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Sample records for rig-i-like receptors rlrs

  1. Role of the RIG-I-like receptors in antiviral response

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    Agnieszka Jabłońska

    2014-01-01

    Full Text Available The innate nonspecific immunity is the first line of defense against viral infection. Toll-like receptors (TLRs and retinoic acid-inducible gene I (RIG-I-like receptors (RLRs are two main receptor families detecting viral nucleic acid. So far, three RLR family members were characterized: RIG-I, MDA5 and LGP2. RLR constitute a family of cytoplasmic helicases, which recognized intracellular single-stranded and double-stranded RNA that is introduced to cytosol during viral infection and replication. In this work we review the current knowledge about the mechanisms of viral recognition by RIG-I-like receptors and their signaling pathways for the activation of type I interferons and pro-inflammatory cytokines synthesis.

  2. RIG-I Like Receptors in Antiviral Immunity and Therapeutic Applications

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    Michael Gale Jr.

    2011-06-01

    Full Text Available The RNA helicase family of RIG-I-like receptors (RLRs is a key component of host defense mechanisms responsible for detecting viruses and triggering innate immune signaling cascades to control viral replication and dissemination. As cytoplasm-based sensors, RLRs recognize foreign RNA in the cell and activate a cascade of antiviral responses including the induction of type I interferons, inflammasome activation, and expression of proinflammatory cytokines and chemokines. This review provides a brief overview of RLR function, ligand interactions, and downstream signaling events with an expanded discussion on the therapeutic potential of targeting RLRs for immune stimulation and treatment of virus infection.

  3. Measles Virus Suppresses RIG-I-like Receptor Activation in Dendritic Cells via DC-SIGN-Mediated Inhibition of PP1 Phosphatases

    NARCIS (Netherlands)

    Mesman, Annelies W.; Zijlstra-Willems, Esther M.; Kaptein, Tanja M.; de Swart, Rik L.; Davis, Meredith E.; Ludlow, Martin; Duprex, W. Paul; Gack, Michaela U.; Gringhuis, Sonja I.; Geijtenbeek, Teunis B. H.

    2014-01-01

    Dendritic cells (DCs) are targets of measles virus (MV) and play central roles in viral dissemination. However, DCs express the RIG-I-like receptors (RLRs) RIG-I and Mda5 that sense MV and induce type I interferon (IFN) production. Given the potency of this antiviral response, RLRs are tightly

  4. Measles virus suppresses RIG-I-like receptor activation in dendritic cells via DC-SIGN-mediated inhibition of PP1 phosphatases

    NARCIS (Netherlands)

    A.W. Mesman (Annelies ); E.M. Zijlstra-Willems (Esther); T.M. Kaptein (Tanja); R.L. de Swart (Rik); M.E. Davis (Meredith); M. Ludlow (Martin); W.P. Duprex (Paul); M.U. Gack (Michaela); S.I. Gringhuis (Sonja); T.B.H. Geijtenbeek (Teunis)

    2014-01-01

    textabstractDendritic cells (DCs) are targets of measles virus (MV) and play central roles in viral dissemination. However, DCs express the RIG-I-like receptors (RLRs) RIG-I and Mda5 that sense MV and induce type I interferon (IFN) production. Given the potency of this antiviral response, RLRs are

  5. What Really Rigs Up RIG-I?

    Science.gov (United States)

    Barik, Sailen

    2016-01-01

    RIG-I (retinoic acid-inducible gene 1) is an archetypal member of the cytoplasmic DEAD-box dsRNA helicase family (RIG-I-like receptors or RLRs), the members of which play essential roles in the innate immune response of the metazoan cell. RIG-I functions as a pattern recognition receptor that detects nonself RNA as a pathogen-associated molecular pattern (PAMP). However, the exact molecular nature of the viral RNAs that act as a RIG-I ligand has remained a mystery and a matter of debate. In this article, we offer a critical review of the actual viral RNAs that act as PAMPs to activate RIG-I, as seen from the perspective of a virologist, including a recent report that the viral Leader-read-through transcript is a novel and effective RIG-I ligand. © 2016 S. Karger AG, Basel.

  6. 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 B; Jensen, Søren B; Nielsen, Christoffer

    2009-01-01

    The innate antiviral response is initiated by pattern recognition receptors, which recognize viral pathogen-associated molecular patterns. Here we show that retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) in cooperation with Toll-like receptor (TLR) 9 is required for expression of type I...... 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...

  7. De Novo Transcriptome Analysis Shows That SAV-3 Infection Upregulates Pattern Recognition Receptors of the Endosomal Toll-Like and RIG-I-Like Receptor Signaling Pathways in Macrophage/Dendritic Like TO-Cells

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    Cheng Xu

    2016-04-01

    Full Text Available A fundamental step in cellular defense mechanisms is the recognition of “danger signals” made of conserved pathogen associated molecular patterns (PAMPs expressed by invading pathogens, by host cell germ line coded pattern recognition receptors (PRRs. In this study, we used RNA-seq and the Kyoto encyclopedia of genes and genomes (KEGG to identify PRRs together with the network pathway of differentially expressed genes (DEGs that recognize salmonid alphavirus subtype 3 (SAV-3 infection in macrophage/dendritic like TO-cells derived from Atlantic salmon (Salmo salar L headkidney leukocytes. Our findings show that recognition of SAV-3 in TO-cells was restricted to endosomal Toll-like receptors (TLRs 3 and 8 together with RIG-I-like receptors (RLRs and not the nucleotide-binding oligomerization domain-like receptors NOD-like receptor (NLRs genes. Among the RLRs, upregulated genes included the retinoic acid inducible gene I (RIG-I, melanoma differentiation association 5 (MDA5 and laboratory of genetics and physiology 2 (LGP2. The study points to possible involvement of the tripartite motif containing 25 (TRIM25 and mitochondrial antiviral signaling protein (MAVS in modulating RIG-I signaling being the first report that links these genes to the RLR pathway in SAV-3 infection in TO-cells. Downstream signaling suggests that both the TLR and RLR pathways use interferon (IFN regulatory factors (IRFs 3 and 7 to produce IFN-a2. The validity of RNA-seq data generated in this study was confirmed by quantitative real time qRT-PCR showing that genes up- or downregulated by RNA-seq were also up- or downregulated by RT-PCR. Overall, this study shows that de novo transcriptome assembly identify key receptors of the TLR and RLR sensors engaged in host pathogen interaction at cellular level. We envisage that data presented here can open a road map for future intervention strategies in SAV infection of salmon.

  8. UBXN1 Interferes with Rig-I-like Receptor-Mediated Antiviral Immune Response by Targeting MAVS

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    Penghua Wang

    2013-04-01

    Full Text Available RNA viruses are sensed by RIG-I-like receptors (RLRs, which signal through a mitochondria-associated adaptor molecule, MAVS, resulting in systemic antiviral immune responses. Although RLR signaling is essential for limiting RNA virus replication, it must be stringently controlled to prevent damage from inflammation. We demonstrate here that among all tested UBX-domain-containing protein family members, UBXN1 exhibits the strongest inhibitory effect on RNA-virus-induced type I interferon response. UBXN1 potently inhibits RLR- and MAVS-induced, but not TLR3-, TLR4-, or DNA-virus-induced innate immune responses. Depletion of UBXN1 enhances virus-induced innate immune responses, including those resulting from RNA viruses such as vesicular stomatitis, Sendai, West Nile, and dengue virus infection, repressing viral replication. Following viral infection, UBXN1 is induced, binds to MAVS, interferes with intracellular MAVS oligomerization, and disrupts the MAVS/TRAF3/TRAF6 signalosome. These findings underscore a critical role of UBXN1 in the modulation of a major antiviral signaling pathway.

  9. Duck RIG-I CARD Domain Induces the Chicken IFN-β by Activating NF-κB

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    Yang Chen

    2015-01-01

    Full Text Available Retinoic acid-inducible gene I- (RIG-I- like receptors (RLRs have recently been identified as cytoplasmic sensors for viral RNA. RIG-I, a member of RLRs family, plays an important role in innate immunity. Although previous investigations have proved that RIG-I is absent in chickens, it remains largely unknown whether the chicken can respond to RIG-I ligand. In this study, the eukaryotic expression vectors encoding duRIG-I full length (duck RIG-I, containing all domains, duRIG-I N-terminal (containing the two caspase activation and recruitment domain, CARDs, and duRIG-I C-terminal (containing helicase and regulatory domains labeled with 6*His tags were constructed successfully and detected by western blotting. Luciferase reporter assay and enzyme-linked immunosorbent assay (ELISA detected the duRIG-I significantly activated NF-κB and induced the expression of IFN-β when polyinosinic-polycytidylic acid (poly[I:C], synthetic double-stranded RNA challenges chicken embryonic fibroblasts cells (DF1 cells, while the duRIG-I was inactive in the absence of poly[I:C]. Further analysis revealed that the CARDs (duRIG-I-N induced IFN-β production regardless of the presence of poly[I:C], while the CARD-lacking duRIG-I (duRIG-I-C was not capable of activating downstream signals. These results indicate that duRIG-I CARD domain plays an important role in the induction of IFN-β and provide a basis for further studying the function of RIG-I in avian innate immunity.

  10. RIG-I-Like Receptor Signaling in Singleton-Merten Syndrome

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    Changming Lu

    2017-09-01

    Full Text Available Singleton-Merten syndrome (SMS is an autosomal dominant, multi-system innate immune disorder characterized by early and severe aortic and valvular calcification, dental and skeletal abnormalities, psoriasis, glaucoma, and other varying clinical findings. Recently we identified a specific gain-of-function mutation in IFIH1, interferon induced with helicase C domain 1, segregated with this disease. SMS disease without hallmark dental anomalies, termed atypical SMS, has recently been reported caused by variants in DDX58, DEXD/H-box helicase 58. IFIH1 and DDX58 encode retinoic acid-inducible gene I (RIG-I-like receptors family members melanoma differentiation-associated gene 5 and RIG-I, respectively. These cytosolic pattern recognition receptors function in viral RNA detection initiating an innate immune response through independent pathways that promote type I and type III interferon expression and proinflammatory cytokines. In this review, we focus on SMS as an innate immune disorder summarizing clinical features, molecular aspects of the pathogenetic pathway and discussing underlying mechanisms of the disease.

  11. The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I

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    Chunyuan Zhao

    2017-11-01

    Full Text Available Retinoic acid-inducible gene-I (RIG-I-like receptors (RLRs, including melanoma differentiation-associated gene 5 (MDA5 and RIG-I, are crucial for host recognition of non-self RNAs, especially viral RNA. Thus, the expression and activation of RLRs play fundamental roles in eliminating the invading RNA viruses and maintaining immune homeostasis. However, how RLR expression is tightly regulated remains to be further investigated. In this study, we identified a major histocompatibility complex (MHC-encoded gene, tripartite interaction motif 40 (TRIM40, as a suppressor of RLR signaling by directly targeting MDA5 and RIG-I. TRIM40 binds to MDA5 and RIG-I and promotes their K27- and K48-linked polyubiquitination via its E3 ligase activity, leading to their proteasomal degradation. TRIM40 deficiency enhances RLR-triggered signaling. Consequently, TRIM40 deficiency greatly enhances antiviral immune responses and decreases viral replication in vivo. Thus, we demonstrate that TRIM40 limits RLR-triggered innate activation, suggesting TRIM40 as a potential therapeutic target for the control of viral infection.

  12. Expression and Functional Characterization of the RIG-I-Like Receptors MDA5 and LGP2 in Rainbow Trout (Oncorhynchus mykiss) ▿ †

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    Chang, Mingxian; Collet, Bertrand; Nie, Pin; Lester, Katherine; Campbell, Scott; Secombes, Christopher J.; Zou, Jun

    2011-01-01

    The retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) comprise three homologues: RIG-I, melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). They activate the host interferon (IFN) system upon recognition of viral RNA pathogen-associated molecular patterns (PAMPs) in the cytoplasm. Bioinformatic analysis of the sequenced vertebrate genomes suggests that the cytosolic surveillance system is conserved in lower vertebrates, and recent functional studies have confirmed that RIG-I is important to fish antiviral immunity. In this study, we have identified MDA5 and LGP2 homologues from rainbow trout Oncorhynchus mykiss and an additional LGP2 variant with an incomplete C-terminal domain of RIG-I. Trout MDA5 and LGP2 were constitutively produced in fibroblast and macrophage cell lines and upregulated by poly(I:C), recombinant IFN, or infection by RNA viruses (viral hemorrhagic septicemia virus and salmon alphavirus) with a single-stranded positive or negative genome. Overexpression of MDA5 and LGP2 but not of the LGP2 variant resulted in significant accumulation of Mx transcripts in cultured cells, which correlated with a marked enhancement of protection against viral infection. These results demonstrate that both MDA5 and LGP2 are important RLRs in host surveillance against infection of both negative and positive viruses and that the LGP2 variant with a deletion of 54 amino acids at the C terminus acts as a negative regulator for LGP2-elicited antiviral signaling by competing for the viral RNA PAMPs. Interestingly, MDA5 expression was not affected by overexpressed LGP2 in transfected cells and vice versa, suggesting that they likely act in parallel as positive regulators for IFN production. PMID:21680521

  13. RIG-I antiviral signaling drives interleukin-23 production and psoriasis-like skin disease.

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    Zhu, Huiyuan; Lou, Fangzhou; Yin, Qianqian; Gao, Yuanyuan; Sun, Yang; Bai, Jing; Xu, Zhenyao; Liu, Zhaoyuan; Cai, Wei; Ke, Fang; Zhang, Lingyun; Zhou, Hong; Wang, Hong; Wang, Gang; Chen, Xiang; Zhang, Hongxin; Wang, Zhugang; Ginhoux, Florent; Lu, Chuanjian; Su, Bing; Wang, Honglin

    2017-05-01

    Retinoic acid inducible-gene I (RIG-I) functions as one of the major sensors of RNA viruses. DDX58 , which encodes the RIG-I protein, has been newly identified as a susceptibility gene in psoriasis. Here, we show that the activation of RIG-I by 5'ppp-dsRNA, its synthetic ligand, directly causes the production of IL-23 and triggers psoriasis-like skin disease in mice. Repeated injections of IL-23 to the ears failed to induce IL-23 production and a full psoriasis-like skin phenotype, in either germ-free or RIG-I-deficient mice. RIG-I is also critical for a full development of skin inflammation in imiquimod (IMQ)-induced psoriasis-like mouse model. Furthermore, RIG-I-mediated endogenous IL-23 production was mainly confined to the CD11c + dendritic cells (DCs) via nuclear factor-kappa B (NF-κB) signaling, and stimulated RIG-I expression in an auto-regulatory feedback loop. Thus, our data suggest that the dysregulation in the antiviral immune responses of hosts through the innate pattern recognition receptors may trigger the skin inflammatory conditions in the pathophysiology of psoriasis. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

  14. RIG-I-like receptor-induced IRF3 mediated pathway of apoptosis (RIPA: a new antiviral pathway

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    Saurabh Chattopadhyay

    2016-11-01

    Full Text Available Abstract The innate immune response is the first line of host defense to eliminate viral infection. Pattern recognition receptors in the cytosol, such as RIG-I-like receptors (RLR and Nod-like receptors (NLR, and membrane bound Toll like receptors (TLR detect viral infection and initiate transcription of a cohort of antiviral genes, including interferon (IFN and interferon stimulated genes (ISGs, which ultimately block viral replication. Another mechanism to reduce viral spread is through RIPA, the RLR-induced IRF3-mediated pathway of apoptosis, which causes infected cells to undergo premature death. The transcription factor IRF3 can mediate cellular antiviral responses by both inducing antiviral genes and triggering apoptosis through the activation of RIPA. The mechanism of IRF3 activation in RIPA is distinct from that of transcriptional activation; it requires linear polyubiquitination of specific lysine residues of IRF3. Using RIPA-active, but transcriptionally inactive, IRF3 mutants, it was shown that RIPA can prevent viral replication and pathogenesis in mice.

  15. Functional effects of Toll-like receptor (TLR3, 7, 9, RIG-I and MDA-5 stimulation in nasal epithelial cells.

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    Lotta Tengroth

    Full Text Available The human nasal epithelium is an important physical barrier, and a part of the innate immune defense that protect against pathogens. The epithelial cells recognize microbial components by pattern-recognition receptors (PRRs, and thereby trigger an immune response. Even though TLR3, TLR7, TLR9, RIG-I and MDA-5 are all known to respond to viral stimulation, their potential role in chronic airway inflammation triggered by local cytokine release remains to be established.mRNA and corresponding protein expression of TLR3, TLR7, TLR9, RIG-I and MDA-5 were analyzed in nasal biopsies and various upper airway epithelial cell lines using real-time reverse transcription PCR, immunohistochemistry and flow cytometry. Ligand induced, cytokine release, was evaluated with ELISA.Nasal biopsies were found to express TLR3, TLR7, TLR9, RIG-I and MDA-5, with the most abundant expression in the surface epithelium. These receptors were verified in primary human nasal epithelial cell (HNEC as well as in the airway epithelial cell lines Detroit-562 and FaDu. Poly(I:C (TLR3 and R-837 (TLR7 stimulation increased secretion of IL-6 and GM-CSF from the nasal mucosa and the epithelial cell lines. CpG (TLR9 stimulation caused release of IL-8 in the nasal mucosa and in FaDu. Poly(I:C/LyoVec (RIG-I/MDA-5 stimulation activated the secretion of IFN-β in the nasal mucosa. A corresponding release was also detected from HNEC and Detroit-562.The nasal epithelium has the ability to recognize viral intrusion through TLR and RLR receptors, and the subsequent response might have a role in exacerbation of inflammatory diseases like allergic rhinitis and chronic rhinosinusitis.

  16. Enterovirus 2Apro targets MDA5 and MAVS in infected cells

    NARCIS (Netherlands)

    Feng, Q.; Langereis, M.A.; Lork, M.; Nguyen, M.H.; Hato, S.V.; Lanke, K.H.W.; Emdad, L.; Bhoopathi, P.; Fisher, P.B.; Lloyd, R.E.; Kuppeveld, F.J.M. van

    2014-01-01

    RIG-I-like receptors (RLRs) MDA5 and RIG-I are key players in the innate antiviral response. Upon recognition of viral RNA, they interact with MAVS, eventually inducing type I interferon production. The interferon induction pathway is commonly targeted by viruses. How enteroviruses suppress

  17. Enterovirus 2Apro targets MDA5 and MAVS in infected cells

    NARCIS (Netherlands)

    Feng, Qian; Langereis, Martijn A; Lork, Marie; Nguyen, Mai; Hato, Stanleyson V; Lanke, Kjerstin; Emdad, Luni; Bhoopathi, Praveen; Fisher, Paul B; Lloyd, Richard E; van Kuppeveld, Frank J M

    2014-01-01

    UNLABELLED: RIG-I-like receptors (RLRs) MDA5 and RIG-I are key players in the innate antiviral response. Upon recognition of viral RNA, they interact with MAVS, eventually inducing type I interferon production. The interferon induction pathway is commonly targeted by viruses. How enteroviruses

  18. RIG-I self-oligomerization is either dispensable or very transient for signal transduction.

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    Jade Louber

    Full Text Available Effective host defence against viruses depends on the rapid triggering of innate immunity through the induction of a type I interferon (IFN response. To this end, microbe-associated molecular patterns are detected by dedicated receptors. Among them, the RIG-I-like receptors RIG-I and MDA5 activate IFN gene expression upon sensing viral RNA in the cytoplasm. While MDA5 forms long filaments in vitro upon activation, RIG-I is believed to oligomerize after RNA binding in order to transduce a signal. Here, we show that in vitro binding of synthetic RNA mimicking that of Mononegavirales (Ebola, rabies and measles viruses leader sequences to purified RIG-I does not induce RIG-I oligomerization. Furthermore, in cells devoid of endogenous functional RIG-I-like receptors, after activation of exogenous Flag-RIG-I by a 62-mer-5'ppp-dsRNA or by polyinosinic:polycytidylic acid, a dsRNA analogue, or by measles virus infection, anti-Flag immunoprecipitation and specific elution with Flag peptide indicated a monomeric form of RIG-I. Accordingly, when using the Gaussia Luciferase-Based Protein Complementation Assay (PCA, a more sensitive in cellula assay, no RIG-I oligomerization could be detected upon RNA stimulation. Altogether our data indicate that the need for self-oligomerization of RIG-I for signal transduction is either dispensable or very transient.

  19. Grass Carp Laboratory of Genetics and Physiology 2 Serves As a Negative Regulator in Retinoic Acid-Inducible Gene I- and Melanoma Differentiation-Associated Gene 5-Mediated Antiviral Signaling in Resting State and Early Stage of Grass Carp Reovirus Infection

    OpenAIRE

    Rao, Youliang; Wan, Quanyuan; Yang, Chunrong; Su, Jianguo

    2017-01-01

    Laboratory of genetics and physiology 2 (LGP2) is a key component of RIG-I-like receptors (RLRs). However, the lack of the caspase recruitment domains (CARDs) results in its controversial functional performance as a negative or positive regulator in antiviral responses. Especially, no sufficient evidence uncovers the functional mechanisms of LGP2 in RLR signaling pathways in teleost. Here, negative regulation mechanism of LGP2 in certain situations in retinoic acid-inducible gene I (RIG-I) an...

  20. Apoptosis, Toll-like, RIG-I-like and NOD-like Receptors Are Pathways Jointly Induced by Diverse Respiratory Bacterial and Viral Pathogens

    Science.gov (United States)

    Martínez, Isidoro; Oliveros, Juan C.; Cuesta, Isabel; de la Barrera, Jorge; Ausina, Vicente; Casals, Cristina; de Lorenzo, Alba; García, Ernesto; García-Fojeda, Belén; Garmendia, Junkal; González-Nicolau, Mar; Lacoma, Alicia; Menéndez, Margarita; Moranta, David; Nieto, Amelia; Ortín, Juan; Pérez-González, Alicia; Prat, Cristina; Ramos-Sevillano, Elisa; Regueiro, Verónica; Rodriguez-Frandsen, Ariel; Solís, Dolores; Yuste, José; Bengoechea, José A.; Melero, José A.

    2017-01-01

    Lower respiratory tract infections are among the top five leading causes of human death. Fighting these infections is therefore a world health priority. Searching for induced alterations in host gene expression shared by several relevant respiratory pathogens represents an alternative to identify new targets for wide-range host-oriented therapeutics. With this aim, alveolar macrophages were independently infected with three unrelated bacterial (Streptococcus pneumoniae, Klebsiella pneumoniae, and Staphylococcus aureus) and two dissimilar viral (respiratory syncytial virus and influenza A virus) respiratory pathogens, all of them highly relevant for human health. Cells were also activated with bacterial lipopolysaccharide (LPS) as a prototypical pathogen-associated molecular pattern. Patterns of differentially expressed cellular genes shared by the indicated pathogens were searched by microarray analysis. Most of the commonly up-regulated host genes were related to the innate immune response and/or apoptosis, with Toll-like, RIG-I-like and NOD-like receptors among the top 10 signaling pathways with over-expressed genes. These results identify new potential broad-spectrum targets to fight the important human infections caused by the bacteria and viruses studied here. PMID:28298903

  1. Pathogen recognition in the innate immune response.

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    Kumar, Himanshu; Kawai, Taro; Akira, Shizuo

    2009-04-28

    Immunity against microbial pathogens primarily depends on the recognition of pathogen components by innate receptors expressed on immune and non-immune cells. Innate receptors are evolutionarily conserved germ-line-encoded proteins and include TLRs (Toll-like receptors), RLRs [RIG-I (retinoic acid-inducible gene-I)-like receptors] and NLRs (Nod-like receptors). These receptors recognize pathogens or pathogen-derived products in different cellular compartments, such as the plasma membrane, the endosomes or the cytoplasm, and induce the expression of cytokines, chemokines and co-stimulatory molecules to eliminate pathogens and instruct pathogen-specific adaptive immune responses. In the present review, we will discuss the recent progress in the study of pathogen recognition by TLRs, RLRs and NLRs and their signalling pathways.

  2. Endothelial RIG-I activation impairs endothelial function

    International Nuclear Information System (INIS)

    Asdonk, Tobias; Motz, Inga; Werner, Nikos; Coch, Christoph; Barchet, Winfried; Hartmann, Gunther; Nickenig, Georg; Zimmer, Sebastian

    2012-01-01

    Highlights: ► RIG-I activation impairs endothelial function in vivo. ► RIG-I activation alters HCAEC biology in vitro. ► EPC function is affected by RIG-I stimulation in vitro. -- Abstract: Background: Endothelial dysfunction is a crucial part of the chronic inflammatory atherosclerotic process and is mediated by innate and acquired immune mechanisms. Recent studies suggest that pattern recognition receptors (PRR) specialized in immunorecognition of nucleic acids may play an important role in endothelial biology in a proatherogenic manner. Here, we analyzed the impact of endothelial retinoic acid inducible gene I (RIG-I) activation upon vascular endothelial biology. Methods and results: Wild type mice were injected intravenously with 32.5 μg of the RIG-ligand 3pRNA (RNA with triphosphate at the 5′end) or polyA control every other day for 7 days. In 3pRNA-treated mice, endothelium-depended vasodilation was significantly impaired, vascular oxidative stress significantly increased and circulating endothelial microparticle (EMP) numbers significantly elevated compared to controls. To gain further insight in RIG-I dependent endothelial biology, cultured human coronary endothelial cells (HCAEC) and endothelial progenitor cells (EPC) were stimulated in vitro with 3pRNA. Both cells types express RIG-I and react with receptor upregulation upon stimulation. Reactive oxygen species (ROS) formation is enhanced in both cell types, whereas apoptosis and proliferation is not significantly affected in HCAEC. Importantly, HCAEC release significant amounts of proinflammatory cytokines in response to RIG-I stimulation. Conclusion: This study shows that activation of the cytoplasmatic nucleic acid receptor RIG-I leads to endothelial dysfunction. RIG-I induced endothelial damage could therefore be an important pathway in atherogenesis.

  3. Structural basis for m7G recognition and 2'-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I

    Energy Technology Data Exchange (ETDEWEB)

    Devarkar, Swapnil C.; Wang, Chen; Miller, Matthew T.; Ramanathan, Anand; Jiang, Fuguo; Khan, Abdul G.; Patel, Smita S.; Marcotrigiano, Joseph

    2016-01-05

    The cytosolic innate immune receptor Retinoic Acid Inducible Gene-I (RIG-I) is the principal detector of pathogenic RNAs carrying a 5'-triphosphate (5'ppp). Self RNAs like mRNAs evade recognition by RIG-I due to posttranscriptional modifications like 5'-end capping with 7-methyl guanosine (m7G) and 2'-O-methylation of 5'-end nucleotides. Viruses have also evolved mechanisms to mimic these modifications, which in part is believed to aid in immune evasion. Currently, it is unclear how these modifications modulate RIG-I recognition. This paper provides structural and mechanistic insights into the roles of the m7G cap and 2'-O-methylation in RIG-I evasion. We show that RIG-I accommodates the m7G base while maintaining the 5'ppp contacts and can recognize Cap-0 RNAs but not Cap-1.

  4. MAVS is not a Likely Susceptibility Locus for Addison's Disease and Type 1 Diabetes.

    Science.gov (United States)

    Zurawek, Magdalena; Fichna, Marta; Kazimierska, Marta; Fichna, Piotr; Dzikiewicz-Krawczyk, Agnieszka; Przybylski, Grzegorz; Ruchala, Marek; Nowak, Jerzy

    2017-06-01

    Mitochondrial antiviral signaling (MAVS) protein is an intracellular adaptor molecule, downstream of viral sensors, retinoid acid-inducible gene I (RIG-I)-like receptors (RLRs). Impaired antiviral cell signaling might contribute to autoimmunity. Studies have recently shown variations in genes encoding RLRs as risk factors for autoimmune diseases. We investigated whether MAVS coding polymorphisms are associated with Addison's disease (AD) and type 1 diabetes (T1D) in Polish population. We genotyped 140 AD, 532 T1D patients and 600 healthy controls for MAVS rs17857295, rs7262903, rs45437096 and rs7269320. Genotyping was performed by TaqMan assays. Distribution of the MAVS genotypes and alleles did not reveal significant differences between patients and controls (p > 0.05). This analysis did not indicate the association of the MAVS locus with susceptibility to AD and T1D.

  5. Endothelial RIG-I activation impairs endothelial function

    Energy Technology Data Exchange (ETDEWEB)

    Asdonk, Tobias, E-mail: tobias.asdonk@ukb.uni-bonn.de [Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Motz, Inga; Werner, Nikos [Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Coch, Christoph; Barchet, Winfried; Hartmann, Gunther [Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Nickenig, Georg; Zimmer, Sebastian [Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany)

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer RIG-I activation impairs endothelial function in vivo. Black-Right-Pointing-Pointer RIG-I activation alters HCAEC biology in vitro. Black-Right-Pointing-Pointer EPC function is affected by RIG-I stimulation in vitro. -- Abstract: Background: Endothelial dysfunction is a crucial part of the chronic inflammatory atherosclerotic process and is mediated by innate and acquired immune mechanisms. Recent studies suggest that pattern recognition receptors (PRR) specialized in immunorecognition of nucleic acids may play an important role in endothelial biology in a proatherogenic manner. Here, we analyzed the impact of endothelial retinoic acid inducible gene I (RIG-I) activation upon vascular endothelial biology. Methods and results: Wild type mice were injected intravenously with 32.5 {mu}g of the RIG-ligand 3pRNA (RNA with triphosphate at the 5 Prime end) or polyA control every other day for 7 days. In 3pRNA-treated mice, endothelium-depended vasodilation was significantly impaired, vascular oxidative stress significantly increased and circulating endothelial microparticle (EMP) numbers significantly elevated compared to controls. To gain further insight in RIG-I dependent endothelial biology, cultured human coronary endothelial cells (HCAEC) and endothelial progenitor cells (EPC) were stimulated in vitro with 3pRNA. Both cells types express RIG-I and react with receptor upregulation upon stimulation. Reactive oxygen species (ROS) formation is enhanced in both cell types, whereas apoptosis and proliferation is not significantly affected in HCAEC. Importantly, HCAEC release significant amounts of proinflammatory cytokines in response to RIG-I stimulation. Conclusion: This study shows that activation of the cytoplasmatic nucleic acid receptor RIG-I leads to endothelial dysfunction. RIG-I induced endothelial damage could therefore be an important pathway in atherogenesis.

  6. Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in vitro.

    Science.gov (United States)

    Yoshino, Hironori; Iwabuchi, Miyu; Kazama, Yuka; Furukawa, Maho; Kashiwakura, Ikuo

    2018-04-01

    Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are pattern-recognition receptors that recognize pathogen-associated molecular patterns and induce antiviral immune responses. Recent studies have demonstrated that RLR activation induces antitumor immunity and cytotoxicity against different types of cancer, including lung cancer. However a previous report has demonstrated that ionizing radiation exerts a limited effect on RLR in human monocytic cell-derived macrophages, suggesting that RLR agonists may be used as effective immunostimulants during radiation therapy. However, it is unclear whether ionizing radiation affects the cytotoxicity of RLR agonists against cancer cells. Therefore, in the present study the effects of cotreatment with ionizing radiation and RLR agonists on cytotoxicity against human non-small cell lung cancer cells A549 and H1299 was investigated. Treatment with RLR agonist poly(I:C)/LyoVec™ [poly(I:C)] exerted cytotoxic effects against human non-small cell lung cancer. The cytotoxic effects of poly(I:C) were enhanced by cotreatment with ionizing radiation, and poly(I:C) pretreatment resulted in the radiosensitization of non-small cell lung cancer. Furthermore, cotreatment of A549 and H1299 cells with poly(I:C) and ionizing radiation effectively induced apoptosis in a caspase-dependent manner compared with treatment with poly(I:C) or ionizing radiation alone. These results indicate that RLR agonists and ionizing radiation cotreatment effectively exert cytotoxic effects against human non-small cell lung cancer through caspase-mediated apoptosis.

  7. Negative regulation of RIG-I-mediated antiviral signaling by TRK-fused gene (TFG) protein

    International Nuclear Information System (INIS)

    Lee, Na-Rae; Shin, Han-Bo; Kim, Hye-In; Choi, Myung-Soo; Inn, Kyung-Soo

    2013-01-01

    Highlights: •TRK-fused gene product (TFG) interacts with TRIM25 upon viral infection. •TFG negatively regulates RIG-I mediated antiviral signaling. •TFG depletion leads to enhanced viral replication. •TFG act downstream of MAVS. -- Abstract: RIG-I (retinoic acid inducible gene I)-mediated antiviral signaling serves as the first line of defense against viral infection. Upon detection of viral RNA, RIG-I undergoes TRIM25 (tripartite motif protein 25)-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that TRK-fused gene (TFG) protein, previously identified as a TRIM25-interacting protein, binds TRIM25 upon virus infection and negatively regulates RIG-I-mediated type-I IFN signaling. RIG-I-mediated IFN production and nuclear factor (NF)-κB signaling pathways were upregulated by the suppression of TFG expression. Furthermore, vesicular stomatitis virus (VSV) replication was significantly inhibited by small inhibitory hairpin RNA (shRNA)-mediated knockdown of TFG, supporting the suppressive role of TFG in RIG-I-mediated antiviral signaling. Interestingly, suppression of TFG expression increased not only RIG-I-mediated signaling but also MAVS (mitochondrial antiviral signaling protein)-induced signaling, suggesting that TFG plays a pivotal role in negative regulation of RNA-sensing, RIG-I-like receptor (RLR) family signaling pathways

  8. Viral Pseudo Enzymes Activate RIG-I via Deamidation to Evade Cytokine Production

    Science.gov (United States)

    He, Shanping; Zhao, Jun; Song, Shanshan; He, Xiaojing; Minassian, Arlet; Zhou, Yu; Zhang, Junjie; Brulois, Kevin; Wang, Yuqi; Cabo, Jackson; Zandi, Ebrahim; Liang, Chengyu; Jung, Jae U; Zhang, Xuewu; Feng, Pinghui

    2015-01-01

    SUMMARY RIG-I is a pattern recognition receptor that senses viral RNA and is crucial for host innate immune defense. Here we describe a mechanism of RIG-I activation through amidotransferase-mediated deamidation. We show that viral homologues of phosphoribosylformyglycinamide synthase (PFAS), although lacking intrinsic enzyme activity, recruit cellular PFAS to deamidate and activate RIG-I. Accordingly, depletion and biochemical inhibition of PFAS impair RIG-I deamidation and concomitant activation. Purified PFAS and viral homologue thereof deamidate RIG-I in vitro. Ultimately, herpesvirus hijacks activated RIG-I to avoid antiviral cytokine production; loss of RIG-I or inhibition of RIG-I deamidation results in elevated cytokine production. Together, these findings demonstrate a surprising mechanism of RIG-I activation that is mediated by an enzyme. PMID:25752576

  9. The cellular receptors of exogenous RNA

    Directory of Open Access Journals (Sweden)

    Patryk Reniewicz

    2016-04-01

    Full Text Available One of the key determinants of survival for organisms is proper recognition of exogenous and endogenous nucleic acids. Therefore, high eukaryotes developed a number of receptors that allow for discrimination between friend or foe DNA and RNA. Appearance of exogenous RNA in cytoplasm provides a signal of danger and triggers cellular responses that facilitate eradication of a pathogen. Recognition of exogenous RNA is additionally complicated by fact that large amount of endogenous RNA is present in cytoplasm Thus, number of different receptors, found in eukaryotic cells, is able to recognize that nucleic acid. First group of those receptors consist endosomal Toll like receptors, namely TLR3, TLR7, TLR8 and TLR13. Those receptors recognize RNA released from pathogens that enter the cell by endocytosis. The second group includes cytoplasmic sensors like PKR and the family of RLRs comprised of RIG-I, MDA5 and LGP2. Cytoplasmic receptors recognize RNA from pathogens invading the cell by non-endocytic pathway. In both cases binding of RNA by its receptors results in activation of the signalling cascades that lead to the production of interferon and other cytokines.

  10. Targeting the cytosolic innate immune receptors RIG-I and MDA5 effectively counteracts cancer cell heterogeneity in glioblastoma.

    Science.gov (United States)

    Glas, Martin; Coch, Christoph; Trageser, Daniel; Dassler, Juliane; Simon, Matthias; Koch, Philipp; Mertens, Jerome; Quandel, Tamara; Gorris, Raphaela; Reinartz, Roman; Wieland, Anja; Von Lehe, Marec; Pusch, Annette; Roy, Kristin; Schlee, Martin; Neumann, Harald; Fimmers, Rolf; Herrlinger, Ulrich; Brüstle, Oliver; Hartmann, Gunther; Besch, Robert; Scheffler, Björn

    2013-06-01

    Cellular heterogeneity, for example, the intratumoral coexistence of cancer cells with and without stem cell characteristics, represents a potential root of therapeutic resistance and a significant challenge for modern drug development in glioblastoma (GBM). We propose here that activation of the innate immune system by stimulation of innate immune receptors involved in antiviral and antitumor responses can similarly target different malignant populations of glioma cells. We used short-term expanded patient-specific primary human GBM cells to study the stimulation of the cytosolic nucleic acid receptors melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). Specifically, we analyzed cells from the tumor core versus "residual GBM cells" derived from the tumor resection margin as well as stem cell-enriched primary cultures versus specimens without stem cell properties. A portfolio of human, nontumor neural cells was used as a control for these studies. The expression of RIG-I and MDA5 could be induced in all of these cells. Receptor stimulation with their respective ligands, p(I:C) and 3pRNA, led to in vitro evidence for an effective activation of the innate immune system. Most intriguingly, all investigated cancer cell populations additionally responded with a pronounced induction of apoptotic signaling cascades revealing a second, direct mechanism of antitumor activity. By contrast, p(I:C) and 3pRNA induced only little toxicity in human nonmalignant neural cells. Granted that the challenge of effective central nervous system (CNS) delivery can be overcome, targeting of RIG-I and MDA5 could thus become a quintessential strategy to encounter heterogeneous cancers in the sophisticated environments of the brain. Copyright © 2013 AlphaMed Press.

  11. Kinetic discrimination of self/non-self RNA by the ATPase activity of RIG-I and MDA5.

    Science.gov (United States)

    Louber, Jade; Brunel, Joanna; Uchikawa, Emiko; Cusack, Stephen; Gerlier, Denis

    2015-07-28

    The cytoplasmic RIG-like receptors are responsible for the early detection of viruses and other intracellular microbes by activating the innate immune response mediated by type I interferons (IFNs). RIG-I and MDA5 detect virus-specific RNA motifs with short 5'-tri/diphosphorylated, blunt-end double-stranded RNA (dsRNA) and >0.5-2 kb long dsRNA as canonical agonists, respectively. However, in vitro, they can bind to many RNA species, while in cells there is an activation threshold. As SF2 helicase/ATPase family members, ATP hydrolysis is dependent on co-operative RNA and ATP binding. Whereas simultaneous ATP and cognate RNA binding is sufficient to activate RIG-I by releasing autoinhibition of the signaling domains, the physiological role of the ATPase activity of RIG-I and MDA5 remains controversial. A cross-analysis of a rationally designed panel of RNA binding and ATPase mutants and truncated receptors, using type I IFN promoter activation as readout, allows us to refine our understanding of the structure-function relationships of RIG-I and MDA5. RNA activation of RIG-I depends on multiple critical RNA binding sites in its helicase domain as confirmed by functional evidence using novel mutations. We found that RIG-I or MDA5 mutants with low ATP hydrolysis activity exhibit constitutive activity but this was fully reverted when associated with mutations preventing RNA binding to the helicase domain. We propose that the turnover kinetics of the ATPase domain enables the discrimination of self/non-self RNA by both RIG-I and MDA5. Non-cognate, possibly self, RNA binding would lead to fast ATP turnover and RNA disassociation and thus insufficient time for the caspase activation and recruitment domains (CARDs) to promote downstream signaling, whereas tighter cognate RNA binding provides a longer time window for downstream events to be engaged. The exquisite fine-tuning of RIG-I and MDA5 RNA-dependent ATPase activity coupled to CARD release allows a robust IFN response

  12. Pigeon RIG-I Function in Innate Immunity against H9N2 IAV and IBDV

    Directory of Open Access Journals (Sweden)

    Wenping Xu

    2015-07-01

    Full Text Available Retinoic acid-inducible gene I (RIG-I, a cytosolic pattern recognition receptor (PRR, can sense various RNA viruses, including the avian influenza virus (AIV and infectious bursal disease virus (IBDV, and trigger the innate immune response. Previous studies have shown that mammalian RIG-I (human and mice and waterfowl RIG-I (ducks and geese are essential for type I interferon (IFN synthesis during AIV infection. Like ducks, pigeons are also susceptible to infection but are ineffective propagators and disseminators of AIVs, i.e., “dead end” hosts for AIVs and even highly pathogenic avian influenza (HPAI. Consequently, we sought to identify pigeon RIG-I and investigate its roles in the detection of A/Chicken/Shandong/ZB/2007 (H9N2 (ZB07, Gansu/Tianshui (IBDV TS and Beijing/CJ/1980 (IBDV CJ-801 strains in chicken DF-1 fibroblasts or human 293T cells. Pigeon mRNA encoding the putative pigeon RIG-I analogs was identified. The exogenous expression of enhanced green fluorescence protein (EGFP-tagged pigeon RIG-I and caspase activation and recruitment domains (CARDs, strongly induced antiviral gene (IFN-β, Mx, and PKR mRNA synthesis, decreased viral gene (M gene and VP2 mRNA expression, and reduced the viral titers of ZB07 and IBDV TS/CJ-801 virus strains in chicken DF-1 cells, but not in 293T cells. We also compared the antiviral abilities of RIG-I proteins from waterfowl (duck and goose and pigeon. Our data indicated that waterfowl RIG-I are more effective in the induction of antiviral genes and the repression of ZB07 and IBDV TS/CJ-801 strain replication than pigeon RIG-I. Furthermore, chicken melanoma differentiation associated gene 5(MDA5/ mitochondrial antiviral signaling (MAVS silencing combined with RIG-I transfection suggested that pigeon RIG-I can restore the antiviral response in MDA5-silenced DF-1 cells but not in MAVS-silenced DF-1 cells. In conclusion, these results demonstrated that pigeon RIG-I and CARDs have a strong antiviral

  13. The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection.

    Science.gov (United States)

    Ramanathan, Anand; Devarkar, Swapnil C; Jiang, Fuguo; Miller, Matthew T; Khan, Abdul G; Marcotrigiano, Joseph; Patel, Smita S

    2016-01-29

    RIG-I (Retinoic Acid Inducible Gene-I) is a cytosolic innate immune receptor that detects atypical features in viral RNAs as foreign to initiate a Type I interferon signaling response. RIG-I is present in an autoinhibited state in the cytoplasm and activated by blunt-ended double-stranded (ds)RNAs carrying a 5' triphosphate (ppp) moiety. These features found in many pathogenic RNAs are absent in cellular RNAs due to post-transcriptional modifications of RNA ends. Although RIG-I is structurally well characterized, the mechanistic basis for RIG-I's remarkable ability to discriminate between cellular and pathogenic RNAs is not completely understood. We show that RIG-I's selectivity for blunt-ended 5'-ppp dsRNAs is ≈3000 times higher than non-blunt ended dsRNAs commonly found in cellular RNAs. Discrimination occurs at multiple stages and signaling RNAs have high affinity and ATPase turnover rate and thus a high katpase/Kd. We show that RIG-I uses its autoinhibitory CARD2-Hel2i (second CARD-helicase insertion domain) interface as a barrier to select against non-blunt ended dsRNAs. Accordingly, deletion of CARDs or point mutations in the CARD2-Hel2i interface decreases the selectivity from ≈3000 to 150 and 750, respectively. We propose that the CARD2-Hel2i interface is a 'gate' that prevents cellular RNAs from generating productive complexes that can signal. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  14. Innate immune receptors in human airway smooth muscle cells: activation by TLR1/2, TLR3, TLR4, TLR7 and NOD1 agonists.

    Directory of Open Access Journals (Sweden)

    Anne Månsson Kvarnhammar

    Full Text Available BACKGROUND: Pattern-recognition receptors (PRRs, including Toll-like receptors (TLRs, NOD-like receptors (NLRs and RIG-I-like receptors (RLRs, recognize microbial components and trigger a host defense response. Respiratory tract infections are common causes of asthma exacerbations, suggesting a role for PRRs in this process. The present study aimed to examine the expression and function of PRRs on human airway smooth muscle cells (HASMCs. METHODS: Expression of TLR, NLR and RLR mRNA and proteins was determined using real-time RT-PCR, flow cytometry and immunocytochemistry. The functional responses to ligand stimulation were investigated in terms of cytokine and chemokine release, cell surface marker expression, proliferation and proteins regulating the contractile state. RESULTS: HASMCs expressed functional TLR2, TLR3, TLR4, TLR7 and NOD1. Stimulation with the corresponding agonists Pam3CSK4, poly(I:C, LPS, R-837 and iE-DAP, respectively, induced IL-6, IL-8 and GM-CSF release and up-regulation of ICAM-1 and HLA-DR, while poly(I:C also affected the release of eotaxin and RANTES. The proliferative response was slightly increased by LPS. Stimulation, most prominently with poly(I:C, down-regulated myosin light chain kinase and cysteinyl leukotriene 1 receptor expression and up-regulated β2-adrenoceptor expression. No effects were seen for agonist to TLR2/6, TLR5, TLR8, TLR9, NOD2 or RIG-I/MDA-5. CONCLUSION: Activation of TLR2, TLR3, TLR4, TLR7 and NOD1 favors a synthetic phenotype, characterized by an increased ability to release inflammatory mediators, acquire immunomodulatory properties by recruiting and interacting with other cells, and reduce the contractile state. The PRRs might therefore be of therapeutic use in the management of asthma and infection-induced disease exacerbations.

  15. Accessory factors of cytoplasmic viral RNA sensors required for antiviral innate immune response

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    Hiroyuki eOshiumi

    2016-05-01

    Full Text Available Type I interferon (IFN induces many antiviral factors in host cells. RIG-I-like receptors (RLRs are cytoplasmic viral RNA sensors that trigger the signal to induce the innate immune response that includes type I IFN production. RIG-I and MDA5 are RLRs that form nucleoprotein filaments along viral double-stranded RNA, resulting in the activation of MAVS adaptor molecule. The MAVS protein forms a prion-like aggregation structure, leading to type I IFN production. RIG-I and MDA5 undergo post-translational modification. TRIM25 and Riplet ubiquitin ligases deliver a K63-linked polyubiquitin moiety to the RIG-I N-terminal caspase activation and recruitment domains (CARDs and C-terminal region; the polyubiquitin chain then stabilizes the two-CARD tetramer structure required for MAVS assembly. MDA5 activation is regulated by phosphorylation. RIOK3 is a protein kinase that phosphorylates the MDA5 protein in a steady state, and PP1α/γ dephosphorylate this protein, resulting in its activation. RIG-I and MDA5 require cytoplasmic RNA helicases for their efficient activation. LGP2, another RLR, is an RNA helicase involved in RLR signaling. This protein does not possess N-terminal CARDs and thus cannot trigger downstream signaling by itself. Recent studies have revealed that this protein modulates MDA5 filament formation, resulting in enhanced type I IFN production. Several other cytoplasmic RNA helicases are involved in RLR signaling. DDX3, DHX29, DHX36, and DDX60 RNA helicases have been reported to be involved in RLR-mediated type I IFN production after viral infection. However, the underlying mechanism is largely unknown. Future studies are required to reveal the role of RNA helicases in the RLR signaling pathway.

  16. Genetic variation in toll-like receptors and retinoic acid-inducible gene I and outcome of hepatitis C virus infection

    DEFF Research Database (Denmark)

    Clausen, L N; Ladelund, S; Weis, N

    2014-01-01

    We evaluated the effects of genetic variation in toll-like receptors (TLR), retinoic acid-inducible gene I (RIG-I) and their signalling pathways on spontaneous hepatitis C virus (HCV) resolution. We screened 95 single-nucleotide polymorphisms (SNPs) in 22 genes. SNPs significantly associated...... with resolution in the discovery cohort were genotyped in a validation cohort. Multivariate logistic regression adjusted for sex, hepatitis B surface antigen, HIV infection and the interleukin-28B rs12979860 SNP was performed in the combined cohort. Haplotype reconstruction and linkage disequilibrium analysis...

