Department of Clinical Genetics, Oxford (United Kingdom)

    2017-07-15

    Trichorhinophalangeal syndrome type II is a rare genetic disorder with the few published case reports mainly reporting the radiographic skeletal manifestations. There are no published imaging reports of long bone cysts involving multiple bones in this condition. We report a unique case of bone cysts involving multiple long bones detected with MRI in a patient with trichorhinophalangeal syndrome type II complicated by a subsequent pathological fracture. It is possible that the bone cysts are a previously undescribed feature of this syndrome; however, the evidence is insufficient to establish a definite association. Chromosomal abnormality identified in this patient is consistent with trichorhinophalangeal