  17. Both RIG-I and MDA5 detect alphavirus replication in concentration-dependent mode

    Energy Technology Data Exchange (ETDEWEB)

    Akhrymuk, Ivan; Frolov, Ilya; Frolova, Elena I., E-mail: evfrolova@UAB.edu

    2016-01-15

    Alphaviruses are a family of positive-strand RNA viruses that circulate on all continents between mosquito vectors and vertebrate hosts. Despite a significant public health threat, their biology is not sufficiently investigated, and the mechanisms of alphavirus replication and virus–host interaction are insufficiently understood. In this study, we have applied a variety of experimental systems to further understand the mechanism by which infected cells detect replicating alphaviruses. Our new data strongly suggest that activation of the antiviral response by alphavirus-infected cells is determined by the integrity of viral genes encoding proteins with nuclear functions, and by the presence of two cellular pattern recognition receptors (PRRs), RIG-I and MDA5. No type I IFN response is induced in their absence. The presence of either of these PRRs is sufficient for detecting virus replication. However, type I IFN activation in response to pathogenic alphaviruses depends on the basal levels of RIG-I or MDA5. - Highlights: • Both RIG-I and MDA5 detect alphavirus replication. • Alphavirus-induced transcriptional shutoff affects type I IFN induction. • Sensing of alphavirus replication by RIG-I and MDA5 depends on their concentrations. • High basal level of RIG-I and MDA5 allows IFN induction by pathogenic alphaviruses. • This dependence determines the discrepancy between the in vivo and in vitro data.

  18. Selective RNA targeting and regulated signaling by RIG-I is controlled by coordination of RNA and ATP binding.

    Science.gov (United States)

    Fitzgerald, Megan E; Rawling, David C; Potapova, Olga; Ren, Xiaoming; Kohlway, Andrew; Pyle, Anna Marie

    2017-02-17

    RIG-I is an innate immune receptor that detects and responds to infection by deadly RNA viruses such as influenza, and Hepatitis C. In the cytoplasm, RIG-I is faced with a difficult challenge: it must sensitively detect viral RNA while ignoring the abundance of host RNA. It has been suggested that RIG-I has a ‘proof-reading’ mechanism for rejecting host RNA targets, and that disruptions of this selectivity filter give rise to autoimmune diseases. Here, we directly monitor RNA proof-reading by RIG-I and we show that it is controlled by a set of conserved amino acids that couple RNA and ATP binding to the protein (Motif III). Mutations of this motif directly modulate proof-reading by eliminating or enhancing selectivity for viral RNA, with major implications for autoimmune disease and cancer. More broadly, the results provide a physical explanation for the ATP-gated behavior of SF2 RNA helicases and receptor proteins.

  19. Identification of DreI as an antiviral factor regulated by RLR signaling pathway.

    Directory of Open Access Journals (Sweden)

    Shun Li

    Full Text Available BACKGROUND: Retinoic acid-inducible gene I (RIG-I-like receptors (RLRs had been demonstrated to prime interferon (IFN response against viral infection via the conserved RLR signaling in fish, and a novel fish-specific gene, the grass carp reovirus (GCRV-induced gene 2 (Gig2, had been suggested to play important role in host antiviral response. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we cloned and characterized zebrafish Gig2 homolog (named Danio rerio Gig2-I, DreI, and revealed its antiviral role and expressional regulation signaling pathway. RT-PCR, Western blot and promoter activity assay indicate that DreI can be induced by poly I:C, spring viremia of carp virus (SVCV and recombinant IFN (rIFN, showing that DreI is a typical ISG. Using the pivotal signaling molecules of RLR pathway, including RIG-I, MDA5 and IRF3 from crucian carp, it is found that DreI expression is regulated by RLR cascade and IRF3 plays an important role in this regulation. Furthermore, promoter mutation assay confirms that the IFN-stimulated regulatory elements (ISRE in the 5' flanking region of DreI is essential for its induction. Finally, overexpression of DreI leads to establish a strong antiviral state against SVCV and Rana grylio virus (RGV infection in EPC (Epithelioma papulosum cyprinid cells. CONCLUSIONS/SIGNIFICANCE: These data indicate that DreI is an antiviral protein, which is regulated by RLR signaling pathway.

  20. Triggering of the dsRNA sensors TLR3, MDA5, and RIG-I induces CD55 expression in synovial fibroblasts.

    Directory of Open Access Journals (Sweden)

    Olga N Karpus

    Full Text Available CD55 (decay-accelerating factor is a complement-regulatory protein highly expressed on fibroblast-like synoviocytes (FLS. CD55 is also a ligand for CD97, an adhesion-type G protein-coupled receptor abundantly present on leukocytes. Little is known regarding the regulation of CD55 expression in FLS.FLS isolated from arthritis patients were stimulated with pro-inflammatory cytokines and Toll-like receptor (TLR ligands. Transfection with polyinosinic-polycytidylic acid (poly(I:C and 5'-triphosphate RNA were used to activate the cytoplasmic double-stranded (dsRNA sensors melanoma differentiation-associated gene 5 (MDA5 and retinoic acid-inducible gene-I (RIG-I. CD55 expression, cell viability, and binding of CD97-loaded beads were quantified by flow cytometry.CD55 was expressed at equal levels on FLS isolated from patients with rheumatoid arthritis (RA, osteoarthritis, psoriatic arthritis and spondyloarthritis. CD55 expression in RA FLS was significantly induced by IL-1β and especially by the TLR3 ligand poly(I:C. Activation of MDA5 and RIG-I also enhanced CD55 expression. Notably, activation of MDA5 dose-dependently induced cell death, while triggering of TLR3 or RIG-I had a minor effect on viability. Upregulation of CD55 enhanced the binding capacity of FLS to CD97-loaded beads, which could be blocked by antibodies against CD55.Activation of dsRNA sensors enhances the expression of CD55 in cultured FLS, which increases the binding to CD97. Our findings suggest that dsRNA promotes the interaction between FLS and CD97-expressing leukocytes.

  1. Mutual antagonism between the Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome.

    Science.gov (United States)

    Luthra, Priya; Ramanan, Parameshwaran; Mire, Chad E; Weisend, Carla; Tsuda, Yoshimi; Yen, Benjamin; Liu, Gai; Leung, Daisy W; Geisbert, Thomas W; Ebihara, Hideki; Amarasinghe, Gaya K; Basler, Christopher F

    2013-07-17

    The cytoplasmic pattern recognition receptor RIG-I is activated by viral RNA and induces type I IFN responses to control viral replication. The cellular dsRNA binding protein PACT can also activate RIG-I. To counteract innate antiviral responses, some viruses, including Ebola virus (EBOV), encode proteins that antagonize RIG-I signaling. Here, we show that EBOV VP35 inhibits PACT-induced RIG-I ATPase activity in a dose-dependent manner. The interaction of PACT with RIG-I is disrupted by wild-type VP35, but not by VP35 mutants that are unable to bind PACT. In addition, PACT-VP35 interaction impairs the association between VP35 and the viral polymerase, thereby diminishing viral RNA synthesis and modulating EBOV replication. PACT-deficient cells are defective in IFN induction and are insensitive to VP35 function. These data support a model in which the VP35-PACT interaction is mutually antagonistic and plays a fundamental role in determining the outcome of EBOV infection. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Functional characterizations of RIG-I to GCRV and viral/bacterial PAMPs in grass carp Ctenopharyngodon idella.

    Directory of Open Access Journals (Sweden)

    Lijun Chen

    Full Text Available BACKGROUND: RIG-I (retinoic acid inducible gene-I is one of the key cytosolic pattern recognition receptors (PRRs for detecting nucleotide pathogen associated molecular patterns (PAMPs and mediating the induction of type I interferon and inflammatory cytokines in innate immune response. Though the mechanism is well characterized in mammals, the study of the accurate function of RIG-I in teleosts is still in its infancy. METHODOLOGY/PRINCIPAL FINDINGS: To clarify the functional characterizations of RIG-I in grass carp Ctenopharyngodon idella (CiRIG-I, six representative overexpression plasmids were constructed and transfected into C. idella kidney (CIK cell lines to obtain stably expressing recombinant proteins, respectively. A virus titer test and 96-well plate staining assay showed that all constructs exhibited the antiviral activity somewhat. The quantitative real-time RT-PCR (qRT-PCR demonstrated that mRNA expressions of CiIPS-1, CiIFN-I and CiMx2 were regulated by not only virus (GCRV or viral PAMP (poly(IC challenge but also bacterial PAMPs (LPS and PGN stimulation in the steadily transfected cells. The results showed that the full-length CiRIG-I played a key role in RLR pathway. The repressor domain (RD exerted an inhibitory function of the signaling channel under all utilized challenges. Caspase activation and recruitment domains (CARDs showed a positive role in GCRV and poly(I:C challenge. Helicase motifs were crucial for the signaling pathway upon LPS and PGN stimulation. Interestingly, ΔCARDs (CARDs deleted showed positive modulation in RIG-I signal transduction. CONCLUSIONS/SIGNIFICANCE: The results provided some novel insights into RIG-I sensing with a strikingly broad regulation in teleosts, responding not only to the dsRNA virus or synthetic dsRNA but also bacterial PAMPs.

  3. Structural basis for Marburg virus VP35-mediated immune evasion mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Ramanan, Parameshwaran; Edwards, Megan R.; Shabman, Reed S.; Leung, Daisy W.; Endlich-Frazier, Ariel C.; Borek, Dominika M.; Otwinowski, Zbyszek; Liu, Gai; Huh, Juyoung; Basler, Christopher F.; Amarasinghe, Gaya K. [Sinai; (WU-MED); (UTSMC)

    2013-07-22

    Filoviruses, marburgvirus (MARV) and ebolavirus (EBOV), are causative agents of highly lethal hemorrhagic fever in humans. MARV and EBOV share a common genome organization but show important differences in replication complex formation, cell entry, host tropism, transcriptional regulation, and immune evasion. Multifunctional filoviral viral protein (VP) 35 proteins inhibit innate immune responses. Recent studies suggest double-stranded (ds)RNA sequestration is a potential mechanism that allows EBOV VP35 to antagonize retinoic-acid inducible gene-I (RIG-I) like receptors (RLRs) that are activated by viral pathogen–associated molecular patterns (PAMPs), such as double-strandedness and dsRNA blunt ends. Here, we show that MARV VP35 can inhibit IFN production at multiple steps in the signaling pathways downstream of RLRs. The crystal structure of MARV VP35 IID in complex with 18-bp dsRNA reveals that despite the similar protein fold as EBOV VP35 IID, MARV VP35 IID interacts with the dsRNA backbone and not with blunt ends. Functional studies show that MARV VP35 can inhibit dsRNA-dependent RLR activation and interferon (IFN) regulatory factor 3 (IRF3) phosphorylation by IFN kinases TRAF family member-associated NFkb activator (TANK) binding kinase-1 (TBK-1) and IFN kB kinase e (IKKe) in cell-based studies. We also show that MARV VP35 can only inhibit RIG-I and melanoma differentiation associated gene 5 (MDA5) activation by double strandedness of RNA PAMPs (coating backbone) but is unable to inhibit activation of RLRs by dsRNA blunt ends (end capping). In contrast, EBOV VP35 can inhibit activation by both PAMPs. Insights on differential PAMP recognition and inhibition of IFN induction by a similar filoviral VP35 fold, as shown here, reveal the structural and functional plasticity of a highly conserved virulence factor.

  4. Nucleic acid-induced antiviral immunity in invertebrates: an evolutionary perspective.

    Science.gov (United States)

    Wang, Pei-Hui; Weng, Shao-Ping; He, Jian-Guo

    2015-02-01

    Nucleic acids derived from viral pathogens are typical pathogen associated molecular patterns (PAMPs). In mammals, the recognition of viral nucleic acids by pattern recognition receptors (PRRs), which include Toll-like receptors (TLRs) and retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), induces the release of inflammatory cytokines and type I interferons (IFNs) through the activation of nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) 3/7 pathways, triggering the host antiviral state. However, whether nucleic acids can induce similar antiviral immunity in invertebrates remains ambiguous. Several studies have reported that nucleic acid mimics, especially dsRNA mimic poly(I:C), can strongly induce non-specific antiviral immune responses in insects, shrimp, and oyster. This behavior shows multiple similarities to the hallmarks of mammalian IFN responses. In this review, we highlight the current understanding of nucleic acid-induced antiviral immunity in invertebrates. We also discuss the potential recognition and regulatory mechanisms that confer non-specific antiviral immunity on invertebrate hosts. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Alveolar macrophage–derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes

    Science.gov (United States)

    Goritzka, Michelle; Makris, Spyridon; Kausar, Fahima; Durant, Lydia R.; Pereira, Catherine; Kumagai, Yutaro; Culley, Fiona J.; Mack, Matthias; Akira, Shizuo

    2015-01-01

    Type I interferons (IFNs) are important for host defense from viral infections, acting to restrict viral production in infected cells and to promote antiviral immune responses. However, the type I IFN system has also been associated with severe lung inflammatory disease in response to respiratory syncytial virus (RSV). Which cells produce type I IFNs upon RSV infection and how this directs immune responses to the virus, and potentially results in pathological inflammation, is unclear. Here, we show that alveolar macrophages (AMs) are the major source of type I IFNs upon RSV infection in mice. AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)–coupled retinoic acid–inducible gene 1 (RIG-I)–like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV. This is largely attributable to loss of type I IFN–dependent induction of monocyte chemoattractants and subsequent reduced recruitment of inflammatory monocytes (infMo) to the lungs. Notably, the latter have potent antiviral activity and are essential to control infection and lessen disease severity. Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN–mediated antiviral activity. Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation. PMID:25897172

  6. Toscana virus NSs protein inhibits the induction of type I interferon by interacting with RIG-I.

    Science.gov (United States)

    Gori-Savellini, Gianni; Valentini, Melissa; Cusi, Maria Grazia

    2013-06-01

    Toscana virus (TOSV) is a phlebovirus, of the Bunyaviridae family, that is responsible for central nervous system (CNS) injury in humans. Previous data have shown that the TOSV NSs protein is a gamma interferon (IFN-β) antagonist when transiently overexpressed in mammalian cells, inhibiting IRF-3 induction (G. Gori Savellini, F. Weber, C. Terrosi, M. Habjan, B. Martorelli, and M. G. Cusi, J. Gen. Virol. 92:71-79, 2011). In this study, we investigated whether an upstream sensor, which has a role in the signaling cascade leading to the production of type I IFN, was involved. We found a significant decrease in RIG-I protein levels in cells overexpressing TOSV NSs, suggesting that the nonstructural protein interacts with RIG-I and targets it for proteasomal degradation. In fact, the MG-132 proteasome inhibitor was able to restore IFN-β promoter activation in cells expressing NSs, demonstrating the existence of an evasion mechanism based on inhibition of the RIG-I sensor. Furthermore, a C-terminal truncated NSs protein (ΔNSs), although able to interact with RIG-I, did not affect the RIG-I-mediated IFN-β promoter activation, suggesting that the NSs domains responsible for RIG-I-mediated signaling and interaction with RIG-I are mapped on different regions. These results contribute to identify a novel mechanism for bunyaviruses by which TOSV NSs counteracts the early IFN response.

  7. Negative Role of RIG-I Serine 8 Phosphorylation in the Regulatin of Interferon-beta Production

    Energy Technology Data Exchange (ETDEWEB)

    E Nistal-Villan; M Gack; G Martinez-Delgado; N Maharaj; K Inn; H Yang; R Wang; A Aggarwal; J Jung; A Garcia-Sastre

    2011-12-31

    RIG-I (retinoic acid-inducible gene I) and TRIM25 (tripartite motif protein 25) have emerged as key regulatory factors to induce interferon (IFN)-mediated innate immune responses to limit viral replication. Upon recognition of viral RNA, TRIM25 E3 ligase binds the first caspase recruitment domain (CARD) of RIG-I and subsequently induces lysine 172 ubiquitination of the second CARD of RIG-I, which is essential for the interaction with downstream MAVS/IPS-1/CARDIF/VISA and, thereby, IFN-beta mRNA production. Although ubiquitination has emerged as a major factor involved in RIG-I activation, the potential contribution of other post-translational modifications, such as phosphorylation, to the regulation of RIG-I activity has not been addressed. Here, we report the identification of serine 8 phosphorylation at the first CARD of RIG-I as a negative regulatory mechanism of RIG-I-mediated IFN-beta production. Immunoblot analysis with a phosphospecific antibody showed that RIG-I serine 8 phosphorylation steady-state levels were decreased upon stimulation of cells with IFN-beta or virus infection. Substitution of serine 8 in the CARD RIG-I functional domain with phosphomimetic aspartate or glutamate results in decreased TRIM25 binding, RIG-I ubiquitination, MAVS binding, and downstream signaling. Finally, sequence comparison reveals that only primate species carry serine 8, whereas other animal species carry an asparagine, indicating that serine 8 phosphorylation may represent a primate-specific regulation of RIG-I activation. Collectively, these data suggest that the phosphorylation of RIG-I serine 8 operates as a negative switch of RIG-I activation by suppressing TRIM25 interaction, further underscoring the importance of RIG-I and TRIM25 connection in type I IFN signal transduction.

  8. Coxsackievirus cloverleaf RNA containing a 5' triphosphate triggers an antiviral response via RIG-I activation.

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    Qian Feng

    Full Text Available Upon viral infections, pattern recognition receptors (PRRs recognize pathogen-associated molecular patterns (PAMPs and stimulate an antiviral state associated with the production of type I interferons (IFNs and inflammatory markers. Type I IFNs play crucial roles in innate antiviral responses by inducing expression of interferon-stimulated genes and by activating components of the adaptive immune system. Although pegylated IFNs have been used to treat hepatitis B and C virus infections for decades, they exert substantial side effects that limit their use. Current efforts are directed toward the use of PRR agonists as an alternative approach to elicit host antiviral responses in a manner similar to that achieved in a natural infection. RIG-I is a cytosolic PRR that recognizes 5' triphosphate (5'ppp-containing RNA ligands. Due to its ubiquitous expression profile, induction of the RIG-I pathway provides a promising platform for the development of novel antiviral agents and vaccine adjuvants. In this study, we investigated whether structured RNA elements in the genome of coxsackievirus B3 (CVB3, a picornavirus that is recognized by MDA5 during infection, could activate RIG-I when supplied with 5'ppp. We show here that a 5'ppp-containing cloverleaf (CL RNA structure is a potent RIG-I inducer that elicits an extensive antiviral response that includes induction of classical interferon-stimulated genes, as well as type III IFNs and proinflammatory cytokines and chemokines. In addition, we show that prophylactic treatment with CVB3 CL provides protection against various viral infections including dengue virus, vesicular stomatitis virus and enterovirus 71, demonstrating the antiviral efficacy of this RNA ligand.

  9. Changing the insulin receptor to possess insulin-like growth factor I ligand specificity

    International Nuclear Information System (INIS)

    Andersen, A.S.; Kjeldsen, T.; Wiberg, F.C.; Christensen, P.M.; Rasmussen, J.S.; Norris, K.; Moeller, K.B.; Moeller, N.P.H.

    1990-01-01

    To examine the role of the N-terminal part of the insulin-like growth factor I (IGF-I) receptor and insulin receptor in determining ligand specificity, the authors prepared an expression vector encoding a hybrid receptor where exon 1 (encoding the signal peptide and seven amino acids of the α-subunit), exon 2, and exon 3 of the insulin receptor were replaced with the corresponding IGF-I receptor cDNA (938 nucleotides). To allow direct quantitative comparison of the binding capabilities of this hybrid receptor with those of the human IGF-I receptor and the insulin receptor, all three receptors were expressed in baby hamster kidney (BHK) cells as soluble molecules and partially purified before characterization. The hybrid IGF-I/insulin receptor bound IGF-I with an affinity comparable to that of the wild-type IGF-I receptor. In contrast, the hybrid receptor no longer displayed high-affinity binding of insulin. These results directly demonstrate that it is possible to change the specificity of the insulin receptor to that of the IGF-I receptor and, furthermore, that the binding specificity for IGF-I is encoded within the nucleotide sequence from 135 to 938 of the IGF-I receptor cDNA. Since the hybrid receptor only bound insulin with low affinity, the insulin binding region is likely to be located within exons 2 and 3 of the insulin receptor

  10. Immunomics of the koala (Phascolarctos cinereus).

    Science.gov (United States)

    Abts, Kendra C; Ivy, Jamie A; DeWoody, J Andrew

    2015-06-01

    The study of the koala transcriptome has the potential to advance our understanding of its immunome--immunological reaction of a given host to foreign antigens--and to help combat infectious diseases (e.g., chlamydiosis) that impede ongoing conservation efforts. We used Illumina sequencing of cDNA to characterize genes expressed in two different koala tissues of immunological importance, blood and spleen. We generated nearly 600 million raw sequence reads, and about 285 million of these were subsequently assembled and condensed into ~70,000 subcomponents that represent putative transcripts. We annotated ~16% of these subcomponents and identified those related to infection and the immune response, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), major histocompatibility complex (MHC) genes, and koala retrovirus (KoRV). Using phylogenetic analyses, we identified 29 koala genes in these target categories and report their concordance with currently accepted gene groups. By mapping multiple sequencing reads to transcripts, we identified 56 putative SNPs in genes of interest. The distribution of these SNPs indicates that MHC genes (34 SNPs) are more diverse than KoRV (12 SNPs), TLRs (8 SNPs), or RLRs (2 SNPs). Our sequence data also indicate that KoRV sequences are highly expressed in the transcriptome. Our efforts have produced full-length sequences for potentially important immune genes in koala, which should serve as targets for future investigations that aim to conserve koala populations.

  11. Transfected poly(I:C) activates different dsRNA receptors, leading to apoptosis or immunoadjuvant response in androgen-independent prostate cancer cells.

    Science.gov (United States)

    Palchetti, Sara; Starace, Donatella; De Cesaris, Paola; Filippini, Antonio; Ziparo, Elio; Riccioli, Anna

    2015-02-27

    Despite the effectiveness of surgery or radiation therapy for the treatment of early-stage prostate cancer (PCa), there is currently no effective strategy for late-stage disease. New therapeutic targets are emerging; in particular, dsRNA receptors Toll-like receptor 3 (TLR3) and cytosolic helicases expressed by cancer cells, once activated, exert a pro-apoptotic effect in different tumors. We previously demonstrated that the synthetic analog of dsRNA poly(I:C) induces apoptosis in the androgen-dependent PCa cell line LNCaP in a TLR3-dependent fashion, whereas only a weak apoptotic effect is observed in the more aggressive and androgen-independent PCa cells PC3 and DU145. In this paper, we characterize the receptors and the signaling pathways involved in the remarkable apoptosis induced by poly(I:C) transfected by Lipofectamine (in-poly(I:C)) compared with the 12-fold higher free poly(I:C) concentration in PC3 and DU145 cells. By using genetic inhibition of different poly(I:C) receptors, we demonstrate the crucial role of TLR3 and Src in in-poly(I:C)-induced apoptosis. Therefore, we show that the increased in-poly(I:C) apoptotic efficacy is due to a higher binding of endosomal TLR3. On the other hand, we show that in-poly(I:C) binding to cytosolic receptors MDA5 and RIG-I triggers IRF3-mediated signaling, leading uniquely to the up-regulation of IFN-β, which likely in turn induces increased TLR3, MDA5, and RIG-I proteins. In summary, in-poly(I:C) activates two distinct antitumor pathways in PC3 and DU145 cells: one mediated by the TLR3/Src/STAT1 axis, leading to apoptosis, and the other one mediated by MDA5/RIG-I/IRF3, leading to immunoadjuvant IFN-β expression. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. DMPD: MDA5/RIG-I and virus recognition. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18272355 MDA5/RIG-I and virus recognition. Takeuchi O, Akira S. Curr Opin Immunol. ...2008 Feb;20(1):17-22. Epub 2008 Feb 12. (.png) (.svg) (.html) (.csml) Show MDA5/RIG-I and virus recognition.... PubmedID 18272355 Title MDA5/RIG-I and virus recognition. Authors Takeuchi O, Akira S. Publication Curr Opi

  13. DMPD: Toll-like receptors and Type I interferons. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available m. 2007 May 25;282(21):15319-23. Epub 2007 Mar 29. (.png) (.svg) (.html) (.csml) Show Toll-like receptors and Type I interferons. Pub...medID 17395581 Title Toll-like receptors and Type I interferons. Authors Uematsu S,

  14. Post-translational Control of Intracellular Pathogen Sensing Pathways.

    Science.gov (United States)

    Chiang, Cindy; Gack, Michaela U

    2017-01-01

    Mammalian cells recognize virus-derived nucleic acids using a defined set of intracellular sensors including the DNA sensors cyclic GMP-AMP (cGAMP) synthase (cGAS) and interferon gamma (IFNγ)-inducible protein 16 (IFI16) as well as viral RNA receptors of the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family. Following innate immune recognition, these sensors launch an immune response that is characterized by the transcriptional upregulation of many antiviral molecules, including proinflammatory cytokines, chemokines, and IFN-stimulated genes. Recent studies have demonstrated that the signal transduction initiated by these sensors is sophisticatedly regulated by post-translational modifications (PTMs) resulting in a robust yet 'tunable' cytokine response to maintain immune homeostasis. Here we summarize recent advances in our understanding of how PTMs and regulatory enzymes control the signaling activity of RLRs, cGAS, and IFI16 as well as their proximal adaptor proteins. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Differential expression of viral PAMP receptors mRNA in peripheral blood of patients with chronic hepatitis C infection

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    Riñón Marta

    2007-11-01

    Full Text Available Abstract Background Pathogen-associated molecular patterns (PAMP receptors play a key role in the early host response to viruses. In this work, we determined mRNA levels of two members of the Toll-like Receptors family, (TLR3 and TLR7 and the helicase RIG-I, all of three recognizing viral RNA products, in peripheral blood of healthy donors and hepatitis C virus (HCV patients, to observe if their transcripts are altered in this disease. Methods IFN-α, TLR3, TLR7 and RIG-I levels in peripheral blood from healthy controls (n = 18 and chronic HCV patients (n = 18 were quantified by real-time polymerase chain reaction. Results Our results show that IFN-α, TLR3, TLR7 and RIG-I mRNA levels are significantly down-regulated in patients with chronic HCV infection when compared with healthy controls. We also found that the measured levels of TLR3 and TLR7, but not RIG-I, correlated significantly with those of IFN-α Conclusion Monitoring the expression of RNA-sensing receptors like TLR3, TLR7 and RIG-I during the different clinical stages of infection could bring a new source of data about the prognosis of disease.

  16. Reprogramming of murine macrophages through TLR2 confers viral resistance via TRAF3-mediated, enhanced interferon production.

    Directory of Open Access Journals (Sweden)

    Darren J Perkins

    Full Text Available The cell surface/endosomal Toll-like Receptors (TLRs are instrumental in initiating immune responses to both bacteria and viruses. With the exception of TLR2, all TLRs and cytosolic RIG-I-like receptors (RLRs with known virus-derived ligands induce type I interferons (IFNs in macrophages or dendritic cells. Herein, we report that prior ligation of TLR2, an event previously shown to induce "homo" or "hetero" tolerance, strongly "primes" macrophages for increased Type I IFN production in response to subsequent TLR/RLR signaling. This occurs by increasing activation of the transcription factor, IFN Regulatory Factor-3 (IRF-3 that, in turn, leads to enhanced induction of IFN-β, while expression of other pro-inflammatory genes are suppressed (tolerized. In vitro or in vivo "priming" of murine macrophages with TLR2 ligands increase virus-mediated IFN induction and resistance to infection. This priming effect of TLR2 is mediated by the selective upregulation of the K63 ubiquitin ligase, TRAF3. Thus, we provide a mechanistic explanation for the observed antiviral actions of MyD88-dependent TLR2 and further define the role of TRAF3 in viral innate immunity.

  17. Viral evasion of intracellular DNA and RNA sensing

    Science.gov (United States)

    Chan, Ying Kai; Gack, Michaela U.

    2016-01-01

    The co-evolution of viruses with their hosts has led to the emergence of viral pathogens that are adept at evading or actively suppressing host immunity. Pattern recognition receptors (PRRs) are key components of antiviral immunity that detect conserved molecular features of viral pathogens and initiate signalling that results in the expression of antiviral genes. In this Review, we discuss the strategies that viruses use to escape immune surveillance by key intracellular sensors of viral RNA or DNA, with a focus on RIG-I-like receptors (RLRs), cyclic GMP–AMP synthase (cGAS) and interferon-γ (IFNγ)-inducible protein 16 (IFI16). Such viral strategies include the sequestration or modification of viral nucleic acids, interference with specific post-translational modifications of PRRs or their adaptor proteins, the degradation or cleavage of PRRs or their adaptors, and the sequestration or relocalization of PRRs. An understanding of viral immune-evasion mechanisms at the molecular level may guide the development of vaccines and antivirals. PMID:27174148

  18. Leukocyte Ig-Like Receptors – a model for MHC class I disease associations

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    Rachel Louise Allen

    2016-07-01

    Full Text Available MHC class I (MHC-I polymorphisms are associated with the outcome of some viral infections and autoimmune diseases. MHC-I proteins present antigenic peptides and are recognised by receptors on Natural Killer cells and Cytotoxic T lymphocytes, thus enabling the immune system to detect self-antigens and eliminate targets lacking self or expressing foreign antigens. Recognition of MHC-I, however, extends beyond receptors on cytotoxic leukocytes. Members of the Leukocyte Ig-like receptor (LILR family are expressed on monocytic cells and can recognise both classical and non-classical MHC-I alleles. Despite their relatively broad specificity when compared to the T Cell Receptor or Killer Ig-like Receptors, variations in the strength of LILR binding between different MHC-I alleles have recently been shown to correlate with control of HIV infection. We suggest that LILR recognition may mediate MHC-I disease association in a manner that does not depend on a binary discrimination of self/non-self by cytotoxic cells. Instead, the effects of LILR activity following engagement by MHC-I may represent a degrees of self model, whereby strength of binding to different alleles determines the degree of influence exerted by these receptors on immune cell functions. LILR are expressed by myelomonocytic cells and lymphocytes, extending their influence across antigen presenting cell subsets including dendritic cells, macrophages and B cells. They have been identified as important players in the response to infection, inflammatory diseases and cancer, with recent literature to indicate that MHC-I recognition by these receptors and consequent allelic effects could extend an influence beyond the immune system.

  19. Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity.

    Science.gov (United States)

    Chiang, Jessica J; Sparrer, Konstantin M J; van Gent, Michiel; Lässig, Charlotte; Huang, Teng; Osterrieder, Nikolaus; Hopfner, Karl-Peter; Gack, Michaela U

    2018-01-01

    The sensor RIG-I detects double-stranded RNA derived from RNA viruses. Although RIG-I is also known to have a role in the antiviral response to DNA viruses, physiological RNA species recognized by RIG-I during infection with a DNA virus are largely unknown. Using next-generation RNA sequencing (RNAseq), we found that host-derived RNAs, most prominently 5S ribosomal RNA pseudogene 141 (RNA5SP141), bound to RIG-I during infection with herpes simplex virus 1 (HSV-1). Infection with HSV-1 induced relocalization of RNA5SP141 from the nucleus to the cytoplasm, and virus-induced shutoff of host protein synthesis downregulated the abundance of RNA5SP141-interacting proteins, which allowed RNA5SP141 to bind RIG-I and induce the expression of type I interferons. Silencing of RNA5SP141 strongly dampened the antiviral response to HSV-1 and the related virus Epstein-Barr virus (EBV), as well as influenza A virus (IAV). Our findings reveal that antiviral immunity can be triggered by host RNAs that are unshielded following depletion of their respective binding proteins by the virus.

  20. Alternative Pre-mRNA Splicing in Mammals and Teleost Fish: A Effective Strategy for the Regulation of Immune Responses Against Pathogen Infection.

    Science.gov (United States)

    Chang, Ming Xian; Zhang, Jie

    2017-07-15

    Pre-mRNA splicing is the process by which introns are removed and the protein coding elements assembled into mature mRNAs. Alternative pre-mRNA splicing provides an important source of transcriptome and proteome complexity through selectively joining different coding elements to form mRNAs, which encode proteins with similar or distinct functions. In mammals, previous studies have shown the role of alternative splicing in regulating the function of the immune system, especially in the regulation of T-cell activation and function. As lower vertebrates, teleost fish mainly rely on a large family of pattern recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) from various invading pathogens. In this review, we summarize recent advances in our understanding of alternative splicing of piscine PRRs including peptidoglycan recognition proteins (PGRPs), nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) and their downstream signaling molecules, compared to splicing in mammals. We also discuss what is known and unknown about the function of splicing isoforms in the innate immune responses against pathogens infection in mammals and teleost fish. Finally, we highlight the consequences of alternative splicing in the innate immune system and give our view of important directions for future studies.

  1. Dose dependent activation of retinoic acid-inducible gene-I promotes both proliferation and apoptosis signals in human head and neck squamous cell carcinoma.

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    Jingzhou Hu

    Full Text Available The retinoic-acid-inducible gene (RIG-like receptor (RLR family proteins are major pathogen reorganization receptors (PRR responsible for detection of viral RNA, which initiates antiviral response. Here, we evaluated the functional role of one RLR family member, RIG-I, in human head and neck squamous cell carcinoma (HNSCC. RIG-I is abundantly expressed both in poorly-differentiated primary cancer and lymph node metastasis, but not in normal adjacent tissues. Activation of RIG-I by transfection with low dose of 5'-triphosphate RNA (3p-RNA induces low levels of interferon and proinflammatory cytokines and promotes NF-κB- and Akt-dependent cell proliferation, migration and invasion. In contrast, activation of RIG-I by a high dose of 3p-RNA induces robust mitochondria-derived apoptosis accompanied by decreased activation of Akt, which is independent of the interferon and TNFα receptor, but can be rescued by over-expression of constitutively active Akt. Furthermore, co-immunoprecipitation experiments indicate that the CARD domain of RIG-I is essential for inducing apoptosis by interacting with caspase-9. Together, our results reveal a dual role of RIG-I in HNSCC through regulating activation of Akt, in which RIG-I activation by low-dose viral dsRNA increases host cell survival, whereas higher level of RIG-I activation leads to apoptosis. These findings highlight the therapeutic potential of dsRNA mediated RIG-I activation in the treatment of HNSCC.

  2. An Overview of Pathogen Recognition Receptors for Innate Immunity in Dental Pulp

    Directory of Open Access Journals (Sweden)

    Ji-Hyun Jang

    2015-01-01

    Full Text Available Pathogen recognition receptors (PRRs are a class of germ line-encoded receptors that recognize pathogen-associated molecular patterns (PAMPs. The activation of PRRs is crucial for the initiation of innate immunity, which plays a key role in first-line defense until more specific adaptive immunity is developed. PRRs differ in the signaling cascades and host responses activated by their engagement and in their tissue distribution. Currently identified PRR families are the Toll-like receptors (TLRs, the C-type lectin receptors (CLRs, the nucleotide-binding oligomerization domain-like receptors (NLRs, the retinoic acid-inducible gene-I-like receptors (RLRs, and the AIM2-like receptor (ALR. The environment of the dental pulp is substantially different from that of other tissues of the body. Dental pulp resides in a low compliance root canal system that limits the expansion of pulpal tissues during inflammatory processes. An understanding of the PRRs in dental pulp is important for immunomodulation and hence for developing therapeutic targets in the field of endodontics. Here we comprehensively review recent finding on the PRRs and the mechanisms by which innate immunity is activated. We focus on the PRRs expressed on dental pulp and periapical tissues and their role in dental pulp inflammation.

  3. Viral RNA-Unprimed Rig-I Restrains Stat3 Activation in the Modulation of Regulatory T Cell/Th17 Cell Balance.

    Science.gov (United States)

    Yang, Hui; Guo, He-Zhou; Li, Xian-Yang; Lin, Jian; Zhang, Wu; Zhao, Jun-Mei; Zhang, Hong-Xin; Chen, Sai-Juan; Chen, Zhu; Zhu, Jiang

    2017-07-01

    Innate immunity activation by viral RNA-primed retinoid acid inducible gene-I (Rig-I) in CD4 + T cells antagonizes TGFβ signaling to suppress the differentiation of regulatory T cells (Tregs). However, how viral RNA-unliganded Rig-I (apo-Rig-I) modulates Treg generation remains unclear. In this article, we show that, in the absence of viral infection, Treg differentiation of Rig-I -/- CD4 + T cells was compromised, in the presence of increased generation of Th17 cells and overactivation of Stat3, a critical regulator tilting the Treg/Th17 cell balance. Mechanistically, apo-Rig-I physically associates with Stat3, thereby inhibiting Jak1's association with Stat3 while facilitating Shp2's association to inhibit p-Stat3 levels. Interestingly, inhibition of Stat3 ameliorates the Treg/Th17 imbalance and the colitis observed in Rig-I -/- mice. Collectively, these results uncover an independent functional contribution of the apo-Rig-I/Stat3 interaction in the maintenance of Treg/Th17 cell balance. Copyright © 2017 by The American Association of Immunologists, Inc.

  4. Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin

    International Nuclear Information System (INIS)

    Lesniak, M.A.; Hill, J.M.; Kiess, W.; Rojeski, M.; Pert, C.B.; Roth, J.

    1988-01-01

    Receptors for insulin-like growth factor I (IGF-I) in rat brain were visualized using autoradiography with [125I]IGF-I. The binding of the labeled peptide was competed for fully by high concentrations of unlabeled IGF-I. At intermediate concentrations of unlabeled peptide the binding of [125I]IGF-I was competed for by unlabeled IGF-I more effectively than by IGF-II or insulin, which is typical of receptors for IGF-I. Essentially every brain section shows specific binding of IGF-I, and the pattern of binding of IGF-I to its receptors correlated well with the cytoarchitectonic structures. In parallel studies we showed that [125I]IGF-II was bound to tissue sections of rat brain and that the binding was competed for by an excess of unlabeled IGF-II. However, intermediate concentrations of unlabeled peptides gave inconclusive results. To confirm that the binding of [125I]IGF-II was to IGF-II receptors, we showed that antibodies specific for the IGF-II receptor inhibited the binding of labeled IGF-II. Furthermore, the binding of the antibody to regions of the brain section, visualized by the application of [125I]protein-A, gave patterns indistinguishable from those obtained with [125I]IGF-II alone. Again, the binding was very widely distributed throughout the central nervous system, and the patterns of distribution corresponded well to the underlying neural structures. Densitometric analysis of the receptors enabled us to compare the distribution of IGF-I receptors with that of IGF-II receptors as well as retrospectively with that of insulin receptors

  5. Innate and intrinsic antiviral immunity in skin.

    Science.gov (United States)

    Kawamura, Tatsuyoshi; Ogawa, Youichi; Aoki, Rui; Shimada, Shinji

    2014-09-01

    As the body's most exposed interface with the environment, the skin is constantly challenged by potentially pathogenic microbes, including viruses. To sense the invading viruses, various types of cells resident in the skin express many different pattern-recognition receptors (PRRs) such as C-type lectin receptors (CLRs), Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and cytosolic DNA sensors, that can detect the pathogen-associated molecular patterns (PAMPs) of the viruses. The detection of viral PAMPs initiates two major innate immune signaling cascades: the first involves the activation of the downstream transcription factors, such as interferon regulatory factors (IRFs), nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), which cooperate to induce the transcription of type I interferons and pro-inflammatory cytokines. The second signaling pathway involves the caspase-1-mediated processing of IL-1β and IL-18 through the formation of an inflammasome complex. Cutaneous innate immunity including the production of the innate cytokines constitutes the first line of host defence that limits the virus dissemination from the skin, and also plays an important role in the activation of adaptive immune response, which represents the second line of defence. More recently, the third immunity "intrinsic immunity" has emerged, that provides an immediate and direct antiviral defense mediated by host intrinsic restriction factors. This review focuses on the recent advances regarding the antiviral immune systems, highlighting the innate and intrinsic immunity against the viral infections in the skin, and describes how viral components are recognized by cutaneous immune systems. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts

    International Nuclear Information System (INIS)

    Flier, J.S.; Usher, P.; Moses, A.C.

    1986-01-01

    Insulin and insulin-like growth factor type I (IGF-I) stimulate an overlapping spectrum of biological responses in human skin fibroblasts. Although insulin and IGF-I are known to stimulate the incorporation of [ 3 H]thymidine into DNA in these cells, the identify of the receptor(s) that mediates this effect has not been fully clarified. The mouse anti-human IGF-I receptor antibody αIR-3 binds with specificity to IGF-I but not to insulin receptors in human placental membranes; it also specifically inhibits the binding of 125 I-labeled IGF-I but not 125 I-labeled insulin to suspensions of human skin fibroblasts in a dose-dependent manner. αIR-3 competitively inhibits IGF-I-mediated stimulation of [ 3 H]thymidine incorporation into DNA. This inhibition is dependent on the concentration of αIR-3 and in the presence of a fixed antibody concentration can be partially overcome by high concentrations of IGF-I. In contrast, at concentrations of 3 H]thymidine incorporation is not inhibited by αIR-3. However, the incremental effects of higher concentrations (> 1 μg/ml) of insulin on [ 3 H]thymidine incorporation are inhibited by αIR-3. αIR-3 is a highly specific antagonist of IGF-I receptor-mediated mitogenesis in human skin fibroblasts. By using this antibody, it is shown directly that insulin can act through the IGF-I receptor to stimulate DNA synthesis but can also activate this effect through the insulin receptor itself

  7. Human gestation-associated tissues express functional cytosolic nucleic acid sensing pattern recognition receptors.

    Science.gov (United States)

    Bryant, A H; Menzies, G E; Scott, L M; Spencer-Harty, S; Davies, L B; Smith, R A; Jones, R H; Thornton, C A

    2017-07-01

    The role of viral infections in adverse pregnancy outcomes has gained interest in recent years. Innate immune pattern recognition receptors (PRRs) and their signalling pathways, that yield a cytokine output in response to pathogenic stimuli, have been postulated to link infection at the maternal-fetal interface and adverse pregnancy outcomes. The objective of this study was to investigate the expression and functional response of nucleic acid ligand responsive Toll-like receptors (TLR-3, -7, -8 and -9), and retinoic acid-inducible gene 1 (RIG-I)-like receptors [RIG-I, melanoma differentiation-associated protein 5 (MDA5) and Laboratory of Genetics and Physiology 2(LGP2)] in human term gestation-associated tissues (placenta, choriodecidua and amnion) using an explant model. Immunohistochemistry revealed that these PRRs were expressed by the term placenta, choriodecidua and amnion. A statistically significant increase in interleukin (IL)-6 and/or IL-8 production in response to specific agonists for TLR-3 (Poly(I:C); low and high molecular weight), TLR-7 (imiquimod), TLR-8 (ssRNA40) and RIG-I/MDA5 (Poly(I:C)LyoVec) was observed; there was no response to a TLR-9 (ODN21798) agonist. A hierarchical clustering approach was used to compare the response of each tissue type to the ligands studied and revealed that the placenta and choriodecidua generate a more similar IL-8 response, while the choriodecidua and amnion generate a more similar IL-6 response to nucleic acid ligands. These findings demonstrate that responsiveness via TLR-3, TLR-7, TLR-8 and RIG-1/MDA5 is a broad feature of human term gestation-associated tissues with differential responses by tissue that might underpin adverse obstetric outcomes. © 2017 British Society for Immunology.

  8. Cell-Cell Adhesion and Insulin-Like Growth Factor I Receptor in Breast Cancer

    National Research Council Canada - National Science Library

    Bartucci, Monica

    2001-01-01

    .... Our goal was to study the role of the insulin-like growth factor I receptor (IGF-IR) in breast cancer. The IGF-IR is a multifunctional tyrosine kinase that has been recently implicated in breast tumor development and progression...

  9. Systemic administration of kainic acid induces selective time dependent decrease in [125I]insulin-like growth factor I, [125I]insulin-like growth factor II and [125I]insulin receptor binding sites in adult rat hippocampal formation

    International Nuclear Information System (INIS)

    Quirion, R.; Chabot, J.-G.; Dore, S.; Seto, D.; Kar, S.

    1997-01-01

    Administration of kainic acid evokes acute seizure in hippocampal pathways that results in a complex sequence of functional and structural alterations resembling human temporal lobe epilepsy. The structural alterations induced by kainic acid include selective loss of neurones in CA1-CA3 subfields and the hilar region of the dentate gyrus followed by sprouting and permanent reorganization of the synaptic connections of the mossy fibre pathways. Although the neuronal degeneration and process of reactive synaptogenesis have been extensively studied, at present little is known about means to prevent pathological conditions leading to kainate-induced cell death. In the present study, to address the role of insulin-like growth factors I and II, and insulin in neuronal survival as well as synaptic reorganization following kainate-induced seizure, the time course alterations of the corresponding receptors were evaluated. Additionally, using histological preparations, the temporal profile of neuronal degeneration and hypertrophy of resident astroglial cells were also studied. [ 125 I]Insulin-like growth factor I binding was found to be decreased transiently in almost all regions of the hippocampal formation at 12 h following treatment with kainic acid. The dentate hilar region however, exhibited protracted decreases in [ 125 I]insulin-like growth factor I receptor sites throughout (i.e. 30 days) the study. [ 125 I]Insulin-like growth factor II receptor binding sites in the hippocampal formation were found to be differentially altered following systemic administration of kainic acid. A significant decrease in [ 125 I]insulin-like growth factor II receptor sites was observed in CA1 subfield and the pyramidal cell layer of the Ammon's horn at all time points studied whereas the hilar region and the stratum radiatum did not exhibit alteration at any time. A kainate-induced decrease in [ 125 I]insulin receptor binding was noted at all time points in the molecular layer of the

  10. Hepatitis C Virus Frameshift/Alternate Reading Frame Protein Suppresses Interferon Responses Mediated by Pattern Recognition Receptor Retinoic-Acid-Inducible Gene-I.

    Directory of Open Access Journals (Sweden)

    Seung Bum Park

    Full Text Available Hepatitis C virus (HCV actively evades host interferon (IFN responses but the mechanisms of how it does so are not completely understood. In this study, we present evidence for an HCV factor that contributes to the suppression of retinoic-acid-inducible gene-I (RIG-I-mediated IFN induction. Expression of frameshift/alternate reading frame protein (F/ARFP from HCV -2/+1 frame in Huh7 hepatoma cells suppressed type I IFN responses stimulated by HCV RNA pathogen-associated molecular pattern (PAMP and poly(IC. The suppression occurred independently of other HCV factors; and activation of interferon stimulated genes, TNFα, IFN-λ1, and IFN-λ2/3 was likewise suppressed by HCV F/ARFP. Point mutations in the full-length HCV sequence (JFH1 genotype 2a strain were made to introduce premature termination codons in the -2/+1 reading frame coding for F/ARFP while preserving the original reading frame, which enhanced IFNα and IFNβ induction by HCV. The potentiation of IFN response by the F/ARFP mutations was diminished in Huh7.5 cells, which already have a defective RIG-I, and by decreasing RIG-I expression in Huh7 cells. Furthermore, adding F/ARFP back via trans-complementation suppressed IFN induction in the F/ARFP mutant. The F/ARFP mutants, on the other hand, were not resistant to exogenous IFNα. Finally, HCV-infected human liver samples showed significant F/ARFP antibody reactivity, compared to HCV-uninfected control livers. Therefore, HCV F/ARFP likely cooperates with other viral factors to suppress type I and III IFN induction occurring through the RIG-I signaling pathway. This study identifies a novel mechanism of pattern recognition receptor modulation by HCV and suggests a biological function of the HCV alternate reading frame in the modulation of host innate immunity.

  11. Hepatitis E virus persists in the presence of a type III interferon response.

    Science.gov (United States)

    Yin, Xin; Li, Xinlei; Ambardekar, Charuta; Hu, Zhimin; Lhomme, Sébastien; Feng, Zongdi

    2017-05-01

    The RIG-I-like RNA helicase (RLR)-mediated interferon (IFN) response plays a pivotal role in the hepatic antiviral immunity. The hepatitis A virus (HAV) and the hepatitis C virus (HCV) counter this response by encoding a viral protease that cleaves the mitochondria antiviral signaling protein (MAVS), a common signaling adaptor for RLRs. However, a third hepatotropic RNA virus, the hepatitis E virus (HEV), does not appear to encode a functional protease yet persists in infected cells. We investigated HEV-induced IFN responses in human hepatoma cells and primary human hepatocytes. HEV infection resulted in persistent virus replication despite poor spread. This was companied by a type III IFN response that upregulated multiple IFN-stimulated genes (ISGs), but type I IFNs were barely detected. Blocking type III IFN production or signaling resulted in reduced ISG expression and enhanced HEV replication. Unlike HAV and HCV, HEV did not cleave MAVS; MAVS protein size, mitochondrial localization, and function remained unaltered in HEV-replicating cells. Depletion of MAVS or MDA5, and to a less extent RIG-I, also diminished IFN production and increased HEV replication. Furthermore, persistent activation of the JAK/STAT signaling rendered infected cells refractory to exogenous IFN treatment, and depletion of MAVS or the receptor for type III IFNs restored the IFN responsiveness. Collectively, these results indicate that unlike other hepatotropic RNA viruses, HEV does not target MAVS and its persistence is associated with continuous production of type III IFNs.

  12. One big rig, two valuable functions

    Energy Technology Data Exchange (ETDEWEB)

    Anon

    2004-11-01

    A hybrid coil tubing and conventional workover rig, tailor-made for conditions on Alaska's remote North Slope is described. The dual function rig, owned by BP Exploration, towers 142 feet above the barren Arctic tundra, and weighs between 1.5 and 2 million pounds, rests on eight enormous wheels that stand 11.5 feet tall and 3.5 feet wide, and is supported by 64 smaller tires in between. The rig includes the hybrid coiled tubing rig and a conventional workover rig; it exerts less than 100 pounds per square inch of pressure on the tender Arctic surface as it moves forward at a top speed of two miles per hour. It is considered by its developers as the next-step change in providing cost-effective access to reserves in the large, mature and remote oilfields such as those of Alaska's Prudhoe Bay. The rig is the product of cooperation between Schlumberger expertise in coiled tubing drilling and Nordic-Calista's know-how of jointed pipe operations and operating rigs in an Arctic environment. It is the first time in Prudhoe Bay, and probably in the world, that a coiled tubing unit was installed on a rig to do coiled-tubing sidetracks, i.e to drill a secondary wellbore away from the original wellbore. Since the first unit was commissioned in 1996, the rig has drilled 280 wells. Rig No. 2, much improved and commissioned in 2002, drilled about 30 wells to date. Unlike Rig No, 1, Rig No. 2 can change reels without a crane, and it has a hydraulic pipe skate that moves jointed pipe to and from the rig floor without human aid. The expectation is that using this rig it will be possible to do micro-hole exploration drilling on the North Slope (i.e. drilling a small surface hole with jointed pipe and then switch to coiled tubing), substantially cutting the cost of exploration.

  13. Rig it right! Maya animation rigging concepts

    CERN Document Server

    O'Hailey, Tina

    2013-01-01

    Rigging a character can be a complicated undertaking. Move from a bi-pedal character to a quad- or poly-pedal and, well, things just got real. Where do you begin? Unlike all of those button-pushing manuals out there, Rig it Right! breaks down rigging so that you can achieve a fundamental understanding of the concept, allowing you to rig more intuitively in your own work. Veteran animation professor Tina O'Hailey will get you up and rigging in a matter of hours with step-by-step tutorials covering multiple animation control types, connection methods, interactive skinning, Blend

  14. The molecular mechanisms of signaling by cooperative assembly formation in innate immunity pathways.

    Science.gov (United States)

    Vajjhala, Parimala R; Ve, Thomas; Bentham, Adam; Stacey, Katryn J; Kobe, Bostjan

    2017-06-01

    The innate immune system is the first line of defense against infection and responses are initiated by pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs). PRRs also detect endogenous danger-associated molecular patterns (DAMPs) that are released by damaged or dying cells. The major PRRs include the Toll-like receptor (TLR) family members, the nucleotide binding and oligomerization domain, leucine-rich repeat containing (NLR) family, the PYHIN (ALR) family, the RIG-1-like receptors (RLRs), C-type lectin receptors (CLRs) and the oligoadenylate synthase (OAS)-like receptors and the related protein cyclic GMP-AMP synthase (cGAS). The different PRRs activate specific signaling pathways to collectively elicit responses including the induction of cytokine expression, processing of pro-inflammatory cytokines and cell-death responses. These responses control a pathogenic infection, initiate tissue repair and stimulate the adaptive immune system. A central theme of many innate immune signaling pathways is the clustering of activated PRRs followed by sequential recruitment and oligomerization of adaptors and downstream effector enzymes, to form higher-order arrangements that amplify the response and provide a scaffold for proximity-induced activation of the effector enzymes. Underlying the formation of these complexes are co-operative assembly mechanisms, whereby association of preceding components increases the affinity for downstream components. This ensures a rapid immune response to a low-level stimulus. Structural and biochemical studies have given key insights into the assembly of these complexes. Here we review the current understanding of assembly of immune signaling complexes, including inflammasomes initiated by NLR and PYHIN receptors, the myddosomes initiated by TLRs, and the MAVS CARD filament initiated by RIG-1. We highlight the co-operative assembly mechanisms during assembly of each of these complexes. Copyright

  15. Overexpression of the transcription factor Sp1 activates the OAS-RNAse L-RIG-I pathway.

    Directory of Open Access Journals (Sweden)

    Valéryane Dupuis-Maurin

    Full Text Available Deregulated expression of oncogenes or transcription factors such as specificity protein 1 (Sp1 is observed in many human cancers and plays a role in tumor maintenance. Paradoxically in untransformed cells, Sp1 overexpression induces late apoptosis but the early intrinsic response is poorly characterized. In the present work, we studied increased Sp1 level consequences in untransformed cells and showed that it turns on an early innate immune transcriptome. Sp1 overexpression does not activate known cellular stress pathways such as DNA damage response or endoplasmic reticulum stress, but induces the activation of the OAS-RNase L pathway and the generation of small self-RNAs, leading to the upregulation of genes of the antiviral RIG-I pathway at the transcriptional and translational levels. Finally, Sp1-induced intrinsic innate immune response leads to the production of the chemokine CXCL4 and to the recruitment of inflammatory cells in vitro and in vivo. Altogether our results showed that increased Sp1 level in untransformed cells constitutes a novel danger signal sensed by the OAS-RNase L axis leading to the activation of the RIG-I pathway. These results suggested that the OAS-RNase L-RIG-I pathway may be activated in sterile condition in absence of pathogen.

  16. Advancing rig design: latest rig technologies improving efficiency and safety

    Energy Technology Data Exchange (ETDEWEB)

    Greenaway, R.

    1997-12-01

    Recent advances in drilling rig technologies that improve the ways for finding oil and natural gas, and are also solving some safety and transportation problems, have been reviewed. The coiled tubing drilling rig developed by joint venture TransOcean Ensign Drilling Technology was one of the innovations described. It is able to run a three-and-a-quarter inch coiled tubing, the only system capable of doing this in a land-based application. Tesco Corporation`s new casing drilling rig, which is expected to lower the cost of moving the rig, and Brinkerhoff Drilling`s new generation modular (NGM)-rig, claimed to be the most mobile rig in North America, are other new developments worthy of note. Tesco`s casing drilling rig has the potential to reduce drilling costs by as much as 30 to 40 per cent, while the NGM-rig could reduce rig mobilization time by 50 to 80 per cent, and the number of wells drilled by the same rig could increase by 20 per cent, due to the NGM-rig`s versatility and flexibility.

  17. Regulation of insulin-like growth factor I receptors on vascular smooth muscle cells by growth factors and phorbol esters.

    Science.gov (United States)

    Ververis, J J; Ku, L; Delafontaine, P

    1993-06-01

    Insulin-like growth factor I (IGF I) is an important mitogen for vascular smooth muscle cells. To characterize regulation of vascular IGF I receptors, we performed radioligand displacement experiments using rat aortic smooth muscle cells (RASMs). Serum deprivation for 48 hours caused a 40% decrease in IGF I receptor number. Exposure of quiescent RASMs to platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), or angiotensin II (Ang II) caused a 1.5-2.0-fold increase in IGF I receptors per cell. After FGF exposure, there was a marked increase in the mitogenic response to IGF I. IGF I downregulated its receptors in the presence of platelet-poor plasma. Stimulation of protein kinase C (PKC) by exposure of quiescent RASMs to phorbol 12-myristate 13-acetate caused a biphasic response in IGF I binding; there was a 42% decrease in receptor number at 45 minutes and a 238% increase at 24 hours. To determine the role of PKC in growth factor-induced regulation of IGF I receptors, we downregulated PKC by exposing RASMs to phorbol 12,13-dibutyrate (PDBu) for 48 hours. PDGF- and FGF- but not Ang II-mediated upregulation of IGF I receptors was completely inhibited in PDBu-treated cells. Thus, acute PKC activation by phorbol esters inhibits IGF I binding, whereas chronic PKC activation increases IGF I binding. PDGF and FGF but not Ang II regulate vascular IGF I receptors through a PKC-dependent pathway. These data provide new insights into the regulation of vascular smooth muscle cell IGF I receptors in vitro and are of potential importance in characterizing vascular proliferative responses in vivo.

  18. Sensor Asam Nukleat Sebagai Aktivator Imunitas Intrinsik Terhadap Patogen Intraseluler

    Directory of Open Access Journals (Sweden)

    Usmar Usmar

    2017-12-01

    Full Text Available Vertebrata, termasuk manusia, dilengkapi dengan sistem imun alamiah dan sistem imun adaptif yang saling bekerjasama untuk melindungi tubuh dari material berbahaya, termasuk berbagai patogen dan sel-sel kanker. Kedua sistem imun tersebut secara rutin melakukan pengecekan terhadap beragam material yang ada di dalam tubuh. Salah satu cara yang digunakan oleh sistem imun dalam melaksanakan tugasnya adalah melalui pengaktifan sensor asam nukleat yang berfungsi untuk memberikan informasi keberadaan DNA atau RNA asing maupun kemungkinan adanya salinan DNA inang di sitoplasma atau lokasi lain yang tidak semestinya. Ketika genom patogen terdeteksi oleh sensor-sensor tersebut, selanjutnya efektor sistem imun akan diaktivasi melalui serangkaian proses dan berakhir dengan eradikasi asam nukleat target atau bahkan induksi apoptosis sel yang bersangkutan. Beberapa sensor asam nukleat yang telah ditemukan antara lain adalah Toll-like receptor (TLR, RIG-I-like receptors (RLRs, cyclic GMP-AMP synthase (cGAS, dan interferon-γ-inducible protein 16 (IFI16. Namun, sejumlah patogen telah memiliki mekanisme untuk menghindari sensor-sensor tersebut sehingga infeksi tetap dapat terjadi. Dengan demikian, berbagai penelitian untuk meningkatkan pengetahuan tentang bagaimana sensor asam nukleat bekerja sebagai salah satu respon imun intraseluler serta mekanisme terbentuknya resistensi patogen terhadap deteksi sensor tersebut sangat penting untuk didorong. Hal ini akan memberikan wawasan baru dalam pengembangan berbagai sediaan farmasi terkait seperti vaksin dan antimikroba intraseluler.

  19. DMPD: Translational mini-review series on Toll-like receptors: recent advances inunderstanding the role of Toll-like receptors in anti-viral immunity. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17223961 Translational mini-review series on Toll-like receptors: recent advances i...147(2):217-26. (.png) (.svg) (.html) (.csml) Show Translational mini-review series on Toll-like receptors: r...nity. PubmedID 17223961 Title Translational mini-review series on Toll-like receptors: recent advances inund

  20. Expression of an IRF-3 fusion protein and mouse estrogen receptor, inhibits hepatitis C viral replication in RIG-I-deficient Huh 7.5 cells

    Directory of Open Access Journals (Sweden)

    Liu Chen

    2011-09-01

    Full Text Available Abstract Interferon Regulatory Factor-3 (IRF-3 plays a central role in the induction of interferon (IFN production and succeeding interferon-stimulated genes (ISG expression en route for restraining hepatitis C virus (HCV infection. Here, we established a stable Huh7.5-IRF3ER cell line expressing a fusion protein of IRF-3 and mouse estrogen receptor (ER to examine IFN production and anti-HCV effects of IRF-3 in retinoic acid inducible-gene-I (RIG-I deficient Huh 7.5 cells. Homodimerization of the IRF-3ER fusion protein was detected by Western blotting after treatment with the estrogen receptor agonist 4-hydrotamoxifen (4-HT in Huh7.5-IRF3ER cells. Expression of IFN-α, IFN-β, and their inhibitory effects on HCV replication were demonstrated by real-time polymerase chain reaction (PCR. Peak expression of IFN-α and IFN-β was achieved 24-hours post 4-HT treatment, coinciding with the appearance of phosphorylated signal transducer and activator of transcription (STAT proteins. Additionally, HCV viral replication declined in time-dependent fashion. In previous studies, a novel IFN-mediated pathway regulating expression of 1-8U and heterogeneous nuclear ribonucleoprotein M (hnRNP M inhibited HCV internal ribosomal entry site (IRES-dependent translation. When expression of ISGs such as 1-8U and hnRNP M were measured in 4-HT-treated Huh7.5-IRF3ER cells, both genes were positively regulated by activation of the IRF-3ER fusion protein. In conclusion, the anti-HCV effects of IRF-3ER homodimerization inhibited HCV RNA replication as well as HCV IRES-dependent translation in Huh7.5-IRF3ER cells. The results of this study indicate that IRF-3ER homodimerization is a key step to restore IFN expression in Huh7.5-IRF3ER cells and in achieving its anti-HCV effects.

  1. Body Language Advanced 3D Character Rigging

    CERN Document Server

    Allen, Eric; Fong, Jared; Sidwell, Adam G

    2011-01-01

    Whether you're a professional Character TD or just like to create 3D characters, this detailed guide reveals the techniques you need to create sophisticated 3D character rigs that range from basic to breathtaking. Packed with step-by-step instructions and full-color illustrations, Body Language walks you through rigging techniques for all the body parts to help you create realistic and believable movements in every character you design. You'll learn advanced rigging concepts that involve MEL scripting and advanced deformation techniques and even how to set up a character pipeline.

  2. Insulin-like growth factor-I and insulin-like growth factor binding proteins in the bovine mammary gland: Receptors, endogenous secretion, and appearance in milk

    International Nuclear Information System (INIS)

    Campbell, P.G.

    1988-01-01

    This is the first study to characterize both insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding proteins (IGFBPs) in bovine milk, to characterize the IGF-I receptor in the dry and lactating mammary gland, and to report de novo synthesis and secretion of IGF-I and IGFBP from normal mammary tissue. Immunoreactive IGF-I was principally associated with 45 kDa IGFBP in milk. Multiparous cows had a higher IGF-I concentration of 307 ng/ml than primiparous cows at 147 ng/ml. IGF-I concentration on day 56 of lactation was 34 ng/ml for combined parity groups. At parturition, IGF-I mass in blood and milk pools was 1.4 and 1.2 mg, respectively. Binding of 125 I-IGF-I was specific for IGF-I with anIC 50 of 2.2 ng which was a 10- and 1273-fold greater affinity than IGF-II and insulin, respectively. Association constants, as determined by Scatchard analysis, were similar for both pregnant and lactating cows at 3.5 and 4.0 L/nM, respectively. In addition, estimated mean receptor concentration was 0.25 and 0.23 pM/mg protein for pregnant and lactating cows, respectively. In a survey of mammary microscomes prepared from 48 cows, 125 I-IGF-I binding declined with progressing lactation and a similar trend was observed during pregnancy

  3. Structural analogs of human insulin-like growth factor I with reduced affinity for serum binding proteins and the type 2 insulin-like growth factor receptor

    International Nuclear Information System (INIS)

    Bayne, M.L.; Applebaum, J.; Chicchi, G.G.; Hayes, N.S.; Green, B.G.; Cascieri, M.A.

    1988-01-01

    Four structural analogs of human insulin-like growth factor I (hIGF-I) have been prepared by site-directed mutagenesis of a synthetic IGF-I gene and subsequent expression and purification of the mutant protein from the conditioned media of transformed yeast. [Phe -1 , Val 1 , Asn 2 , Gln 3 , His 4 , Ser 8 , His 9 , Glu 12 , Tyr 15 , Leu 16 ]IGF-I (B-chain mutant), in which the first 16 amino acids of hIGF-I were replaced with the first 17 amino acids of the B-chain of insulin, has >1000-, 100-, and 2-fold reduced potency for human serum binding proteins, the rat liver type 2 IGF receptor, and the human placental type 1 IGF receptor, respectively. The B-chain mutant also has 4-fold increased affinity for the human placental insulin receptor. [Gln 3 , Ala 4 ] IGF-I has 4-fold reduced affinity for human serum binding proteins, but is equipotent to hIGF-I at the types 1 and 2 IGF and insulin receptors. [Tyr 15 , Leu 16 ] IGH-I has 4-fold reduced affinity for human serum binding proteins and 10-fold increased affinity for the insulin receptor. The peptide in which these four-point mutations are combined, [Gln 3 , Ala 4 , Tyr 15 ,Leu 16 ]IGF-I, has 600-fold reduced affinity for the serum binding proteins. All four of these mutants stimulate DNA synthesis in the rat vascular smooth muscle cell line A10 with potencies reflecting their potency at the type 1 IGF receptor. These studies identify some of the domains of hIGF-I which are responsible for maintaining high affinity binding with the serum binding protein and the type 2 IGF receptor. In addition, These peptides will be useful in defining the role of the type 2 IGF receptor and serum binding proteins in the physiological actions of hIGF-I

  4. Hoisting and Rigging (Formerly Hoisting and Rigging Manual)

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-06-01

    This standard is intended as a reference document to be used by supervisors, line managers, safety personnel, equipment operators, and any other personnel responsible for safety of hoisting and rigging operations at DOE sites. It quotes or paraphrases the US OSHA and ANSI requirements. It also encompasses, under one cover,hoisting and rigging requirements, codes, standards, and regulations, eliminating the need to maintain extensive (and often incomplete) libraries of hoisting and rigging standards throughout DOE. The standard occasionally goes beyond the minimum general industry standards established by OSHA and ANSI, and also delineates the more stringent requirements necessary to accomplish the complex, diversified, critical, and often hazardous hoisting and rigging work found with the DOE complex.

  5. Direct demonstration of rapid insulin-like growth factor II receptor internalization and recycling in rat adipocytes. Insulin stimulates 125I-insulin-like growth factor II degradation by modulating the IGF-II receptor recycling process

    International Nuclear Information System (INIS)

    Oka, Y.; Rozek, L.M.; Czech, M.P.

    1985-01-01

    The photoactive insulin-like growth factor (IGF)-II analogue 4-azidobenzoyl- 125 I-IGF-II was synthesized and used to label specifically and covalently the Mr = 250,000 Type II IGF receptor. When rat adipocytes are irradiated after a 10-min incubation with 4-azidobenzoyl- 125 I-IGF-II at 10 degrees C and immediately homogenized, most of the labeled IGF-II receptors are associated with the plasma membrane fraction, indicating that receptors accessible to the labeling reagent at low temperature are on the cell surface. However, when the photolabeled cells are incubated at 37 degrees C for various times before homogenization, labeled IGF-II receptors are rapidly internalized with a half-time of 3.5 min as evidenced by a loss from the plasma membrane fraction and a concomitant appearance in the low density microsome fraction. The steady state level of cell surface IGF-II receptors in the presence or absence of IGF-II remains constant under these conditions, demonstrating that IGF-II receptors rapidly recycle back to the cell surface at the same rate as receptor internalization. Using the above methodology, it is shown that acute insulin action: 1) increases the steady state number of cell surface IGF-II receptors; 2) increases the number of ligand-bound IGF-II receptors that are internalized per unit of time; and 3) increases the rate of cellular 125 I-IGF-II degradation by a process that is blocked by anti-IGF-II receptor antibody

  6. Mammal-like striatal functions in Anolis. I. Distribution of serotonin receptor subtypes, and absence of striosome and matrix organization.

    Science.gov (United States)

    Clark, E C; Baxter, L R

    2000-11-01

    Serotonin (5-HT) 5-HT(2A) and 5-HT(2C) receptors are thought to play important roles in the mammalian striatum. As basal ganglia functions in general are thought highly conserved among amniotes, we decided to use in situ autoradiographic methods to determine the occurrence and distribution of pharmacologically mammal-like 5-HT(2A) and 5-HT(2C) receptors in the lizard, Anolis carolinensis, with particular attention to the striatum. We also determined the distributions of 5-HT(1A), 5-HT(1B/D), 5 HT(3), and 5-HT(uptake) receptors for comparison. All 5-HT receptors examined showed pharmacological binding specificity, and forebrain binding density distributions that resembled those reported for mammals. Anolis 5 HT(2A/C) and 5-HT(1A) site distributions were similar in both in vivo and ex vivo binding experiments. 5-HT(2A & C) receptors occur in both high and low affinity states, the former having preferential affinity for (125)I-(+/-)-2,5-dimethoxy-4-iodo-amphetamine hydrochloride ((125)I-DOI). In mammals (125)I-DOI binding shows a patchy density distribution in the striatum, being more dense in striosomes than in surrounding matrix. There was no evidence of any such patchy density of (125)I-DOI binding in the anole striatum, however. As a further indication that anoles do not possess a striosome and matrix striatal organization, neither (3)H-naloxone binding nor histochemical staining for acetylcholinesterase activity (AChE) were patchy. AChE did show a band-like striatal distribution, however, similar to that seen in birds. Copyright 2001 S. Karger AG, Basel

  7. The phosphatidylinositol-3 kinase pathway is not essential for insulin-like growth factor I receptor-mediated clonogenic radioresistance

    International Nuclear Information System (INIS)

    Yu, Dong; Watanabe, Hiroshi; Shibuya, Hitoshi; Miura, Masahiko

    2002-01-01

    The insulin-like growth factor I receptor (IGF-IR) is known to induce clonogenic radioresistance in cells following ionizing irradiation. To explore the downstream signaling pathways, we focused on the phosphatidylinositol-3 kinase (PI3-K) pathway, which is thought to be the primary cell survival signal originating from the receptor. For this purpose, R- cells deficient in the endogenous IGF-IR were used as a recipient of the human IGF-IR with or without mutations at potential PI3-K activation sites: NPXY 950 and Y 1316 XXM. Mutats with double mutation at Y950/Y1316 exhibited not abrogated, but reduced activation of insulin receptor substance-1 (IRS-1), PI3-K, and Akt upon IGF-I stimulation. However, the mutants had the same clonogenic radioresistance as cells with wild type (WT) receptors. Neither wortmannin nor LY294002, specific inhibitors of PI3-K, affected the radioresistance of cells with WT receptors at concentrations specific for PI3-K. Collectively, these results indicate that the PI3-K pathway is not essential for IGF-IR-mediated clonogenic radioresistance. (author)

  8. [Differences in dynamics of insulin and insulin-like growth I (IGF-I) receptors internalization in isolated rat hepatocytes].

    Science.gov (United States)

    Kolychev, A P; Ternovskaya, E E; Arsenieva, A V; Shapkina, E V

    2013-01-01

    Insulin and IGF-I are two related peptides performing in the mammalian body functionally different roles of the metabolic and growth hormones, respectively. Internalization of the insulin-receptor complex (IRC) is the most important chain of mechanism of the action of hormone. To elucidate differences in the main stages of internalization of the two related hormones, the internalization dynamics of 125I-insulin and 125I-IGF-I was traced in isolated rat hepatocytes at 37 and 12 degrees C. There were established marked differences in the process of internalization of labeled hormones, which is stimulated by insulin and IGF-I. At 37 degrees C the insulin-stimulated internalization, unlike the process initiated by IGF-I, did not reach the maximal level for 1 h of incubation. However, essential differences in the internalization course of these two related peptide were obvious at the temperature of 12 degrees C. The internalization level of insulin receptors at 12 degrees C decreased by one third in spite of a significant increase of the insulin receptor binding on the hepatocytes plasma membrane. At 12 degrees C a slight decrease of the proportion of intracellular 125I-IGF-I correlated with a decrease in the 125I-IGF-I binding to receptors on the cell membrane. Internalization of IGF-I receptors was not affected by low temperature, as neither its level, nor the rate changed at 12 degrees C. The paradoxical decrease of the insulin-stimulated internalization at low temperature seems to represent a peculiar "inhibition mechanism" of immersion of IRC into the cell, which leads to accumulation of the complexes on the cell surface and possibly to a readjustment of the insulin biological activity. The resistance of internalization of the IGF-I receptor to cold seems to be related to the more ancient origin of this mechanism in the poikilothermal vertebrates.

  9. Expression of pattern recognition receptors in liver biopsy specimens of children chronically infected with HBV and HCV

    Directory of Open Access Journals (Sweden)

    Wojciech Służewski

    2011-10-01

    Full Text Available Pattern recognition receptors (PRRs constitute a pivotal arm of innate immunity. Their distribution is widespread and not limited to cells of the immune system. Following our previous findings concerning the expression of Toll-like receptors (TLRs 2, 3 and 4 in chronic viral hepatitis C of children, we wished to search for other PRRs, including other TLRs, NOD-like receptors (NLRs and RIG-1-like helicase receptors (RLR in infected hepatocytes. Liver biopsy fragments from ten children with chronic hepatitis B and C were used and two others in which hepatotropic virus infection was excluded. Frozen sections of liver samples were subjected to ABC immunohistochemistry (IHC following incubation with a set of antibodies. Results of IHC findings were screened for correlation with clinical/laboratory data of patients. It was found that several PRRs could be shown in affected hepatocytes, but the incidence was higher in hepatitis C than in B. In hepatitis C, TLR1, 2, 4, NALP and RIG-1 helicase showed the most marked expression. In hepatitis B, TLR1, 3, 9, NOD1 and NALP expression were the most conspicuous. Expression PRRs in liver from hepatitis of unknown origin was much lower. It was also the case in cytospins from human hepatoma cell line. Several correlations between PRRs expression and clinical findings in patients could be shown by statistical exploration. In conclusion, this data suggests some role for PRRs in the pathogenesis of chronic viral hepatitis. (<i>Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 3, pp. 410–416i>

  10. Toll-like receptors and NOD-like receptors in rheumatic diseases.

    LENUS (Irish Health Repository)

    McCormack, William J

    2012-02-01

    The past 10 years have seen the description of families of receptors that drive proinflammatory cytokine production in infection and tissue injury. Two major classes have been examined in the context of inflammatory joint disease--the Toll-like receptors (TLRs) and NOD-like receptors (NLRs). TLRs such as TLR2 and TLR4 are being implicated in the pathology of rheumatoid arthritis, ankylosing spondylitis, lyme arthritis and osteoarthritis. Nalp3 has been identified as a key NLR for IL-1beta production and has been shown to have a particular role in gout. These findings present new therapeutic opportunities, possibly allowing for the replacement of biologics with small molecule inhibitors.

  11. Understanding Rig Rates

    OpenAIRE

    Petter Osmundsen; Knut Einar Rosendahl; Terje Skjerpen

    2013-01-01

    We examine the largest cost component in offshore development projects, drilling rates, which have been high over the last years. To our knowledge, rig rates have not been analysed empirically before in the economic literature. By econometric analysis we examine the effects on Gulf of Mexico rig rates of gas and oil prices, rig capacity utilization, contract length and lead time, and rig specific characteristics. Having access to a unique data set containing contract information, we are able ...

  12. Toll-like receptor 2 or toll-like receptor 4 deficiency does not modify lupus in MRLlpr mice.

    Directory of Open Access Journals (Sweden)

    Simon J Freeley

    Full Text Available Systemic lupus erythematosus is an autoimmune disease with a high morbidity and nephritis is a common manifestation. Previous studies in murine lupus models have suggest a role for Toll-like receptor 2 and 4. We examined the role of these molecules in MRL lpr mice which is one of the most established and robust murine models. We compared disease parameters in Toll-like receptor 2 or Toll-like receptor 4 deficient mice with their littermate controls. We found no difference in the severity of glomerulonephritis as assessed by histology, serum creatinine and albuminuria when Toll-like receptor 2 or Toll-like receptor 4 deficient MRLlpr mice were compared with Toll-like receptor sufficient controls. We also found similar levels of anti-dsDNA and anti-ssDNA antibodies. These results show that Toll-like receptor 2 and Toll-like receptor 4 do not play a significant role in MRLlpr mice, and therefore they may not be important in human lupus.

  13. DMPD: Toll-like receptor 3: a link between toll-like receptor, interferon and viruses. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15031527 Toll-like receptor 3: a link between toll-like receptor, interferon and virus... (.csml) Show Toll-like receptor 3: a link between toll-like receptor, interferon and viruses. PubmedID 1503...1527 Title Toll-like receptor 3: a link between toll-like receptor, interferon and virus

  14. The art of rigging

    CERN Document Server

    Biddlecombe, George

    1990-01-01

    The best manual ever produced on rigging a sailing ship, based on extensively revised and updated 1848 edition prepared by Biddlecombe, Master in the Royal Navy. Complete definition of terms, on-shore operations, process of rigging ships, reeving the running rigging and bending sails, rigging brigs, yachts and small vessels, more. 17 plates.

  15. rigor mortis encodes a novel nuclear receptor interacting protein required for ecdysone signaling during Drosophila larval development.

    Science.gov (United States)

    Gates, Julie; Lam, Geanette; Ortiz, José A; Losson, Régine; Thummel, Carl S

    2004-01-01

    Pulses of the steroid hormone ecdysone trigger the major developmental transitions in Drosophila, including molting and puparium formation. The ecdysone signal is transduced by the EcR/USP nuclear receptor heterodimer that binds to specific response elements in the genome and directly regulates target gene transcription. We describe a novel nuclear receptor interacting protein encoded by rigor mortis (rig) that is required for ecdysone responses during larval development. rig mutants display defects in molting, delayed larval development, larval lethality, duplicated mouth parts, and defects in puparium formation--phenotypes that resemble those seen in EcR, usp, E75A and betaFTZ-F1 mutants. Although the expression of these nuclear receptor genes is essentially normal in rig mutant larvae, the ecdysone-triggered switch in E74 isoform expression is defective. rig encodes a protein with multiple WD-40 repeats and an LXXLL motif, sequences that act as specific protein-protein interaction domains. Consistent with the presence of these elements and the lethal phenotypes of rig mutants, Rig protein interacts with several Drosophila nuclear receptors in GST pull-down experiments, including EcR, USP, DHR3, SVP and betaFTZ-F1. The ligand binding domain of betaFTZ-F1 is sufficient for this interaction, which can occur in an AF-2-independent manner. Antibody stains reveal that Rig protein is present in the brain and imaginal discs of second and third instar larvae, where it is restricted to the cytoplasm. In larval salivary gland and midgut cells, however, Rig shuttles between the cytoplasm and nucleus in a spatially and temporally regulated manner, at times that correlate with the major lethal phase of rig mutants and major switches in ecdysone-regulated gene expression. Taken together, these data indicate that rig exerts essential functions during larval development through gene-specific effects on ecdysone-regulated transcription, most likely as a cofactor for one or more

  16. Partial characterization of insulin-like growth factor I in primary human lung cancers using immunohistochemical and receptor autoradiographic techniques

    International Nuclear Information System (INIS)

    Shigematsu, K.; Kataoka, Y.; Kamio, T.; Kurihara, M.; Niwa, M.; Tsuchiyama, H.

    1990-01-01

    We investigated primary human lung cancers resected surgically or obtained at autopsy. Included were squamous cell carcinoma (SQC) (five cases), adenocarcinoma (ADC) (six cases), large cell carcinoma (LCC) (four cases), and small cell carcinoma (SCC) (two cases). The objective of the study was to search for the presence of insulin-like growth factor I (IGF-I)-like immunoreactivity using immunohistochemical staining and for the localization of IGF-I binding sites, using in vitro quantitative receptor autoradiographic techniques. IGF-I-like immunostaining was present in all cases of SQC, ADC, and LCC, but not in cases of SCC. Strong immunostaining was observed in cases of SQC. On the other hand, ADC and LCC tissues showed a moderate or weak staining. Specific binding sites for IGF-I were present in all cases of SQC, ADC, LCC, and SCC examined. High densities of 125I-IGF-I binding sites were localized in cases of SQC and SCC. Low to high densities of the binding sites were found in LCC. Cases of ADC showed low densities of 125I-IGF-I binding sites. Specific binding obtained at a concentration of 80 pM 125I-IGF-I was competitively displaced by unlabeled IGF-I, with a 50% inhibitory concentration value of 1.84 +/- 0.31 x 10(-10) mol, whereas human insulin was much less potent in displacing the binding. This specificity profile is consistent with characteristics of IGF-I receptors. Scatchard analysis showed the presence of a single class of high affinity binding sites for IGF-I, with a Kd of approximately 1 nmol. Thus, the possibility that IGF-I may play a role in the growth of human lung cancers would have to be considered

  17. Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells.

    Science.gov (United States)

    Foxman, Ellen F; Storer, James A; Fitzgerald, Megan E; Wasik, Bethany R; Hou, Lin; Zhao, Hongyu; Turner, Paul E; Pyle, Anna Marie; Iwasaki, Akiko

    2015-01-20

    Most isolates of human rhinovirus, the common cold virus, replicate more robustly at the cool temperatures found in the nasal cavity (33-35 °C) than at core body temperature (37 °C). To gain insight into the mechanism of temperature-dependent growth, we compared the transcriptional response of primary mouse airway epithelial cells infected with rhinovirus at 33 °C vs. 37 °C. Mouse airway cells infected with mouse-adapted rhinovirus 1B exhibited a striking enrichment in expression of antiviral defense response genes at 37 °C relative to 33 °C, which correlated with significantly higher expression levels of type I and type III IFN genes and IFN-stimulated genes (ISGs) at 37 °C. Temperature-dependent IFN induction in response to rhinovirus was dependent on the MAVS protein, a key signaling adaptor of the RIG-I-like receptors (RLRs). Stimulation of primary airway cells with the synthetic RLR ligand poly I:C led to greater IFN induction at 37 °C relative to 33 °C at early time points poststimulation and to a sustained increase in the induction of ISGs at 37 °C relative to 33 °C. Recombinant type I IFN also stimulated more robust induction of ISGs at 37 °C than at 33 °C. Genetic deficiency of MAVS or the type I IFN receptor in infected airway cells permitted higher levels of viral replication, particularly at 37 °C, and partially rescued the temperature-dependent growth phenotype. These findings demonstrate that in mouse airway cells, rhinovirus replicates preferentially at nasal cavity temperature due, in part, to a less efficient antiviral defense response of infected cells at cool temperature.

  18. Mobile Digital Recording: Adequacy of the iRig and iOS Device for Acoustic and Perceptual Analysis of Normal Voice.

    Science.gov (United States)

    Oliveira, Gisele; Fava, Gaetano; Baglione, Melody; Pimpinella, Michael

    2017-03-01

    To determine whether the iRig and iOS device recording system is comparable with a standard computer recording system for digital voice recording. Thirty-seven vocally healthy adults, between ages 20 and 62, with a mean age of 33.9 years, 13 males and 24 females, were recruited. Recordings were simultaneously digitalized in an iPad and iPhone using a unidirectional condenser microphone for smartphones/tablets (iRig Mic, IK Multimedia) and in a computer laptop (Dell-Inspiron) using a unidirectional condenser microphone (Samson-CL5) connected to a preamplifier with phantom power. Both microphones were lined up at an equal fixed distance from the subject's mouth. Speech tasks consisted of a sustained vowel "ah" at comfortable pitch/loudness, counting from 1 to 10, and a glissando "ah" from a low to a high note. The samples captured on the iOS devices were transferred via SoundCloud in WAV format, and analyzed using the Praat software. The acoustic parameters measured were mean, min, and max F0, SD F0, jitter local, jitter rap, jitter ppq5, jitter ddp, shimmer local, shimmer local-dB, shimmer apq3, shimmer apq5, shimmer apq11, shimmer dda, NHR, and HNR. There were no statistically significant differences for any parameter and speech task analyzed for both iOS devices as compared with the gold standard computer/preamp system (all P values > 0.050). In addition, there were no statistical differences in the perceptual identification of the recordings among devices (P device may provide reliable digital recording of normal voices. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

  19. Cytokine-like factor-1, a novel soluble protein, shares homology with members of the cytokine type I receptor family.

    Science.gov (United States)

    Elson, G C; Graber, P; Losberger, C; Herren, S; Gretener, D; Menoud, L N; Wells, T N; Kosco-Vilbois, M H; Gauchat, J F

    1998-08-01

    In this report we describe the identification, cloning, and expression pattern of human cytokine-like factor 1 (hCLF-1) and the identification and cloning of its murine homologue. They were identified from expressed sequence tags using amino acid sequences from conserved regions of the cytokine type I receptor family. Human CLF-1 and murine CLF-1 shared 96% amino acid identity and significant homology with many cytokine type I receptors. CLF-1 is a secreted protein, suggesting that it is either a soluble subunit within a cytokine receptor complex, like the soluble form of the IL-6R alpha-chain, or a subunit of a multimeric cytokine, e.g., IL-12 p40. The highest levels of hCLF-1 mRNA were observed in lymph node, spleen, thymus, appendix, placenta, stomach, bone marrow, and fetal lung, with constitutive expression of CLF-1 mRNA detected in a human kidney fibroblastic cell line. In fibroblast primary cell cultures, CLF-1 mRNA was up-regulated by TNF-alpha, IL-6, and IFN-gamma. Western blot analysis of recombinant forms of hCLF-1 showed that the protein has the tendency to form covalently linked di- and tetramers. These results suggest that CLF-1 is a novel soluble cytokine receptor subunit or part of a novel cytokine complex, possibly playing a regulatory role in the immune system and during fetal development.

  20. Experimental diabetes increases insulin-like growth factor I and II receptor concentration and gene expression in kidney

    International Nuclear Information System (INIS)

    Werner, H.; Shen-Orr, Z.; Stannard, B.; Burguera, B.; Roberts, C.T. Jr.; LeRoith, D.

    1990-01-01

    Insulinlike growth factor I (IGF-I) is a mitogenic hormone with important regulatory roles in growth and development. One of the target organs for IGF-I action is the kidney, which synthesizes abundant IGF-I receptors and IGF-I itself. To study the involvement of IGF-I and the IGF-I receptor in the development of nephropathy, one of the major complications of diabetes mellitus, we measured the expression of these genes in the kidney and in other tissues of the streptozocin-induced diabetic rat. The binding of 125I-labeled IGF-I to crude membranes was measured in the same tissues. We observed a 2.5-fold increase in the steady-state level of IGF-I-receptor mRNA in the diabetic kidney, which was accompanied by a 2.3-fold increase in IGF-I binding. In addition to this increase in IGF-I binding to the IGF-I receptor, there was also binding to a lower-molecular-weight material that may represent an IGF-binding protein. No change was detected in the level of IGF-I-peptide mRNA. Similarly, IGF-II-receptor mRNA levels and IGF-II binding were significantly increased in the diabetic kidney. IGF-I- and IGF-II-receptor mRNA levels and IGF-I and IGF-II binding returned to control values after insulin treatment. Because the IGF-I receptor is able to transduce mitogenic signals on activation of its tyrosine kinase domain, we hypothesize that, among other factors, high levels of receptor in the diabetic kidney may also be involved in the development of diabetic nephropathy. Increased IGF-II-receptor expression in the diabetic kidney may be important for the intracellular transport and packaging of lysosomal enzymes, although a role for this receptor in signal transduction cannot be excluded. Finally, the possible role of IGF-binding proteins requires further study

  1. Interaction of Hepatitis C virus proteins with pattern recognition receptors

    Directory of Open Access Journals (Sweden)

    Imran Muhammad

    2012-06-01

    Full Text Available Abstract Hepatitis C virus (HCV is an important human pathogen that causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. This positive stranded RNA virus is extremely efficient in establishing persistent infection by escaping immune detection or hindering the host immune responses. Recent studies have discovered two important signaling pathways that activate the host innate immunity against viral infection. One of these pathways utilizes members of Toll-like receptor (TLR family and the other uses the RNA helicase retinoic acid inducible gene I (RIG-I as the receptors for intracellular viral double stranded RNA (dsRNA, and activation of transcription factors. In this review article, we summarize the interaction of HCV proteins with various host receptors/sensors through one of these two pathways or both, and how they exploit these interactions to escape from host defense mechanisms. For this purpose, we searched data from Pubmed and Google Scholar. We found that three HCV proteins; Core (C, non structural 3/4 A (NS3/4A and non structural 5A (NS5A have direct interactions with these two pathways. Core protein only in the monomeric form stimulates TLR2 pathway assisting the virus to evade from the innate immune system. NS3/4A disrupts TLR3 and RIG-1 signaling pathways by cleaving Toll/IL-1 receptor domain-containing adapter inducing IFN-beta (TRIF and Cardif, the two important adapter proteins of these signaling cascades respectively, thus halting the defense against HCV. NS5A downmodulates the expressions of NKG2D on natural killer cells (NK cells via TLR4 pathway and impairs the functional ability of these cells. TLRs and RIG-1 pathways have a central role in innate immunity and despite their opposing natures to HCV proteins, when exploited together, HCV as an ever developing virus against host immunity is able to accumulate these mechanisms for near unbeatable survival.

  2. Characterization of Toll-like receptors in primary lung epithelial cells: strong impact of the TLR3 ligand poly(I:C on the regulation of Toll-like receptors, adaptor proteins and inflammatory response

    Directory of Open Access Journals (Sweden)

    Weith Andreas

    2005-11-01

    Full Text Available Abstract Background Bacterial and viral exacerbations play a crucial role in a variety of lung diseases including COPD or asthma. Since the lung epithelium is a major source of various inflammatory mediators that affect the immune response, we analyzed the inflammatory reaction of primary lung epithelial cells to different microbial molecules that are recognized by Toll-like receptors (TLR. Methods The effects of TLR ligands on primary small airway epithelial cells were analyzed in detail with respect to cytokine, chemokine and matrix metalloproteinase secretion. In addition, the regulation of the expression of TLRs and their adaptor proteins in small airway epithelial cells was investigated. Results Our data demonstrate that poly(I:C, a synthetic analog of viral dsRNA, mediated the strongest proinflammatory effects among the tested ligands, including an increased secretion of IL-6, IL-8, TNF-α, GM-CSF, GRO-α, TARC, MCP-1, MIP-3α, RANTES, IFN-β, IP-10 and ITAC as well as an increased release of MMP-1, MMP-8, MMP-9, MMP-10 and MMP-13. Furthermore, our data show that poly(I:C as well as type-1 and type-2 cytokines have a pronounced effect on the expression of TLRs and molecules involved in TLR signaling in small airway epithelial cells. Poly(I:C induced an elevated expression of TLR1, TLR2 and TLR3 and increased the gene expression of the general TLR adaptor MyD88 and IRAK-2. Simultaneously, poly(I:C decreased the expression of TLR5, TLR6 and TOLLIP. Conclusion Poly(I:C, an analog of viral dsRNA and a TLR3 ligand, triggers a strong inflammatory response in small airway epithelial cells that is likely to contribute to viral exacerbations of pulmonary diseases like asthma or COPD. The pronounced effects of poly(I:C on the expression of Toll-like receptors and molecules involved in TLR signaling is assumed to influence the immune response of the lung epithelium to viral and bacterial infections. Likewise, the regulation of TLR expression by type

  3. Localization of receptors for bombesin-like peptides in the rat brain

    International Nuclear Information System (INIS)

    Moody, T.W.; Getz, R.; O'Donohue, T.L.; Rosenstein, J.M.

    1988-01-01

    BN-like peptides and receptors are present in discrete areas of the mammalian brain. By radioimmunoassay, endogenous BN/GRP, neuromedin B, and ranatensin-like peptides are present in the rat brain. High-to-moderate concentrations of BN/GRP are present in the rat hypothalamus and thalamus, whereas moderate-to-high densities of neuromedin B and ranatensin-like peptides are present in the olfactory bulb and hippocampus, as well as in the hypothalamus and thalamus. While the distribution of neuromedin B and ranatensin-like peptides appears similar, it is distinct from that of BN/GRP. When released from CNS neurons, these peptides may interact with receptors for BN-like peptides. BN, GRP, ranatensin, and neuromedin B inhibit specific [ 125 I-Tyr4]BN binding with high affinity. By use of in vitro autoradiographic techniques to detect binding of [ 125 I-Tyr4]BN to receptors for BN-like peptides, high grain densities were found in the olfactory bulb and tubercle, the nucleus accumbens, the suprachiasmatic and paraventricular nucleus of the hypothalamus, the central medial and paraventricular thalamic nuclei, the hippocampus, the dentate gyrus, and the amygdala of the rat brain. Some of these receptors may be biologically active and mediate the biological effects of BN-like peptides. For example, when BN is directly injected into the nucleus accumbens, pronounced grooming results and the effects caused by BN are reversed by spantide and [D-Phe12]BN. Thus, the putative BN receptor antagonists may serve as useful agents to investigate the biological significance of BN-like peptides in the CNS

  4. ROLLER RIG TESTING AT THE CZECH TECHNICAL UNIVERSITY

    Directory of Open Access Journals (Sweden)

    J. Kalivoda

    2016-08-01

    . Experiments conducted on the CTU roller rig confirm the possibility to significantly influence railway vehicle running dynamics by actively controlled wheelset guidance. Such concept could be regarded as a possible and likely approach for the design of future railway vehicles running gears.

  5. Mincle suppresses Toll-like receptor 4 activation.

    Science.gov (United States)

    Greco, Stephanie H; Mahmood, Syed Kashif; Vahle, Anne-Kristin; Ochi, Atsuo; Batel, Jennifer; Deutsch, Michael; Barilla, Rocky; Seifert, Lena; Pachter, H Leon; Daley, Donnele; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Miller, George

    2016-07-01

    Regulation of Toll-like receptor responses is critical for limiting tissue injury and autoimmunity in both sepsis and sterile inflammation. We found that Mincle, a C-type lectin receptor, regulates proinflammatory Toll-like receptor 4 signaling. Specifically, Mincle ligation diminishes Toll-like receptor 4-mediated inflammation, whereas Mincle deletion or knockdown results in marked hyperresponsiveness to lipopolysaccharide in vitro, as well as overwhelming lipopolysaccharide-mediated inflammation in vivo. Mechanistically, Mincle deletion does not up-regulate Toll-like receptor 4 expression or reduce interleukin 10 production after Toll-like receptor 4 ligation; however, Mincle deletion decreases production of the p38 mitogen-activated protein kinase-dependent inhibitory intermediate suppressor of cytokine signaling 1, A20, and ABIN3 and increases expression of the Toll-like receptor 4 coreceptor CD14. Blockade of CD14 mitigates the increased sensitivity of Mincle(-/-) leukocytes to Toll-like receptor 4 ligation. Collectively, we describe a major role for Mincle in suppressing Toll-like receptor 4 responses and implicate its importance in nonmycobacterial models of inflammation. © Society for Leukocyte Biology.

  6. DMPD: The Toll-like receptors: analysis by forward genetic methods. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16001129 The Toll-like receptors: analysis by forward genetic methods. Beutler B. I...mmunogenetics. 2005 Jul;57(6):385-92. (.png) (.svg) (.html) (.csml) Show The Toll-like receptors: analysis by forwar...d genetic methods. PubmedID 16001129 Title The Toll-like receptors: analysis by forward genetic meth

  7. Regulation of insulin-like growth factor (IGF) I receptor expression during muscle cell differentiation. Potential autocrine role of IGF-II.

    OpenAIRE

    Rosenthal, S M; Brunetti, A; Brown, E J; Mamula, P W; Goldfine, I D

    1991-01-01

    Muscle is an important target tissue for insulin-like growth factor (IGF) action. The presence of specific, high affinity IGF receptors, as well as the expression of IGF peptides and binding proteins by muscle suggest that a significant component of IGF action in this tissue is mediated through autocrine and/or paracrine mechanisms. To explore autocrine/paracrine action of IGFs in muscle, we studied the regulation of the IGF-I receptor and the expression of IGF peptides during differentiation...

  8. Development of receptors for insulin and insulin-like growth factor-I in head and brain of chick embryos: Autoradiographic localization

    International Nuclear Information System (INIS)

    Bassas, L.; Girbau, M.; Lesniak, M.A.; Roth, J.; de Pablo, F.

    1989-01-01

    In whole brain of chick embryos insulin receptors are highest at the end of embryonic development, while insulin-like growth factor-I (IGF-I) receptors dominate in the early stages. These studies provided evidence for developmental regulation of both types of receptors, but they did not provide information on possible differences between brain regions at each developmental stage or within one region at different embryonic ages. We have now localized the specific binding of [125I]insulin and [125I]IGF-I in sections of head and brain using autoradiography and computer-assisted densitometric analysis. Embryos have been studied from the latter part of organogenesis (days 6 and 12) through late development (day 18, i.e. 3 days before hatching), and the binding patterns have been compared with those in the adult brain. At all ages the binding of both ligands was to discrete anatomical regions. Interestingly, while in late embryos and adult brain the patterns of [125I]insulin and [125I] IGF-I binding were quite distinct, in young embryos both ligands showed very similar localization of binding. In young embryos the retina and lateral wall of the growing encephalic vesicles had the highest binding of both [125I]insulin and [125I]IGF-I. In older embryos, as in the adult brain, insulin binding was high in the paleostriatum augmentatum and molecular layer of the cerebellum, while IGF-I binding was prominent in the hippocampus and neostriatum. The mapping of receptors in a vertebrate embryo model from early prenatal development until adulthood predicts great overlap in any possible function of insulin and IGF-I in brain development, while it anticipates differential localized actions of the peptides in the mature brain

  9. Toll-like receptors in neonatal sepsis.

    LENUS (Irish Health Repository)

    O'Hare, Fiona M

    2013-06-01

    Toll-like receptors are vital transmembrane receptors that initiate the innate immune response to many micro-organisms. The discovery of these receptors has improved our understanding of host-pathogen interactions, and these receptors play an important role in the pathogenesis of multiple neonatal conditions such as sepsis and brain injury. Toll-like receptors, especially TLRs 2 and 4, are associated with necrotizing enterocolitis, periventricular leukomalacia and sepsis.

  10. Challenges associated with pre-border management of biofouling on oil rigs.

    Science.gov (United States)

    Hopkins, Grant A; Forrest, Barrie M

    2010-11-01

    The potential for oil rigs to transport diverse, reef-like communities around the globe makes them high risk vectors for the inadvertent spread of non-indigenous species (NIS). This paper describes two case studies where a suite of pre-border management approaches was applied to semi-submersible drilling rigs. In the first case study, a drilling rig was defouled in-water prior to departure from New Zealand to Australia. Risk mitigation measures were successful in reducing biosecurity risks to the recipient region, but they resulted in the unintentional introduction of the non-indigenous brown mussel (Perna perna) to New Zealand when the rig was defouled in-water by divers. In the second case study, lessons learned from this high-profile incursion resulted in a more structured approach to pre-border management, and this serves as a useful template for future rig transfers. Copyright © 2010 Elsevier Ltd. All rights reserved.

  11. Insulin and insulin-like growth factor-I (IGF-I) receptor phosphorylation in µ-calpain knockout mice

    Science.gov (United States)

    Numerous cellular processes are controlled by insulin and IGF-I signaling pathways. Due to previous work in our laboratories, we hypothesized that insulin (IR) and type 1 IGF-I (IGF-IR) receptor signaling is decreased due to increased protein tyrosine phosphatase 1B (PTP1B) activity. C57BL/6J mice...

  12. AHP 47: A RIG RGAD PO VISITS LHA SA

    Directory of Open Access Journals (Sweden)

    Pad ma skyid པདྨ་སྐྱིད།

    2017-04-01

    Full Text Available My name is Pad ma skyid. I was born in 1981 in Pan yag Community, 'Bo spa Township, Pad ma County, Mgo log Tibetan Autonomous Prefecture, Mtsho sngon (Qinghai Province. I have eight siblings. Growing up in a black yak-hair tent, we spent our days playing with lambs, foals, and calves. We told all sorts of stories when everyone was in bed - stories about King Ge sar, ghosts, marriages, and tricksters. It was a time for my whole family to relax and share. I heard many A rig rgad po stories from my parents, siblings, and guests. A rig rgad po became part of my childhood. These stories bring back many beautiful memories. ...

  13. IGF-I, IGF-II, and Insulin Stimulate Different Gene Expression Responses through Binding to the IGF-I Receptor

    DEFF Research Database (Denmark)

    Versteyhe, Soetkin; Klaproth, Birgit; Borup, Rehannah

    2013-01-01

    Insulin and the insulin-like growth factors (IGF)-I and -II are closely related peptides important for regulation of metabolism, growth, differentiation, and development. The IGFs exert their main effects through the IGF-I receptor. Although the insulin receptor is the main physiological receptor...... for insulin, this peptide hormone can also bind at higher concentrations to the IGF-I receptor and exert effects through it. We used microarray gene expression profiling to investigate the gene expression regulated by IGF-I, IGF-II, and insulin after stimulation of the IGF-I receptor. Fibroblasts from mice......, knockout for IGF-II and the IGF-II/cation-independent mannose-6-phosphate receptor, and expressing functional IGF-I but no insulin receptors, were stimulated for 4 h with equipotent saturating concentrations of insulin, IGF-I, and IGF-II. Each ligand specifically regulated a group of transcripts...

  14. The pro-Forms of Insulin-Like Growth Factor I (IGF-I) Are Predominant in Skeletal Muscle and Alter IGF-I Receptor Activation

    Science.gov (United States)

    Durzyńska, Julia; Philippou, Anastassios; Brisson, Becky K.; Nguyen-McCarty, Michelle

    2013-01-01

    IGF-I is a key regulator of muscle development and growth. The pre-pro-peptide produced by the Igf1gene undergoes several posttranslational processing steps to result in a secreted mature protein, which is thought to be the obligate ligand for the IGF-I receptor (IGF-IR). The goals of this study were to determine what forms of IGF-I exist in skeletal muscle, and whether the mature IGF-I protein was the only form able to activate the IGF-IR. We measured the proportion of IGF-I species in murine skeletal muscle and found that the predominant forms were nonglycosylated pro-IGF-I and glycosylated pro-IGF-I, which retained the C-terminal E peptide extension, instead of mature IGF-I. These forms were validated using samples subjected to viral expression of IGF-I combined with furin and glycosidase digestion. To determine whether the larger molecular weight IGF-I forms were also ligands for the IGF-IR, we generated each specific form through transient transfection of 3T3 cells and used the enriched media to perform kinase receptor activation assays. Compared with mature IGF-I, nonglycosylated pro-IGF-I had similar ability to activate the IGF-IR, whereas glycosylation of pro-IGF-I significantly reduced receptor activation. Thus, it is important to understand not only the quantity, but also the proportion of IGF-I forms produced, to evaluate the true biological activity of this growth factor. PMID:23407451

  15. Equipment available for automating rig operations

    International Nuclear Information System (INIS)

    McNair, W.L.

    1990-01-01

    Several manufacturers are producing automated rig equipment, from complete systems to individual functions for existing drilling rigs. Significant improvements in well site time, costs of operations, and improved drilling performance have led drilling contractors to install this equipment on their rigs. This paper details some of the equipment available for automating rigs

  16. Increased abundance of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of obese subjects is correlated with in vivo insulin sensitivity.

    Science.gov (United States)

    Federici, M; Porzio, O; Lauro, D; Borboni, P; Giovannone, B; Zucaro, L; Hribal, M L; Sesti, G

    1998-08-01

    We reported that in noninsulin-dependent diabetes melitus (NIDDM) patients expression of insulin/insulin-like growth factor I (IGF-I) hybrid receptors is increased in insulin target tissues. Whether this is a defect associated with NIDDM or represents a generalized abnormality associated with insulin resistant states is still unsettled. To address this, we applied a microwell-based immunoassay to measure abundance of insulin receptors, type 1 IGF receptors, and hybrid receptors in muscle of eight normal and eight obese subjects. Maximal insulin binding to insulin receptors was lower in obese than in control subjects (B/T = 1.8 +/- 0.20 and 2.6 +/- 0.30; P < 0.03, respectively) and was negatively correlated with insulinemia (r = -0.60; P < 0.01). Maximal IGF-I binding to type 1 IGF receptors was higher in obese than in controls (B/T = 1.9 +/- 0.20 and 0.86 +/- 0.10; P < 0.0001, respectively) and was negatively correlated with plasma IGF-I levels (r = -0.69; P < 0.003). Hybrid receptor abundance was higher in obese than in normal subjects (B/T = 1.21 +/- 0.14 and 0.44 +/- 0.06; P < 0.0003, respectively) and was negatively correlated with insulin binding (r = -0.60; P < 0.01) and positively correlated with IGF-I binding (r = 0.92; P < 0.0001). Increased abundance of hybrids was correlated with insulinemia (r = 0.70; P < 0.002) and body mass index (r = 0.71; P < 0.0019), whereas it was negatively correlated with in vivo insulin sensitivity measured by ITT (r = -0.67; P < 0.016). These results indicate that downregulation of insulin receptors or upregulation of type 1 IGF receptors because of changes in plasma insulin and IGF-I levels may result in modifications in hybrid receptor abundance.

  17. Involvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test.

    Science.gov (United States)

    Ostadhadi, Sattar; Norouzi-Javidan, Abbas; Chamanara, Mohsen; Akbarian, Reyhaneh; Imran-Khan, Muhammad; Ghasemi, Mehdi; Dehpour, Ahmad-Reza

    2017-09-01

    Tramadol is an analgesic agent that is mainly used to treat moderate to severe pain. There is evidence that tramadol may have antidepressant property. However, the mechanisms underlying the antidepressant effects of tramadol have not been elucidated yet. Considering that fact that N-methyl-d-aspartate (NMDA) receptor signaling may play an important role in the pathophysiology of depression, the aim of the present study was to investigate the role of NMDA receptor signaling in the possible antidepressant-like effects of tramadol in the mouse forced swimming test (mFST). We found that tramadol exerted antidepressant-like effects at high dose (40mg/kg, intraperitoneally [i.p.]) in the mFST. Co-administration of non-effective doses of NMDA receptor antagonists (ketamine [1mg/kg, i.p.], MK-801 [0.05mg/kg, i.p.], or magnesium sulfate [10mg/kg, i.p.]) with sub-effective dose of tramadol (20mg/kg, i.p.) exerted significant antidepressant-like effects in the mFST. The antidepressant-like effects of tramadol (40mg/kg) was also inhibited by pre-treatment with non-effective dose of the NMDA receptor agonist NMDA (75mg/kg, i.p.). Our data suggest a role for NMDA receptor signaling in the antidepressant-like effects of tramadol in the mFST. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. RIG-1 expression is associated with sexual malfunctions of female type 2 diabetic patients

    Directory of Open Access Journals (Sweden)

    Batool Hajebrahimi

    2017-03-01

    Full Text Available Introduction: The patients with type 2 diabetes (T2D suffer from the malfunctions of the sexual behaviors, and several mechanisms have been proposed to describe these disorders. The innate immunity may be involved in the malfunctions of T2D patients. Melanoma differentiation-associated protein 5 (MDA5 and retinoic acid (RA-inducible gene 1 (RIG-1, as the innate immunity receptors, are the responsible molecules for the activation of some intracellular signaling pathways and the induction of inflammation. Thus, this study aimed to examine the molecules which may participate in the induction/stimulation of sexual malfunctions in the female T2D patients. Methods: Sexual functions were evaluated in 41 female T2D patients using the Female Sexual Function Index (FSFI questionnaire. Real-time polymerase chain reaction (PCR technique was used to quantify MDA5 and RIG-1 mRNA levels. Results: Results showed that increased RIG-1 mRNA levels were significantly associated with the bad orgasm in the female T2D patients compared to the female patients with good orgasm. Expression of RIG-1 and MDA5 levels were not associated with other sexual functions’ criteria. Conclusion: The findings of this study demonstrated that bad orgasm is associated with the increased RIG-1 expression. Consequently, the correlation between inflammation and bad orgasm in a RIG-1 dependent manner is suggested.

  19. Insulin-like growth factor I and risk of breast cancer by age and hormone receptor status-A prospective study within the EPIC cohort.

    Science.gov (United States)

    Kaaks, Rudolf; Johnson, Theron; Tikk, Kaja; Sookthai, Disorn; Tjønneland, Anne; Roswall, Nina; Overvad, Kim; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie-Christine; Dossus, Laure; Rinaldi, Sabina; Romieu, Isabelle; Boeing, Heiner; Schütze, Madlen; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Palli, Domenico; Grioni, Sara; Tumino, Rosario; Sacerdote, Carlotta; Panico, Salvatore; Buckland, Genevieve; Argüelles, Marcial; Sánchez, María-José; Amiano, Pilar; Chirlaque, Maria-Dolores; Ardanaz, Eva; Bueno-de-Mesquita, H Bas; van Gils, Carla H; Peeters, Petra H; Andersson, Anne; Sund, Malin; Weiderpass, Elisabete; Gram, Inger Torhild; Lund, Eiliv; Khaw, Kay-Tee; Wareham, Nick; Key, Timothy J; Travis, Ruth C; Merritt, Melissa A; Gunter, Marc J; Riboli, Elio; Lukanova, Annekatrin

    2014-06-01

    Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case-control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR)Q4-Q1 = 1.41 [95% confidence interval (CI) 1.01-1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04-1.33] per 1-standard deviation (SD) increase in IGF-I, ptrend = 0.01) and among women who were diagnosed with breast cancer at 50 years or older (ORQ3-Q1 = 1.38 [95% CI 1.01-1.89]; OR = 1.19 [95% CI 1.04-1.36] per 1-SD increase in IGF-I, ptrend = 0.01) but not with receptor-positive disease diagnosed at an earlier age. No statistically significant associations were observed for ER- breast tumors overall and by age at diagnosis. Tests for heterogeneity by receptor status of the tumor were not statistically significant, except for women diagnosed with breast cancer at 50 years or older (phet = 0.03 for ER+/PR+ vs. ER-/PR- disease). Our data add to a global body of evidence indicating that higher circulating IGF-I levels may increase risk specifically of receptor-positive, but not receptor-negative, breast cancer diagnosed at 50 years or older. © 2013 UICC.

  20. {open_quote}Nintendo Rig{close_quote} lets two men do work of three on traditional servicing rig

    Energy Technology Data Exchange (ETDEWEB)

    Rintoul, B.

    1996-01-01

    New well servicing rig saves costs and increases safety by using a robot derrickman. The rigs is called the Nintendo Rig, taking the name from the joystick that controls the robot on the racking board 25 feet above the ground. An automated tong/slip package permanently mounted on the front of the rig handles pipe and rods on the ground.

  1. The mobile rig industry

    International Nuclear Information System (INIS)

    Karlsen, J.K.

    1992-08-01

    This study is part of the project ''A competitive Norway'', based on the theories and methods presented in the book ''The competitive advantage of nations'', by Michael E. Porter. The rig market may be segmented according to the type of service, the geographical market and the type of equipment. The focus of the report is exploration and appraisal drilling using jackup rigs and semi-submersible rigs in the Northwestern European market. Market shares of Norwegian, other European and US suppliers in the jackup and semi-submerisible market segments on the Norwegian continental shelf and the entire Northwestern market are presented. The main driving force behind the rig demand is the price of oil, but technological trends and changes in relative importance of the various geographical markets are also important. The industry is fairly fragmented on the supplier side, while the oil companies as customers have substantial bargaining power. There are high exit barriers because of the high capital intensity of the business. Combined with a highly volatile demand, this forces the industry through cycles of low capacity utilization and depressed rig day rates. 8 refs., 19 figs., 2 tabs

  2. Characterization and immune response expression of the Rig-I-like receptor mda5 in common carp Cyprinus carpio.

    Science.gov (United States)

    Zhu, Y Y; Xing, W X; Shan, S J; Zhang, S Q; Li, Y Q; Li, T; An, L; Yang, G W

    2016-06-01

    In this study, the full-length complementary (c)DNA of common carp Cyprinus carpio melanoma differentiation-associated gene 5 (mda5) was cloned. The complete open reading frame of C. carpio mda5 contained 2982 bp and encodes 993 amino acids. The deduced amino acids contained six functional domains: two caspase activation and recruitment domains (CARD), a conserved restriction domain of bacterial type III restriction enzyme (ResIII), a DExD/H box-containing domain (DEXDc), a helicase super family C-terminal domain (HELICc) and a C-terminal regulatory domain (RD). The mda5 gene was expressed in all tested tissues, with high levels in the gills and spleen, while lower expressed in gonad and blood. The copy numbers of mda5 were increased in the liver, spleen, head kidney and the mucosal-associated immune tissues such as the foregut, hindgut, gills and skin after stimulation with polyinosinic polycytidylic [poly(I:C)] and Aeromonas hydrophila. The myxovirus resistance gene (mx) messenger (m)RNA levels in the spleen, head kidney, foregut and gills were significantly up-regulated after poly(I:C) injection. When injected with poly(I:C), mda5 and mx transcripts were also significantly induced in vitro. These results implied that mda5 might be involved in both antiviral and antibacterial innate immune processes in C. carpio. © 2016 The Authors. Journal of Fish Biology © 2016 The Fisheries Society of the British Isles. © 2016 The Fisheries Society of the British Isles.

  3. 40th annual Reed rig census

    International Nuclear Information System (INIS)

    Fitts, R.L.; Stokes, T.A.

    1992-01-01

    This paper reports that declines characterize the 1992 rig census-in the number of available drilling rigs, in the number of active rigs, in rig utilization rate, in the number of rig owners and in industry optimism. The number of rotary rigs available for U.S. drilling fell by 255 units (11.3%) during the past 12 months, an attrition rate almost four times greater than in 1991. But despite the high attrition, only 59.7% of remaining rigs were working during the time the census was taken. Results of the 1992 census bring emphasis to an industry trend that became apparent in early 1991. The major oil companies, and many independents, continued their exodus form the U.S., and the remaining independents, which were hurt by low natural gas prices and unfavorable tax treatment of intangible drilling costs, were not able to pick u the drilling slack. Consequently, the past year has been disastrous for many U.S. drilling contractors, and the outlook for this industry segment remains bleak

  4. Rig`s electricity to power top drive drilling system

    Energy Technology Data Exchange (ETDEWEB)

    Liderth, D.

    1996-05-01

    Permanent magnet brushless electric motors to supply torque to more space-efficient top drive drilling assemblies was the solution designed by Kaman Electromagnetic Corporation, working hand-in-hand with Calgary-based Tesco Drilling Technology, to remedy problems created by the bulkiness of standard hydraulic top drive systems. The biggest advantage of using electric over hydraulic top drive systems is the ability to tap into the rig`s existing power source, which lowers both cost and effort. A better power to weight ratio and reduced maintenance requirements are other desirable advantages.

  5. Characterization of insulin-like growth factor I and insulin receptors on cultured bovine adrenal fasciculata cells. Role of these peptides on adrenal cell function

    International Nuclear Information System (INIS)

    Penhoat, A.; Chatelain, P.G.; Jaillard, C.; Saez, J.M.

    1988-01-01

    We have characterized insulin-like growth factor I (IGF-I) and insulin receptors in cultured bovine adrenal cells by binding and cross-linking affinity experiments. At equilibrium the dissociation constant and the number of binding sites per cell for IGF-I were 1.4 +/- (SE) 0.3 x 10(-9) M and 19,200 +/- 2,100, respectively. Under reduction conditions, disuccinimidyl suberate cross-linked [ 125 I]iodo-IGF-I to one receptor complex with an Mr of 125,000. Adrenal cells also contain specific insulin receptors with an apparent dissociation constant (Kd) of 10(-9) M. Under reduction conditions [ 125 I]iodo-insulin binds to one band with an approximate Mr of 125,000. IGF-I and insulin at micromolar concentrations, but not at nanomolar concentrations, slightly stimulated DNA synthesis, but markedly potentiated the mitogenic action of fibroblast growth factor. Adrenal cells cultured in a serum-free medium containing transferrin, ascorbic acid, and insulin (5 micrograms/ml) maintained fairly constant angiotensin-II (A-II) receptor concentration per cell and increased cAMP release on response to ACTH and their steroidogenic response to both ACTH and A-II. When the cells were cultured in the same medium without insulin, the number of A-II receptors significantly decreased to 65% and the increased responsiveness was blunted. Treatment of such cells for 3 days with increasing concentrations of IGF-I (1-100 ng/ml) produced a 2- to 3-fold increase in A-II receptors and enhanced the cAMP response (3- to 4-fold) to ACTH and the steroidogenic response (4- to 6-fold) to ACTH and A-II. These effects were time and dose dependent (ED50 approximately equal to 10(-9) M). Insulin at micromolar concentrations produced an effect similar to that of IGF-I, but at nanomolar concentrations the effect was far less

  6. 39th annual Reed rig census

    International Nuclear Information System (INIS)

    Crowhurst, M.E.; Fitts, R.L.

    1991-01-01

    This paper reports on cutbacks in U.S. exploration and development drilling during the first half of 1991 which squeezed most of the optimism out of the drilling industry. Just how rough the year has been is underscored by the results of this year's rig census. The number of rotary rigs available for U.S. drilling declined by only 69 units (3%) during the past 12 months. But despite those withdrawals from competition, only 66% of the remaining rigs were working at the time the census was taken. Results of the 1991 census contrasted sharply with the stability and optimism that seemed apparent a year ago when 72% of the available rig fleet met the census definition of active. At that time, the mini-boom in horizontal drilling coupled with tax-credit- driven gas drilling led to a relatively high rig utilization rate and suggested that rig supply and demand might be close to an economically acceptable balance. However, it quickly became apparent in early 1991 that industry optimism was unjustified. Horizontal drilling began to drop and the lowest natural gas prices in 12 years triggered rapid declines in gas drilling. Although oil prices have been relatively stable and above $18 per bbl since January 1989, most major operators have concluded that a better return on investment can be had outside the U.S. and have drastically cut their domestic drilling budgets. These factors, combined with softened energy demand from the worldwide recession, further slowed U.S. drilling. The long awaited balance between rig supply and demand has seemingly slipped away. The 1991 Reed rig census describes an industry facing several more rough years. Details of this year's census include: The available U.S. fleet now stands at 2,251 rigs, down by 69 from the 2,320-unit total in 1990, and the lowest since 1976. Rigs meeting the census definition of active numbered 1,485, down 192 (11.4%) from the 1,677 active rigs counted a year earlier

  7. Drilling rig mast

    Energy Technology Data Exchange (ETDEWEB)

    Bulgakov, E.S.; Barashkov, V.A.; Lebedev, A.I.; Panin, N.M.; Sirotkin, N.V.

    1981-01-07

    A drilling rig mast is proposed that contains a portal with a carrier shaft hinged to it and struts with stays. In order to decrease the time expended in the assembly and dessembly of the drilling rig, the portal is constructed from mobile and immobile parts that are connected together by a ball pivot; the immobile section of the portal has a T-shaped recess for directing the mobile section.

  8. Insulin-like growth factor-II (IGF II) receptor from rat brain is of lower apparent molecular weight than the IGF II receptor from rat liver

    International Nuclear Information System (INIS)

    McElduff, A.; Poronnik, P.; Baxter, R.C.

    1987-01-01

    The binding subunits of the insulin and insulin-like growth factor-I (IGF I) receptors from rat brain are of lower molecular weight than the corresponding receptor in rat liver, possibly due to variations in sialic acid content. We have compared the IGF II receptor from rat brain and rat liver. The brain receptor is of smaller apparent mol wt (about 10 K) on sodium dodecyl sulfate polyacrylamide gel electrophoresis. This size difference is independent of ligand binding as it persists in iodinated and specifically immunoprecipitated receptors. From studies of wheat germ agglutinin binding and the effect of neuraminidase on receptor mobility, we conclude that this difference is not simply due to variations in sialic acid content. Treatment with endoglycosidase F results in reduction in the molecular size of both liver and brain receptors and after this treatment the aglycoreceptors are of similar size. We conclude that in rat brain tissue the IGF II receptor like the binding subunits of the insulin and IGF I receptors is of lower molecular size than the corresponding receptors in rat liver. This difference is due to differences in N-linked glycosylation

  9. Replacement team of mining drilling rigs

    OpenAIRE

    Hamodi, Hussan; Lundberg, Jan

    2014-01-01

    This paper presents a practical model to calculate the optimal replacement time (ORT) of drilling rigs used in underground mining. As a case study, cost data for drilling rig were collected over four years from a Swedish mine. The cost data include acquisition, operating, maintenance and downtime costs when using a redundant rig. A discount rate is used to determine the value of these costs over time. The study develops an optimisation model to identify the ORT of a mining drilling rig which ...

  10. IN VITRO INTERACTION OF INFLUENZA VIRUS A(H1N1pdm09 WITH MONOCYTIC MACROPHAGES: INDIVIDUAL RESPONSES OF TLR7 AND RIG1 RECEPTOR GENES

    Directory of Open Access Journals (Sweden)

    T. M. Sokolova

    2017-01-01

    Full Text Available In vitro differentiation of donor blood monocytes to macrophages (Mph following GM-CSF treatment was accompanied by a significant increase in the levels of gene transcription signaling receptors TLR7 or RIG1. The levels of intracellular viral RNA (M1 gene in Mph remained high upon infection by influenza virus A H1N1pdm (Moscow 2009 for 24-96 hours. The innate immunity reactions caused by influenza virus show individual features: they are decreased in Mph from donor 1 which had initially high level of endosomal TLR7 gene activity, and it increased by influenza virus in MPh from donor 2 who had a very low level of TLR7 gene expression. The influenza H1N1pdm virus weakly stimulated expression of gene RIG1 and production of inflammatory cytokines in Mf in donor 1. The differences may be connected with individual sensitivity of the donors to influenza infection.

  11. Insulin and insulin-like growth factor receptors and responses

    International Nuclear Information System (INIS)

    Roth, R.A.; Steele-Perkins, G.; Hari, J.; Stover, C.; Pierce, S.; Turner, J.; Edman, J.C.; Rutter, W.J.

    1988-01-01

    Insulin is a member of a family of structurally related hormones with diverse physiological functions. In humans, the best-characterized members of this family include insulin, insulin-like growth factor (IGF)-I, and IGF-II. Each of these three polypeptide hormones has its own distinct receptor. The structures of each of these receptors have now been deduced from analyses of isolated cDNA clones. To study further the responses mediated through these three different receptors, the authors have been studying cells expressing the proteins encoded by these three cDNAs. The isolated cDNAs have been transfected into Chinese hamster ovary (CHO) cells, and the resulting transfected cell lines have been characterized as to the ligand-binding activities and signal-transducing activities of the expressed proteins

  12. Receptor-like kinase SOBIR1/EVR interacts with receptor-like proteins in plant immunity against fungal infection

    NARCIS (Netherlands)

    Liebrand, T.W.H.; Berg, van den G.C.M.; Zhang, Z.; Smit, P.; Cordewener, J.H.G.; America, A.H.P.; Sklenar, J.; Jones, A.M.E.; Tameling, W.I.L.; Robatzek, S.; Thomma, B.P.H.J.; Joosten, M.H.A.J.

    2013-01-01

    The plant immune system is activated by microbial patterns that are detected as nonself molecules. Such patterns are recognized by immune receptors that are cytoplasmic or localized at the plasma membrane. Cell surface receptors are represented by receptor-like kinases (RLKs) that frequently contain

  13. Panicolytic-like effect of tramadol is mediated by opioid receptors in the dorsal periaqueductal grey.

    Science.gov (United States)

    Fiaes, Gislaine Cardoso de Souza; Roncon, Camila Marroni; Sestile, Caio Cesar; Maraschin, Jhonatan Christian; Souza, Rodolfo Luis Silva; Porcu, Mauro; Audi, Elisabeth Aparecida

    2017-05-30

    Tramadol is a synthetic opioid prescribed for the treatment of moderate to severe pain, acting as agonist of μ-opioid receptors and serotonin (5-HT) and noradrenaline (NE) reuptake inhibitor. This study evaluated the effects of tramadol in rats submitted to the elevated T-maze (ETM), an animal model that evaluates behavioural parameters such as anxiety and panic. Male Wistar rats were intraperitoneally (i.p.) treated acutely with tramadol (16 and 32mg/kg) and were submitted to the ETM. Tramadol (32mg/kg) promoted a panicolytic-like effect. Considering that dorsal periaqueductal grey (dPAG) is the main brain structure related to the pathophysiology of panic disorder (PD), this study also evaluated the participation of 5-HT and opioid receptors located in the dPAG in the panicolytic-like effect of tramadol. Seven days after stereotaxic surgery for implantation of a cannula in the dPAG, the animals were submitted to the test. To assess the involvement of 5-HT 1A receptors on the effect of tramadol, we combined the 5-HT 1A receptor antagonist, WAY100635 (0.37nmol), microinjected intra-dPAG, 10min prior to the administration of tramadol (32mg/kg, i.p.). WAY100635 did not block the panicolytic-like effect of tramadol. We also associated the non-selective opioid receptor antagonist, naloxone, systemically (1mg/kg, i.p.) or intra-dPAG (0.5nmol) administered 10min prior to tramadol (32mg/kg, i.p.). Naloxone blocked the panicolytic-like effect of tramadol in both routes of administrations, showing that tramadol modulates acute panic defensive behaviours through its interaction with opioid receptors located in the dPAG. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Hoisting and rigging manual: Uncontrolled document

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1991-05-01

    This document is a draft copy of a Hoisting and Rigging Manual for the Department of Energy. The manual is divided into ten chapters. The chapter titles follow: terminology and definitions; operator training and qualification; overhead and gantry cranes; mobile cranes; forklift trucks; hoists; hooks; wire rope, slings, and rigging accessories; construction hoisting and rigging equipment requirements; references.

  15. DMPD: Toll-like receptor (TLR)-based networks regulate neutrophilic inflammation inrespiratory disease. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18031251 Toll-like receptor (TLR)-based networks regulate neutrophilic inflammation inrespiratory...l) (.csml) Show Toll-like receptor (TLR)-based networks regulate neutrophilic inflammation inrespiratory dis...utrophilic inflammation inrespiratory disease. Authors Sabroe I, Whyte MK. Publication Biochem Soc Trans. 20

  16. A rigged market

    International Nuclear Information System (INIS)

    Thomas, M.

    2000-01-01

    The mobile rig market remains a unique sector of the global upstream oil and gas industry. Big oil is continuing to emerge blinking from the darkness of its recent cash-starved existence to bask in the glory of a resurgent oil price. But the rig sector is once again lagging behind the pace being set by operators as they open up their wallets for new or delayed exploration and production projects. This paper gives statistics on worldwide count and contracts

  17. Epitope mapping of the alpha-chain of the insulin-like growth factor I receptor using antipeptide antibodies.

    Science.gov (United States)

    Delafontaine, P; Ku, L; Ververis, J J; Cohen, C; Runge, M S; Alexander, R W

    1994-12-01

    Insulin-like growth factor I (IGF I) is an important mitogen for vascular smooth muscle cells (VSMC). The IGF I receptor (IGF IR) is a heterotetramer composed of two cross-linked extracellular alpha-chains and two membrane-spanning beta-chains that contain a tyrosine-kinase domain. It has a high degree of sequence similarity to the insulin receptor (IR), and the putative ligand-specific binding site has been localized to a cysteine-rich region (CRR) of the alpha-chain. To obtain insights into antigenic determinants of the IGF IR, we raised a panel of site-specific polyclonal antibodies against short peptide sequences N-terminal to and within the CRR. Several antibodies raised against linear epitopes within the CRR bound to solubilized and native rat and human IGF IR by ELISA, did not cross-react with IR, but unexpectedly failed to inhibit 125I-IGF I binding. A polyclonal antibody directed against a 48-amino acid synthetic peptide, corresponding to a region of the CRR postulated to be essential for ligand binding, failed to react with either solubilized, reduced or intact IGF IR. Three antibodies specific for the N-terminus of the alpha-chain reacted with solubilized and native IGF IR. One of these, RAB 6, directed against amino acids 38-44 of the IGF IR, inhibited 125I-IGF I binding to rat aortic smooth muscle cells (RASM) and to IGF IR/3T3 cells (overexpressing human IGF IR) by up to 45%. Immunohistochemical analysis revealed strong IGF IR staining in the medial smooth muscle cell layer of rat aorta. These findings are consistent with a model wherein conformational epitopes within the CRR and linear epitopes within the N-terminus of the alpha-chain contribute to the IGF I binding pocket. These antibodies should provide a valuable tool to study structure-function relationships and in vivo regulation of the IGF IR.

  18. Development of irradiation rig in HTTR and dosimetry method. I-I type irradiation equipment

    Energy Technology Data Exchange (ETDEWEB)

    Shibata, Taiju; Kikuchi, Takayuki [Japan Atomic Energy Research Inst., Oarai, Ibaraki (Japan). Oarai Research Establishment; Miyamoto, Satoshi; Ogura, Kazutomo [Japan Atomic Power Co., Tokyo (Japan)

    2002-12-01

    The High Temperature Engineering Test Reactor (HTTR) is a graphite-moderated, helium gas-cooled test reactor with a maximum power of 30 MW. The HTTR aims not only to establish and upgrade the technological basis for the HTGRs but also to perform the innovative basic research on high temperature engineering with high temperature irradiation fields. It is planned that the HTTR is used to perform various engineering tests such as the safety demonstration test, high temperature test operation and irradiation test with large irradiation fields at high temperatures. This paper describes the design of the I-I type irradiation equipment developed as the first irradiation rig for the HTTR and does the planned dosimetry method at the first irradiation test. It was developed to perform in-pile creep test on a stainless steel with large standard size specimens in the HTTR. It can give great loads on the specimens stably and can control the irradiation temperature precisely. The in-core creep properties on the specimens are measured by newly developed differential transformers and the irradiation condition in the core is monitored by thermocouples and self-powered neutron detectors (SPNDs), continuously. The irradiated neutron fluence is assessed by neutron fluence monitors of small metallic wires after the irradiation. The obtained data at the first irradiation test can strongly be contributed to upgrade the technological basis for the HTGRs, since it is the first direct measurement of the in-core irradiation environments of the HTTR. (author)

  19. Reading the viral signature by Toll-like receptors and other pattern recognition receptors.

    Science.gov (United States)

    Mogensen, Trine H; Paludan, Søren R

    2005-03-01

    Successful host defense against viral infections relies on early production of type I interferon (IFN) and subsequent activation of a cellular cytotoxic response. The acute IFN and inflammatory response against virus infections is mediated by cellular pattern-recognition receptors (PRRs) that recognize specific molecular structures on viral particles or products of viral replication. Toll-like receptors (TLRs) constitute a class of membrane-bound PRRs capable of detecting microbial infections. While TLR2 and TLR4, which were first identified to recognize Gram-positive and Gram-negative bacteria, respectively, sense specific viral proteins on the cell surface, TLRs 3, 7, 8, and 9 serve as receptors for viral nucleic acids in endosomic compartments. In addition to TLRs, cells express cytoplasmic PRRs such as the RNA helicase retinoic acid inducible gene I and the kinase double-stranded RNA-activated protein kinase R, both of which sense dsRNA, a characteristic signature of viral replication, and initiate a protective cellular response. Here we review the recent progress in our understanding of PRRs and viral infections and discuss the molecular and cellular responses evoked by virus-activated PRRs. Finally, we look into what is currently known about the role of PRRs in viral infections in vivo.

  20. This immortal coil? New CT rigs duel against singles

    Energy Technology Data Exchange (ETDEWEB)

    Creighton, J.

    1998-12-01

    New competition to conventional single rigs that have changed little in the last four decades face new competition from next-generation coiled tubing (CT) units which have multi-function capabilities, ranging from driving onto leases, drilling and setting surface case to cementing. Several of these new units are ready to challenge the conventional single rigs. Their ability to perform at high penetration rates (up to twice what single rigs can do) is expected to significantly cut drill time, with corresponding cost savings for both contractors and operators. Serval Corporation and Fleet Coiled Services are just two of the drilling service companies that have launched new shallow grass roots coiled tubing drilling units recently, gambling that the new technology will win over conventional methods hands down. Some major companies, like Fracmaster Ltd. and NOWSCO Well Service Ltd., have targeted the re-entry and horizontal markets, a much more difficult technical challenge, sinking billions of dollars of research and development money into advancing the most technically difficult applications of coil technology.

  1. Technology trends, energy prices affect worldwide rig activity

    International Nuclear Information System (INIS)

    Rappold, K.

    1995-01-01

    The major worldwide offshore rig markets have improved slightly this year, while the onshore markets generally lagged slightly. Offshore rig utilization rates have remained strong worldwide, with some areas reaching nearly 100%. Total worldwide offshore rig (jack ups, semisubmersible, drillships, submersibles, and barges) utilization was about 86%. Offshore drilling activity is driven primarily by oil and natural gas price expectations. Natural gas prices tend to drive North American offshore drilling activity, including the shallow waters in the Gulf of Mexico. International offshore drilling activity and deepwater projects in the Gulf of Mexico are more closely tied to oil prices. The paper discusses US rig count, directional drilling activity, jack up rig demand, semisubmersibles demand, rig replacement costs, and new construction

  2. On the ligand binding profile and desensitization of plant ionotropic glutamate receptor (iGluR)-like channels functioning in MAMP-triggered Ca2+ influx

    DEFF Research Database (Denmark)

    Kwaaitaal, Mark Adrianus Cornelis J; Maintz, Jens; Cavdar, Meltem

    2012-01-01

    in the putative agonist binding profile and potential mode of desensitization of MAMP-activated plant iGluRs. Based on results from pharmacological inhibition and desensitization experiments, we propose that plant iGluR complexes responsible for the MAMP-triggered Ca ( 2+) signature have a binding profile...... that combines the specificities of mammalian NMDA-and non-NMDA types of iGluRs, possibly reflecting the evolutionary history of plant and animal iGluRs. We further hypothesize that, analogous to the mammalian NMDA-NR1 receptor, desensitization of plant iGluR-like channels might involve binding of the ubiquitous...

  3. Cellular La protein shields nonsegmented negative-strand RNA viral leader RNA from RIG-I and enhances virus growth by diverse mechanisms.

    Science.gov (United States)

    Bitko, Vira; Musiyenko, Alla; Bayfield, Mark A; Maraia, Richard J; Barik, Sailen

    2008-08-01

    The La antigen (SS-B) associates with a wide variety of cellular and viral RNAs to affect gene expression in multiple systems. We show that La is the major cellular protein found to be associated with the abundant 44-nucleotide viral leader RNA (leRNA) early after infection with respiratory syncytial virus (RSV), a nonsegmented negative-strand RNA virus. Consistent with this, La redistributes from the nucleus to the cytoplasm in RSV-infected cells. Upon RNA interference knockdown of La, leRNA is redirected to associate with the RNA-binding protein RIG-I, a known activator of interferon (IFN) gene expression, and this is accompanied by the early induction of IFN mRNA. These results suggest that La shields leRNA from RIG-I, abrogating the early viral activation of type I IFN. We mapped the leRNA binding function to RNA recognition motif 1 of La and showed that while wild-type La greatly enhanced RSV growth, a La mutant defective in RSV leRNA binding also did not support RSV growth. Comparative studies of RSV and Sendai virus and the use of IFN-negative Vero cells indicated that La supports the growth of nonsegmented negative-strand RNA viruses by both IFN suppression and a potentially novel IFN-independent mechanism.

  4. Are Toll-Like Receptors and Decoy Receptors Involved in the Immunopathogenesis of Systemic Lupus Erythematosus and Lupus-Like Syndromes?

    Directory of Open Access Journals (Sweden)

    Giuliana Guggino

    2012-01-01

    Full Text Available In this paper we focus our attention on the role of two families of receptors, Toll-like receptors (TLR and decoy receptors (DcR involved in the generation of systemic lupus erythematosus (SLE and lupus-like syndromes in human and mouse models. To date, these molecules were described in several autoimmune disorders such as rheumatoid arthritis, antiphospholipids syndrome, bowel inflammation, and SLE. Here, we summarize the findings of recent investigations on TLR and DcR and their role in the immunopathogenesis of the SLE.

  5. Rigged Hilbert spaces for chaotic dynamical systems

    International Nuclear Information System (INIS)

    Suchanecki, Z.; Antoniou, I.; Bandtlow, O.F.

    1996-01-01

    We consider the problem of rigging for the Koopman operators of the Renyi and the baker maps. We show that the rigged Hilbert space for the Renyi maps has some of the properties of a strict inductive limit and give a detailed description of the rigged Hilbert space for the baker maps. copyright 1996 American Institute of Physics

  6. Learning Inverse Rig Mappings by Nonlinear Regression.

    Science.gov (United States)

    Holden, Daniel; Saito, Jun; Komura, Taku

    2017-03-01

    We present a framework to design inverse rig-functions-functions that map low level representations of a character's pose such as joint positions or surface geometry to the representation used by animators called the animation rig. Animators design scenes using an animation rig, a framework widely adopted in animation production which allows animators to design character poses and geometry via intuitive parameters and interfaces. Yet most state-of-the-art computer animation techniques control characters through raw, low level representations such as joint angles, joint positions, or vertex coordinates. This difference often stops the adoption of state-of-the-art techniques in animation production. Our framework solves this issue by learning a mapping between the low level representations of the pose and the animation rig. We use nonlinear regression techniques, learning from example animation sequences designed by the animators. When new motions are provided in the skeleton space, the learned mapping is used to estimate the rig controls that reproduce such a motion. We introduce two nonlinear functions for producing such a mapping: Gaussian process regression and feedforward neural networks. The appropriate solution depends on the nature of the rig and the amount of data available for training. We show our framework applied to various examples including articulated biped characters, quadruped characters, facial animation rigs, and deformable characters. With our system, animators have the freedom to apply any motion synthesis algorithm to arbitrary rigging and animation pipelines for immediate editing. This greatly improves the productivity of 3D animation, while retaining the flexibility and creativity of artistic input.

  7. Endurance test on IR rig for RI production

    International Nuclear Information System (INIS)

    Chung, Heung June; Youn, Y. J.; Han, H. S.; Hong, S. B.; Cho, Y. G.; Ryu, J. S.

    2000-12-01

    This report presents the pressure drop, vibration and endurance test results for IR rig for RI production which were desigened and fabricated by KAERI. From the pressure drop test results, it is noted that the flow rate through the IR rig corresponding to the pressure drop of 200 kPa is measured to be about 3.12 kg/sec. Vibration frequency for the IR rig ranges from 13 to 17 Hz. RMS(Root Mean Square) displacement for the IR rig is less than 30 μm, and the maximum displacement is less than 110μm. These experimental results show that the design criteria of IR rig meet the HANARO limit conditions. Endurance test results show that the appreciable fretting wear for the IR rig does not occur, however tiny trace of wear between contact points is observed

  8. Phosphatidylinositol 3-Kinase (PI3K) Activity Bound to Insulin-like Growth Factor-I (IGF-I) Receptor, which Is Continuously Sustained by IGF-I Stimulation, Is Required for IGF-I-induced Cell Proliferation*

    Science.gov (United States)

    Fukushima, Toshiaki; Nakamura, Yusaku; Yamanaka, Daisuke; Shibano, Takashi; Chida, Kazuhiro; Minami, Shiro; Asano, Tomoichiro; Hakuno, Fumihiko; Takahashi, Shin-Ichiro

    2012-01-01

    Continuous stimulation of cells with insulin-like growth factors (IGFs) in G1 phase is a well established requirement for IGF-induced cell proliferation; however, the molecular components of this prolonged signaling pathway that is essential for cell cycle progression from G1 to S phase are unclear. IGF-I activates IGF-I receptor (IGF-IR) tyrosine kinase, followed by phosphorylation of substrates such as insulin receptor substrates (IRS) leading to binding of signaling molecules containing SH2 domains, including phosphatidylinositol 3-kinase (PI3K) to IRS and activation of the downstream signaling pathways. In this study, we found prolonged (>9 h) association of PI3K with IGF-IR induced by IGF-I stimulation. PI3K activity was present in this complex in thyrocytes and fibroblasts, although tyrosine phosphorylation of IRS was not yet evident after 9 h of IGF-I stimulation. IGF-I withdrawal in mid-G1 phase impaired the association of PI3K with IGF-IR and suppressed DNA synthesis the same as when PI3K inhibitor was added. Furthermore, we demonstrated that Tyr1316-X-X-Met of IGF-IR functioned as a PI3K binding sequence when this tyrosine is phosphorylated. We then analyzed IGF signaling and proliferation of IGF-IR−/− fibroblasts expressing exogenous mutant IGF-IR in which Tyr1316 was substituted with Phe (Y1316F). In these cells, IGF-I stimulation induced tyrosine phosphorylation of IGF-IR and IRS-1/2, but mutated IGF-IR failed to bind PI3K and to induce maximal phosphorylation of GSK3β and cell proliferation in response to IGF-I. Based on these results, we concluded that PI3K activity bound to IGF-IR, which is continuously sustained by IGF-I stimulation, is required for IGF-I-induced cell proliferation. PMID:22767591

  9. Type-I Insulin-Like Growth Factor Receptor (IGF1R)-Estrogen Receptor (ER) Crosstalk Contributes to Antiestrogen Therapy Resistance in Breast Cancer Cells

    Science.gov (United States)

    2013-02-01

    vitro have downregulated J GF1R making antibodies directed agai nst th is receptor ineffective. Inhlbition of IH may be necessary to manage ...monoclonal antibody to insulin-like growth factor receptor 1. J Clin Oncol 2009;27:580Q-7. 31. Drury s. Detre s. Leary A, Salter J, Reis-Filho J

  10. Characterization of insulin-like growth factor I receptors in the median eminence of the brain and their modulation by food restriction

    International Nuclear Information System (INIS)

    Bohannon, N.J.; Corp, E.S.; Wilcox, B.J.; Figlewicz, D.P.; Dorsa, D.M.; Baskin, D.G.

    1988-01-01

    High affinity binding sites for 125I-labeled [Thr59]insulin-like growth factor I (IGF-I) were measured in rat median eminence by in vitro autoradiography with slide-mounted sections of frozen rat brain. Specific binding of 0.1 nM iodo-[Thr59]IGF-I to brain slices reached maximum by 12 h at 4 C and was unchanged at 24 h. Densitometry by computer digital image analysis of autoradiographic images indicated that specific binding of iodo-[Thr59]IGF-I to the median eminence was reversible. The specificity of binding was evaluated with competition of iodo-[Thr59]IGF-I with unlabeled [Thr59]IGF-I, rat IGF-II (multiplication-stimulating activity), and porcine insulin. All were recognized by the binding site, but the rank order of potency was [Thr59]IGF-I greater than IGF-II greater than insulin. Somatostatin was completely ineffective. Further, an antibody against the rat IGF-II receptor did not block binding of iodo-[Thr59]IGF-I to the median eminence. Fourteen days of food restriction (75% of food intake of controls) resulted in significant weight loss and reduction of plasma immunoreactive IGF-I in six food-restricted rats (0.9 +/- 0.1 U/ml) compared with values in six controls (2.6 +/- 0.5 U/ml; P less than 0.001). Binding of 125I-labeled [Thr59]IGF-I in the median eminence was significantly increased in the food-restricted rats, primarily due to an increase in the concentration of iodo-[Thr59]IGF-I-binding sites in the median eminence; the affinity (Kd) of binding was unchanged. The results indicate that the median eminence has type I IGF-I receptors, which become more numerous under metabolic conditions associated with decreased caloric intake and lowered plasma IGF-I levels

  11. Injecting rabies immunoglobulin (RIG) into wounds only: A significant saving of lives and costly RIG.

    Science.gov (United States)

    Bharti, Omesh Kumar; Madhusudana, Shampur Narayan; Wilde, Henry

    2017-04-03

    An increasing number of dog bite victims were being presented to public hospitals in Himachal Pradesh in 2014 amidst virtual non availability of any rabies immunoglobulin (RIG). Only a small quantity of equine rabies immunoglobulin (eRIG) was available from the government owned Central Research Institute (CRI) Kasauli. This available eRIG was used in 269 patients as an emergency response and only for local infiltration of severe bite wounds by suspected rabid dogs. This was followed by rabies vaccination, using the WHO approved intra-dermal Thai Red Cross Society vaccination schedule. A subgroup of 26 patients were later identified who had been severely bitten by laboratory confirmed rabid dogs. They were followed for more than one year and all were found to be alive.

  12. The Impact of HLA Class I-Specific Killer Cell Immunoglobulin-Like Receptors on Antibody-Dependent Natural Killer Cell-Mediated Cytotoxicity and Organ Allograft Rejection.

    Science.gov (United States)

    Rajalingam, Raja

    2016-01-01

    Natural killer (NK) cells of the innate immune system are cytotoxic lymphocytes that play an important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self-human leukocyte antigen (HLA) class I molecules by inhibitory killer cell immunoglobulin-like receptors (KIRs) is involved in the calibration of NK cell effector capacities during the developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self-HLA class I (due to virus infection or tumor transformation) or HLA class I disparities (in the setting of allogeneic transplantation). NK cells expressing an inhibitory KIR-binding self-HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC), triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR-HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants.

  13. The impact of HLA class I-specific killer cell immunoglobulin-like receptors on antibody-dependent natural killer cell-mediated cytotoxicity and organ allograft rejection

    Directory of Open Access Journals (Sweden)

    Raja Rajalingam

    2016-12-01

    Full Text Available Natural killer (NK cells of the innate immune system are cytotoxic lymphocytes that play important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self HLA class I molecules by inhibitory killer cell immunoglobulin-like receptors (KIR is involved in the calibration of NK cell effector capacities during a developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self HLA class I (due to virus infection or tumor transformation or HLA class I disparities (in the setting of allogeneic transplantation. NK cells expressing an inhibitory KIR binding self HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC, triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR-HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants.

  14. Importance of killer immunoglobulin-like receptors in allogeneic hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Danilo Santana Alessio Franceschi

    2011-01-01

    Full Text Available Hematopoietic stem cell transplantation is the treatment of choice for many hematologic diseases, such as multiple myeloma, bone marrow aplasia and leukemia. Human leukocyte antigen (HLA compatibility is an important tool to prevent post-transplant complications such as graft rejection and graft-versus-host disease, but the high rates of relapse limit the survival of transplant patients. Natural Killer cells, a type of lymphocyte that is a key element in the defense against tumor cells, cells infected with viruses and intracellular microbes, have different receptors on their surfaces that regulate their cytotoxicity. Killer immunoglobulin-like receptors are the most important, interacting consistently with human leukocyte antigen class I molecules present in other cells and thus controlling the activation of natural killer cells. Several studies have shown that certain combinations of killer immunoglobulin-like receptors and human leukocyte antigens (in both donors and recipients can affect the chances of survival of transplant patients, particularly in relation to the graft-versusleukemia effect, which may be associated to decreased relapse rates in certain groups. This review aims to shed light on the mechanisms and effects of killer immunoglobulin-like receptors - human leukocyte antigen associations and their implications following hematopoietic stem cell transplantation, and to critically analyze the results obtained by the studies presented herein.

  15. The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/ MDA5 activation.

    Science.gov (United States)

    Ding, Zhen; Fang, Liurong; Yuan, Shuangling; Zhao, Ling; Wang, Xunlei; Long, Siwen; Wang, Mohan; Wang, Dang; Foda, Mohamed Frahat; Xiao, Shaobo

    2017-07-25

    Coronaviruses (CoVs) are a huge threat to both humans and animals and have evolved elaborate mechanisms to antagonize interferons (IFNs). Nucleocapsid (N) protein is the most abundant viral protein in CoV-infected cells, and has been identified as an innate immunity antagonist in several CoVs, including mouse hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV. However, the underlying molecular mechanism(s) remain unclear. In this study, we found that MHV N protein inhibited Sendai virus and poly(I:C)-induced IFN-β production by targeting a molecule upstream of retinoic acid-induced gene I (RIG-I) and melanoma differentiation gene 5 (MDA5). Further studies showed that both MHV and SARS-CoV N proteins directly interacted with protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein that can bind to RIG-I and MDA5 to activate IFN production. The N-PACT interaction sequestered the association of PACT and RIG-I/MDA5, which in turn inhibited IFN-β production. However, the N proteins from porcine epidemic diarrhea virus (PEDV) and porcine reproductive and respiratory syndrome virus (PRRSV), which are also classified in the order Nidovirales, did not interact and counteract with PACT. Taken together, our present study confirms that both MHV and SARS-CoV N proteins can perturb the function of cellular PACT to circumvent the innate antiviral response. However, this strategy does not appear to be used by all CoVs N proteins.

  16. Expression of IGF-I, IGF-I receptor and IGF binding proteins-1, -2, -3, -4 and -5 in human atherectomy specimens.

    Science.gov (United States)

    Grant, M B; Wargovich, T J; Ellis, E A; Tarnuzzer, R; Caballero, S; Estes, K; Rossing, M; Spoerri, P E; Pepine, C

    1996-12-17

    The molecular and cellular processes that induce rapid atherosclerotic plaque progression in patients with unstable angina and initiate restenosis following coronary interventional procedures are uncertain. We examined primary (de novo) and restenotic lesions retrieved at the time of directional coronary atherectomy for expression of insulin-like-growth factor-I (IGF-I). IGF-I receptor, and five IGF binding proteins (IGFBPs), IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 in smooth muscle cells (SMCs) using colloidal gold immunocytochemistry. IGF-1, its receptor and binding proteins were not detected in SMCs of normal coronary arteries. IGF-I localized primarily in synthetic smooth muscle cells (sSMCs) in both de novo and restenotic plaques. IGF-I receptor localized on sSMCs and their processes and colocalized with IGF-I. Although morphometric analysis of IGF-I and IGF-I receptor immunoreactivity in sSMCs of de novo and restenotic lesions showed comparable levels of IGF-I (3.2 +/- 1.0 and 2.9 +/- 0.9, respectively). IGF-I receptor was significantly higher in de novo lesions as compared to restenotic lesions (10.7 +/- 2.5 and 4.2 +/- 1.3, P system.

  17. Function of the cytoplasmic tail of human calcitonin receptor-like receptor in complex with receptor activity-modifying protein 2

    Energy Technology Data Exchange (ETDEWEB)

    Kuwasako, Kenji, E-mail: kuwasako@fc.miyazaki-u.ac.jp [Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan); Kitamura, Kazuo; Nagata, Sayaka; Hikosaka, Tomomi [Division of Circulation and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan); Kato, Johji [Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan)

    2010-02-12

    Receptor activity-modifying protein 2 (RAMP2) enables calcitonin receptor-like receptor (CRLR) to form an adrenomedullin (AM)-specific receptor. Here we investigated the function of the cytoplasmic C-terminal tail (C-tail) of human (h)CRLR by co-transfecting its C-terminal mutants into HEK-293 cells stably expressing hRAMP2. Deleting the C-tail from CRLR disrupted AM-evoked cAMP production or receptor internalization, but did not affect [{sup 125}I]AM binding. We found that CRLR residues 428-439 are required for AM-evoked cAMP production, though deleting this region had little effect on receptor internalization. Moreover, pretreatment with pertussis toxin (100 ng/mL) led to significant increases in AM-induced cAMP production via wild-type CRLR/RAMP2 complexes. This effect was canceled by deleting CRLR residues 454-457, suggesting Gi couples to this region. Flow cytometric analysis revealed that CRLR truncation mutants lacking residues in the Ser/Thr-rich region extending from Ser{sup 449} to Ser{sup 467} were unable to undergo AM-induced receptor internalization and, in contrast to the effect on wild-type CRLR, overexpression of GPCR kinases-2, -3 and -4 failed to promote internalization of CRLR mutants lacking residues 449-467. Thus, the hCRLR C-tail is crucial for AM-evoked cAMP production and internalization of the CRLR/RAMP2, while the receptor internalization is dependent on the aforementioned GPCR kinases, but not Gs coupling.

  18. The Winfrith 9MW heat transfer rig

    International Nuclear Information System (INIS)

    Obertelli, J.D.

    1976-01-01

    The Winfrith 9MW Rig is used for studying heat transfer and flow resistance in a variety of test sections at system pressures up to 68 bar. The basic rig and its instrumentation are discussed together with the characteristics of the test section design. The rig has been used in studies involving the full scale simulation of Steam Generating Heavy Water (SGHW) fuel assemblies and the paper discusses the measurements made in this type of study. (author)

  19. Rig supervisors

    International Nuclear Information System (INIS)

    Nordt, D.P.; Stone, M.S.

    1992-01-01

    This paper helps prepare the inexperienced rig supervisor to manage a drilling operation. It outlines operational-knowledge requirements and optimization concepts for improving drilling performance and lowering drilling costs. It gives guidelines on safety and environmental responsibilities, and provides recommendations on work tools, leadership, and communication

  20. Experimental rigs for MHD studies

    International Nuclear Information System (INIS)

    Venkataramani, N.; Jayakumar, R.; Iyer, D.R.; Dixit, N.S.

    1976-01-01

    An MHD experimental rig is a miniature MHD installation consisting of basic equipments necessary for specific investigations. Some of the experimental rigs used in the investigations being carried out at the Bhabha Atomic Research Centre, Bombay (India) are dealt with. The experiments included diagnostics and evaluation of materials in seeded combustion plasmas and argon plasmas. The design specifications, schematics and some of the results of the investigations are also mentioned. (author)

  1. Estrogen binding, receptor mRNA, and biologic response in osteoblast-like osteosarcoma cells

    International Nuclear Information System (INIS)

    Komm, B.S.; Terpening, C.M.; Benz, D.J.; Graeme, K.A.; Gallegos, A.; Korc, M.; Greene, G.L.; O'Malley, B.W.; Haussler, M.R.

    1988-01-01

    High specific activity estradiol labeled with iodine-125 was used to detect approximately 200 saturable, high-affinity (dissociation constant approximately equal to 1.0 nM) nuclear binding sites in rat (ROS 17/2.8) and human (HOS TE85) clonal osteoblast-like osteosarcoma cells. Of the steroids tested, only testosterone exhibited significant cross-reactivity with estrogen binding. RNA blot analysis with a complementary DNA probe to the human estrogen receptor revealed putative receptor transcripts of 6 to 6.2 kilobases in both rat and human osteosarcoma cells. Type I procollagen and transforming growth factor-beta messenger RNA levels were enhanced in cultured human osteoblast-like cells treated with 1 nM estradiol. Thus, estrogen can act directly on osteoblasts by a receptor-mediated mechanism and thereby modulate the extracellular matrix and other proteins involved in the maintenance of skeletal mineralization and remodeling

  2. Receptors for GRP/bombesin-like peptides in the rat forebrain

    International Nuclear Information System (INIS)

    Wolf, S.S.; Moody, T.W.

    1985-01-01

    Binding sites in the rat forebrain were characterized using ( 125 I-Tyr4)bombesin as a receptor probe. Pharmacology experiments indicate that gastrin releasing peptide (GRP) and the GRP fragments GRP as well as Ac-GRP inhibited radiolabeled (Tyr4)bombesin binding with high affinity. Biochemistry experiments indicated that heat, N-ethyl maleimide or trypsin greatly reduced radiolabeled (Tyr4)bombesin binding. Also, autoradiographic studies indicated that highest grain densities were present in the stria terminalis, periventricular and suprachiasmatic nucleus of the hypothalamus, dorsomedial and rhomboid thalamus, dentate gyrus, hippocampus and medial amygdaloid nucleus. The data suggest that CNS protein receptors, which are discretely distributed in the rat forebrain, may mediate the action of endogenous GRP/bombesin-like peptides

  3. Genetic polymorphisms of dsRNA ligating pattern recognition receptors TLR3, MDA5, and RIG-I. Association with systemic lupus erythematosus and clinical phenotypes

    DEFF Research Database (Denmark)

    Enevold, C; Kjaer, Lasse; Nielsen, Claus Henrik

    2014-01-01

    This study aimed to demonstrate possible associations between genetic polymorphisms in Toll-like receptor 3, interferon induced with helicase C domain 1 (IFIH1) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 and systemic lupus erythematosus (SLE), including the phenotypes lupus nephritis and malar...

  4. Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs?

    Science.gov (United States)

    Barwell, James; Gingell, Joseph J; Watkins, Harriet A; Archbold, Julia K; Poyner, David R; Hay, Debbie L

    2012-05-01

    The calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR) are two of the 15 human family B (or Secretin-like) GPCRs. CTR and CLR are of considerable biological interest as their pharmacology is moulded by interactions with receptor activity-modifying proteins. They also have therapeutic relevance for many conditions, such as osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine and cardiovascular disease. In light of recent advances in understanding ligand docking and receptor activation in both the family as a whole and in CLR and CTR specifically, this review reflects how applicable general family B GPCR themes are to these two idiosyncratic receptors. We review the main functional domains of the receptors; the N-terminal extracellular domain, the juxtamembrane domain and ligand interface, the transmembrane domain and the intracellular C-terminal domain. Structural and functional findings from the CLR and CTR along with other family B GPCRs are critically appraised to gain insight into how these domains may function. The ability for CTR and CLR to interact with receptor activity-modifying proteins adds another level of sophistication to these receptor systems but means careful consideration is needed when trying to apply generic GPCR principles. This review encapsulates current thinking in the realm of family B GPCR research by highlighting both conflicting and recurring themes and how such findings relate to two unusual but important receptors, CTR and CLR. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  5. Agmatine produces antidepressant-like effects by activating AMPA receptors and mTOR signaling.

    Science.gov (United States)

    Neis, Vivian Binder; Moretti, Morgana; Bettio, Luis Eduardo B; Ribeiro, Camille M; Rosa, Priscila Batista; Gonçalves, Filipe Marques; Lopes, Mark William; Leal, Rodrigo Bainy; Rodrigues, Ana Lúcia S

    2016-06-01

    The activation of AMPA receptors and mTOR signaling has been reported as mechanisms underlying the antidepressant effects of fast-acting agents, specially the NMDA receptor antagonist ketamine. In the present study, oral administration of agmatine (0.1mg/kg), a neuromodulator that has been reported to modulate NMDA receptors, caused a significant reduction in the immobility time of mice submitted to the tail suspension test (TST), an effect prevented by the administration of DNQX (AMPA receptor antagonist, 2.5μg/site, i.c.v.), BDNF antibody (1μg/site, i.c.v.), K-252a (TrkB receptor antagonist, 1μg/site, i.c.v.), LY294002 (PI3K inhibitor, 10nmol/site, i.c.v.) or rapamycin (selective mTOR inhibitor, 0.2nmol/site, i.c.v.). Moreover, the administration of lithium chloride (non-selective GSK-3β inhibitor, 10mg/kg, p.o.) or AR-A014418 (selective GSK-3β inhibitor, 0.01μg/site, i.c.v.) in combination with a sub-effective dose of agmatine (0.0001mg/kg, p.o.) reduced the immobility time in the TST when compared with either drug alone. Furthermore, increased immunocontents of BDNF, PSD-95 and GluA1 were found in the prefrontal cortex of mice just 1h after agmatine administration. These results indicate that the antidepressant-like effect of agmatine in the TST may be dependent on the activation of AMPA and TrkB receptors, PI3K and mTOR signaling as well as inhibition of GSK-3β, and increase in synaptic proteins. The results contribute to elucidate the complex signaling pathways involved in the antidepressant effect of agmatine and reinforce the pivotal role of these molecular targets for antidepressant responses. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  6. Plasma membrane Toll-like receptor activation increases bacterial uptake but abrogates endosomal <i>Lactobacillus acidophilusi> induction of interferon-β

    DEFF Research Database (Denmark)

    Boye, Louise; Welsby, Iain; Lund, Lisbeth Drozd

    2016-01-01

    Lactobacillus acidophilus induces a potent interferon-β (IFN-β) response in dendritic cells (DCs) by a Toll-like receptor 2 (TLR2) -dependent mechanism, in turn leading to strong interleukin-12 (IL-12) production. In the present study, we investigated the involvement of different types of endocyt...

  7. 29 CFR 1918.54 - Rigging gear.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Rigging gear. 1918.54 Section 1918.54 Labor Regulations...) SAFETY AND HEALTH REGULATIONS FOR LONGSHORING Vessel's Cargo Handling Gear § 1918.54 Rigging gear. (a... other alternate device shall be provided to allow trimming of the gear and to prevent employees from...

  8. Toll-like receptorer, nye behandlingsstrategier?

    DEFF Research Database (Denmark)

    Pedersen, Claus Vinter Bødker; Østergaard, Lars; Mogensen, Trine

    2007-01-01

    Toll-like receptors (TLRs) comprise a group of recently discovered receptors which are essential molecular structures in the activation of immunity. The discovery of TLRs has provided a substantial increase in the knowledge of immunologic aspects of disease pathology and is presently giving rise...... to new treatment strategies. This review summarizes the current knowledge on TLRs functioning in infections, their possible roles in inflammatory bowl disease and the pivotal role for TLRs in endotoxic shock, an area which is currently subject to development of a new farmakon. Udgivelsesdato: 2007-Jun-4...

  9. Killer Cell Immunoglobulin-like Receptors and their Ligands

    Directory of Open Access Journals (Sweden)

    Tajik N.

    2010-09-01

    Full Text Available The Natural killer (NK cells are a subset of lymphocytes comprising around 10% of total lymphocytes in peripheral blood. Due to their role in the innate response, NK cells provide a ‘first line of defense’ against infectious agents and cancer and are also thought to play a role in autoimmunity. The killer cell immunoglobulin-like receptors (KIR are regulatory surface molecules, found on NK cells and on a subset of T lymphocytes. The genes for KIR are present on chromosome 19 in the leukocyte receptor complex and show a major difference for both the type and number of KIR genes present among different ethnic groups. They have been divided into two groups of 2D or 3D, depending on the number of external immunoglobulin domains. The presence of a long cytoplasmic tail with two immune tyrosine-based inhibitory motifs (ITIM allows the transduction of inhibitory signals and characterizes the inhibitory KIRs (2DL and 3DL, whereas the presence of short cytoplasmic tails corresponds to the activating KIR receptors (2DS and 3DS.These polymorphic receptors interact with specific motifs on human leukocyte antigen (HLA class I molecules, modulate NK cytolytic activity. Some KIRs are known to interact with HLA-C molecules of target cells, HLA-Bw4 molecules and HLA-A3/11. For some KIRs the corresponding ligands are still unknown.

  10. Endurance test of DUPIC irradiation test rig-003

    Energy Technology Data Exchange (ETDEWEB)

    Moon, J.S; Yang, M.S.; Lee, C.Y.; Ryu, J.S.; Jeon, H.G

    2001-04-01

    This report presents the pressure drop, vibration and endurance test results for DUPIC Irradiation Test Rig-003 which was design and fabricated by KAERI. From the pressure drop and vibration test results, it is verified that DUPIC Irradiation Test Rig-003 satisfied the limit conditions of HANARO. And, remarkable wear is not observed in DUPIC Irradiation Test Rig-003 during 40 endurance test days.

  11. Field Demonstraton of Existing Microhole Coiled Tubing Rig (MCTR) Technology

    Energy Technology Data Exchange (ETDEWEB)

    Kent Perry; Samih Batarseh; Sheriff Gowelly; Thomas Hayes

    2006-05-09

    The performance of an advanced Microhole Coiled Tubing Rig (MCTR) has been measured in the field during the drilling of 25 test wells in the Niobrara formation of Western Kansas and Eastern Colorado. The coiled tubing (CT) rig designed, built and operated by Advanced Drilling Technologies (ADT), was documented in its performance by GTI staff in the course of drilling wells ranging in depth from 500 to nearly 3,000 feet. Access to well sites in the Niobrara for documenting CT rig performance was provided by Rosewood Resources of Arlington, VA. The ADT CT rig was selected for field performance evaluation because it is one of the most advanced commercial CT rig designs that demonstrate a high degree of process integration and ease of set-up and operation. Employing an information collection protocol, data was collected from the ADT CT rig during 25 drilling events that encompassed a wide range of depths and drilling conditions in the Niobrara. Information collected included time-function data, selected parametric information indicating CT rig operational conditions, staffing levels, and field observations of the CT rig in each phase of operation, from rig up to rig down. The data obtained in this field evaluation indicates that the ADT CT rig exhibited excellent performance in the drilling and completion of more than 25 wells in the Niobrara under varied drilling depths and formation conditions. In the majority of the 25 project well drilling events, ROP values ranged between 300 and 620 feet per hour. For all but the lowest 2 wells, ROP values averaged approximately 400 feet per hour, representing an excellent drilling capability. Most wells of depths between 500 and 2,000 feet were drilled at a total functional rig time of less than 16 hours; for wells as deep at 2,500 to 3,000 feet, the total rig time for the CT unit is usually well under one day. About 40-55 percent of the functional rig time is divided evenly between drilling and casing/cementing. The balance of

  12. A new generation drilling rig: hydraulically powered and computer controlled

    Energy Technology Data Exchange (ETDEWEB)

    Laurent, M.; Angman, P.; Oveson, D. [Tesco Corp., Calgary, AB, (Canada)

    1999-11-01

    Development, testing and operation of a new generation of hydraulically powered and computer controlled drilling rig that incorporates a number of features that enhance functionality and productivity, is described. The rig features modular construction, a large heated common drilling machinery room, permanently-mounted draw works which, along with the permanently installed top drive, significantly reduces rig-up/rig-down time. Also featured are closed and open hydraulic systems and a unique hydraulic distribution manifold. All functions are controlled through a programmable logic controller (PLC), providing almost unlimited interlocks and calculations to increase rig safety and efficiency. Simplified diagnostic routines, remote monitoring and troubleshooting are also part of the system. To date, two rigs are in operation. Performance of both rigs has been rated as `very good`. Little or no operational problems have been experienced; downtime has averaged 0.61 per cent since August 1998 when the the first of the two rigs went into operation. The most important future application for this rig is for use with the casing drilling process which eliminates the need for drill pipe and tripping. It also reduces the drilling time lost due to unscheduled events such as reaming, fishing and taking kicks while tripping. 1 tab., 6 figs.

  13. Advanced control strategies for a drill rig

    International Nuclear Information System (INIS)

    Banerjee, A.; Hiller, M.; Fink, B.

    1996-01-01

    The construction of tunnels is usually undertaken using a combination of blasting and drilling to achieve rock excavation. Easy handling and high accuracy, and thus greater efficiency, in drilling rigs is an essential ingredient of successful competition in the market place. This article describes a cartesian control concept used for a twin boom drill rig. This simplifies the handling of a drilling boom, reduces the duration of a working cycle and increases security. A remote control system has been added to the drill rig to support the operator working in complicated environments. (UK)

  14. Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice.

    Science.gov (United States)

    Zeng, Yi; Wang, Ping-Han; Zhang, Mao; Du, Jun-Rong

    2016-02-01

    The predominant distribution of the antiaging Klotho protein in both the kidneys and brain may point to its essential role in protecting against dysfunction of the kidney-brain axis during the aging process. Our previous study showed that the downregulation of Klotho was involved in aging-related cognitive impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. The present study investigated the potential role of Klotho in aging-associated inflammation and renal injury. Age- and gender-matched groups of SAMP8 mice and their corresponding normal control senescence-accelerated mouse resistant-1 (SAMR1) were used to investigate the potential role of Klotho in aging-associated inflammation and renal injury. Compared with aged SAMR1 controls, early-stage chronic kidney disease (CKD), which is associated with an increase in the urinary albumin-to-creatinine ratio, inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis, was observed in aged SAMP8 mice. Furthermore, the aging-related loss of Klotho-induced activation of the retinoic acid-inducible gene 1/nuclear factor-κB (RIG-I/NF-κB) signaling pathway and subsequent production of the proinflammatory mediators tumor necrosis factor α, interleukin-6, and inducible nitric oxide synthase in the kidneys of aged SAMP8 mice compared with SAMR1 controls. The present results suggest that aging-related inflammation and the development of early-stage CKD are likely associated with the downregulation of Klotho and induction of the RIG-I/NF-κB signaling pathway in 12-month-old SAMP8 mice. Moreover, aged SAMP8 mice with cognitive deficits and renal damage may be a potential mouse model for investigating the kidney-brain axis in the aging process.

  15. Nature and regulation of the receptors for insulin-like growth factors

    International Nuclear Information System (INIS)

    Rechler, M.M.; Nissley, S.P.

    1985-01-01

    Two subtypes of IGF receptors have been identified. Type I IGF receptors have a Mr greater than 300,000 and are composed of disulfide-linked 130,000-dalton (alpha) and approximately 90,000-dalton (beta) subunits. Type I receptors preferentially bind IGF-I but also bind IGF-II and, more weakly, insulin. Type II IGF receptors consist of a 250,000-dalton protein that contains internal disulfide bonds but is not linked to other membrane components. Type II receptors bind IGF-II with higher affinity than IGF-I. They do not interact with even very high concentrations of insulin. Type I IGF receptors and insulin receptors are homologous structures. Type II IGF receptors do not appear to be homologous to type I receptors. Type II receptors do not appear to be downregulated. Insulin acutely upregulates type II IGF receptors in intact rat adipose cells by effecting a redistribution of receptors cycling between a large intracellular pool and the plasma membrane. Insulin and the IGFs elicit the same biological responses, either by cross-reacting with one of the receptors for the heterologous ligand or by concurrent activation of convergent effector pathways by binding to the homologous receptor. Which mechanism is utilized appears to depend more on the tissue than on the biological response. Insulin desensitizes rat hepatoma cells to the actions of insulin and IGFs, mediated by both insulin and IGF receptors, by mechanisms distal to hormone binding and possibly common to IGF and insulin effector pathways

  16. Gulf of Mexico rig activity up, international lags

    International Nuclear Information System (INIS)

    Rappold, K.

    1994-01-01

    Demand for jack up and semisubmersible rigs has improved in the Gulf of Mexico following a decline in activity earlier this year. International drilling activity, however, has shown slight declines in several regions. Relatively firm natural gas prices have helped buoy rig activity in North America. Rig day rates have not followed suit, mainly because of the influx of rigs from weaker international markets. Day rates in the US may not increase until international activity picks up and the world-wide drilling market tightens. Oil prices have hit almost $20/bbl, mainly because of the recent oil worker' strike in Nigeria and good demand. Natural gas prices in the US have hovered around $2.00/MMBTU, and many industry analysts expect gas prices to remain strong over the next few years. This paper gives data on drilling rig counts and crude oil and gas prices in the Gulf of Mexico and onshore

  17. Fixed ratio combinations of glucagon like peptide 1 receptor agonists with basal insulin: a systematic review and meta-analysis.

    Science.gov (United States)

    Liakopoulou, Paraskevi; Liakos, Aris; Vasilakou, Despoina; Athanasiadou, Eleni; Bekiari, Eleni; Kazakos, Kyriakos; Tsapas, Apostolos

    2017-06-01

    Basal insulin controls primarily fasting plasma glucose but causes hypoglycaemia and weight gain, whilst glucagon like peptide 1 receptor agonists induce weight loss without increasing risk for hypoglycaemia. We conducted a systematic review and meta-analysis of randomised controlled trials to investigate the efficacy and safety of fixed ratio combinations of basal insulin with glucagon like peptide 1 receptor agonists. We searched Medline, Embase, and the Cochrane Library as well as conference abstracts up to December 2016. We assessed change in haemoglobin A 1c , body weight, and incidence of hypoglycaemia and gastrointestinal adverse events. We included eight studies with 5732 participants in the systematic review. Switch from basal insulin to fixed ratio combinations with a glucagon like peptide 1 receptor agonist was associated with 0.72% reduction in haemoglobin A 1c [95% confidence interval -1.03 to -0.41; I 2  = 93%] and 2.35 kg reduction in body weight (95% confidence interval -3.52 to -1.19; I 2  = 93%), reducing also risk for hypoglycaemia [odds ratio 0.70; 95% confidence interval 0.57 to 0.86; I 2  = 85%] but increasing incidence of nausea (odds ratio 6.89; 95% confidence interval 3.73-12.74; I 2  = 79%). Similarly, switching patients from treatment with a glucagon like peptide 1 receptor agonist to a fixed ratio combination with basal insulin was associated with 0.94% reduction in haemoglobin A 1c (95% confidence interval -1.11 to -0.77) and an increase in body weight by 2.89 kg (95% confidence interval 2.17-3.61). Fixed ratio combinations of basal insulin with glucagon like peptide 1 receptor agonists improve glycaemic control whilst balancing out risk for hypoglycaemia and gastrointestinal side effects.

  18. Intracellular postsynaptic cannabinoid receptors link thyrotropin-releasing hormone receptors to TRPC-like channels in thalamic paraventricular nucleus neurons.

    Science.gov (United States)

    Zhang, L; Kolaj, M; Renaud, L P

    2015-12-17

    In rat thalamic paraventricular nucleus of thalamus (PVT) neurons, activation of thyrotropin-releasing hormone (TRH) receptors enhances excitability via concurrent decrease in G protein-coupled inwardly-rectifying potassium (GIRK)-like and activation of transient receptor potential cation (TRPC)4/5-like cationic conductances. An exploration of intracellular signaling pathways revealed the TRH-induced current to be insensitive to phosphatidylinositol-specific phospholipase C (PI-PLC) inhibitors, but reduced by D609, an inhibitor of phosphatidylcholine-specific PLC (PC-PLC). A corresponding change in the I-V relationship implied suppression of the cationic component of the TRH-induced current. Diacylglycerol (DAG) is a product of the hydrolysis of PC. Studies focused on the isolated cationic component of the TRH-induced response revealed a reduction by RHC80267, an inhibitor of DAG lipase, the enzyme involved in the hydrolysis of DAG to the endocannabinoid 2-arachidonoylglycerol (2-AG). Further investigation revealed enhancement of the cationic component in the presence of either JZL184 or WWL70, inhibitors of enzymes involved in the hydrolysis of 2-AG. A decrease in the TRH-induced response was noted in the presence of rimonabant or SR144528, membrane permeable CB1 and CB2 receptor antagonists, respectively. A decrease in the TRH-induced current by intracellular, but not by bath application of the membrane impermeable peptide hemopressin, selective for CB1 receptors, suggests a postsynaptic intracellular localization of these receptors. The TRH-induced current was increased in the presence of arachidonyl-2'-chloroethylamide (ACEA) or JWH133, CB1 and CB2 receptor agonists, respectively. The PI3-kinase inhibitor LY294002, known to inhibit TRPC translocation, decreased the response to TRH. In addition, a TRH-induced enhancement of the low-threshold spike was prevented by both rimonabant, and SR144528. TRH had no influence on excitatory or inhibitory miniature

  19. Customization creates more efficient, cleaner rigs

    Energy Technology Data Exchange (ETDEWEB)

    Budd, G.

    2002-08-01

    Technological advances in drilling equipment are essential to improving efficiency in the oilpatch; getting the technological upper hand on the competition is no less important for drilling equipment manufacturers than for actors in other sectors of the industry. While off-the-shelf uniformity that reduces unit cost has been the trend in fabricating field gas compression modules, custom manufacturing has become very popular in the rig manufacturing sector. Examples from Crown Energy Technologies and Tesco Corporation, both of Calgary, Aecon Industrial's Edmonton operations, PCL Industrial Construction Ltd of Nisku, and Toromont Process Systems of Houston and Calgary are described to illustrate the widespread demand for customized drilling rigs, including the growing preference for electric drives. Top drive systems, as opposed to rotary drives also have become very popular; six out of ten rigs are sold with electric top drives today compared with fewer than 10 rigs a decade ago. At the same time, Tesco has recently signed a deal with Conoco Inc to construct three revolutionary drilling rigs using Tesco's proprietary Casing Drilling Technology, which uses standard oilfield casing instead of drill pipe, allowing operators to simultaneously drill, case and evaluate oil and gas wells. Aecon and PCL Industrial Construction have had much demand for customized spools and modules particularly from the oil sands industry, while Toromont Process Systems is also expanding its Calgary facilities to meet the demand for its dual gas compression equipment used by power stations for gas compression and co-generation, natural gas refrigeration and specialty gas processing.

  20. Deep water challenges for drilling rig design

    Energy Technology Data Exchange (ETDEWEB)

    Roth, M [Transocean Sedco Forex, Houston, TX (United States)

    2001-07-01

    Drilling rigs designed for deep water must meet specific design considerations for harsh environments. The early lessons for rig design came from experiences in the North Sea. Rig efficiency and safety considerations must include structural integrity, isolated/redundant ballast controls, triple redundant DP systems, enclosed heated work spaces, and automated equipment such as bridge cranes, pipe handling gear, offline capabilities, subsea tree handling, and computerized drill floors. All components must be designed to harmonize man and machine. Some challenges which are unique to Eastern Canada include frequent storms and fog, cold temperature, icebergs, rig ice, and difficult logistics. This power point presentation described station keeping and mooring issues in terms of dynamic positioning issues. The environmental influence on riser management during forced disconnects was also described. Design issues for connected deep water risers must insure elastic stability, and control deflected shape. The design must also keep stresses within acceptable limits. Codes and standards for stress limits, flex joints and tension were also presented. tabs., figs.

  1. The method of rigged spaces in singular perturbation theory of self-adjoint operators

    CERN Document Server

    Koshmanenko, Volodymyr; Koshmanenko, Nataliia

    2016-01-01

    This monograph presents the newly developed method of rigged Hilbert spaces as a modern approach in singular perturbation theory. A key notion of this approach is the Lax-Berezansky triple of Hilbert spaces embedded one into another, which specifies the well-known Gelfand topological triple. All kinds of singular interactions described by potentials supported on small sets (like the Dirac δ-potentials, fractals, singular measures, high degree super-singular expressions) admit a rigorous treatment only in terms of the equipped spaces and their scales. The main idea of the method is to use singular perturbations to change inner products in the starting rigged space, and the construction of the perturbed operator by the Berezansky canonical isomorphism (which connects the positive and negative spaces from a new rigged triplet). The approach combines three powerful tools of functional analysis based on the Birman-Krein-Vishik theory of self-adjoint extensions of symmetric operators, the theory of singular quadra...

  2. Insulin-like Growth Factor Receptor Inhibitors: Baby or the Bathwater?

    OpenAIRE

    Yee, Douglas

    2012-01-01

    The success of targeted therapies for cancer is undisputed; strong preclinical evidence has resulted in the approval of several new agents for cancer treatment. The type I insulin-like growth factor receptor (IGF1R) appeared to be one of these promising new targets. Substantial population and preclinical data have all pointed toward this pathway as an important regulator of tumor cell biology. Although early results from clinical trials that targeted the IGF1R showed some evidence of response...

  3. Pharmacological and expression profile of the prostaglandin I(2) receptor in the rat craniovascular system

    DEFF Research Database (Denmark)

    Myren, Maja; Olesen, Jes; Gupta, Saurabh

    2012-01-01

    Activation of the trigeminal nerve terminals around cerebral and meningeal arteries is thought to be an important patho-mechanism in migraine. Vasodilatation of the cranial arteries may also play a role in increasing nociception. Prostaglandin I(2) (PGI(2)) is capable of inducing a headache...... in healthy volunteers, a response that is likely to be mediated by the prostaglandin I(2) receptor (IP). This study investigates the functional and molecular characteristics of the IP receptor in the rat craniovascular system. In the closed cranial window model, iloprost, an IP receptor agonist, dilated...

  4. Innovative technology for a cost-effective land rig

    Energy Technology Data Exchange (ETDEWEB)

    Mehra, S.; Bryce, T.

    1996-05-01

    Sedco Forex has recently completed a new land drilling rig, currently deployed in Gabon, that integrates well construction activities with multiskilling to create cost savings across the board in drilling operations. Historically, operators have produced a comprehensive tender package specifying strictly the type and size of individual rig components and the number of personnel required to drill. In this case, the drilling contractor provides a fit-for-purpose rig, consistent with field location, well profile, operator`s priorities, and local constraints.

  5. Innovative technology for a cost-effective land rig

    International Nuclear Information System (INIS)

    Mehra, S.; Bryce, T.

    1996-01-01

    Sedco Forex has recently completed a new land drilling rig, currently deployed in Gabon, that integrates well construction activities with multiskilling to create cost savings across the board in drilling operations. Historically, operators have produced a comprehensive tender package specifying strictly the type and size of individual rig components and the number of personnel required to drill. In this case, the drilling contractor provides a fit-for-purpose rig, consistent with field location, well profile, operator's priorities, and local constraints

  6. Insulin-like growth factor-II receptors in cultured rat hepatocytes: regulation by cell density

    International Nuclear Information System (INIS)

    Scott, C.D.; Baxter, R.C.

    1987-01-01

    Insulin-like growth factor-II (IGF-II) receptors in primary cultures of adult rat hepatocytes were characterized and their regulation by cell density examined. In hepatocytes cultured at 5 X 10(5) cells per 3.8 cm2 plate [ 125 I]IGF-II bound to specific, high affinity receptors (Ka = 4.4 +/- 0.5 X 10(9) l/mol). Less than 1% cross-reactivity by IGF-I and no cross-reactivity by insulin were observed. IGF-II binding increased when cells were permeabilized with 0.01% digitonin, suggesting the presence of an intracellular receptor pool. Determined by Scatchard analysis and by polyacrylamide gel electrophoresis after affinity labeling, the higher binding was due solely to an increase in binding sites present on 220 kDa type II IGF receptors. In hepatocytes cultured at low densities, the number of cell surface receptors increased markedly, from 10-20,000 receptors per cell at a culture density of 6 X 10(5) cells/well to 70-80,000 receptors per cell at 0.38 X 10(5) cells/well. The increase was not due simply to the exposure of receptors from the intracellular pool, as a density-related increase in receptors was also seen in cells permeabilized with digitonin. There was no evidence that IGF binding proteins, either secreted by hepatocytes or present in fetal calf serum, had any effect on the measurement of receptor concentration or affinity. We conclude that rat hepatocytes in primary culture contain specific IGF-II receptors and that both cell surface and intracellular receptors are regulated by cell density

  7. Computer gaming comes to service rig training

    Energy Technology Data Exchange (ETDEWEB)

    Mowers, J.

    2007-05-15

    This article addressed the challenge of providing service rig workers with a good understanding of the tasks and risks involved in the job before they even step out into the field. The product, SimuLynx was presented. SimuLynx is based on video and gaming technology to immerse the user in the service rig work environment with other crew members. The user tries to perform the different steps of a junior floorhand's job while a coach gives directions. The article discussed how the system works. For example, when faced with a task, the user chooses from several options. The coach informs the virtual junior floorhand if the decision was right or wrong. He will also give warnings and let the user realize the consequences of a wrong action. The benefits of the system were also presented. For example, instead of 30 days of on-the-job training, an employee may only need several days after going through the program. Other benefits that were reviewed included reduced accident risk-levels for new workers; higher rig efficiency; and, lower training costs. In addition, a potential recruit can decide if the job is right for him before signing up for an expensive course or starting off with a service rig company. As well, the rig company can decide if someone is suitable before hiring that person. 3 figs.

  8. 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...

  9. Mannose-Binding Lectin and Toll-Like Receptor Polymorphisms and Chagas Disease in Chile

    Science.gov (United States)

    Zulantay, Inés; Danquah, Ina; Hamann, Lutz; Schumann, Ralf R.; Apt, Werner; Mockenhaupt, Frank P.

    2012-01-01

    Mannose-binding lectin (MBL) and Toll-like receptor (TLR) polymorphisms may influence susceptibility and manifestation of Trypanosoma cruzi infection. In northern Chile, we examined 61 asymptomatic patients with chronic Chagas disease (CD), 64 patients with chronic Chagas cardiomyopathy (CCC), and 45 healthy individuals. Low-producer MBL2*B genotypes were more common in CD patients (48%) than healthy individuals (31%; adjusted odds ratio = 2.3, 95% confidence interval = 1.01–5.4, P = 0.047) but did not differ with manifestation. In contrast, the heterozygous Toll-like receptor 4 (TLR4)-deficiency genotype D299G/T399I occurred more frequently in asymptomatic (14.8%) than CCC patients (3.1%; P = 0.02). TLR1-I602S, TLR2-R753Q, TLR6-S249P, and MAL/TIRAP-S180L did not associate with CD or CCC. These findings support the complement system to be involved in defense against Trypanosoma cruzi infection and indicate that curbed TLR4 activation might be beneficial in preventing CCC. PMID:22302853

  10. Let-7i attenuates human brain microvascular endothelial cell damage in oxygen glucose deprivation model by decreasing toll-like receptor 4 expression.

    Science.gov (United States)

    Xiang, Wei; Tian, Canhui; Peng, Shunli; Zhou, Liang; Pan, Suyue; Deng, Zhen

    2017-11-04

    The let-7 family of microRNAs (miRNAs) plays an important role on endothelial cell function. However, there have been few studies on their role under ischemic conditions. In this study, we demonstrate that let-7i, belonging to the let-7 family, rescues human brain microvascular endothelial cells (HBMECs) in an oxygen-glucose deprivation (OGD) model. Our data show that the expression of let-7 family miRNAs was downregulated after OGD. Overexpression of let-7i significantly alleviated cell death and improved survival of OGD-treated HBMECs. Let-7i also protected permeability in an in vitro blood brain barrier (BBB) model. Further, let-7i downregulated the expression of toll-like receptor 4 (TLR4), an inflammation trigger. Moreover, overexpression of let-7i decreased matrix metallopeptidase 9 (MMP9) and inducible nitric oxide synthase (iNOS) expression under OGD. Upon silencing TLR4 expression in HBMECs, the anti-inflammatory effect of let-7i was abolished. Our research suggests that let-7i promotes OGD-induced inflammation via downregulating TLR4 expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. DMPD: Viral recognition by Toll-like receptors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17336545 Viral recognition by Toll-like receptors. Barton GM. Semin Immunol. 2007 F...eb;19(1):33-40. Epub 2007 Mar 2. (.png) (.svg) (.html) (.csml) Show Viral recognition by Toll-like receptors.... PubmedID 17336545 Title Viral recognition by Toll-like receptors. Authors Barton GM. Publication Semin Imm

  12. Lycopene Enhances Docetaxel's Effect in Castration-Resistant Prostate Cancer Associated with Insulin-like Growth Factor I Receptor Levels1

    Science.gov (United States)

    Tang, Yaxiong; Parmakhtiar, Basmina; Simoneau, Anne R; Xie, Jun; Fruehauf, John; Lilly, Michael; Zi, Xiaolin

    2011-01-01

    Docetaxel is currently the most effective drug for the treatment of castration-resistant prostate cancer (CRPC), but it only extends life by an average of 2 months. Lycopene, an antioxidant phytochemical, has antitumor activity against prostate cancer (PCa) in several models and is generally safe. We present data on the interaction between docetaxel and lycopene in CRPC models. The growth-inhibitory effect of lycopene on PCa cell lines was positively associated with insulin-like growth factor I receptor (IGF-IR) levels. In addition, lycopene treatment enhanced the growth-inhibitory effect of docetaxel more effectively on DU145 cells with IGF-IR high expression than on those PCa cell lines with IGF-IR low expression. In a DU145 xenograft tumor model, docetaxel plus lycopene caused tumor regression, with a 38% increase in antitumor efficacy (P = .047) when compared with docetaxel alone. Lycopene inhibited IGF-IR activation through inhibiting IGF-I stimulation and by increasing the expression and secretion of IGF-BP3. Downstream effects include inhibition of AKT kinase activity and survivin expression, followed by apoptosis. Together, the enhancement of docetaxel's antitumor efficacy by lycopene supplementation justifies further clinical investigation of lycopene and docetaxel combination for CRPC patients. CRPC patients with IGF-IR-overexpressing tumors may be most likely to benefit from this combination. PMID:21403837

  13. Interferon Induction by RNA Viruses and Antagonism by Viral Pathogens

    Directory of Open Access Journals (Sweden)

    Yuchen Nan

    2014-12-01

    Full Text Available Interferons are a group of small proteins that play key roles in host antiviral innate immunity. Their induction mainly relies on host pattern recognition receptors (PRR. Host PRR for RNA viruses include Toll-like receptors (TLR and retinoic acid-inducible gene I (RIG-I like receptors (RLR. Activation of both TLR and RLR pathways can eventually lead to the secretion of type I IFNs, which can modulate both innate and adaptive immune responses against viral pathogens. Because of the important roles of interferons, viruses have evolved multiple strategies to evade host TLR and RLR mediated signaling. This review focuses on the mechanisms of interferon induction and antagonism of the antiviral strategy by RNA viruses.

  14. DMPD: Endogenous ligands of Toll-like receptors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15178705 Endogenous ligands of Toll-like receptors. Tsan MF, Gao B. J Leukoc Biol. ...2004 Sep;76(3):514-9. Epub 2004 Jun 3. (.png) (.svg) (.html) (.csml) Show Endogenous ligands of Toll-like re...ceptors. PubmedID 15178705 Title Endogenous ligands of Toll-like receptors. Authors Tsan MF, Gao B. Publicat

  15. A Killer Immunoglobulin - Like Receptor Gene - Content Haplotype and A Cognate Human Leukocyte Antigen Ligand are Associated with Autism

    OpenAIRE

    Torres, Anthony; Westover, Jonna; Benson, Michael; Johnson, Randall; Dykes, Annelise

    2016-01-01

    The killing activity of natural killer cells is largely regulated by the binding of class I human leukocyte antigen cognate ligands to killer cell immunoglobulin - like receptor proteins. The killer cell immunoglobulin - like receptor gene - complex contains genes that activate and others that inhibit the killing state of natural killer cells depending on the binding of specific human leukocyte antigen cognate ligands. It has been suggested in previous publications that activating human leuko...

  16. Coxsackievirus cloverleaf RNA containing a 5' triphosphate triggers an antiviral response via RIG-I activation

    NARCIS (Netherlands)

    Feng, Qian; Langereis, Martijn A; Olagnier, David; Chiang, Cindy; van de Winkel, Roel; van Essen, Peter; Zoll, Jan; Hiscott, John; van Kuppeveld, Frank J M

    2014-01-01

    Upon viral infections, pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) and stimulate an antiviral state associated with the production of type I interferons (IFNs) and inflammatory markers. Type I IFNs play crucial roles in innate antiviral responses by

  17. The role of the rigged Hilbert space in quantum mechanics

    International Nuclear Information System (INIS)

    Madrid, Rafael de la

    2005-01-01

    There is compelling evidence that, when a continuous spectrum is present, the natural mathematical setting for quantum mechanics is the rigged Hilbert space rather than just the Hilbert space. In particular, Dirac's braket formalism is fully implemented by the rigged Hilbert space rather than just by the Hilbert space. In this paper, we provide a pedestrian introduction to the role the rigged Hilbert space plays in quantum mechanics, by way of a simple, exactly solvable example. The procedure will be constructive and based on a recent publication. We also provide a thorough discussion on the physical significance of the rigged Hilbert space

  18. DMPD: Translational mini-review series on Toll-like receptors: networks regulated byToll-like receptors mediate innate and adaptive immunity. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17223959 Translational mini-review series on Toll-like receptors: networks regulate...ol. 2007 Feb;147(2):199-207. (.png) (.svg) (.html) (.csml) Show Translational mini-review series on Toll-lik... immunity. PubmedID 17223959 Title Translational mini-review series on Toll-like receptors: networks regulat

  19. Studies on binding and mitogenic effect of insulin and insulin-like growth factor I in glomerular mesangial cells

    International Nuclear Information System (INIS)

    Conti, F.G.; Striker, L.J.; Lesniak, M.A.; MacKay, K.; Roth, J.; Striker, G.E.

    1988-01-01

    The mesangial cells are actively involved in regulating glomerular hemodynamics. Their overlying endothelium is fenestrated; therefore, these cells are directly exposed to plasma substances, including hormones such as insulin and insulin-like growth factor I (IGF-I). These peptides may contribute to the mesangial sclerosis and cellular hyperplasia that characterize diabetic glomerulopathy. We report herein the characterization of the receptors and the mitogenic effects of IGF-I and insulin on mouse glomerular mesangial cells in culture. The IGF-I receptor was characterized on intact cells. The Kd of the IGF-I receptor was 1.47 X 10(-9) M, and the estimated number of sites was 64,000 receptors/cell. The binding was time, temperature, and pH dependent, and the receptor showed down-regulation after exposure to serum. The expression of the receptor did not change on cells at different densities. The specific binding for insulin was too low to allow characterization of the insulin receptor on intact cells. However, it was possible to identify the insulin receptor in a wheat germ agglutinin-purified preparation of solubilized mesangial cells. This receptor showed the characteristic features of the insulin receptor, including pH dependence of binding and a curvilinear Scatchard plot. The mitogenic effects of insulin and IGF-I on mesangial cells were measured by the incorporation of [3H]thymidine into DNA. IGF-I was more potent than insulin. The half-maximal response to IGF-I stimulation occurred at 1.3 X 10(-10) M, and a similar increase with insulin was observed at concentrations in the range of 10(-7) M, suggesting that this insulin action was mediated through the IGF-I receptor. These data show that the mouse microvascular smooth muscle cells of the glomerulus express a cell surface receptor for IGF-I in vitro and that this peptide is a potent mitogen for these mesangial cells

  20. 21. century drilling rigs -- Tesco introduces new modular design

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    1998-10-01

    Development of a modular, hydraulic, self-elevating drilling rig, dubbed the `21. century drilling rig` was announced by the Tesco Corporation. The rig equipment is housed in 8 by 20 by 8.5 feet high sea containers that can be handled by a 20-ton oilfield picker. These containers, weighing about 15,000 to 20,000 pounds on average, eliminate the need for heavy and bulky standard oilfield skid buildings, besides avoiding costly over-width and over-weight permits. The containers can be easily shipped around the world at a fraction of the cost of shipping standard oilfield skid buildings. Time for shipping on land is comparable to conventional rigs, but with the added advantage of smaller and lighter loads, promising fewer transportation problems during spring breakup. Tesco also designed and built an 85-foot long, triple-axle, 24-wheel catwalk trailer to transport the top drive, drawworks and double telescoping mast as one unit. Another novel characteristic of this unit is that the hydraulic system is capable of selectable distribution of power to the main functions such as the top drive, drawworks, or mud pump, similar to the electric SCR rig. The rig also features a computerized control system managed by programmable logic controllers. The split crown and split block to facilitate wireline work, are other innovative features worthy of note.

  1. Statistikeren skiftede spor som 49-årig

    DEFF Research Database (Denmark)

    Sølund, Sune; Rootzén, Helle

    2010-01-01

    En uddannelse til coach har ændret Helle Rototzens liv. Som 49-årig forlod hun et forskerliv på deltid til fordel for en karriere som DTU's eneste kvindelige institutdirektør.......En uddannelse til coach har ændret Helle Rototzens liv. Som 49-årig forlod hun et forskerliv på deltid til fordel for en karriere som DTU's eneste kvindelige institutdirektør....

  2. Minimal disturbance : Ensign's ADR-1000-CT rig aimed at CBM market

    International Nuclear Information System (INIS)

    Roche, P.

    2005-01-01

    Ensign Resource Services Group Inc. has recently designed a light, mobile rig aimed at Western Canada's coalbed methane (CBM) market. With a 1000 metre depth rating, the automated ADR-1000-CT rig can drill with either jointed pipe or 3 and a half-inch coil. Tractor units are used to move the rig to avoid the extra traffic generated by third-party trucks. The rig's self-levelling capability creates less environmental disturbance. Each component works on sites with as much as 2 metres difference in elevation, which reduces the need for earth-moving equipment. As drilling moves closer to farms and acreages, minimal environmental disturbance is crucial to the CBM industry. The rig won a 2005 Alberta government award for innovations in workplace health and safety as the design eliminates many of the tasks where injuries occur on conventional rigs. On conventional rigs, drill-strings are suspended from a travelling block which is suspended from the crown of a large, heavy derrick. With the ADR, hydraulic cylinders bear the weight of the drill string, and the derrick serves mainly to guide the top drive. When drilling only with jointed pipe, the coiled-tubing reel is a separate load so that drilling crews don't have to transport it around on programs requiring only jointed pipe. If coil is needed, the reel can be trucked to the site and plugged in to the rest of the rig. Tubing is expected to last 3 times as long as on a regular coiled-tubing rig, as the reel is positioned directly over the rotary table. The rigs have been used for various drilling projects and have performed satisfactorily with high penetration rates due to their large mud pumps. It was concluded that the ADR-1000-CT rig's hydraulic self-levelling capability and agility are helpful features when drilling in a minimal disturbance environment. 3 figs

  3. A study of natural circulation cooling using a flow visualization rig

    International Nuclear Information System (INIS)

    Bowman, W.C.; Ferch, R.L.; Omar, A.M.

    1985-01-01

    A flow visualization rig has been built at Monserco Limited to provide visual insight into the thermalhydraulic phenomena which occur during single phase and two phase thermosyphoning in a figure-of-eight heat transport loop. Tests performed with the rig have provided design information for the scaling and instrumentation of a high pressure rig being investigated for simulating CANDU reactor conditions during natural circulation cooling. A videotape was produced, for viewing at this presentation, to show important thermalhydraulic features of the thermosyphoning process. The rig is a standard figure-of-eight loop with two steam generators and three heated channels per pass. An elevated surge tank open to atmosphere was used for pressure control. Two variable speed pumps provided forced circulation for warming up the rig, and for establishing the desired initial conditions for testing. Test rig power could be varied between 0 and 15 kW

  4. The CCK(-like) receptor in the animal kingdom: functions, evolution and structures.

    Science.gov (United States)

    Staljanssens, Dorien; Azari, Elnaz Karimian; Christiaens, Olivier; Beaufays, Jérôme; Lins, Laurence; Van Camp, John; Smagghe, Guy

    2011-03-01

    In this review, the cholecystokinin (CCK)(-like) receptors throughout the animal kingdom are compared on the level of physiological functions, evolutionary basis and molecular structure. In vertebrates, the CCK receptor is an important member of the G-protein coupled receptors as it is involved in the regulation of many physiological functions like satiety, gastrointestinal motility, gastric acid secretion, gall bladder contraction, pancreatic secretion, panic, anxiety and memory and learning processes. A homolog for this receptor is also found in nematodes and arthropods, called CK receptor and sulfakinin (SK) receptor, respectively. These receptors seem to have evolved from a common ancestor which is probably still closely related to the nematode CK receptor. The SK receptor is more closely related to the CCK receptor and seems to have similar functions. A molecular 3D-model for the CCK receptor type 1 has been built together with the docking of the natural ligands for the CCK and SK receptors in the CCK receptor type 1. These molecular models can help to study ligand-receptor interactions, that can in turn be useful in the development of new CCK(-like) receptor agonists and antagonists with beneficial health effects in humans or potential for pest control. Copyright © 2010 Elsevier Inc. All rights reserved.

  5. Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan.

    Science.gov (United States)

    Nguyen, Linda; Robson, Matthew J; Healy, Jason R; Scandinaro, Anna L; Matsumoto, Rae R

    2014-01-01

    Dextromethorphan is an antitussive with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 (σ1) receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and the involvement of σ1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, σ1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of σ receptors in its antidepressant-like effects. Quinidine, a cytochrome P450 (CYP) 2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the σ1 receptor. Our results revealed dextromethorphan displays antidepressant-like effects in the forced swim test that can be attenuated by pretreatment with σ1 receptor antagonists, with BD1063 causing a shift to the right in the dextromethorphan dose response curve. Concomitant administration of quinidine potentiated the antidepressant-like effects of dextromethorphan. Saturation binding assays revealed that a Ki concentration of dextromethorphan reduces both the Kd and the Bmax of [(3)H](+)-pentazocine binding to σ1 receptors. Taken together, these data suggest that dextromethorphan exerts some of its antidepressant actions through σ1 receptors.

  6. Co-evolution of human leukocyte antigen (HLA class I ligands with killer-cell immunoglobulin-like receptors (KIR in a genetically diverse population of sub-Saharan Africans.

    Directory of Open Access Journals (Sweden)

    Paul J Norman

    2013-10-01

    Full Text Available Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR control natural killer cell (NK functions in immunity and reproduction. Encoded by genes on different chromosomes, these polymorphic ligands and receptors correlate highly with disease resistance and susceptibility. Although studied at low-resolution in many populations, high-resolution analysis of combinatorial diversity of HLA class I and KIR is limited to Asian and Amerindian populations with low genetic diversity. At the other end of the spectrum is the West African population investigated here: we studied 235 individuals, including 104 mother-child pairs, from the Ga-Adangbe of Ghana. This population has a rich diversity of 175 KIR variants forming 208 KIR haplotypes, and 81 HLA-A, -B and -C variants forming 190 HLA class I haplotypes. Each individual we studied has a unique compound genotype of HLA class I and KIR, forming 1-14 functional ligand-receptor interactions. Maintaining this exceptionally high polymorphism is balancing selection. The centromeric region of the KIR locus, encoding HLA-C receptors, is highly diverse whereas the telomeric region encoding Bw4-specific KIR3DL1, lacks diversity in Africans. Present in the Ga-Adangbe are high frequencies of Bw4-bearing HLA-B*53:01 and Bw4-lacking HLA-B*35:01, which otherwise are identical. Balancing selection at key residues maintains numerous HLA-B allotypes having and lacking Bw4, and also those of stronger and weaker interaction with LILRB1, a KIR-related receptor. Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression. Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution. These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa. Because of the prevalence of malaria in the Ga-Adangbe and

  7. Interaction of insulin-like growth factor I with porcine thyroid cells cultured in monolayer

    International Nuclear Information System (INIS)

    Saji, M.; Tsushima, T.; Isozaki, O.; Murakami, H.; Ohba, Y.; Sato, K.; Arai, M.; Mariko, A.; Shizume, K.

    1987-01-01

    The interaction of insulin-like growth factor I (IGF-I) with porcine thyroid cells cultured in monolayer was studied. Specific binding of [ 125 I]iodo-IGF-I to thyroid cells was a reversible process dependent on the time and temperature of incubation. A steady state was achieved in 18 h at 4 C and averaged 14.2 +/- 2% (mean +/- SD)/10(6) cells. Binding of [ 125 I]iodo-IGF-I was inhibited by unlabeled IGF-I; half-maximal inhibition occurred at concentrations of 2-5 ng/ml. Multiplication-stimulating activity (rat IGF-II) and pork insulin had relative potencies of 1:20 and 1:300 compared with IGF-I. Scatchard analysis of binding data revealed a single class of IGF-I receptors with a Ka of 4.3 X 10(10) M-1, 49,000 binding sites were estimated per cell. Affinity cross-linking and autoradiography demonstrated the presence of type I IGF receptors. Thyroid cells also had specific receptors for insulin, but specific binding of [ 125 I]iodoinsulin was much lower than that of [ 125 I]iodo-IGF-I. Preincubation of thyroid cells with IGF-I or insulin caused a concentration-dependent decrease in [ 125 I]iodo-IGF-I binding due to an apparent loss of receptors. Preincubation with epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, or TSH did not alter subsequent binding of [ 125 I]iodo-IGF-I. Low concentrations of IGF-I stimulated DNA synthesis and proliferation of thyroid cells and acted synergistically with epidermal growth factor. Multiplication-stimulating activity and insulin had relative potencies in stimulating DNA synthesis comparable to their abilities to inhibit the binding of [ 125 I]iodo-IGF-I to thyroid cells

  8. Specific, high affinity receptors for insulin-like growth factor II in the rat kidney glomerulus

    International Nuclear Information System (INIS)

    Haskell, J.F.; Pillion, D.J.; Meezan, E.

    1988-01-01

    Rat renal glomeruli were isolated by a technique involving kidney perfusion with a solution containing magnetic iron oxide particles, followed by homogenization, sieving, and concentration over a strong magnet. Isolated glomeruli were treated with 1% Triton X-100 to solubilize plasma membrane components, while insoluble basement membrane components were removed by centrifugation. [ 125 I]Insulin-like growth factor II (IGF-II) binding to this preparation was competitively inhibited by increasing amounts of unlabeled IGF-II, with 50% inhibition at an IGF-II concentration of 1 ng/ml. [ 125 I]IGF-II was covalently cross-linked with disuccinimidyl suberate to its receptor in rat renal glomeruli and a specific high mol wt (255,000) band could be identified on autoradiograms of dodecyl sulfate-polyacrylamide gels. [ 125 I]IGF-II binding and cross-linking to this band was inhibited by a polyclonal antibody against the type II IGF receptor. These results demonstrate for the first time that the isolated rat renal glomerulus contains a high affinity receptor for IGF-II

  9. Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Uddman Rolf

    2005-09-01

    Full Text Available Abstract Background Toll-like receptors enable the host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharide, viral RNA, CpG-containing DNA and flagellin. Toll-like receptors have also been shown to play a pivotal role in both innate and adaptive immune responses. The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. The present study was designed to examine the expression of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with intermittent allergic rhinitis, focusing on changes induced by exposure to pollen. Methods 27 healthy controls and 42 patients with seasonal allergic rhinitis volunteered for the study. Nasal biopsies were obtained before and during pollen season as well as before and after allergen challenge. The seasonal material was used for mRNA quantification of Toll-like receptors 2, 3 and 4 with real-time polymerase chain reaction, whereas specimens achieved in conjunction with allergen challenge were used for immunohistochemical localization and quantification of corresponding proteins. Results mRNA and protein representing Toll-like receptors 2, 3 and 4 could be demonstrated in all specimens. An increase in protein expression for all three receptors could be seen following allergen challenge, whereas a significant increase of mRNA only could be obtained for Toll-like receptor 3 during pollen season. Conclusion The up-regulation of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with symptomatic allergic rhinitis supports the idea of a role for Toll-like receptors in allergic airway inflammation.

  10. Mammary tumors that become independent of the type I insulin-like growth factor receptor express elevated levels of platelet-derived growth factor receptors

    Directory of Open Access Journals (Sweden)

    Campbell Craig I

    2011-11-01

    Full Text Available Abstract Background Targeted therapies are becoming an essential part of breast cancer treatment and agents targeting the type I insulin-like growth factor receptor (IGF-IR are currently being investigated in clinical trials. One of the limitations of targeted therapies is the development of resistant variants and these variants typically present with unique gene expression patterns and characteristics compared to the original tumor. Results MTB-IGFIR transgenic mice, with inducible overexpression of the IGF-IR were used to model mammary tumors that develop resistance to IGF-IR targeting agents. IGF-IR independent mammary tumors, previously shown to possess characteristics associated with EMT, were found to express elevated levels of PDGFRα and PDGFRβ. Furthermore, these receptors were shown to be inversely expressed with the IGF-IR in this model. Using cell lines derived from IGF-IR-independent mammary tumors (from MTB-IGFIR mice, it was demonstrated that PDGFRα and to a lesser extent PDGFRβ was important for cell migration and invasion as RNAi knockdown of PDGFRα alone or PDGFRα and PDGFRβ in combination, significantly decreased tumor cell migration in Boyden chamber assays and suppressed cell migration in scratch wound assays. Somewhat surprisingly, concomitant knockdown of PDGFRα and PDGFRβ resulted in a modest increase in cell proliferation and a decrease in apoptosis. Conclusion During IGF-IR independence, PDGFRs are upregulated and function to enhance tumor cell motility. These results demonstrate a novel interaction between the IGF-IR and PDGFRs and highlight an important, therapeutically relevant pathway, for tumor cell migration and invasion.

  11. Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan.

    Directory of Open Access Journals (Sweden)

    Linda Nguyen

    Full Text Available Dextromethorphan is an antitussive with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 (σ1 receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and the involvement of σ1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, σ1 receptor antagonists (BD1063 and BD1047 were evaluated in conjunction with dextromethorphan to determine the involvement of σ receptors in its antidepressant-like effects. Quinidine, a cytochrome P450 (CYP 2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the σ1 receptor. Our results revealed dextromethorphan displays antidepressant-like effects in the forced swim test that can be attenuated by pretreatment with σ1 receptor antagonists, with BD1063 causing a shift to the right in the dextromethorphan dose response curve. Concomitant administration of quinidine potentiated the antidepressant-like effects of dextromethorphan. Saturation binding assays revealed that a Ki concentration of dextromethorphan reduces both the Kd and the Bmax of [(3H](+-pentazocine binding to σ1 receptors. Taken together, these data suggest that dextromethorphan exerts some of its antidepressant actions through σ1 receptors.

  12. DMPD: Toll like receptors and autoimmunity: a critical appraisal. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17959357 Toll like receptors and autoimmunity: a critical appraisal. Papadimitraki ...ml) Show Toll like receptors and autoimmunity: a critical appraisal. PubmedID 17959357 Title Toll like receptors and auto

  13. LWR primary coolant pipe rupture test rig

    International Nuclear Information System (INIS)

    Yoshitoshi, Shyoji

    1978-01-01

    The rupture test rig for primary coolant pipes is constructed in the Japan Atomic Energy Research Institute to verify the reliability of the primary coolant pipes for both PWRs and BWRs. The planned test items consisted of reaction force test, restraint test, whip test, jet test and continuous release test. A pressure vessel of about 4 m 3 volume, a circulating pump, a pressurizer, a heater, an air cooler and the related instrumentation and control system are included in this test rig. The coolant test condition is 160 kg/cm 2 g, 325 deg C for PWR test, and 70 kg/cm 2 g, saturated water and steam for BWR test, 100 ton of test load for the ruptured pipe bore of 8B Schedule 160, and 20 lit/min. discharge during 20 h for continuous release of coolant. The maximum pit internal pressure was estimated for various pipe diameters and time under the PWR and BWR conditions. The spark rupturing device was adopted for the rupture mechanics in this test rig. The computer PANAFACOM U-300 is used for the data processing. This test rig is expected to operate in 1978 effectively for the improvement of reliability of LWR primary coolant pipes. (Nakai, Y.)

  14. mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR.

    Science.gov (United States)

    Yin, Yancun; Hua, Hui; Li, Minjing; Liu, Shu; Kong, Qingbin; Shao, Ting; Wang, Jiao; Luo, Yuanming; Wang, Qian; Luo, Ting; Jiang, Yangfu

    2016-01-01

    Mammalian target of rapamycin (mTOR) is a core component of raptor-mTOR (mTORC1) and rictor-mTOR (mTORC2) complexes that control diverse cellular processes. Both mTORC1 and mTORC2 regulate several elements downstream of type I insulin-like growth factor receptor (IGF-IR) and insulin receptor (InsR). However, it is unknown whether and how mTOR regulates IGF-IR and InsR themselves. Here we show that mTOR possesses unexpected tyrosine kinase activity and activates IGF-IR/InsR. Rapamycin induces the tyrosine phosphorylation and activation of IGF-IR/InsR, which is largely dependent on rictor and mTOR. Moreover, mTORC2 promotes ligand-induced activation of IGF-IR/InsR. IGF- and insulin-induced IGF-IR/InsR phosphorylation is significantly compromised in rictor-null cells. Insulin receptor substrate (IRS) directly interacts with SIN1 thereby recruiting mTORC2 to IGF-IR/InsR and promoting rapamycin- or ligand-induced phosphorylation of IGF-IR/InsR. mTOR exhibits tyrosine kinase activity towards the general tyrosine kinase substrate poly(Glu-Tyr) and IGF-IR/InsR. Both recombinant mTOR and immunoprecipitated mTORC2 phosphorylate IGF-IR and InsR on Tyr1131/1136 and Tyr1146/1151, respectively. These effects are independent of the intrinsic kinase activity of IGF-IR/InsR, as determined by assays on kinase-dead IGF-IR/InsR mutants. While both rictor and mTOR immunoprecitates from rictor(+/+) MCF-10A cells exhibit tyrosine kinase activity towards IGF-IR and InsR, mTOR immunoprecipitates from rictor(-/-) MCF-10A cells do not induce IGF-IR and InsR phosphorylation. Phosphorylation-deficient mutation of residue Tyr1131 in IGF-IR or Tyr1146 in InsR abrogates the activation of IGF-IR/InsR by mTOR. Finally, overexpression of rictor promotes IGF-induced cell proliferation. Our work identifies mTOR as a dual-specificity kinase and clarifies how mTORC2 promotes IGF-IR/InsR activation.

  15. Argentina's YPF outlines plan for sale of rigs

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    This paper reports that state owned Yacimientos Petroliferos Fiscales (YPF) has unveiled the schedule it plans to follow to privatize oil and gas contract drilling in Argentine. YPF proposes to exit the drilling business by selling state owned drilling rigs, drill pipe, and accessories in a series of auctions beginning next month and lasting through first quarter 1993. YPF intends to open bids Dec. 16 for a completion unit and 30 drilling rigs, several working under contract. Bids will be opened during first quarter 1993 for new and used YPF drill pipe and collars, spare equipment and accessories, and an inventory of fishing tools said to be one of the largest in South America. Winners are to be notified immediately after each auction. YPF plans to hand over by Feb. 1, 1993, the rigs sold in December. Companies buying YPF drilling assets in first quarter 1993, the rigs sold in December. Companies buying YPF drilling assets in first quarter 1993 are to assume ownership by Mar. 24, 1993

  16. Essays on bid rigging

    NARCIS (Netherlands)

    Seres, Gyula

    2016-01-01

    Manipulating prices in auctions raises antitrust concerns. Collusion lowers the revenue of the auctioneer and creates information rents. Bid rigging is a prevalent phenomenon and the affected market is enormous. Public procurement amounts to between 10 and 25 percent of national GDP in

  17. In Vivo Screening of Chemically Modified RNA duplexes for their Ability to Induce Innate Immune Responses

    DEFF Research Database (Denmark)

    Schyth, Brian Dall; Bramsen, Jesper Bertram; Kjems, Jørgen

    RNAs include the 2´-5´ oligoadenylate synthetase system, the protein kinase R, RIG-I and Toll-like receptor activated pathways all resulting in antiviral defence mechanism. We have previously shown that antiviral innate immune reactions against double stranded RNAs could be detected in vivo as partial...

  18. The development of fuel pins and material specimens mixed loading irradiation test rig in the experimental fast reactor Joyo. The development of the fuel-material hybrid rig

    International Nuclear Information System (INIS)

    Oyamatsu, Yasuko; Someya, Hiroyuki

    2013-02-01

    In the experimental fast reactor Joyo, there were many tests using the irradiation rigs that it was possible to be set irradiation conditions for each compartment independently. In case of no alternative fuel element to irradiate after unloading the irradiated compartments, the irradiation test was restarted with the dummy compartment which the fuel elements was not mounted. If the material specimens are mounted in this space, it is possible to use the irradiation space effectively. For these reasons, the irradiation rig (hybrid rig) is developed that is consolidated with material specimens compartment and fuel elements compartment. Fuel elements and material specimens differ greatly with heat generation, so that the most important issue in developing of hybrid rig is being able to distribute appropriately the coolant flow which satisfies irradiation conditions. The following is described by this report. (1) It was confirmed that the flow distribution of loading the same irradiation rig with the compartment from which a flow demand differs could be satisfied. (2) It was confirmed that temperature setting range of hybrid rig could be equivalent to that of irradiation condition. (3) By standardizing the coolant entrance structure of the compartment lower part, the prospect which can perform easily recombination of the compartment from which a type differs between irradiation rigs was acquired. (author)

  19. Distribution and levels of [125I]IGF-I, [125I]IGF-II and [125I]insulin receptor binding sites in the hippocampus of aged memory-unimpaired and -impaired rats

    International Nuclear Information System (INIS)

    Quirion, R.; Rowe, W.; Kar, S.; Dore, S.

    1997-01-01

    The insulin-like growth factors (IGF-I and IGF-II) and insulin are localized within distinct brain regions and their respective functions are mediated by specific membrane receptors. High densities of binding sites for these growth factors are discretely and differentially distributed throughout the brain, with prominent levels localized to the hippocampal formation. IGFs and insulin, in addition to their growth promoting actions, are considered to play important roles in the development and maintenance of normal cell functions throughout life. We compared the anatomical distribution and levels of IGF and insulin receptors in young (five month) and aged (25 month) memory-impaired and memory-unimpaired male Long-Evans rats as determined in the Morris water maze task in order to determine if alterations in IGF and insulin activity may be related to the emergence of cognitive deficits in the aged memory-impaired rat. In the hippocampus, [ 125 I]IGF-I receptors are concentrated primarily in the dentate gyrus (DG) and the CA3 sub-field while high amounts of [ 125 I]IGF-II binding sites are localized to the pyramidal cell layer, and the granular cell layer of the DG. [ 125 I]insulin binding sites are mostly found in the molecular layer of the DG and the CA1 sub-field. No significant differences were found in [ 125 I]IGF-I, [ 125 I]IGF-II or [ 125 I]insulin binding levels in any regions or laminae of the hippocampus of young vs aged rats, and deficits in cognitive performance did not relate to altered levels of these receptors in aged memory-impaired vs aged memory-unimpaired rats. Other regions, including various cortical areas, were also examined and failed to reveal any significant differences between the three groups studied.It thus appears that IGF-I, IGF-II and insulin receptor sites are not markedly altered during the normal ageing process in the Long-Evans rat, in spite of significant learning deficits in a sub-group (memory-impaired) of aged animals. Hence

  20. Tetherin Suppresses Type I Interferon Signaling by Targeting MAVS for NDP52-Mediated Selective Autophagic Degradation in Human Cells.

    Science.gov (United States)

    Jin, Shouheng; Tian, Shuo; Luo, Man; Xie, Weihong; Liu, Tao; Duan, Tianhao; Wu, Yaoxing; Cui, Jun

    2017-10-19

    Tetherin (BST2/CD317) is an interferon-inducible antiviral factor known for its ability to block the release of enveloped viruses from infected cells. Yet its role in type I interferon (IFN) signaling remains poorly defined. Here, we demonstrate that Tetherin is a negative regulator of RIG-I like receptor (RLR)-mediated type I IFN signaling by targeting MAVS. The induction of Tetherin by type I IFN accelerates MAVS degradation via ubiquitin-dependent selective autophagy in human cells. Moreover, Tetherin recruits E3 ubiquitin ligase MARCH8 to catalyze K27-linked ubiquitin chains on MAVS at lysine 7, which serves as a recognition signal for NDP52-dependent autophagic degradation. Taken together, our findings reveal a negative feedback loop of RLR signaling generated by Tetherin-MARCH8-MAVS-NDP52 axis and provide insights into a better understanding of the crosstalk between selective autophagy and optimal deactivation of type I IFN signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Development of real-time reverse transcription polymerase chain reaction assays to quantify insulin-like growth factor receptor and insulin receptor expression in equine tissue

    Directory of Open Access Journals (Sweden)

    Stephen B. Hughes

    2013-08-01

    Full Text Available The insulin-like growth factor system (insulin-like growth factor 1, insulin-like growth factor 2, insulin-like growth factor 1 receptor, insulin-like growth factor 2 receptor and six insulin-like growth factor-binding proteins and insulin are essential to muscle metabolism and most aspects of male and female reproduction. Insulin-like growth factor and insulin play important roles in the regulation of cell growth, differentiation and the maintenance of cell differentiation in mammals. In order to better understand the local factors that regulate equine physiology, such as muscle metabolism and reproduction (e.g., germ cell development and fertilisation, real-time reverse transcription polymerase chain reaction assays for quantification of equine insulin-like growth factor 1 receptor and insulin receptor messenger ribonucleic acid were developed. The assays were sensitive: 192 copies/µLand 891 copies/µL for insulin-like growth factor 1 receptor, messenger ribonucleic acid and insulin receptor respectively (95%limit of detection, and efficient: 1.01 for the insulin-like growth factor 1 receptor assay and 0.95 for the insulin receptor assay. The assays had a broad linear range of detection (seven logs for insulin-like growth factor 1 receptor and six logs for insulin receptor. This allowed for analysis of very small amounts of messenger ribonucleic acid. Low concentrations of both insulin-like growth factor 1 receptor and insulin receptor messenger ribonucleic acid were detected in endometrium, lung and spleen samples, whilst high concentrations were detected in heart, muscle and kidney samples, this was most likely due to the high level of glucose metabolism and glucose utilisation by these tissues. The assays developed for insulin-like growth factor 1 receptor and insulin receptor messenger ribonucleic acid expression have been shown to work on equine tissue and will contribute to the understanding of insulin and insulin-like growth factor 1

  2. Possible involvement of neuropeptide Y Y1 receptors in antidepressant like effect of agmatine in rats.

    Science.gov (United States)

    Kotagale, Nandkishor R; Paliwal, Nikhilesh P; Aglawe, Manish M; Umekar, Milind J; Taksande, Brijesh G

    2013-09-01

    Agmatine and neuropeptide Y (NPY) are widely distributed in central nervous system and critically involved in modulation of depressive behavior in experimental animals. However their mutual interaction, if any, in regulation of depression remain largely unexplored. In the present study we explored the possible interaction between agmatine and neuropeptide Y in regulation of depression like behavior in forced swim test. We found that acute intracerebroventricular (i.c.v.) administration of agmatine (20-40μg/rat), NPY (5 and 10μg/rat) and NPY Y1 receptor agonist, [Leu(31), Pro(34)]-NPY (0.4 and 0.8ng/rat) dose dependently decreased immobility time in forced swim test indicating their antidepressant like effects. In combination studies, the antidepressant like effect of agmatine (10μg/rat) was significantly potentiated by NPY (1 and 5μg/rat, icv) or [Leu(31), Pro(34)]-NPY (0.2 and 0.4ng/rat, icv) pretreatment. Conversely, pretreatment of animals with NPY Y1 receptor antagonist, BIBP3226 (0.1ng/rat, i.c.v.) completely blocked the antidepressant like effect of agmatine (20-40μg/rat) and its synergistic effect with NPY (1μg/rat, icv) or [Leu(31), Pro(34)]-NPY (0.2ng/rat, icv). The results of the present study showed that, agmatine exerts antidepressant like effects via NPYergic system possibly mediated by the NPY Y1 receptor subtypes and suggest that interaction between agmatine and neuropeptide Y may be relevant to generate the therapeutic strategies for the treatment of depression. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. RIG-I Helicase-Independent Pathway in Sendai Virus-Activated Dendritic Cells Is Critical for Preventing Lung Metastasis of AT6.3 Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Tomonori Kato

    2010-11-01

    Full Text Available We recently demonstrated highly efficient antitumor immunity against dermal tumors of B16F10 murine melanoma with the use of dendritic cells (DCs activated by replication-competent, as well as nontransmissible-type, recombinant Sendai viruses (rSeV, and proposed a new concept, “immunostimulatory virotherapy,” for cancer immunotherapy. However, there has been little information on the efficacies of thismethod: 1 inmore clinically relevant situations including metastatic diseases, 2 on other tumor types and other animal species, and 3 on the related molecular/cellular mechanisms. In this study, therefore, we investigated the efficacy of vaccinating DCs activated by fusion gene-deleted nontransmissible rSeV on a rat model of lung metastasis using a highly malignant subline of Dunning R-3327 prostate cancer, AT6.3. rSeV/dF-green fluorescent protein (GFP-activated bone marrow-derived DCs (rSeV/dF-GFP-DC, consistent with results previously observed in murine DCs. Vaccination of rSeV/dF-GFP-DC was highly effective at preventing lung metastasis after intravenous loading of R-3327 tumor cells, compared with the effects observed with immature DCs or lipopolysaccharide-activated DCs. Interestingly, neither CTL activity nor DC trafficking showed any apparent difference among groups. Notably, rSeV/dF-DCs expressing a dominant-negative mutant of retinoic acid-inducible gene I (RIG-I (rSeV/dF-RIGIC-DC, an RNA helicase that recognizes the rSeV genome for inducing type I interferons, largely lost the expression of proinflammatory cytokines without any impairment of antitumor activity. These results indicate the essential role of RIG-I-independent signaling on antimetastatic effect induced by rSeV-activated DCs and may provide important insights to DC-based immunotherapy for advanced malignancies.

  4. Lapland longspur mortality at an oil well drilling rig site, Laramie County, Wyoming

    Science.gov (United States)

    Ramirez, Pedro; Dickerson, Kimberly K.; Lindstrom, Jim; Meteyer, Carol U.; Darrah, Scott

    2015-01-01

    Two hundred fifty-one Lapland longspur (Calcarius lapponicus) carcasses were recovered around an oil well drilling rig in Laramie County, Wyoming, USA, on December 13–14, 2010, apparent victims of a winter storm and “light entrapment” from the lights on the drilling rig during foggy conditions. We found Lapland longspur carcasses distributed around the drilling rig from 33 m to 171 m. Investigators did not find evidence of bird carcasses on the drilling rig deck or equipment immediately adjacent to the drilling rig. We ruled out chemical toxins and disease as a cause of mortality. Weather conditions, the circular depositional pattern of carcasses around the drilling rig, and bird necropsy results led investigators to conclude that the Lapland longspur mortality was the result of the migrating birds entering the area illuminated by the drilling rig lights in freezing fog and the birds repeatedly circling the drilling rig until they fell to the ground in exhaustion and dying from subsequent trauma. Further research is needed to understand how to most effectively adjust lighting of onshore drilling rigs to reduce the potential for avian light entrapment. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  5. Professional development of new rig supervisors a must

    International Nuclear Information System (INIS)

    Nordt, D.P.; Stone, M.S.

    1992-01-01

    This paper reports that because the number of drilling personnel has dropped dramatically over the last decade, many operators now face a shortage of competent rig supervisors. To be effective, the rig supervisor must develop a knowledge of drilling operations, apply optimization techniques to improve drilling performance, demand safe work practices, and protect the environment. Petroleum engineering degree programs and industry training programs can teach the rig supervisor specific technical and management skills; however, traditionally, the supervisor trainee shadows an experienced company man to learn how to direct a drilling operation. The success of this method depends not only on the skills and learning capabilities of the trainee but also on the trainer's time, motivation, knowledge, and ability to teach the skills necessary to direct drilling activities

  6. The Ebola virus VP35 protein binds viral immunostimulatory and host RNAs identified through deep sequencing.

    Directory of Open Access Journals (Sweden)

    Kari A Dilley

    Full Text Available Ebola virus and Marburg virus are members of the Filovirdae family and causative agents of hemorrhagic fever with high fatality rates in humans. Filovirus virulence is partially attributed to the VP35 protein, a well-characterized inhibitor of the RIG-I-like receptor pathway that triggers the antiviral interferon (IFN response. Prior work demonstrates the ability of VP35 to block potent RIG-I activators, such as Sendai virus (SeV, and this IFN-antagonist activity is directly correlated with its ability to bind RNA. Several structural studies demonstrate that VP35 binds short synthetic dsRNAs; yet, there are no data that identify viral immunostimulatory RNAs (isRNA or host RNAs bound to VP35 in cells. Utilizing a SeV infection model, we demonstrate that both viral isRNA and host RNAs are bound to Ebola and Marburg VP35s in cells. By deep sequencing the purified VP35-bound RNA, we identified the SeV copy-back defective interfering (DI RNA, previously identified as a robust RIG-I activator, as the isRNA bound by multiple filovirus VP35 proteins, including the VP35 protein from the West African outbreak strain (Makona EBOV. Moreover, RNAs isolated from a VP35 RNA-binding mutant were not immunostimulatory and did not include the SeV DI RNA. Strikingly, an analysis of host RNAs bound by wild-type, but not mutant, VP35 revealed that select host RNAs are preferentially bound by VP35 in cell culture. Taken together, these data support a model in which VP35 sequesters isRNA in virus-infected cells to avert RIG-I like receptor (RLR activation.

  7. The Ebola virus VP35 protein binds viral immunostimulatory and host RNAs identified through deep sequencing.

    Science.gov (United States)

    Dilley, Kari A; Voorhies, Alexander A; Luthra, Priya; Puri, Vinita; Stockwell, Timothy B; Lorenzi, Hernan; Basler, Christopher F; Shabman, Reed S

    2017-01-01

    Ebola virus and Marburg virus are members of the Filovirdae family and causative agents of hemorrhagic fever with high fatality rates in humans. Filovirus virulence is partially attributed to the VP35 protein, a well-characterized inhibitor of the RIG-I-like receptor pathway that triggers the antiviral interferon (IFN) response. Prior work demonstrates the ability of VP35 to block potent RIG-I activators, such as Sendai virus (SeV), and this IFN-antagonist activity is directly correlated with its ability to bind RNA. Several structural studies demonstrate that VP35 binds short synthetic dsRNAs; yet, there are no data that identify viral immunostimulatory RNAs (isRNA) or host RNAs bound to VP35 in cells. Utilizing a SeV infection model, we demonstrate that both viral isRNA and host RNAs are bound to Ebola and Marburg VP35s in cells. By deep sequencing the purified VP35-bound RNA, we identified the SeV copy-back defective interfering (DI) RNA, previously identified as a robust RIG-I activator, as the isRNA bound by multiple filovirus VP35 proteins, including the VP35 protein from the West African outbreak strain (Makona EBOV). Moreover, RNAs isolated from a VP35 RNA-binding mutant were not immunostimulatory and did not include the SeV DI RNA. Strikingly, an analysis of host RNAs bound by wild-type, but not mutant, VP35 revealed that select host RNAs are preferentially bound by VP35 in cell culture. Taken together, these data support a model in which VP35 sequesters isRNA in virus-infected cells to avert RIG-I like receptor (RLR) activation.

  8. Drilling rig

    Energy Technology Data Exchange (ETDEWEB)

    Galiopa, A A; Yegorov, E K

    1981-01-04

    A drilling rig is proposed which contains a tower, lifter in the form of n infinite chain, and mobile rotator with holding device connected to the chain, and pipe holder. In order to accelerate the auxiliary operations to move the drilling string and unloaded rotator, the rotator is equipped with a clamp with means for transverse connection of it to both branches of the chain, while the pipe holders equipped with a clamp with means of connecting it to one of the branches of the chain.

  9. Bloqueo del receptor del factor de crecimiento semejante a la Insulina Tipo I utilizando oligodeoxinucleótidos antisentido en cáncer de mama experimental Type I insulin-like growth factor receptor antisense strategies in experimental breast cancer

    Directory of Open Access Journals (Sweden)

    Mariana Salatino

    2004-04-01

    Full Text Available Evaluamos el efecto del bloqueo de la expresión del receptor del factor de crecimiento semejante a la insulina tipo I (IGF-IR sobre el crecimiento in vivo de cáncer de mama empleando una estrategia "antisentido". Utilizamos el adenocarcinoma mamario murino progestágeno-dependiente C4HD. La administración intratumoral o sistémica de oligodeoxinucleótidos antisentido fosfotiolados al ARNm del IGF-IR (AS[S]ODN inhibió el crecimiento tumoral. El efecto antitumoral fue específico debido a su dosis-dependencia y a la falta de efecto en ratones tratados con el S[S]ODN "sentido". Los tumores obtenidos de ratones tratados con AS[S]ODN mostraron: disminución en la expresión de IGF-IR y en la fosforilación del sustrato del receptor de insulina-1, inhibición de la activación de PI-3K/Akt, p42/p44MAPK y ErbB-2, mientras que la expresión y activación del receptor de progesterona no se afectó. Es la primera demostración que el crecimiento de cáncer de mama puede ser inhibido por la administración in vivo de AS[S]ODN al IGF-IR.We addressed the effect of targeting type I insulin-like growth factor receptor (IGF-IR, with antisense strategies in in vivo growth of breast cancer cells. We used C4HD tumors from an experimental model of hormonal carcinogenesis in which medroxyprogesterone acetate induced mammary adenocarcinomas in Balb/c mice. Intratumor or systemic administration of phosphorothiolated antisense oligodeoxynucleotides (AS[S]ODN to IGF-IR mRNA resulted in a significant inhibition of C4HD tumor growth. The antitumor effect was specific since inhibition of tumor growth was dose-dependent and no effect was observed in mice treated with sense S[S]ODN. Tumors from AS[S]ODN-treated mice showed a decrease in IGF-IR expression and in insulin receptor substrate-1 tyrosine phosphorylation. Activation of PI-3K/Akt, p42/p44 MAPK and ErbB-2 was abolished in tumors treated with AS[S]ODN. Progesterone receptor expression or activity remained

  10. Flow Rate Measurement in Multiphase Flow Rig: Radiotracer and Conventional

    International Nuclear Information System (INIS)

    Nazrul Hizam Yusoff; Noraishah Othman; Nurliyana Abdullah; Amirul Syafiq Mohd Yunos; Rasif Mohd Zain; Roslan Yahya

    2015-01-01

    Applications of radiotracer technology are prevalent throughout oil refineries worldwide, and this industry is one of the main users and beneficiaries of the technology. Radioactive tracers have been used to a great extent in many applications i.e. flow rate measurement, RTD, plant integrity evaluation and enhancing oil production in oil fields. Chemical and petrochemical plants are generally continuously operating and technically complex where the radiotracer techniques are very competitive and largely applied for troubleshooting inspection and process analysis. Flow rate measurement is a typical application of radiotracers. For flow measurements, tracer data are important, rather than the RTD models. Research is going on in refining the existing methods for single phase flow measurement, and in developing new methods for multiphase flow without sampling. The tracer techniques for single phase flow measurements are recognized as ISO standards. This paper presents technical aspect of laboratory experiments, which have been carried out using Molybdenum-99 - Mo99 (radiotracer) to study and determine the flow rate of liquid in multiphase flow rig. The multiphase flow rig consists of 58.7 m long and 20 cm diameter pipeline that can accommodate about 0.296 m 3 of liquid. Tap water was used as liquid flow in pipeline and conventional flow meters were also installed at the flow rig. The flow rate results; radiotracer and conventional flow meter were compared. The total count method was applied for radiotracer technique and showed the comparable results with conventional flow meter. (author)

  11. Inhibition of Group I Metabotropic Glutamate Receptors Reverses Autistic-Like Phenotypes Caused by Deficiency of the Translation Repressor eIF4E Binding Protein 2.

    Science.gov (United States)

    Aguilar-Valles, Argel; Matta-Camacho, Edna; Khoutorsky, Arkady; Gkogkas, Christos; Nader, Karim; Lacaille, Jean-Claude; Sonenberg, Nahum

    2015-08-05

    Exacerbated mRNA translation during brain development has been linked to autism spectrum disorders (ASDs). Deletion of the eukaryotic initiation factor 4E (eIF4E)-binding protein 2 gene (Eif4ebp2), encoding the suppressor of mRNA translation initiation 4E-BP2, leads to an imbalance in excitatory-to-inhibitory neurotransmission and ASD-like behaviors. Inhibition of group I metabotropic glutamate receptors (mGluRs) mGluR1 and mGluR5 reverses the autistic phenotypes in several ASD mouse models. Importantly, these receptors control synaptic physiology via activation of mRNA translation. We investigated the potential reversal of autistic-like phenotypes in Eif4ebp2(-/-) mice by using antagonists of mGluR1 (JNJ16259685) or mGluR5 (fenobam). Augmented hippocampal mGluR-induced long-term depression (LTD; or chemically induced mGluR-LTD) in Eif4ebp2(-/-) mice was rescued by mGluR1 or mGluR5 antagonists. While rescue by mGluR5 inhibition occurs through the blockade of a protein synthesis-dependent component of LTD, normalization by mGluR1 antagonists requires the activation of protein synthesis. Synaptically induced LTD was deficient in Eif4ebp2(-/-) mice, and this deficit was not rescued by group I mGluR antagonists. Furthermore, a single dose of mGluR1 (0.3 mg/kg) or mGluR5 (3 mg/kg) antagonists in vivo reversed the deficits in social interaction and repetitive behaviors (marble burying) in Eif4ebp2(-/-) mice. Our results demonstrate that Eif4ebp2(-/-) mice serve as a relevant model to test potential therapies for ASD symptoms. In addition, we provide substantive evidence that the inhibition of mGluR1/mGluR5 is an effective treatment for physiological and behavioral alterations caused by exacerbated mRNA translation initiation. Exacerbated mRNA translation during brain development is associated with several autism spectrum disorders (ASDs). We recently demonstrated that the deletion of a negative regulator of mRNA translation initiation, the eukaryotic initiation factor 4E

  12. Hot corrosion testing of Ni-based alloys and coatings in a modified Dean rig

    Science.gov (United States)

    Steward, Jason Reid

    Gas turbine blades are designed to withstand a variety of harsh operating conditions. Although material and coating improvements are constantly administered to increase the mean time before turbine refurbishment or replacement, hot corrosion is still considered as the major life-limiting factor in many industrial and marine gas turbines. A modified Dean rig was designed and manufactured at Tennessee Technological University to simulate the accelerated hot corrosion conditions and to conduct screening tests on the new coatings on Ni-based superalloys. Uncoated Ni-based superalloys, Rene 142 and Rene 80, were tested in the modified Dean rig to establish a testing procedure for Type I hot corrosion. The influence of surface treatments on the hot corrosion resistance was then investigated. It was found that grit-blasted specimens showed inferior hot corrosion resistance than that of the polished counterpart. The Dean rig was also used to test model MCrAlY alloys, pack cementation NiAl coatings, and electro-codeposited MCrAlY coatings. Furthermore, the hot corrosion attack on the coated-specimens were also assessed using a statistical analysis approach.

  13. Study in flow rig by using radiotracer

    International Nuclear Information System (INIS)

    Widatalla, R. K.

    2012-06-01

    Application of radioisotope technology have proved itself to be effective techniques for troubleshooting and optimizing industrial process in petrochemical industry In this study gamma scanning technique has been employed for better understanding of malfunctions by using the flow rig system. The scanning were carried out using 9 9mT C gamma radiation source with activity of 1 mCi and quantity of 5 ml to measure the flow rate for the water flow rig The experiment was repeated by reducing the data interval time to get more precise result. The investigations were also carried out using 5 ml of 9 9mT C with activity of 0.3 mCi for measuring the Residence Time Distribution (RTD) inside the flow rig tank which enables calculating the effective volume for the operating tank and its dead volume. The results proved that the technique is sensitive, reliable and can be adopted to investigate industrial reactors. (Author)

  14. A constructive presentation of rigged Hilbert spaces

    International Nuclear Information System (INIS)

    Celeghini, Enrico

    2015-01-01

    We construct a rigged Hilbert space for the square integrable functions on the line L2(R) adding to the generators of the Weyl-Heisenberg algebra a new discrete operator, related to the degree of the Hermite polynomials. All together, continuous and discrete operators, constitute the generators of the projective algebra io(2). L 2 (R) and the vector space of the line R are shown to be isomorphic representations of such an algebra and, as both these representations are irreducible, all operators defined on the rigged Hilbert spaces L 2 (R) or R are shown to belong to the universal enveloping algebra of io(2). The procedure can be extended to orthogonal and pseudo-orthogonal spaces of arbitrary dimension by tensorialization.Circumventing all formal problems the paper proposes a kind of toy model, well defined from a mathematical point of view, of rigged Hilbert spaces where, in contrast with the Hilbert spaces, operators with different cardinality are allowed. (paper)

  15. Toll-Like Receptors: Role in Dermatological Disease

    Directory of Open Access Journals (Sweden)

    Aswin Hari

    2010-01-01

    Full Text Available Toll-like receptors (TLRs are a class of conserved receptors that recognize pathogen-associated molecular patterns (PAMPs present in microbes. In humans, at least ten TLRs have been identified, and their recognition targets range from bacterial endotoxins to lipopeptides, DNA, dsRNA, ssRNA, fungal products, and several host factors. Of dermatological interest, these receptors are expressed on several skin cells including keratinocytes, melanocytes, and Langerhans cells. TLRs are essential in identifying microbial products and are known to link the innate and adaptive immune systems. Over the years, there have been significant advances in our understanding of TLRs in skin inflammation, cutaneous malignancies, and defence mechanisms. In this paper, we will describe the association between TLRs and various skin pathologies and discuss proposed TLR therapeutics.

  16. Epidermal growth factor and insulin-like growth factor I upregulate the expression of the epidermal growth factor system in rat liver

    DEFF Research Database (Denmark)

    Bor, M V; Sørensen, B S; Vinter-Jensen, L

    2000-01-01

    BACKGROUND/AIM: Both epidermal growth factor and insulin-like growth factor I play a role in connection with the liver. In the present study, the possible interaction of these two growth factor systems was studied by investigating the effect of epidermal growth factor or insulin-like growth factor...... I treatment on the expression of the epidermal growth factor receptor, and its activating ligands, transforming growth factor-alpha and epidermal growth factor. METHODS: Fifty-five male rats received no treatment, human recombinant epidermal growth factor or human recombinant insulin-like growth.......8+/-1.6 fmol/mg protein epidermal growth factor and 144+/-22 fmol/mg protein transforming growth factor-alpha. Both epidermal growth factor and insulin-like growth factor I treatment increased the expression of mRNA for transforming growth factor-alpha and epidermal growth factor receptor, as well...

  17. Current Views of Toll-Like Receptor Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Masahiro Yamamoto

    2010-01-01

    Full Text Available On microbial invasion, the host immediately evokes innate immune responses. Recent studies have demonstrated that Toll-like receptors (TLRs play crucial roles in innate responses that lead not only to the clearance of pathogens but also to the efficient establishment of acquired immunity by directly detecting molecules from microbes. In terms of intracellular TLR-mediated signaling pathways, cytoplasmic adaptor molecules containing Toll/IL-1R (TIR domains play important roles in inflammatory immune responses through the production of proinflammatory cytokines, nitric oxide, and type I interferon, and upregulation of costimulatory molecules. In this paper, we will describe our current understanding of the relationship between TLRs and their ligands derived from pathogens such as viruses, bacteria, fungi, and parasites. Moreover, we will review the historical and current literature to describe the mechanisms behind TLR-mediated activation of innate immune responses.

  18. Epilepsy, E/I balance and GABAA receptor plasticity

    Directory of Open Access Journals (Sweden)

    Jean-Marc Fritschy

    2008-03-01

    Full Text Available GABAA receptors mediate most of the fast inhibitory transmission in the CNS. They form heteromeric complexes assembled from a large family of subunit genes. The existence of multiple GABAA receptor subtypes differing in subunit composition, localization and functional properties underlies their role for fi ne-tuning of neuronal circuits and genesis of network oscillations. The differential regulation of GABAA receptor subtypes represents a major facet of homeostatic synaptic plasticity and contributes to the excitation/inhibition (E/I balance under physiological conditions and upon pathological challenges. The purpose of this review is to discuss recent fi ndings highlighting the signifi cance of GABAA receptor heterogeneity for the concept of E/I balance and its relevance for epilepsy. Specifi cally, we address the following issues: (1 role for tonic inhibition, mediated by extrasynaptic GABAA receptors, for controlling neuronal excitability; (2 signifi cance of chloride ion transport for maintenance of the E/I balance in adult brain; and (3 molecular mechanisms underlying GABAA receptor regulation (traffi cking, posttranslational modifi cation, gene transcription that are important for homoeostatic plasticity. Finally, the relevance of these fi ndings is discussed in light of the involvement of GABAA receptors in epileptic disorders, based on recent experimental studies of temporal lobe epilepsy (TLE and absence seizures and on the identifi cation of mutations in GABAA receptor subunit genes underlying familial forms of epilepsy.

  19. Expressions of toll-like receptors 2 and 4, and relative cellular ...

    African Journals Online (AJOL)

    Purpose: To investigate the expressions of toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNF-α), IFN-γ (IFN- gamma), interleukin 2 (IL-2), interleukin 6 (IL-6) and interleukin 10 (IL-10) in human immunodeficiency virus (HIV) patients with tuberculosis (TB) infection. Methods: Two groups of ...

  20. Toll-Like Receptor Pathways in Autoimmune Diseases.

    Science.gov (United States)

    Chen, Ji-Qing; Szodoray, Peter; Zeher, Margit

    2016-02-01

    Autoimmune diseases are a family of chronic systemic inflammatory disorders, characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen. Several studies suggest that Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. TLRs belong to the family of pattern recognition receptors (PRRs) that recognize a wide range of pathogen-associated molecular patterns (PAMPs). TLRs are type I transmembrane proteins and located on various cellular membranes. Two main groups have been classified based on their location; the extracelluar group referred to the ones located on the plasma membrane while the intracellular group all located in endosomal compartments responsible for the recognition of nucleic acids. They are released by the host cells and trigger various intracellular pathways which results in the production of proinflammatory cytokines, chemokines, as well as the expression of co-stimulatory molecules to protect against invading microorganisms. In particular, TLR pathway-associated proteins, such as IRAK, TRAF, and SOCS, are often dysregulated in this group of diseases. TLR-associated gene expression profile analysis together with single nucleotide polymorphism (SNP) assessment could be important to explain the pathomechanism driving autoimmune diseases. In this review, we summarize recent findings on TLR pathway regulation in various autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis.

  1. DMPD: Function of RIG-I-like receptors in antiviral innate immunity. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available File (.html) CSML File (.csml) Open .csml file with CIOPlayer Open .csml file with CIOPlayer - ※CIO Playerのご利用上の注意 Open .csml file with CIO Open .csml file with CIO - ※CIOのご利用上の注意 ...

  2. Operating experience of a sodium rig following the ingress of oil

    Energy Technology Data Exchange (ETDEWEB)

    Bell, A C; Mehew, R D; Robertson, C M [UKAEA, Dounreay, Thurso, Caithness, Scotland (United Kingdom)

    1980-05-01

    The experience of operating the Small Water Leak Rig at Dounreay in the two years following the ingress into the sodium of silicone oil from the pump is reported. The carbon penetration into the rig pipework has been monitored and has been found to agree with a diffusion model. The predictions based on this model have enabled an operating strategy to be determined to allow continued operation of the rig. (author)

  3. Operating experience of a sodium rig following the ingress of oil

    International Nuclear Information System (INIS)

    Bell, A.C.; Mehew, R.D.; Robertson, C.M.

    1980-01-01

    The experience of operating the Small Water Leak Rig at Dounreay in the two years following the ingress into the sodium of silicone oil from the pump is reported. The carbon penetration into the rig pipework has been monitored and has been found to agree with a diffusion model. The predictions based on this model have enabled an operating strategy to be determined to allow continued operation of the rig. (author)

  4. B-Cell Activation and Tolerance Mediated by B-Cell Receptor, Toll-Like Receptor and Survival Signal Crosstalk in SLE Pathogenesis

    Science.gov (United States)

    2015-10-01

    H. Wagner, K. Takeda, and S. Akira. 2000 . A Toll-like receptor recognizes bacterial DNA. Nature 408: 740–745. 2. Kawai, T., and S. Akira. 2010. The...I. M. Carr , J. C. Fuller, R. M. Jackson, T. Lamb, T. A. Briggs, et al. 2009. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as...Moreover, recent studies from Riley and colleagues (27) suggest that ABCs negatively influence B-lineage commitment or development of bone marrow

  5. Expression of insulin-like growth factor I receptors at mRNA and protein levels during metamorphosis of Japanese flounder (Paralichthys olivaceus).

    Science.gov (United States)

    Zhang, Junling; Shi, Zhiyi; Cheng, Qi; Chen, Xiaowu

    2011-08-01

    Insulin-like growth factor I (IGF-I) is an important regulator of fish growth and development, and its biological actions are initiated by binding to IGF-I receptor (IGF-IR). Our previous study has revealed that IGF-I could play an important role during metamorphosis of Japanese flounder, Paralichthys olivaceus. The analysis of IGF-IR expression thus helps further elucidate the IGF-I regulation of metamorphic processes. In this study, the spatial-temporal expression of two distinct IGF-IR mRNAs was investigated by real-time RT-PCR. The spatial distribution of two IGF-IR mRNAs in adult tissues is largely overlapped, but they exhibit distinct temporal expression patterns during larval development. A remarkable decrease in IGF-IR-2 mRNA was detected during metamorphosis. In contrast, a significant increase in IGF-IR-1 mRNA was determined from pre-metamorphosis to metamorphic completion. These indicate that they may play different function roles during the flounder metamorphosis. The levels and localization of IGF-IR proteins during larval development were further studied by Western blotting and immunohistochemistry. Immunoreactive IGF-IRs were detected throughout larval development, and the IGF-IR proteins displayed a relatively abundant expression during metamorphosis. Moreover, the IGF-IR proteins appeared in key tissues, such as thickened skin beneath the migrating eye, developing intestine, gills and kidney during metamorphosis. These results further suggest that the IGF-I system may be involved in metamorphic development of Japanese flounder. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Dynamic evolution of toll-like receptor multigene families in echinoderms

    Directory of Open Access Journals (Sweden)

    Katherine M Buckley

    2012-06-01

    Full Text Available The genome of the purple sea urchin, Strongylocentrotus purpuratus, was the first to be sequenced from a long-lived large invertebrate. Analysis of this genome uncovered a surprisingly complex immune system in which the moderately sized sets of pattern recognition receptors that form the core of vertebrate innate immunity are encoded in large multigene families. The sea urchin genome contains 253 Toll-like receptor (TLR genes, more than 200 Nod-like receptors and 1095 scavenger receptor cysteine-rich domains, a ten-fold expansion relative to vertebrates. Given their stereotypic structure and simple intron-exon architecture, the TLRs are the most tractable of these families for more detailed analysis. An immune defense role for these receptors is suggested by their sequence diversity and expression in immunologically active tissues, including phagocytes. This complexity of the sea urchin TLR multigene families largely derives from expansions that are independent of those in vertebrates and protostomes, although a small family of TLRs with structure similar to that of Drosophila Toll likely originated in an ancient eumetazoan ancestor. Several other invertebrate deuterostome genomes have been sequenced, including the cephalochordate, Branchiostoma floridae and the sea urchin Lytechinus variegatus, as well as partial sequences from two other sea urchin species. Here, we present an analysis of the invertebrate deuterostome TLRs with emphasis on the echinoderms. Representatives of most of the S. purpuratus TLR subfamilies and homologs of the protostome-like sequences are found in L. variegatus. The phylogeny of these genes within sea urchins highlights lineage-specific expansions at higher resolution than is evident at the phylum level. These analyses identify quickly evolving TLR subfamilies that are likely to have novel functions and other, more stable, subfamilies that may function similarly to those of vertebrates.

  7. Advantages and limitations of remotely operated sea floor drill rigs

    Science.gov (United States)

    Freudenthal, T.; Smith, D. J.; Wefer, G.

    2009-04-01

    A variety of research targets in marine sciences including the investigation of gas hydrates, slope stability, alteration of oceanic crust, ore formation and palaeoclimate can be addressed by shallow drilling. However, drill ships are mostly used for deep drillings, both because the effort of building up a drill string from a drill ship to the deep sea floor is tremendous and control on drill bit pressure from a movable platform and a vibrating drill string is poor especially in the upper hundred meters. During the last decade a variety of remotely operated drill rigs have been developed, that are deployed on the sea bed and operated from standard research vessels. These developments include the BMS (Bentic Multicoring System, developed by Williamson and Associates, operated by the Japanese Mining Agency), the PROD (Portable Remotely Operated Drill, developed and operated by Benthic Geotech), the Rockdrill 2 (developed and operated by the British geological Survey) and the MeBo (German abbreviation for sea floor drill rig, developed and operated by Marum, University of Bremen). These drill rigs reach drilling depths between 15 and 100 m. For shallow drillings remotely operated drill rigs are a cost effective alternative to the services of drill ships and have the major advantage that the drilling operations are performed from a stable platform independent of any ship movements due to waves, wind or currents. Sea floor drill rigs can be deployed both in shallow waters and the deep sea. A careful site survey is required before deploying the sea floor drill rig. Slope gradient, small scale topography and soil strength are important factors when planning the deployment. The choice of drill bits and core catcher depend on the expected geology. The required drill tools are stored on one or two magazines on the drill rig. The MeBo is the only remotely operated drill rig world wide that can use wire line coring technique. This method is much faster than conventional

  8. Receptors for insulin-like growth factor II (IGF-II) in the rat kidney glomerulus

    International Nuclear Information System (INIS)

    Haskell, J.F.; Pillion, D.J.; Meezan, E.

    1986-01-01

    Renal glomeruli were isolated by a technique involving renal perfusion with a solution containing magnetic iron oxide particles, followed by homogenization, sieving and isolation over a strong magnet. Isolated glomeruli were treated with 1% Triton X-100 to solubilize plasma membrane components while insoluble basement membrane components were removed by centrifugation. [ 125 I]Insulin-like growth factor-II (IGF-II) binding to this preparation was competitively inhibited by increasing amounts of unlabelled IGF-II, with 50% inhibition of binding observed at an IGF-II concentration of 1 ng/ml. [ 125 I]IGF-II was covalently cross-linked to its receptor with disuccinimidyl suberate in two tissues known to contain IGF-II receptors, the rat chondrosarcoma chondrocyte and the rat kidney tubule, as well as in rat renal glomeruli. In all three cases, a specific high-molecular weight (Mr = 255,000) band could be identified on autoradiograms of dodecyl sulfate polyacrylamide gels. These results indicate that the rat glomerulus contains a high-affinity receptor for IGF-II. This finding is consistent with the hypothesis that IGF-II plays a role in glomerular growth and differentiation

  9. DMPD: NOD-like receptors (NLRs): bona fide intracellular microbial sensors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18585455 NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Shaw...tml) (.csml) Show NOD-like receptors (NLRs): bona fide intracellular microbial sensors. PubmedID 18585455 Ti...tle NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Authors

  10. Insulin-like growth factor receptor inhibitors: baby or the bathwater?

    Science.gov (United States)

    Yee, Douglas

    2012-07-03

    The success of targeted therapies for cancer is undisputed; strong preclinical evidence has resulted in the approval of several new agents for cancer treatment. The type I insulin-like growth factor receptor (IGF1R) appeared to be one of these promising new targets. Substantial population and preclinical data have all pointed toward this pathway as an important regulator of tumor cell biology. Although early results from clinical trials that targeted the IGF1R showed some evidence of response, larger randomized phase III trials have not shown clear clinical benefit of targeting this pathway in combination with conventional strategies. These disappointing results have resulted in the discontinuation of several anti-IGF1R programs. However, the conduct of these trials has brought to the forefront several important factors that need to be considered in the conduct of future clinical trials. The need to develop biomarkers, a clearer understanding of insulin receptor function, and defining rational combination regimens all require further consideration. In this commentary, the current state of IGF1R inhibitors in cancer therapy is reviewed.

  11. Identification and phylogeny of the tomato receptor-like proteins family

    Directory of Open Access Journals (Sweden)

    Ermis Yanes-Paz

    2017-03-01

    Full Text Available The receptor-like proteins (RLPs play multiple roles in development and defense. In the current work 75 RLPs were identified in tomato (Solanum lycopersicum L. using iterative BLAST searches and domain prediction. A phylogenetic tree including all the identified RLPs from tomato and some functionally characterized RLPs from other species was built to identify their putative homologues in tomato. We first tested whether C3-F-based phylogeny was a good indicator of functional relation between related proteins of different species. Indeed, the functionally characterized CLAVATA2 (CLV2, the maize ortholog FASCIATED EAR2 (FEA2 and a putative tomato CLV2 described in Uniprot clustered together, which validates the approach. Using this approach Solyc12g042760.1.1 was identified as the putative tomato homologue of TOO MANY MOUTHS (TMM. It was shown that proteins in the same cluster of the phylogenetic tree share functional relations since several clusters of functionally related proteins i.e. the Ve cluster, the Cf cluster, and the Eix clade were formed.   Keywords: phylogeny, receptors, RLP, tomato

  12. Opioid/NMDA receptors blockade reverses the depressant-like behavior of foot shock stress in the mouse forced swimming test.

    Science.gov (United States)

    Haj-Mirzaian, Arya; Ostadhadi, Sattar; Kordjazy, Nastaran; Dehpour, Ahmad Reza; Ejtemaei Mehr, Shahram

    2014-07-15

    Opioid and glutamatergic receptors have a key role in depression following stress. In this study, we assessed opioid and glutamatergic receptors interaction with the depressant-like behavior of acute foot-shock stress in the mouse forced swimming test. Stress was induced by intermittent foot shock stimulation during 30min and swim periods were afterwards conducted by placing mice in separated glass cylinders filled with water for 6min. The immobility time during the last 4min of the test was considered. Acute foot-shock stress significantly increased the immobility time of mice compared to non-stressed control group (P≤0.01). Administration of non-selective opioid receptors antagonist, naltrexone (1 and 2mg/kg, i.p.), and the selective non-competitive NMDA receptor antagonist, MK-801 (0.05mg/kg, i.p.), and the selective serotonin reuptake inhibitor, fluoxetine (5mg/kg), significantly reduced the immobility time in stressed animals (P≤0.01). Lower doses of MK-801 (0.01mg/kg), naltrexone (0.3mg/kg), NMDA (75mg/kg) and morphine(5mg/kg) had no effect on foot-shock stressed mice. Combined treatment of sub-effective doses of naltrexone and MK-801 significantly showed an antidepressant-like effect (P≤0.001). On the other hand, co-administration of non-effective doses of NMDA and morphine with effective doses of naltrexone and MK-801 reversed the anti-immobility effect of these drugs. Taken together, we have for the first time demonstrated the possible role of opioid/NMDA receptors signaling in the depressant-like effect of foot-shock stress, and proposed the use of drugs that act like standard anti-depressants in stress-induced depression. Copyright © 2014. Published by Elsevier B.V.

  13. Identification of an Activating Chicken Ig-like Receptor Recognizing Avian Influenza Viruses

    NARCIS (Netherlands)

    Jansen, Christine A; van Haarlem, Daphne A; Sperling, Beatrice; van Kooten, Peter J; de Vries, Erik; Viertlboeck, Birgit C; Vervelde, Lonneke; Göbel, Thomas W

    2016-01-01

    Chicken Ig-like receptors (CHIRs) represent a multigene family encoded by the leukocyte receptor complex that encodes a variety of receptors that are subdivided into activating CHIR-A, inhibitory CHIR-B, and bifunctional CHIR-AB. Apart from CHIR-AB, which functions as an Fc receptor, CHIR ligands

  14. Toll-like receptor-2 deficiency enhances non-alcoholic steatohepatitis

    Directory of Open Access Journals (Sweden)

    Brady Kristen

    2010-05-01

    Full Text Available Abstract Background Previously we reported that mice deficient in toll-like receptor 4 (TLR-4 signalling were protected from diet-induced non-alcoholic steatohepatitis (NASH. Another member of the toll-like receptor family, TLR-2, has been shown to play a role in lipid trafficking via uptake of diacylated lipoproteins. However, a role for TLR-2 in NASH has not been elucidated. The objectives of the current study were to examine the influence of dietary fat quality and TLR-2 on NASH pathogenesis. Methods Steatohepatitis was induced in male Db, C57BL/6 and TLR-2-/- mice by feeding an L-amino acid-defined diet that was deficient in methionine and choline (MCDD. Mice fed the base diet supplemented with methionine and choline (control diet; CD were used as controls. To determine the role of fat quality, MCDD was enriched with polyunsaturated corn oil (PUFA or coconut oil that is comprised mostly of saturated fat (SAFA; the total amount of each fat was 112.9 g/kg of diet. After 8 weeks of feeding CD or MCDD, hepatic steatosis, inflammation and necrosis were evaluated in histological sections. Total RNA was extracted from frozen liver samples and mRNA expression of TNFα, collagen α1, IL-10, peroxisome proliferator-activated receptor-γ (PPAR-γ, TLR-4, and CD14, was analyzed via real-time PCR. Protein levels of TLR-2 were analyzed by western blot. Results Panlobular macrovessicular steatosis and diffuse leukocyte infiltration were noted in PUFA-fed Db mice. Histological scores demonstrated significantly less steatosis, inflammation and necrosis in SAFA-fed mice of all mouse strains. However, compared to wild type mice, hepatocellular damage was notably more severe in TLR-2-/- mice. Consistent with histological findings, mRNA expression of TNFα was elevated by approximately 3-fold in TLR-2-/- mice; PPAR-γ expression was blunted in this strain compared to wild type. Expression of the matrix protein collagen αI was also significantly higher in TLR-2

  15. DMPD: Role of Toll-like receptor responses for sepsis pathogenesis. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18086373 Role of Toll-like receptor responses for sepsis pathogenesis. Weighardt H,... of Toll-like receptor responses for sepsis pathogenesis. PubmedID 18086373 Title Role of Toll-like receptor... responses for sepsis pathogenesis. Authors Weighardt H, Holzmann B. Publication

  16. Computers make rig life extension an option

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-10-01

    The worldwide semisubmersible drilling rig fleet is approaching retirement. But replacement is not an attractive option even though dayrates are reaching record highs. In 1991, Schlumberger Sedco Forex managers decided that an alternative might exist if regulators and insurers could be convinced to extend rig life expectancy through restoration. Sedco Forex chose their No. 704 semisubmersible, an 18-year North Sea veteran, to test their process. The first step was to determine what required restoration, meaning fatigue life analysis of each weld on the huge vessel. If inspected, the task would be unacceptably time-consuming and of questionable accuracy. Instead a suite of computer programs modeled the stress seen by each weld, statistically estimated the sea states seen by the rig throughout its North Sea service and calibrated a beam-element model on which to run their computer simulations. The elastic stiffness of the structure and detailed stress analysis of each weld was performed with ANSYS, a commercially available finite-element analysis program. The use of computer codes to evaluate service life extension is described.

  17. DMPD: Toll-like receptors regulation of viral infection and disease. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18280610 Toll-like receptors regulation of viral infection and disease. Thompson JM...how Toll-like receptors regulation of viral infection and disease. PubmedID 18280610 Title Toll-like recepto...rs regulation of viral infection and disease. Authors Thompson JM, Iwasaki A. Pub

  18. The Effect of Glucagon-Like Peptide 1 Receptor Agonists on Weight Loss in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Jessica E Potts

    Full Text Available To determine the effects of glucagon-like peptide-1 receptor agonists compared with placebo and other anti-diabetic agents on weight loss in overweight or obese patients with type 2 diabetes mellitus.Electronic searches were conducted for randomised controlled trials that compared a glucagon-like peptide-1 receptor agonist therapy at a clinically relevant dose with a comparator treatment (other type 2 diabetes treatment or placebo in adults with type 2 diabetes and a mean body mass index ≥ 25 kg/m2. Pair-wise meta-analyses and mixed treatment comparisons were conducted to examine the difference in weight change at six months between the glucagon-like peptide-1 receptor agonists and each comparator.In the mixed treatment comparison (27 trials, the glucagon-like peptide-1 receptor agonists were the most successful in terms of weight loss; exenatide 2 mg/week: -1.62 kg (95% CrI: -2.95 kg, -0.30 kg, exenatide 20 μg: -1.37 kg (95% CI: -222 kg, -0.52 kg, liraglutide 1.2 mg: -1.01 kg (95%CrI: -2.41 kg, 0.38 kg and liraglutide 1.8 mg: -1.51 kg (95% CI: -2.67 kg, -0.37 kg compared with placebo. There were no differences between the GLP-1 receptor agonists in terms of weight loss.This review provides evidence that glucagon-like peptide-1 receptor agonist therapies are associated with weight loss in overweight or obese patients with type 2 diabetes with no difference in weight loss seen between the different types of GLP-1 receptor agonists assessed.

  19. Developmental test report, assessment of XT-70E percussion drill rig operation in tank farms

    International Nuclear Information System (INIS)

    Dougherty, L.F.

    1996-01-01

    The following report documents the testing of the XT-70E percussion drill rig for use in the 241-SX Tank Farm. The test is necessary to support evaluation of the safety and authorization level of the proposed activity of installing up to three new drywells in the 241- SX Tank Farm. The proposed activity plans to install drywells by percussion drilling 7 inch O.D./6 inch I.D. pipe in close proximity of underground storage tanks and associated equipment. The load transmitted from the drill rig's percussion hammer through the ground to the tank structure and equipment is not known and therefore testing is required to ensure the activity is safe and authorized

  20. Die Expression des Calcitonin receptor-like receptors in humanen Gliomen

    OpenAIRE

    Kappus, Christoph

    2014-01-01

    In dieser Arbeit wurden humane Gliome vom WHO-Grad II-IV auf das Vorkommen des Calcitonin receptor-like Rezeptors untersucht. Hierzu erfolgte zunächst der Nachweis der CRLR-RNS in den humanen Gliomzellinien G 109 und G 139, welche sich eindeutig posi-tiv zeigten. Sodann wurden paraffinasservierte Schnitte aus humanen Gliomen mittels im-munhistochemischer Färbung auf das Vorkommen des CRLRs untersucht. Hierzu diente ein Antikörper ...

  1. Identification of Insulin-Like Growth Factor-I Receptor (IGF-IR) Gene Promoter-Binding Proteins in Estrogen Receptor (ER)-Positive and ER-Depleted Breast Cancer Cells

    International Nuclear Information System (INIS)

    Sarfstein, Rive; Belfiore, Antonino; Werner, Haim

    2010-01-01

    The insulin-like growth factor I receptor (IGF-IR) has been implicated in the etiology of breast cancer. Overexpression of the IGF-IR gene is a typical feature of most primary breast cancers, whereas low IGF-IR levels are seen at advanced stages. Hence, evaluation of IGF-IR levels might be important for assessing prognosis. In the present study, we employed a proteomic approach based on DNA affinity chromatography followed either by mass spectroscopy (MS) or Western blot analysis to identify transcription factors that may associate with the IGF-IR promoter in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. A biotinylated IGF-IR promoter fragment was bound to streptavidin magnetic beads and incubated with nuclear extracts of breast cancer cells. IGF-IR promoter-binding proteins were eluted with high salt and analyzed by MS and Western blots. Among the proteins that were found to bind to the IGF-IR promoter we identified zinc finger transcription factors Sp1 and KLF6, ER-α, p53, c-jun, and poly (ADP-ribosylation) polymerase. Furthermore, chromatin immune-precipitation (ChIP) analysis confirmed the direct in vivo binding of some of these transcription factors to IGF-IR promoter DNA. The functional relevance of binding data was assessed by cotransfection experiments with specific expression vectors along with an IGF-IR promoter reporter. In summary, we identified nuclear proteins that are potentially responsible for the differential expression of the IGF-IR gene in ER-positive and ER-depleted breast cancer cells

  2. Identification of Insulin-Like Growth Factor-I Receptor (IGF-IR) Gene Promoter-Binding Proteins in Estrogen Receptor (ER)-Positive and ER-Depleted Breast Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Sarfstein, Rive [Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel); Belfiore, Antonino [Department of Clinical and Experimental Medicine, University Magna Graecia of Catanzaro, Catanzaro 88100 (Italy); Werner, Haim, E-mail: hwerner@post.tau.ac.il [Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel)

    2010-03-25

    The insulin-like growth factor I receptor (IGF-IR) has been implicated in the etiology of breast cancer. Overexpression of the IGF-IR gene is a typical feature of most primary breast cancers, whereas low IGF-IR levels are seen at advanced stages. Hence, evaluation of IGF-IR levels might be important for assessing prognosis. In the present study, we employed a proteomic approach based on DNA affinity chromatography followed either by mass spectroscopy (MS) or Western blot analysis to identify transcription factors that may associate with the IGF-IR promoter in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. A biotinylated IGF-IR promoter fragment was bound to streptavidin magnetic beads and incubated with nuclear extracts of breast cancer cells. IGF-IR promoter-binding proteins were eluted with high salt and analyzed by MS and Western blots. Among the proteins that were found to bind to the IGF-IR promoter we identified zinc finger transcription factors Sp1 and KLF6, ER-α, p53, c-jun, and poly (ADP-ribosylation) polymerase. Furthermore, chromatin immune-precipitation (ChIP) analysis confirmed the direct in vivo binding of some of these transcription factors to IGF-IR promoter DNA. The functional relevance of binding data was assessed by cotransfection experiments with specific expression vectors along with an IGF-IR promoter reporter. In summary, we identified nuclear proteins that are potentially responsible for the differential expression of the IGF-IR gene in ER-positive and ER-depleted breast cancer cells.

  3. Independent, parallel pathways to CXCL10 induction in HCV-infected hepatocytes.

    Science.gov (United States)

    Brownell, Jessica; Wagoner, Jessica; Lovelace, Erica S; Thirstrup, Derek; Mohar, Isaac; Smith, Wesley; Giugliano, Silvia; Li, Kui; Crispe, I Nicholas; Rosen, Hugo R; Polyak, Stephen J

    2013-10-01

    The pro-inflammatory chemokine CXCL10 is induced by HCV infection in vitro and in vivo, and is associated with outcome of IFN (interferon)-based therapy. We studied how hepatocyte sensing of early HCV infection via TLR3 (Toll-like receptor 3) and RIG-I (retinoic acid inducible gene I) led to expression of CXCL10. CXCL10, type I IFN, and type III IFN mRNAs and proteins were measured in PHH (primary human hepatocytes) and hepatocyte lines harboring functional or non-functional TLR3 and RIG-I pathways following HCV infection or exposure to receptor-specific stimuli. HuH7 human hepatoma cells expressing both TLR3 and RIG-I produced maximal CXCL10 during early HCV infection. Neutralization of type I and type III IFNs had no impact on virus-induced CXCL10 expression in TLR3+/RIG-I+ HuH7 cells, but reduced CXCL10 expression in PHH. PHH cultures were positive for monocyte, macrophage, and dendritic cell mRNAs. Immunodepletion of non-parenchymal cells (NPCs) eliminated marker expression in PHH cultures, which then showed no IFN requirement for CXCL10 induction during HCV infection. Immunofluorescence studies also revealed a positive correlation between intracellular HCV Core and CXCL10 protein expression (r(2) = 0.88, p ≤ 0.001). While CXCL10 induction in hepatocytes during the initial phase of HCV infection is independent of hepatocyte-derived type I and type III IFNs, NPC-derived IFNs contribute to CXCL10 induction during HCV infection in PHH cultures. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  4. The influence of chemicals on water quality in a high pressure separation rig

    Energy Technology Data Exchange (ETDEWEB)

    Johnsen, Einar E.; Hemmingsen, Paal V.; Mediaas, Heidi; Svarstad, May Britt E.; Westvik, Arild

    2006-03-15

    In the research laboratory of Statoil at Rotvoll, Trondheim, a high pressure experimental rig used for separation and foaming studies has been developed. There have been several studies to ensure that the high pressure separation rig produces reliable and consistent results with regard to the water-in-oil and oil-in-water contents. The results are consistent with available field data and, just as important, consistent when changing variables like temperature, pressure drop and water cut. The results are also consistent when changing hydrodynamic variables like flow velocity and mixing point (using different choke valves) and when using oil with and without gas saturation. At equal experimental conditions, the high pressure separation rig is able to differentiate between separation characteristics of oil and water from different fields and from different wells at the same field. The high pressure separation and foam rig can be used from -10 deg C to 175 deg C and at pressures up to 200 bar. Crude oil and water are studied under relevant process conditions with respect to temperature, pressure, shear, water cut and separation time. In the present work the influence of chemicals on the oil and water quality has been studied. Chemicals have been mixed into the oil and/or water beforehand or added in situ (on-stream; simulated well stream). The amount of oil in the water after a given residence time in the separation cell has been measured. The results from the high pressure rig show that some demulsifiers, with their primary purpose of giving less water in oil, also have influence on the water quality. Improvement of water quality has been observed as well as no effect or aggravation. The experimental results have been compared to results from bottle tests at the field. The results from the bottle tests and from the laboratory are not corresponding, and only a full-scale field test can tell which of them are the correct results, if any. (Experience from corresponding

  5. The machinery of Nod-like receptors: refining the paths to immunity and cell death.

    Science.gov (United States)

    Saleh, Maya

    2011-09-01

    One of the fundamental aspects of the innate immune system is its capacity to discriminate between self and non-self or altered self, and to quickly respond by eliciting effector mechanisms that act in concert to restore normalcy. This capacity is determined by a set of evolutionarily conserved pattern recognition receptors (PRRs) that sense the presence of microbial motifs or endogenous danger signals, including tissue damage, cellular transformation or metabolic perturbation, and orchestrate the nature, duration and intensity of the innate immune response. Nod-like receptors (NLRs), a group of intracellular PRRs, are particularly essential as evident by the high incidence of genetic variations in their genes in various diseases of homeostasis. Here, I overview the signaling mechanisms of NLRs and discuss the mounting evidence of evolutionary conservation between their pathways and the cell death machinery. I also describe their effector functions that link the sensing of danger to the induction of inflammation, autophagy or cell death. © 2011 John Wiley & Sons A/S.

  6. The effect of BLA GABAB receptors in anxiolytic-like effect and aversive memory deficit induced by ACPA

    Directory of Open Access Journals (Sweden)

    Katayoon Kangarlu Haghighi

    2016-07-01

    Full Text Available Background: As a psychoactive plant, Cannabis sativa (Marijuana is widely used throughout the world. Several investigations have indicated that administration of Marijuana affects various cognitive and non-cognitive behaviors. These include anxiety-like behaviors and learning and memory deficit. It has been shown that three main cannabinoid receptors [i.e. CB1, CB2 and CB3 are involved in cannabinoids’ functions. CB1 receptors are abundantly expressed in the central nervous system regions such as hippocampus, amygdala, cerebellum and the cortex. Therefore, the neuropsychological functions of endocannabinoids are thought to be more linked to CB1 receptors. Among other brain regions, CB1 is highly expressed in the amygdala which is an integral component of the limbic circuitry. The amygdala plays a major role in the control of emotional behavior, including conditioned fear and anxiety. In present study we examined the possible roles of basolateral amygdala (BLA GABAB receptors in arachydonilcyclopropylamide (ACPA-induced anxiolytic-like effect and aversive memory deficit in adult male mice. Methods: This experimental study was conducted from September 2013 to December 2014 in Institute for Studies in Theoretical Physics and Mathematics, School of Cognitive Sciences, Tehran and Male albino NMRI mice (Pasture Institute, Iran, weighting 27-30 g, were used. Bilateral guide-cannulae were implanted to allow intra BLA microinjection of the drugs. We used Elevated Plus Maze (EPM to examine memory and anxiety behavior (test-retest protocol. ACPA administrate intra-peritoneal and GABAB agonist and antagonist administrated intra-amygdala. Results: Data showed that pre-test treatment with ACPA induced anxiolytic-like and aversive memory deficit The results revealed that pre-test intra-BLA infusion of baclofen (GABAB receptor agonist impaired the aversive memory while phaclofen (GABAB receptor antagonist improved it. Interestingly, pretreatment with a sub

  7. The laboratory test rig with miniature jet engine to research aviation fuels combustion process

    Directory of Open Access Journals (Sweden)

    Gawron Bartosz

    2015-12-01

    Full Text Available This article presents laboratory test rig with a miniature turbojet engine (MiniJETRig – Miniature Jet Engine Test Rig, that was built in the Air Force Institute of Technology. The test rig has been developed for research and development works aimed at modelling and investigating processes and phenomena occurring in full scale jet engines. In the article construction of a test rig is described, with a brief discussion on the functionality of each of its main components. Additionally examples of measurement results obtained during the realization of the initial tests have been included, presenting the capabilities of the test rig.

  8. IT that works on the rig floor : computers on drilling rigs need to be certified and built with features that can handle the environment

    Energy Technology Data Exchange (ETDEWEB)

    Balsaver, N.

    2010-07-15

    This article discussed the design challenges faced in developing hazardous-location computers for rig-floor use and other recently introduced products from Laversab. Rig-floor computers must not only be certified as Zone-1 or Zone-2 compliant but must also have features that make them work dependably in an extreme environment, including a wide operating temperature range, an ability to withstand severe vibration, immunity to salt fog, a viewable display in bright daylight, networking capability, USB and serial interfaces, and touch screens. Size and weight has been a major obstacle, but recent innovations have made Zone-1 computers intrinsically safe (IS), making them much smaller and lighter. Wireless networking eliminates the need for installing copper and fibre-optic cabling, but the wireless interface must be strong enough to overcome the many obstructions that are typically present on oil rigs. The computer models described, including a Driller's Display designed to be IS for Zone-1 applications and a Directional MWD Surface System designed for Zone-2 applications, provide solutions to the challenges of a working rig-floor environment. 3 figs.

  9. Glucocorticoids facilitate the transcription from the human cytomegalovirus major immediate early promoter in glucocorticoid receptor- and nuclear factor-I-like protein-dependent manner

    International Nuclear Information System (INIS)

    Inoue-Toyoda, Maki; Kato, Kohsuke; Nagata, Kyosuke; Yoshikawa, Hiroyuki

    2015-01-01

    Human cytomegalovirus (HCMV) is a common and usually asymptomatic virus agent in healthy individuals. Initiation of HCMV productive infection depends on expression of the major immediate early (MIE) genes. The transcription of HCMV MIE genes is regulated by a diverse set of transcription factors. It was previously reported that productive HCMV infection is triggered probably by elevation of the plasma hydroxycorticoid level. However, it is poorly understood whether the transcription of MIE genes is directly regulated by glucocorticoid. Here, we found that the dexamethasone (DEX), a synthetic glucocorticoid, facilitates the transcription of HCMV MIE genes through the MIE promoter and enhancer in a glucocorticoid receptor (GR)-dependent manner. By competitive EMSA and reporter assays, we revealed that an NF-I like protein is involved in DEX-mediated transcriptional activation of the MIE promoter. Thus, this study supports a notion that the increased level of hydroxycorticoid in the third trimester of pregnancy reactivates HCMV virus production from the latent state. - Highlights: • DEX facilitates the transcription from the HCMV MIE promoter. • GR is involved in DEX-dependent transcription from the HCMV MIE promoter. • A 17 bp repeat is responsible for the HCMV MIE promoter activation by DEX. • An NF-I-like protein is involved in the HCMV MIE promoter activation by DEX

  10. A Universal Rig for Supporting Large Hammer Drills: Reduced Injury Risk and Improved Productivity.

    Science.gov (United States)

    Rempel, David; Barr, Alan

    2015-10-01

    Drilling holes into concrete with heavy hammer and rock drills is one of the most physically demanding tasks performed in commercial construction and poses risks for musculoskeletal disorders, noise induced hearing loss, hand arm vibration syndrome and silicosis. The aim of this study was to (1) use a participatory process to develop a rig to support pneumatic rock drills or large electric hammer drills in order to reduce the health risks and (2) evaluate the usability of the rig. Seven prototype rigs for supporting large hammer drills were developed and modified with feedback from commercial contractors and construction workers. The final design was evaluated by laborers and electricians (N=29) who performed their usual concrete drilling with the usual method and the new rig. Subjective regional fatigue was significantly less in the neck, shoulders, hands and arms, and lower back) when using the universal rig compared to the usual manual method. Usability ratings for the rig were significantly better than the usual method on stability, control, drilling, accuracy, and vibration. Drilling time was reduced by approximately 50% with the rig. Commercial construction contractors, laborers and electricians who use large hammer drills for drilling many holes should consider using such a rig to prevent musculoskeletal disorders, fatigue, and silicosis.

  11. A mollusk VDR/PXR/CAR-like (NR1J) nuclear receptor provides insight into ancient detoxification mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Cruzeiro, Catarina, E-mail: catarinarcruzeiro@hotmail.com [ICBAS - Institute of Biomedical Sciences Abel Salazar, U. Porto - University of Porto (Portugal); CIIMAR/CIMAR - Interdisciplinary Center of Marine and Environmental Research, U. Porto (Portugal); Lopes-Marques, Mónica, E-mail: monicaslm@hotmail.com [ICBAS - Institute of Biomedical Sciences Abel Salazar, U. Porto - University of Porto (Portugal); CIIMAR/CIMAR - Interdisciplinary Center of Marine and Environmental Research, U. Porto (Portugal); Ruivo, Raquel, E-mail: ruivo.raquel@gmail.com [CIIMAR/CIMAR - Interdisciplinary Center of Marine and Environmental Research, U. Porto (Portugal); Rodrigues-Oliveira, Nádia, E-mail: nadia.oliveira@ciimar.up.pt [CIIMAR/CIMAR - Interdisciplinary Center of Marine and Environmental Research, U. Porto (Portugal); Santos, Miguel M., E-mail: santos@ciimar.up.pt [CIIMAR/CIMAR - Interdisciplinary Center of Marine and Environmental Research, U. Porto (Portugal); FCUP - Faculty of Sciences, Department of Biology, U. Porto (Portugal); Rocha, Maria João, E-mail: mjsrocha@netcabo.pt [ICBAS - Institute of Biomedical Sciences Abel Salazar, U. Porto - University of Porto (Portugal); CIIMAR/CIMAR - Interdisciplinary Center of Marine and Environmental Research, U. Porto (Portugal); Rocha, Eduardo, E-mail: erocha@icbas.up.pt [ICBAS - Institute of Biomedical Sciences Abel Salazar, U. Porto - University of Porto (Portugal); CIIMAR/CIMAR - Interdisciplinary Center of Marine and Environmental Research, U. Porto (Portugal); Castro, L. Filipe C., E-mail: filipe.castro@ciimar.up.pt [CIIMAR/CIMAR - Interdisciplinary Center of Marine and Environmental Research, U. Porto (Portugal); FCUP - Faculty of Sciences, Department of Biology, U. Porto (Portugal)

    2016-05-15

    Highlights: • A nuclear receptor orthologue of the NR1J group is isolated from a mollusc. • The molluscan NR1J transactivates gene expression upon exposure to okadaic acid but not a pesticide, esfenvarelate and triclosan. • Lineage specific gene duplications and gene loss have occurred in the NR1J of protostomes with likely impacts on detoxification mechanisms. - Abstract: The origin and diversification of the metazoan endocrine systems represents a fundamental research issue in biology. Nuclear receptors are critical components of these systems. A particular group named VDR/PXR/CAR (NR1I/J) is central in the mediation of detoxification responses. While orthologues have been thoroughly characterized in vertebrates, a sparse representation is currently available for invertebrates. Here, we provide the first isolation and characterization of a lophotrochozoan protostome VDR/PXR/CAR nuclear receptor (NR1J), in the estuarine bivalve the peppery furrow shell (Scrobicularia plana). Using a reporter gene assay, we evaluated the xenobiotic receptor plasticity comparing the human PXR with the S. plana NR1Jβ. Our results show that the molluscan receptor responds to a natural toxin (okadaic acid) in a similar fashion to that reported for other invertebrates. In contrast, the pesticide esfenvalerate displayed a unique response, since it down regulated transactivation at higher concentrations, while for triclosan no response was observed. Additionally, we uncovered lineage specific gene duplications and gene loss in the gene group encoding NRs in protostomes with likely impacts on the complexity of detoxification mechanisms across different phyla. Our findings pave the way for the development of multi-specific sensor tools to screen xenobiotic compounds acting via the NR1I/J group.

  12. A mollusk VDR/PXR/CAR-like (NR1J) nuclear receptor provides insight into ancient detoxification mechanisms

    International Nuclear Information System (INIS)

    Cruzeiro, Catarina; Lopes-Marques, Mónica; Ruivo, Raquel; Rodrigues-Oliveira, Nádia; Santos, Miguel M.; Rocha, Maria João; Rocha, Eduardo; Castro, L. Filipe C.

    2016-01-01

    Highlights: • A nuclear receptor orthologue of the NR1J group is isolated from a mollusc. • The molluscan NR1J transactivates gene expression upon exposure to okadaic acid but not a pesticide, esfenvarelate and triclosan. • Lineage specific gene duplications and gene loss have occurred in the NR1J of protostomes with likely impacts on detoxification mechanisms. - Abstract: The origin and diversification of the metazoan endocrine systems represents a fundamental research issue in biology. Nuclear receptors are critical components of these systems. A particular group named VDR/PXR/CAR (NR1I/J) is central in the mediation of detoxification responses. While orthologues have been thoroughly characterized in vertebrates, a sparse representation is currently available for invertebrates. Here, we provide the first isolation and characterization of a lophotrochozoan protostome VDR/PXR/CAR nuclear receptor (NR1J), in the estuarine bivalve the peppery furrow shell (Scrobicularia plana). Using a reporter gene assay, we evaluated the xenobiotic receptor plasticity comparing the human PXR with the S. plana NR1Jβ. Our results show that the molluscan receptor responds to a natural toxin (okadaic acid) in a similar fashion to that reported for other invertebrates. In contrast, the pesticide esfenvalerate displayed a unique response, since it down regulated transactivation at higher concentrations, while for triclosan no response was observed. Additionally, we uncovered lineage specific gene duplications and gene loss in the gene group encoding NRs in protostomes with likely impacts on the complexity of detoxification mechanisms across different phyla. Our findings pave the way for the development of multi-specific sensor tools to screen xenobiotic compounds acting via the NR1I/J group.

  13. Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis.

    Science.gov (United States)

    Saldana, Sandra M; Lee, Heng-Huan; Lowery, Frank J; Khotskaya, Yekaterina B; Xia, Weiya; Zhang, Chenyu; Chang, Shih-Shin; Chou, Chao-Kai; Steeg, Patricia S; Yu, Dihua; Hung, Mien-Chie

    2013-01-01

    Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of phospho-AKT and phospho-p70s6k, as well as decreased migration and invasion of MDA-MB-231Br brain-seeking cells. In addition, transient ablation of IGFBP3, which is overexpressed in brain-seeking cells, blocks IGF-IR activation. Using an in vivo experimental brain metastasis model, we show that IGF-IR knockdown brain-seeking cells have reduced potential to establish brain metastases. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system.

  14. Endurance test for IR rig for RI production assembly (test procedure)

    International Nuclear Information System (INIS)

    Chung, Heung June; Ryu, Jeong Soo

    2000-08-01

    This test procedure details the test loop, test method, and test procedure for pressure drop, vibration and endurance test of IR Rig for RI production. From the pressure drop test, the hydraulic design requirements of the capsule are verified. HANARO limit condition is checked and the compatibility with HANARO core is verified. From flow induced vibration test vibration frequency and displacement are investigated. The wear of IR Rig is investigated through endurance test, and these data are used to evaluate the expected wear at maximum resident time of the IR Rig for RI production

  15. Receptor-like Molecules on Human Intestinal Epithelial Cells Interact with an Adhesion Factor from Lactobacillus reuteri.

    Science.gov (United States)

    Matsuo, Yosuke; Miyoshi, Yukihiro; Okada, Sanae; Satoh, Eiichi

    2012-01-01

    A surface protein of Lactobacillus reuteri, mucus adhesion-promoting protein (MapA), is considered to be an adhesion factor. MapA is expressed in L. reuteri strains and adheres to piglet gastric mucus, collagen type I, and human intestinal epithelial cells such as Caco-2. The aim of this study was to identify molecules that mediate the attachment of MapA from L. reuteri to the intestinal epithelial cell surface by investigating the adhesion of MapA to receptor-like molecules on Caco-2 cells. MapA-binding receptor-like molecules were detected in Caco-2 cell lysates by 2D-PAGE. Two proteins, annexin A13 (ANXA13) and paralemmin (PALM), were identified by MALDI TOF-MS. The results of a pull-down assay showed that MapA bound directly to ANXA13 and PALM. Fluorescence microscopy studies confirmed that MapA binding to ANXA13 and PALM was colocalized on the Caco-2 cell membrane. To evaluate whether ANXA13 and PALM are important for MapA adhesion, ANXA13 and PALM knockdown cell lines were established. The adhesion of MapA to the abovementioned cell lines was reduced compared with that to wild-type Caco-2 cells. These knockdown experiments established the importance of these receptor-like molecules in MapA adhesion.

  16. Insulin-like growth factor (IGF)-I obliterates the pregnancy-associated protection against mammary carcinogenesis in rats: evidence that IGF-I enhances cancer progression through estrogen receptor-α activation via the mitogen-activated protein kinase pathway

    International Nuclear Information System (INIS)

    Thordarson, Gudmundur; Slusher, Nicole; Leong, Harriet; Ochoa, Dafne; Rajkumar, Lakshmanaswamy; Guzman, Raphael; Nandi, Satyabrata; Talamantes, Frank

    2004-01-01

    Pregnancy protects against breast cancer development in humans and rats. Parous rats have persistently reduced circulating levels of growth hormone, which may affect the activity of the growth hormone/insulin-like growth factor (IGF)-I axis. We investigated the effects of IGF-I on parity-associated protection against mammary cancer. Three groups of rats were evaluated in the present study: IGF-I-treated parous rats; parous rats that did not receive IGF-I treatment; and age-matched virgin animals, which also did not receive IGF-I treatment. Approximately 60 days after N-methyl-N-nitrosourea injection, IGF-I treatment was discontinued and all of the animal groups were implanted with a silastic capsule containing 17β-estradiol and progesterone. The 17β-estradiol plus progesterone treatment continued for 135 days, after which the animals were killed. IGF-I treatment of parous rats increased mammary tumor incidence to 83%, as compared with 16% in parous rats treated with 17β-estradiol plus progesterone only. Tumor incidence and average number of tumors per animal did not differ between IGF-I-treated parous rats and age-matched virgin rats. At the time of N-methyl-N-nitrosourea exposure, DNA content was lowest but the α-lactalbumin concentration highest in the mammary glands of untreated parous rats in comparison with age-matched virgin and IGF-I-treated parous rats. The protein levels of estrogen receptor-α in the mammary gland was significantly higher in the age-matched virgin animals than in untreated parous and IGF-I-treated parous rats. Phosphorylation (activation) of the extracellular signal-regulated kinase-1/2 (ERK1/2) and expression of the progesterone receptor were both increased in IGF-I-treated parous rats, as compared with those in untreated parous and age-matched virgin rats. Expressions of cyclin D 1 and transforming growth factor-β 3 in the mammary gland were lower in the age-matched virgin rats than in the untreated parous and IGF-I-treated parous

  17. Plant cell wall signalling and receptor-like kinases.

    Science.gov (United States)

    Wolf, Sebastian

    2017-02-15

    Communication between the extracellular matrix and the cell interior is essential for all organisms as intrinsic and extrinsic cues have to be integrated to co-ordinate development, growth, and behaviour. This applies in particular to plants, the growth and shape of which is governed by deposition and remodelling of the cell wall, a rigid, yet dynamic, extracellular network. It is thus generally assumed that cell wall surveillance pathways exist to monitor the state of the wall and, if needed, elicit compensatory responses such as altered expression of cell wall remodelling and biosynthesis genes. Here, I highlight recent advances in the field of cell wall signalling in plants, with emphasis on the role of plasma membrane receptor-like kinase complexes. In addition, possible roles for cell wall-mediated signalling beyond the maintenance of cell wall integrity are discussed. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  18. Intracellular delivery of poly(I:C) induces apoptosis of fibroblast-like synoviocytes via an unknown dsRNA sensor

    Energy Technology Data Exchange (ETDEWEB)

    Karpus, Olga N.; Hsiao, Cheng-Chih; Kort, Hanneke de; Tak, Paul P.; Hamann, Jörg, E-mail: j.hamann@amc.uva.nl

    2016-08-26

    Fibroblast-like synoviocytes (FLS) express functional membranous and cytoplasmic sensors for double-stranded (ds)RNA. Notably, FLS undergo apoptosis upon transfection with the synthetic dsRNA analog poly(I:C). We here studied the mechanism of intracellular poly(I:C) recognition and subsequent cell death in FLS. FLS responded similarly to poly(I:C) or 3pRNA transfection; however, only intracellular delivery of poly(I:C) induced significant cell death, accompanied by upregulation of pro-apoptotic proteins Puma and Noxa, caspase 3 cleavage, and nuclear segregation. Knockdown of the DExD/H-box helicase MDA5 did not affect the response to intracellular poly(I:C); in contrast, knockdown of RIG-I abrogated the response to 3pRNA. Knockdown of the downstream adaptor proteins IPS, STING, and TRIF or inhibition of TBK1 did not affect the response to intracellular poly(I:C), while knockdown of IFNAR blocked intracellular poly(I:C)-mediated signaling and cell death. We conclude that a so far unknown intracellular sensor recognizes linear dsRNA and induces apoptosis in FLS. - Highlights: • Intracellular poly(I:C) and 3pRNA evoke immune responses in FLS. • Only intracellular delivery of poly(I:C) induces FLS apoptosis. • FLS do not require MDA5 for their response to intracellular poly(I:C). • FLS respond to intracellular poly(I:C) independent of IPS and STING. • An unknown intracellular sensor recognizes linear dsRNA in FLS.

  19. Integrative function of adrenaline receptors for glucagon-like peptide-1 exocytosis in enteroendocrine L cell line GLUTag.

    Science.gov (United States)

    Harada, Kazuki; Kitaguchi, Tetsuya; Tsuboi, Takashi

    2015-05-15

    Adrenaline reacts with three types of adrenergic receptors, α1, α2 and β-adrenergic receptors (ARs), inducing many physiological events including exocytosis. Although adrenaline has been shown to induce glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells, the precise molecular mechanism by which adrenaline regulates GLP-1 secretion remains unknown. Here we show by live cell imaging that all types of adrenergic receptors are stimulated by adrenaline in enteroendocrine L cell line GLUTag cells and are involved in GLP-1 exocytosis. We performed RT-PCR analysis and found that α1B-, α2A-, α2B-, and β1-ARs were expressed in GLUTag cells. Application of adrenaline induced a significant increase of intracellular Ca(2+) and cAMP concentration ([Ca(2+)]i and [cAMP]i, respectively), and GLP-1 exocytosis in GLUTag cells. Blockade of α1-AR inhibited adrenaline-induced [Ca(2+)]i increase and exocytosis but not [cAMP]i increase, while blockade of β1-AR inhibited adrenaline-induced [cAMP]i increase and exocytosis but not [Ca(2+)]i increase. Furthermore, overexpression of α2A-AR suppressed the adrenaline-induced [cAMP]i increase and exocytosis. These results suggest that the fine-turning of GLP-1 secretion from enteroendocrine L cells is established by the balance between α1-, α2-, and β-ARs activation. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. The economics and related factors involved in the replacement of land drilling rigs

    International Nuclear Information System (INIS)

    Holm, D.W.

    1992-01-01

    The principal purpose of this paper is to evaluate the construction cost of a medium depth land rig made from all NEW components and the resulting effect on drilling contractor economics. This evaluation will include an inventory of the proposed NEW rig, with a comparison of the costs of a similar rig built in 1981-1982, and a similar rig built from existing UNUSED equipment in manufacturer's current inventory. The paper discusses the problems encountered in obtaining quotations for NEW equipment from manufacturers, the current attitudes of equipment manufacturers, the potential for problems from the use of existing UNUSED equipment in manufacturers inventory, and finally the possible effect on the day rates needed to justify the construction of NEW land rigs. Probable reasons for the attitudes of the manufacturing industry and alternatives for the drilling contractor will be reviewed

  1. DMPD: Proximal effects of Toll-like receptor activation in dendritic cells. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17142025 Proximal effects of Toll-like receptor activation in dendritic cells. Watt...) (.svg) (.html) (.csml) Show Proximal effects of Toll-like receptor activation in dendritic cells. PubmedID... 17142025 Title Proximal effects of Toll-like receptor activation in dendritic ce

  2. The immune-endocrine loop during aging: role of growth hormone and insulin-like growth factor-I.

    Science.gov (United States)

    Burgess, W; Liu, Q; Zhou, J; Tang, Q; Ozawa, A; VanHoy, R; Arkins, S; Dantzer, R; Kelley, K W

    1999-01-01

    Why a primary lymphoid organ such as the thymus involutes during aging remains a fundamental question in immunology. Aging is associated with a decrease in plasma growth hormone (somatotropin) and IGF-I, and this somatopause of aging suggests a connection between the neuroendocrine and immune systems. Several investigators have demonstrated that treatment with either growth hormone or IGF-I restores architecture of the involuted thymus gland by reversing the loss of immature cortical thymocytes and preventing the decline in thymulin synthesis that occurs in old or GH-deficient animals and humans. The proliferation, differentiation and functions of other components of the immune system, including T and B cells, macrophages and neutrophils, also demonstrate age-associated decrements that can be restored by IGF-I. Knowledge of the mechanism by which cytokines and hormones influence hematopoietic cells is critical to improving the health of aged individuals. Our laboratory has recently demonstrated that IGF-I prevents apoptosis in promyeloid cells, which subsequently permits these cells to differentiate into neutrophils. We also demonstrated that IL-4 acts much like IGF-I to promote survival of promyeloid cells and to activate the enzyme phosphatidylinositol 3'-kinase (PI 3-kinase). However, the receptors for IGF-I and IL-4 are completely different, with the intracellular beta chains of the IGF receptor possessing intrinsic tyrosine kinase activity and the alpha and gammac subunit of the heterodimeric IL-4 receptor utilizing the Janus kinase family of nonreceptor protein kinases to tyrosine phosphorylate downstream targets. Both receptors share many of the components of the PI 3-kinase signal transduction pathway, converging at the level of insulin receptor substrate-1 or insulin receptor subtrate-2 (formally known as 4PS, or IL-4 Phosphorylated Substrate). Our investigations with IGF-I and IL-4 suggest that PI 3-kinase inhibits apoptosis by maintaining high levels of

  3. A power recirculating test rig for ball screw endurance tests

    Directory of Open Access Journals (Sweden)

    Giberti Hermes

    2016-01-01

    Full Text Available A conceptual design of an innovative test rig for endurance tests of ball screws is presented in this paper. The test rig layout is based on the power recirculating principle and it also allows to overtake the main critical issues of the ball screw endurance tests. Among these there are the high power required to make the test, the lengthy duration of the same and the high loads between the screw and the frame that holds it. The article describes the test rig designed scheme, the kinematic expedients to be adopted in order to obtain the required performance and functionality and the sizing procedure to choose the actuation system.

  4. Toll-Like Receptors in the Pathogenesis of Autoimmune Diseases

    OpenAIRE

    Mohammad Hosseini, Akbar; Majidi, Jafar; Baradaran, Behzad; Yousefi, Mehdi

    2015-01-01

    Human Toll-like receptors (TLRs) are a family of transmembrane receptors, which play a key role in both innate and adaptive immune responses. Beside of recognizing specific molecular patterns that associated with different types of pathogens, TLRs may also detect a number of self-proteins and endogenous nucleic acids. Activating TLRs lead to the heightened expression of various inflammatory genes, which have a protective role against infection. Data rising predominantly from human patients an...

  5. DMPD: The negative regulation of Toll-like receptor and associated pathways. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17621314 The negative regulation of Toll-like receptor and associated pathways. Lan...) Show The negative regulation of Toll-like receptor and associated pathways. PubmedID 17621314 Title The ne...gative regulation of Toll-like receptor and associated pathways. Authors Lang T,

  6. Saving money on rig refurbishments through foreign trade zones or duty-drawback

    International Nuclear Information System (INIS)

    Ward, R.J. Jr.

    1997-01-01

    The recent boom in day rates for rigs capable of drilling in deep water and harsh environments has created a frenzy of rig refurbishment activity in shipyards located in US Gulf states. In most instances, the destination for the rigs upon completion is the US Outer Continental Shelf (USOCS) in the Gulf of Mexico. The problem faced by contractors/operators planning to use US shipyards is that this circumstance has caused difficulty in shielding rigs and their foreign-sourced components from US Customs duties. Under US Customs law, a bona fide exportation requires severance from US commerce and joining to the commerce of some foreign country or, in the case of a vessel supply, a qualifying international voyage. The USOCS does not qualify as an exportation, nor do movements to drilling sites located on it qualify as an international voyage. Described here are two possible solutions to this economic dilemma and an example of how the foreign trade zone solution was applied by Global marine in its plans for upgrading some of its semisubmersible drilling rigs for deepwater USOCS work

  7. TITAN - a 9 MW, 179 bar pressurised water rig

    International Nuclear Information System (INIS)

    Mogford, D.J.; Lee, D.H.

    1987-02-01

    The report describes the TITAN rig built at Winfrith for thermal hydraulic experiments with water at up to 179 bar pressure. A power supply of 9 MW is available. The report describes three typical experiments that show the versatility of the rig. The first is a 25 rod pressurized water reactor fuel bundle critical heat flux experiment, the second is a parallel channel evaporator test and the third is a model jet pump test. (author)

  8. Virus Infection Triggers MAVS Polymers of Distinct Molecular Weight

    Directory of Open Access Journals (Sweden)

    Natalia Zamorano Cuervo

    2018-01-01

    Full Text Available The mitochondrial antiviral signaling (MAVS adaptor protein is a central signaling hub required for cells to mount an antiviral response following virus sensing by retinoic acid-inducible gene I (RIG-I-like receptors. MAVS localizes in the membrane of mitochondria and peroxisomes and in mitochondrial-associated endoplasmic reticulum membranes. Structural and functional studies have revealed that MAVS activity relies on the formation of functional high molecular weight prion-like aggregates. The formation of protein aggregates typically relies on a dynamic transition between oligomerization and aggregation states. The existence of intermediate state(s of MAVS polymers, other than aggregates, has not yet been documented. Here, we used a combination of non-reducing SDS-PAGE and semi-denaturing detergent agarose gel electrophoresis (SDD-AGE to resolve whole cell extract preparations to distinguish MAVS polymerization states. While SDD-AGE analysis of whole cell extracts revealed the formation of previously described high molecular weight prion-like aggregates upon constitutively active RIG-I ectopic expression and virus infection, non-reducing SDS-PAGE allowed us to demonstrate the induction of lower molecular weight oligomers. Cleavage of MAVS using the NS3/4A protease revealed that anchoring to intracellular membranes is required for the appropriate polymerization into active high molecular weight aggregates. Altogether, our data suggest that RIG-I-dependent MAVS activation involves the coexistence of MAVS polymers with distinct molecular weights.

  9. Involvement of N-methyl-d-aspartate receptors in the antidepressant-like effect of 5-hydroxytryptamine 3 antagonists in mouse forced swimming test and tail suspension test.

    Science.gov (United States)

    Kordjazy, Nastaran; Haj-Mirzaian, Arya; Amiri, Shayan; Ostadhadi, Sattar; Amini-Khoei, Hossein; Dehpour, Ahmad Reza

    2016-02-01

    Recent evidence indicates that 5-hydroxytryptamine 3 (5-HT3) antagonists such as ondansetron and tropisetron exert positive behavioral effects in animal models of depression. Due to the ionotropic nature of 5-HT3 and N-methyl-d-aspartate (NMDA) receptors, plus their contribution to the pathophysiology of depression, we investigated the possible role of NMDA receptors in the antidepressant-like effect of 5-HT3 receptor antagonists in male mice. In order to evaluate the animals' behavior in response to different treatments, we performed open-field test (OFT), forced swimming test (FST), and tail-suspension test (TST), which are considered as valid tasks for measuring locomotor activity and depressive-like behaviors in mice. Our data revealed that intraperitoneal (i.p.) administration of tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01, and 0.1μg/kg) significantly decreased the immobility time in FST and TST. Also, co-administration of subeffective doses of tropisetron (1mg/kg, i.p.) or ondansetron (0.001μg/kg, i.p.) with subeffective doses of NMDA receptor antagonists, ketamine (1mg/kg, i.p.), MK-801 (0.05mg/kg, i.p.) and magnesium sulfate (10mg/kg, i.p.) resulted in a reduced immobility time both in FST and TST. The subeffective dose of NMDA (NMDA receptor agonist, 75mg/kg, i.p.) abolished the effects of 5-HT3 antagonists in FST and TST, further supporting the presumed interaction between 5-HT3 and NMDA receptors. These treatments did not affect the locomotor behavior of animals in OFT. Finally, the results of our study suggest that the positive effects of 5-HT3 antagonists on the coping behavior of mice in FST and TST are at least partly mediated through NMDA receptors participation. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Receptor-like proteins involved in plant disease resistance

    NARCIS (Netherlands)

    Kruijt, M.; Kock, de M.J.D.; Wit, de P.J.G.M.

    2005-01-01

    Race-specific resistance in plants against microbial pathogens is governed by several distinct classes of resistance (R) genes. This review focuses on the class that consists of the plasma membrane-bound leucine-rich repeat proteins known as receptor-like proteins (RLPs). The first isolated

  11. Aberrant dopamine D2-like receptor function in a rodent model of schizophrenia.

    Science.gov (United States)

    Perez, Stephanie M; Lodge, Daniel J

    2012-11-01

    Based on the observation that antipsychotic medications display antagonist properties at dopamine D2-like receptors, aberrant dopamine signaling has been proposed to underlie psychosis in patients with schizophrenia. Thus, it is not surprising that considerable research has been devoted to understanding the mechanisms involved in the antipsychotic action of these compounds. It is important to note that the majority of these studies have been performed in "normal" experimental animals. Given that these animals do not possess the aberrant neuronal information processing typically associated with schizophrenia, the aim of the current study was to examine the dopamine D2 receptor system in a rodent model of schizophrenia. Here, we demonstrate that methylazoxymethanol acetate (MAM)-treated rats display an enhanced effect of quinpirole on dopamine neuron activity and an aberrant locomotor response to D2-like receptor activation, suggesting changes in postsynaptic D2-like receptor function. To better understand the mechanisms underlying the enhanced response to D2-like ligands in MAM-treated rats, we examined the expression of D2, D3, and dopamine transporter mRNA in the nucleus accumbens and ventral tegmental area by quantitative reverse transcription-polymerase chain reaction. MAM-treated rats displayed a significant increase in dopamine D3 receptor mRNA expression in the nucleus accumbens with no significant changes in the expression of the D2 receptor. Taken together, these data demonstrate robust alterations in dopamine D2-like receptor function in a rodent model of schizophrenia and provide evidence that preclinical studies examining the mechanisms of antipsychotic drug action should be performed in animal models that mirror aspects of the abnormal neuronal transmission thought to underlie symptoms of schizophrenia.

  12. Speeding up : new Atlas Copco rig meant to cut non-drilling time

    Energy Technology Data Exchange (ETDEWEB)

    Roche, P.

    2009-06-15

    Automation has significantly reduced the time needed to drill shallow to medium-depth wells. The time it takes for a drill to reach the production zone is decreasing because newly developed hydraulic systems are able to maintain a constant pace. However, a great deal of time is still consumed by demobilization, transportation and setting up to drill the next well. Atlas Copco Drilling Solutions, a Swedish-based global maker of industrial equipment such as mining and mineral exploration rigs, designed a new Predator drilling system that consists of a mobile rig, a substructure and a pipe-handling skate. The Predator drilling system reduces non-drilling time and the associated costs. This article described the design of this new drilling system with particular reference to how it combines the mobile rig, the substructure and the pipe-handling skate into a three-load package. In order to reduce rig weight and improve mobility, the system is designed so that the table, master bushing, hydraulic slips and iron roughneck are part of the substructure that travel together. The rig has a working hook load capacity of 200,000 pounds, translating into a nominal depth capacity of 8,000 to 10,000 feet. The article also described the mounting of the rig, maneuverability, hydraulic control, and pipe-handling safety. Its various components were also described. 1 ref., 1 fig.

  13. GMP-140 binds to a glycoprotein receptor on human neutrophils: Evidence for a lectin-like interaction

    International Nuclear Information System (INIS)

    Moore, K.L.; Varki, A.; McEver, R.P.

    1991-01-01

    GMP-140 is a rapidly inducible receptor for neutrophils and monocytes expressed on activated platelets and endothelial cells. It is a member of the selectin family of lectin-like cell surface molecules that mediate leukocyte adhesion. We used a radioligand binding assay to characterize the interaction of purified GMP-140 with human neutrophils. Unstimulated neutrophils rapidly bound [125I]GMP-140 at 4 degrees C, reaching equilibrium in 10-15 min. Binding was Ca2+ dependent, reversible, and saturable at 3-6 nM free GMP-140 with half-maximal binding at approximately 1.5 nM. Receptor density and apparent affinity were not altered when neutrophils were stimulated with 4 beta-phorbol 12-myristate 13-acetate. Treatment of neutrophils with proteases abolished specific binding of [125I]GMP-140. Binding was also diminished when neutrophils were treated with neuraminidase from Vibrio cholerae, which cleaves alpha 2-3-, alpha 2-6-, and alpha 2-8-linked sialic acids, or from Newcastle disease virus, which cleaves only alpha 2-3- and alpha 2-8-linked sialic acids. Binding was not inhibited by an mAb to the abundant myeloid oligosaccharide, Lex (CD15), or by the neoglycoproteins Lex-BSA and sialyl-Lex-BSA. We conclude that neutrophils constitutively express a glycoprotein receptor for GMP-140, which contains sialic acid residues that are essential for function. These findings support the concept that GMP-140 interacts with leukocytes by a lectin-like mechanism

  14. Robotics Test Rig

    International Nuclear Information System (INIS)

    Schuurmans, P.

    2007-01-01

    The experimental Accelerator Driven System XT-ADS is being developed within the European 6th framework programme EUROTRANS using the MYRRHA DRAFT-2 as starting point. The aim for the XT-ADS is to demonstrate the feasibility of the ADS concept at reasonable power levels and to serve as a high performance, multi-purpose experimental irradiation device. One of the fundamental design options that has been taken is to do all maintenance and in-service inspection and repair duties by remote handling. Outside the XT-ADS vessel in a controlled though radio-active environment, remote handling concepts as those already in use at e.g. the Joint European Torus (JET) can be used. Extrapolation to remote handling inside the lead-bismuth eutectic filled main vessel of the XT-ADS is in principle feasible as was shown in a 2003 study performed by Oxford Technologies ltd for the case of MYRRHA. Nevertheless, it is clear that all critical remote handling components need to be qualified for use in liquid LBE. Thus, as a first step, a proof of principle (POP) experimental test rig is require. The principal goal of this work is to identify the critical technological issues that must be resolved to allow operation of remote handling manipulators inside the LBE filled main vessel of the XT-ADS and to propose a concept design and specification catalogue for a proof of principle test rig that is able to experimentally verify the main aspects of manipulator design

  15. Testing of elastomer seals using small-size rigs

    International Nuclear Information System (INIS)

    Leeks, C.W.E.; Dunford, B.; Barnfield, J.H.; Gray, I.L.S.

    1997-01-01

    This paper looks at the use of small size seal leakage test rigs to demonstrate the compliance of full size container seals against the IAEA Transport Regulation's limits for activity release for normal transport and accident conditions. The detailed requirements of the regulations are discussed and it is concluded that an appropriate test programme to meet these requirements using only small size test rigs, can normally be set up and carried out on a relatively short time scale. It is important that any small test rigs should be designed to represent the relevant features of the seal arrangement and the overall test programme should cover all of the conditions, specified by the regulations, for the type, classification and contents of the container under consideration. The parameters of elastomer O-rings, which affect their sealing ability, are considered and those which are amenable to small scale testing or have to be modelled at full size are identified. Generally, the seals used in leakage tests have to be modelled with a full size cross-section but can have a reduced peripheral length. (Author)

  16. Automatic X-ray television rig for high-speed radiography of polycrystals

    International Nuclear Information System (INIS)

    Bezbakh, V.D.; Garasim, Yu.A.; Oshkaderov, S.P.; Pet'kov, V.V.

    1993-01-01

    The high-speed radiography method is used for studying the phase and structural transformation in metals and alloys during rapid changes in temperature. In order to improve the effectiveness of this method the Institute of Metal Physics, Ukrainian Academy of Sciences, has developed an automatic rig for high-speed radiography of polycrystalline materials using a television method for recording the x-ray diffraction patterns. The rig, described here, consists of an x-ray block, a vacuum chamber, a device for programmed electro-contact heating of specimens, a system for imaging and scanning x-ray diffraction patterns, and a system for collecting and analyzing the data. Focusing is carried out by the Zeeman-Bolin method. The new rig helps to significantly reduce the recording time and ensures adequate quality and reliability of the recorded diffraction image over a wide range of temperatures. Data using the rig is presented for high-speed radiography for cooling a specimen of G20 steel. 4 refs., 4 figs

  17. Toll-like receptors in brain development and homeostasis

    DEFF Research Database (Denmark)

    Larsen, Peter H; Holm, Thomas Hellesøe; Owens, Trevor

    2007-01-01

    Toll-like receptors (TLRs) are best known as initiators of the innate immune response to pathogens. Recent reports now reveal intriguing roles for TLRs in the central nervous system (CNS). These include the regulation of neuroinflammation and of neurite outgrowth. The archetypal Toll protein in D...

  18. Experimental Analysis of Mast Lifting and Bending Forces on Vibration Patterns Before and After Pinion Reinstallation in an OH-58 Transmission Test Rig

    Science.gov (United States)

    Huff, Edward M.; Lewicki, David G.; Tumer, Irem Y.; Decker, Harry; Barszez, Eric; Zakrajsek, James J.; Norvig, Peter (Technical Monitor)

    2000-01-01

    As part of a collaborative research program between NASA Ames Research Center (ARC), NASA Glenn Research Center (GRC), and the US Army Laboratory, a series of experiments is being performed in GRC's 500 HP OH-58 Transmission Test Rig facility and ARC's AH-I Cobra and OH-58c helicopters. The findings reported in this paper were drawn from Phase-I of a two-phase test-rig experiment, and are focused on the vibration response of an undamaged pinion gear operating in the transmission test rig. To simulate actual flight conditions, the transmission system was run at three torque levels, as well as two mast lifting and two mast bending levels. The test rig was also subjected to disassembly and reassembly of the main pinion housing to simulate the effect of maintenance operations. An analysis of variance based on the total power of the spectral distribution indicates the relative effect of each experimental factor, including Wong interactions with torque. Reinstallation of the main pinion assembly is shown to introduce changes in the vibration signature, suggesting the possibility of a strong effect of maintenance on HUMS design and use. Based on these results, further research will be conducted to compare these vibration responses with actual OH58c helicopter transmission vibration patterns.

  19. Negative regulation of Toll-like receptor signalling 

    Directory of Open Access Journals (Sweden)

    Halina Antosz

    2013-04-01

    Full Text Available The mechanism of innate immunity is based on the pattern recognition receptors (PRR that recognize molecular patterns associated with pathogens (PAMPs. Among PRR receptors Toll-like receptors (TLR are distinguished. As a result of contact with pathogens, TLRs activate specific intracellular signaling pathways. It happens through proteins such as adaptor molecules, e.g. MyD88, TIRAP, TRIF, TRAM, and IPS-1, which participate in the cascade activation of kinases (IKK, MAP, RIP-1, TBK-1 as well as transcription factors (NF-κB, AP-1 and regulatory factor (IRF3. The result of this activation is the production of active proinflammatory cytokines, chemokines, interferons and enzymes. The PRR pathways are controlled by extra – and intracellular molecules to prevent overexpression of PRR. They include soluble receptors (sTLR, transmembrane proteins (ST2, SIGIRR, RP105, TRAIL-R and intracellular inhibitors (SOCS-1, SOCS-3, sMyD88, TOLLIP, IRAK-M, SARM, A20, β-arrestin, CYLD, SHP. These molecules maintain the balance between activation and inhibition and ensure balancing of the beneficial and adverse effects of antigen recognition.

  20. Purification of family B G protein-coupled receptors using nanodiscs: Application to human glucagon-like peptide-1 receptor.

    Directory of Open Access Journals (Sweden)

    Yingying Cai

    Full Text Available Family B G protein-coupled receptors (GPCRs play vital roles in hormone-regulated homeostasis. They are drug targets for metabolic diseases, including type 2 diabetes and osteoporosis. Despite their importance, the signaling mechanisms for family B GPCRs at the molecular level remain largely unexplored due to the challenges in purification of functional receptors in sufficient amount for biophysical characterization. Here, we purified the family B GPCR human glucagon-like peptide-1 (GLP-1 receptor (GLP1R, whose agonists, e.g. exendin-4, are used for the treatment of type 2 diabetes mellitus. The receptor was expressed in HEK293S GnTl- cells using our recently developed protocol. The protocol incorporates the receptor into the native-like lipid environment of reconstituted high density lipoprotein (rHDL particles, also known as nanodiscs, immediately after the membrane solubilization step followed by chromatographic purification, minimizing detergent contact with the target receptor to reduce denaturation and prolonging stabilization of receptor in lipid bilayers without extra steps of reconstitution. This method yielded purified GLP1R in nanodiscs that could bind to GLP-1 and exendin-4 and activate Gs protein. This nanodisc purification method can potentially be a general strategy to routinely obtain purified family B GPCRs in the 10s of microgram amounts useful for spectroscopic analysis of receptor functions and activation mechanisms.

  1. Purification of family B G protein-coupled receptors using nanodiscs: Application to human glucagon-like peptide-1 receptor.

    Science.gov (United States)

    Cai, Yingying; Liu, Yuting; Culhane, Kelly J; DeVree, Brian T; Yang, Yang; Sunahara, Roger K; Yan, Elsa C Y

    2017-01-01

    Family B G protein-coupled receptors (GPCRs) play vital roles in hormone-regulated homeostasis. They are drug targets for metabolic diseases, including type 2 diabetes and osteoporosis. Despite their importance, the signaling mechanisms for family B GPCRs at the molecular level remain largely unexplored due to the challenges in purification of functional receptors in sufficient amount for biophysical characterization. Here, we purified the family B GPCR human glucagon-like peptide-1 (GLP-1) receptor (GLP1R), whose agonists, e.g. exendin-4, are used for the treatment of type 2 diabetes mellitus. The receptor was expressed in HEK293S GnTl- cells using our recently developed protocol. The protocol incorporates the receptor into the native-like lipid environment of reconstituted high density lipoprotein (rHDL) particles, also known as nanodiscs, immediately after the membrane solubilization step followed by chromatographic purification, minimizing detergent contact with the target receptor to reduce denaturation and prolonging stabilization of receptor in lipid bilayers without extra steps of reconstitution. This method yielded purified GLP1R in nanodiscs that could bind to GLP-1 and exendin-4 and activate Gs protein. This nanodisc purification method can potentially be a general strategy to routinely obtain purified family B GPCRs in the 10s of microgram amounts useful for spectroscopic analysis of receptor functions and activation mechanisms.

  2. Characterization of glucagon-like peptide-1 receptor beta-arrestin 2 interaction: a high-affinity receptor phenotype

    DEFF Research Database (Denmark)

    Jorgensen, Rasmus; Martini, Lene; Schwartz, Thue W

    2005-01-01

    To dissect the interaction between beta-arrestin ((beta)arr) and family B G protein-coupled receptors, we constructed fusion proteins between the glucagon-like peptide 1 receptor and (beta)arr2. The fusion constructs had an increase in apparent affinity selectively for glucagon, suggesting...... that (beta)arr2 interaction locks the receptor in a high-affinity conformation, which can be explored by some, but not all, ligands. The fusion constructs adopted a signaling phenotype governed by the tethered (beta)arr2 with an attenuated G protein-mediated cAMP signal and a higher maximal internalization...... of that which has previously been characterized for family A G protein-coupled receptors, suggesting similarities in the effect of (beta)arr interaction between family A and B receptors also at the molecular level....

  3. Overexpression of insulin-like growth factor (IGF)-I receptor enhances inhibition of DNA replication in mouse cells exposed to x-rays

    International Nuclear Information System (INIS)

    Wang, Y.; Cheong, N.; Miura, M.; Iliakis, G.

    1997-01-01

    Previous studies from our laboratory provided evidence for the operation of signal transduction pathways involving ras, myc, and staurosporine-sensitive protein kinases in the regulation of DNA replication in irradiated cells. Because ras and myc are also involved in the signal transduction elicited in response to ligand activation of growth factor receptors, we wondered whether growth factor receptors are upstream elements in the regulation of DNA replication in irradiated cells. Here, we report on the role of insulin-like growth factor I receptor (IGF-IR) in the regulation of DNA replication in irradiated cells. We compare radiation-induced inhibition of DNA replication in BALB/c 3T3 cells with that in P6 cells. P6 cells are derived from BALB/c 3T3 cells by transfection with a vector expressing IGF-IR, leading to 30-fold overexpression. We observe a significantly stronger inhibition of DNA replication after irradiation in P6 as compared with BALB/c 3T3 cells at all doses examined. Sedimentation in alkaline sucrose gradients shows that the increased inhibition in P6 cells is due to an increased inhibition of replicon initiation, the main controlling event in DNA replication. Staurosporine at 20 nM reduces radiation-induced inhibition of DNA replication in BALB/c 3T3 cells, but has only a small effect in P6 cells. Caffeine at a concentration of 1 mM, on the other hand, removes over 60% of the inhibition in both cell lines. The results implicate IGF-IR in the regulation of DNA replication in irradiated cells, but also suggest differences between cells of different origins in the proteins involved in the regulating signal transduction pathway. (orig.). With 5 figs

  4. PNNL Hoisting and Rigging Manual

    Energy Technology Data Exchange (ETDEWEB)

    Haynie, Todd O.; Fullmer, Michael W.

    2008-12-29

    This manual describes the safe and cost effective operation, inspection, maintenance, and repair requirements for cranes, hoists, fork trucks, slings, rigging hardware, and hoisting equipment. It is intended to be a user's guide to requirements, codes, laws, regulations, standards, and practices that apply to Pacific Northwest National Laboratory (PNNL) and its subcontractors.

  5. Partial separation of platelet and placental adenosine receptors from adenosine A2-like binding protein

    International Nuclear Information System (INIS)

    Zolnierowicz, S.; Work, C.; Hutchison, K.; Fox, I.H.

    1990-01-01

    The ubiquitous adenosine A2-like binding protein obscures the binding properties of adenosine receptors assayed with 5'-N-[ 3 H]ethylcarboxamidoadenosine [( 3 H]NECA). To solve this problem, we developed a rapid and simple method to separate adenosine receptors from the adenosine A2-like binding protein. Human platelet and placental membranes were solubilized with 1% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. The soluble platelet extract was precipitated with polyethylene glycol and the fraction enriched in adenosine receptors was isolated from the precipitate by differential centrifugation. The adenosine A2-like binding protein was removed from the soluble placental extract with hydroxylapatite and adenosine receptors were precipitated with polyethylene glycol. The specificity of the [ 3 H]NECA binding is typical of an adenosine A2 receptor for platelets and an adenosine A1 receptor for placenta. This method leads to enrichment of adenosine A2 receptors for platelets and adenosine A1 receptors for placenta. This provides a useful preparation technique for pharmacologic studies of adenosine receptors

  6. A Dynamic Behavior of the Nuclear Test Rig with Coolant using the Fluid-Structural interaction Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Tae-Ho; Hong, Jintae; Ahn, Sung-Ho; Joung, Chang-Young; Jang, Seo-Yun [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Yeon, Kon-Whi [Chungnam National University, Daejeon (Korea, Republic of)

    2016-10-15

    In this paper, the dynamic behavior of the test rig in the coolant flow simulator is evaluated by using the 2-way fluid-structural interaction analysis. The maximum value and location of the deformation and equivalent stress in the test rig is confirmed. The fluid-structural interaction analysis is applied to perform the fluid and structural analysis A fluid-structure interaction analysis is used to simulate the relationship between the deformation and hydraulic pressure. There are two types of fluid-structural interaction analysis. One is a 1-way direction analysis in which the hydraulic pressure is calculated by a CFD and transmitted to the surface of the structure, and a structural analysis is then performed. The other is a 2-way direction analysis that is performed by changing the data between the deformation of the structural and pressure of the coolant water for every time step. The location of the maximum deformation of the test rig is the bottom parts of the test rig. It is expected that the equivalent stress of the test rig is occurred. The maximum equivalent stress in the test rig under the circulation of the coolant is 90.1 MPa. The location of the maximum stress in the test rig is the connect part between the fuel rod and flow divider. A safety factor on the test rig is 3, approximately. The deformation motion of the test rig at the bottom part of the test rig is caused about the fluid-induced vibration. A test on the fluid-induced vibration of the test rig will be performed and compared with results of the analysis in further paper.

  7. Plasma and tissue insulin-like growth factor-I receptor (IGF-IR) as a prognostic marker for prostate cancer and anti-IGF-IR agents as novel therapeutic strategy for refractory cases: a review.

    Science.gov (United States)

    Ozkan, Emine Elif

    2011-09-15

    Cancer database analysis indicates that prostate cancer is one of the most seen cancers in men meanwhile composing the leading cause of morbidity and mortality among developed countries. Current available therapies are surgery, radiotherapy and androgene ablation for prostate carcinoma. The response rate is as high nearly 90% however, most of these recur or become refractory and androgene independent (AI). Therefore recent studies intensified on molecular factors playing role on development of prostate carcinoma and novel treatment strategies targetting these factors and their receptors. Insulin-like growth factor-I (IGF-I) and its primary receptor insulin-like growth factor receptor-I (IGF-IR) are among these factors. Biologic functions and role in malign progression are primarily achieved via IGF-IR which is a type 2 tyrosine kinase receptor. IGF-IR plays an important role in mitogenesis, angiogenesis, transformation, apoptosis and cell motility. It also generates intensive proliferative signals leading to carcinogenesis in prostate tissue. So IGF-IR and its associated signalling system have provoked considerable interest over recent years as a novel therapeutic target in cancer. In this paper it is aimed to sum up the lately published literature searching the relation of IGF-IR and prostate cancer in terms of incidence, pathologic features, and prognosis. This is followed by a discussion of the different possible targets within the IGF-1R system, and drugs developed to interact at each target. A systems-based approach is then used to review the in vitro and in vivo data in the published literature of the following compounds targeting IGF-1R components using specific examples: growth hormone releasing hormone antagonists (e.g. JV-1-38), growth hormone receptor antagonists (e.g. pegvisomant), IGF-1R antibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12, SCH-717454, BIIB022, AMG 479, MK-0646/h7C10), and IGF-1R tyrosine kinase inhibitors (e.g. BMS-536942, BMS-554417

  8. Probing natural killer cell education by Ly49 receptor expression analysis and computational modelling in single MHC class I mice.

    Directory of Open Access Journals (Sweden)

    Sofia Johansson

    Full Text Available Murine natural killer (NK cells express inhibitory Ly49 receptors for MHC class I molecules, which allows for "missing self" recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I molecules impose an "educating impact" on the NK cell pool. As a result, mice with different MHC class I expression display different frequency distributions of Ly49 receptor combinations on NK cells. Two models have been put forward to explain this impact. The two-step selection model proposes a stochastic Ly49 receptor expression followed by selection for NK cells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentially expresses Ly49 receptors until an interaction of sufficient magnitude with self-class I MHC is reached for the NK cell to mature. With the aim to clarify which one of these models is most likely to reflect the actual biological process, we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, which were analyzed in mice expressing single MHC class I molecules. Our results favour the two-step selection model over the sequential model. Furthermore, the MHC class I environment favoured maturation of NK cells expressing one or a few self receptors, suggesting a possible step of positive selection in NK cell education. Based on the predicted Ly49 binding preferences revealed by the model, we also propose, that Ly49 receptors are more promiscuous than previously thought in their interactions with MHC class I molecules, which was supported by functional studies of NK cell subsets expressing individual Ly49 receptors.

  9. Technical and economic evaluation of selected compact drill rigs for drilling 10,000 foot geothermal production wells

    Energy Technology Data Exchange (ETDEWEB)

    Huttrer, G.W. [Geothermal Management Company, Inc., Frisco, CO (United States)

    1997-11-01

    This report summarizes the investigation and evaluation of several {open_quotes}compact{close_quotes} drill rigs which could be used for drilling geothermal production wells. Use of these smaller rigs would save money by reducing mobilization costs, fuel consumption, crew sizes, and environmental impact. Advantages and disadvantages of currently-manufactured rigs are identified, and desirable characteristics for the {open_quotes}ideal{close_quotes} compact rig are defined. The report includes a detailed cost estimate of a specific rig, and an evaluation of the cost/benefit ratio of using this rig. Industry contacts for further information are given.

  10. DMPD: Toll-like receptors: novel pharmacological targets for the treatment ofneurological diseases. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17974478 Toll-like receptors: novel pharmacological targets for the treatment ofneu...png) (.svg) (.html) (.csml) Show Toll-like receptors: novel pharmacological targets for the treatment ofneur...ological diseases. PubmedID 17974478 Title Toll-like receptors: novel pharmacological target

  11. DMPD: Innate immunity and toll-like receptors: clinical implications of basic scienceresearch. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15069387 Innate immunity and toll-like receptors: clinical implications of basic science...te immunity and toll-like receptors: clinical implications of basic scienceresearch. PubmedID 15069387 Title... Innate immunity and toll-like receptors: clinical implications of basic sciencer

  12. BURNER RIG TESTING OF A500 C/SiC

    Science.gov (United States)

    2018-03-17

    AFRL-RX-WP-TR-2018-0071 BURNER RIG TESTING OF A500® C /SiC Larry P. Zawada Universal Technology Corporation Jennifer Pierce UDRI...TITLE AND SUBTITLE BURNER RIG TESTING OF A500® C /SiC 5a. CONTRACT NUMBER In-House 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 62102F 6...test program characterized the durability behavior of A500® C /SiC ceramic matrix composite material at room and elevated temperature. Specimens were

  13. Design and Checkout of a High Speed Research Nozzle Evaluation Rig

    Science.gov (United States)

    Castner, Raymond S.; Wolter, John D.

    1997-01-01

    The High Flow Jet Exit Rig (HFJER) was designed to provide simulated mixed flow turbojet engine exhaust for one- seventh scale models of advanced High Speed Research test nozzles. The new rig was designed to be used at NASA Lewis Research Center in the Nozzle Acoustic Test Rig and the 8x6 Supersonic Wind Tunnel. Capabilities were also designed to collect nozzle thrust measurement, aerodynamic measurements, and acoustic measurements when installed at the Nozzle Acoustic Test Rig. Simulated engine exhaust can be supplied from a high pressure air source at 33 pounds of air per second at 530 degrees Rankine and nozzle pressure ratios of 4.0. In addition, a combustion unit was designed from a J-58 aircraft engine burner to provide 20 pounds of air per second at 2000 degrees Rankine, also at nozzle pressure ratios of 4.0. These airflow capacities were designed to test High Speed Research nozzles with exhaust areas from eighteen square inches to twenty-two square inches. Nozzle inlet flow measurement is available through pressure and temperature sensors installed in the rig. Research instrumentation on High Speed Research nozzles is available with a maximum of 200 individual pressure and 100 individual temperature measurements. Checkout testing was performed in May 1997 with a 22 square inch ASME long radius flow nozzle. Checkout test results will be summarized and compared to the stated design goals.

  14. Jet Exit Rig Six Component Force Balance

    Science.gov (United States)

    Castner, Raymond; Wolter, John; Woike, Mark; Booth, Dennis

    2012-01-01

    A new six axis air balance was delivered to the NASA Glenn Research Center. This air balance has an axial force capability of 800 pounds, primary airflow of 10 pounds per second, and a secondary airflow of 3 pounds per second. Its primary use was for the NASA Glenn Jet Exit Rig, a wind tunnel model used to test both low-speed, and high-speed nozzle concepts in a wind tunnel. This report outlines the installation of the balance in the Jet Exit Rig, and the results from an ASME calibration nozzle with an exit area of 8 square-inches. The results demonstrated the stability of the force balance for axial measurements and the repeatability of measurements better than 0.20 percent.

  15. The evaluation of secondary system oxygen-scavenging chemicals using a water-circulating rig

    Energy Technology Data Exchange (ETDEWEB)

    Collins, M.W. [Nuclear Dept., HMS Sultan (United Kingdom)

    2002-07-01

    To assess the efficiency, mode of action and possible by-products of chemical dosing agents, e.g. oxygen scavengers, a circulating water rig was constructed. The rig uses a demineralized water supply as a source of make-up water to fill a recirculating loop of approx. 10 litres volume. The rig pipework is made of polythene with standard off-the shelf pipe fittings and connectors. The following parameters can be measured within the rig: pH and conductivity measured by in-line monitor, dissolved oxygen level, temperature. The system has already been used for some preliminary testing. The following oxygen scavengers have been used for tests: ascorbic acid (vitamin C), N,N-diethyl-hydroxylamine (DEHA), Hydroquinone, hydrazine hydrate and anhydrous sodium sulfite. (authors)

  16. The evaluation of secondary system oxygen-scavenging chemicals using a water-circulating rig

    International Nuclear Information System (INIS)

    Collins, M.W.

    2002-01-01

    To assess the efficiency, mode of action and possible by-products of chemical dosing agents, e.g. oxygen scavengers, a circulating water rig was constructed. The rig uses a demineralized water supply as a source of make-up water to fill a recirculating loop of approx. 10 litres volume. The rig pipework is made of polythene with standard off-the shelf pipe fittings and connectors. The following parameters can be measured within the rig: pH and conductivity measured by in-line monitor, dissolved oxygen level, temperature. The system has already been used for some preliminary testing. The following oxygen scavengers have been used for tests: ascorbic acid (vitamin C), N,N-diethyl-hydroxylamine (DEHA), Hydroquinone, hydrazine hydrate and anhydrous sodium sulfite. (authors)

  17. Toll-like receptor activation in the pathogenesis of lupus nephritis.

    Science.gov (United States)

    Lorenz, Georg; Lech, Maciej; Anders, Hans-Joachim

    2017-12-01

    The pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis is complex but no longer enigmatic. Much progress has been made to on the polygenetic origin of lupus in identifying gene variants that permit the loss of tolerance against nuclear autoantigens. Along the same line in about 50% of lupus patients additional genetic weaknesses promote immune complex glomerulonephritis and filtration barrier dysfunction. Here we briefly summarize the pathogenesis of SLE with a focus on loss of tolerance and the role of toll-like receptors in the "pseudo"-antiviral immunity concept of systemic lupus. In addition, we discuss the local role of Toll-like receptors in intrarenal inflammation and kidney remodeling. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats.

    Science.gov (United States)

    Rudoy, C A; Van Bockstaele, E J

    2007-06-30

    Anxiety has been indicated as one of the main symptoms of the cocaine withdrawal syndrome in human addicts and severe anxiety during withdrawal may potentially contribute to relapse. As alterations in noradrenergic transmission in limbic areas underlie withdrawal symptomatology for many drugs of abuse, the present study sought to determine the effect of cocaine withdrawal on beta-adrenergic receptor (beta(1) and beta(2)) expression in the amygdala. Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that beta(1)-adrenergic receptor, but not beta(2)-adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with betaxolol, a highly selective beta(1)-adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 h following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 h following the last betaxolol injection. Following behavioral testing, betaxolol effects on beta(1)-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal. Animals treated with betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline. Furthermore

  19. Stochastic programming of drilling rigs supplies; Programacao estocastica de suprimentos de sondas

    Energy Technology Data Exchange (ETDEWEB)

    Vieira, Bruno Ferreira; Ferreira Filho, Virgilio Jose Martins [Coordenacao dos Programas de Pos-Graduacao de Engenharia (COPPE/UFRJ), RJ (Brazil)

    2012-07-01

    The goal of this work is to use techniques of stochastic programming to reduce logistic costs regarding offshore drilling rigs. This theme is of great interest to Brazilian oil industry since there is an increasing number of wells that need to be perforated so that Brazilian oil production can reach its expected growth over the next ten years (PETROBRAS in particular has an ambitious strategy in this respect). Proper treatment of the uncertainties involved in the deliveries of supplies to offshore drilling rigs is essential, namely, these uncertainties need to be included in the models used in logistic models. Delays in the deliveries of products such as chemicals, perforation fluids and tubes may force drilling rigs to stop their operations what highly increases costs. The daily hiring rates of drilling rigs represent the highest cost in the perforation and completion of a well. (author)

  20. Involvement of AMPA receptors in the antidepressant-like effects of dextromethorphan in mice.

    Science.gov (United States)

    Nguyen, Linda; Matsumoto, Rae R

    2015-12-15

    Dextromethorphan (DM) is an antitussive with rapid acting antidepressant potential based on pharmacodynamic similarities to ketamine. Building upon our previous finding that DM produces antidepressant-like effects in the mouse forced swim test (FST), the present study aimed to establish the antidepressant-like actions of DM in the tail suspension test (TST), another well-established model predictive of antidepressant efficacy. Additionally, using the TST and FST, we investigated the role of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in the antidepressant-like properties of DM because accumulating evidence suggests that AMPA receptors play an important role in the pathophysiology of depression and may contribute to the efficacy of antidepressant medications, including that of ketamine. We found that DM displays antidepressant-like effects in the TST similar to the conventional and fast acting antidepressants characterized by imipramine and ketamine, respectively. Moreover, decreasing the first-pass metabolism of DM by concomitant administration of quinidine (CYP2D6 inhibitor) potentiated antidepressant-like actions, implying DM itself has antidepressant efficacy. Finally, in both the TST and FST, pretreatment with the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide) significantly attenuated the antidepressant-like behavior elicited by DM. Together, the data show that DM exerts antidepressant-like actions through AMPA receptors, further suggesting DM may act as a safe and effective fast acting antidepressant drug. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Osteoblasts extracellular matrix induces vessel like structures through glycosylated collagen I

    Energy Technology Data Exchange (ETDEWEB)

    Palmieri, D. [Genetics, DIBIO, University of Genova, Corso Europa 26, 16132 Genova (Italy); Valli, M.; Viglio, S. [Department of Biochemistry, University of Pavia (Italy); Ferrari, N. [Istituto Nazionale per la ricerca sul Cancro, Genova (Italy); Ledda, B.; Volta, C. [Genetics, DIBIO, University of Genova, Corso Europa 26, 16132 Genova (Italy); Manduca, P., E-mail: man-via@unige.it [Genetics, DIBIO, University of Genova, Corso Europa 26, 16132 Genova (Italy)

    2010-03-10

    Extracellular matrix (ECM) plays a fundamental role in angiogenesis affecting endothelial cells proliferation, migration and differentiation. Vessels-like network formation in vitro is a reliable test to study the inductive effects of ECM on angiogenesis. Here we utilized matrix deposed by osteoblasts as substrate where the molecular and structural complexity of the endogenous ECM is preserved, to test if it induces vessel-like network formation by endothelial cells in vitro. ECM is more similar to the physiological substrate in vivo than other substrates previously utilized for these studies in vitro. Osteogenic ECM, prepared in vitro from mature osteoblasts at the phase of maximal deposition and glycosylation of collagen I, induces EAhy926, HUVEC, and HDMEC endothelial cells to form vessels-like structures and promotes the activation of metalloproteinase-2 (MMP-2); the functionality of the p-38/MAPK signaling pathway is required. Osteogenic ECM also induces a transient increase of CXCL12 and a decrease of the receptor CXCR4. The induction of vessel-like networks is dependent from proper glycosylation of collagens and does not occur on osteogenic ECMs if deglycosylated by -galactosidase or on less glycosylated ECMs derived from preosteoblasts and normal fibroblasts, while is sustained on ECM from osteogenesis imperfecta fibroblasts only when their mutation is associated with over-glycosylation of collagen type I. These data support that post-translational glycosylation has a role in the induction in endothelial cells in vitro of molecules conductive to self-organization in vessels-like structures.

  2. Osteoblasts extracellular matrix induces vessel like structures through glycosylated collagen I

    International Nuclear Information System (INIS)

    Palmieri, D.; Valli, M.; Viglio, S.; Ferrari, N.; Ledda, B.; Volta, C.; Manduca, P.

    2010-01-01

    Extracellular matrix (ECM) plays a fundamental role in angiogenesis affecting endothelial cells proliferation, migration and differentiation. Vessels-like network formation in vitro is a reliable test to study the inductive effects of ECM on angiogenesis. Here we utilized matrix deposed by osteoblasts as substrate where the molecular and structural complexity of the endogenous ECM is preserved, to test if it induces vessel-like network formation by endothelial cells in vitro. ECM is more similar to the physiological substrate in vivo than other substrates previously utilized for these studies in vitro. Osteogenic ECM, prepared in vitro from mature osteoblasts at the phase of maximal deposition and glycosylation of collagen I, induces EAhy926, HUVEC, and HDMEC endothelial cells to form vessels-like structures and promotes the activation of metalloproteinase-2 (MMP-2); the functionality of the p-38/MAPK signaling pathway is required. Osteogenic ECM also induces a transient increase of CXCL12 and a decrease of the receptor CXCR4. The induction of vessel-like networks is dependent from proper glycosylation of collagens and does not occur on osteogenic ECMs if deglycosylated by -galactosidase or on less glycosylated ECMs derived from preosteoblasts and normal fibroblasts, while is sustained on ECM from osteogenesis imperfecta fibroblasts only when their mutation is associated with over-glycosylation of collagen type I. These data support that post-translational glycosylation has a role in the induction in endothelial cells in vitro of molecules conductive to self-organization in vessels-like structures.

  3. DMPD: Toll-like receptors: paving the path to T cell-driven autoimmunity? [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17888644 Toll-like receptors: paving the path to T cell-driven autoimmunity? Marsla... Toll-like receptors: paving the path to T cell-driven autoimmunity? PubmedID 17888644 Title Toll-like recep...tors: paving the path to T cell-driven autoimmunity? Authors Marsland BJ, Kopf M.

  4. Substantial Fatigue Similarity of a New Small-Scale Test Rig to Actual Wheel-Rail System

    NARCIS (Netherlands)

    Naeimi, M.; Li, Z.; Petrov, R.H.; Dollevoet, R.P.B.J.; Sietsma, J.; Wu, J.

    2014-01-01

    The substantial similarity of fatigue mechanism in a new test rig for rolling contact fatigue (RCF) has been investigated. A new reduced-scale test rig is designed to perform controlled RCF tests in wheel-rail materials. The fatigue mechanism of the rig is evaluated in this study using a combined

  5. Work over rig itinerary optimization; Otimizacao do itinerario de sondas de intervencao

    Energy Technology Data Exchange (ETDEWEB)

    Paiva, Ronaldo Oliveira de

    1997-07-01

    The costs of work over and the loss of revenue in wells waiting work over rigs are very high. This work proposes methods to prioritize these wells in order to minimize the total cost. To determine the work over sequence it is necessary to compare the rig expense with the wells losses. For calculating the wells losses, it is necessary to analyze the monetary influence of the well shutdown in the production curves. In this work, this analysis is made by using a numerical reservoir simulator. Simplified calculation procedures are also presented. The priority of the wells is based on the reduction of the total cost, which consists of the rig costs plus the revenue losses due to work over waiting. There are many algorithms able to determine the ideal rig path. Simple and intuitive algorithms are implemented and compared. The Simulated Annealing algorithm is recommended. This algorithm was implemented to optimize work over rig routes in a brazilian production region. Optimization of the work over sequence carried out in that region in 1996 identified a potential economy of 15% in the production losses, equivalent to 4.000m{sup 3}/year of oil (25.000 b bl/year). (author)

  6. Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations

    DEFF Research Database (Denmark)

    Silkoff, Philip E; Flavin, Susan; Gordon, Robert

    2017-01-01

    BACKGROUND: Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. OBJECTIVE: We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO3157......, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV1 during 10 days after inoculation. RESULTS: In asthmatic patients (n = 63) CNTO3157 provided......: In summary, CNTO3157 was ineffective in attenuating the effect of HRV-16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought...

  7. Development of TIG Welding System for a Nuclear Fuel Test Rig

    Energy Technology Data Exchange (ETDEWEB)

    Joung, Changyoung; Ahn, Sungho; Hong, Jintae; Kim, Kahye [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2013-05-15

    The welding process is one of the most important among the instrumentation processes of the nuclear fuel test rig and rods. To manufacture the nuclear fuel test rig, a precision welding system needs to be fabricated to develop various welding technologies of the fuel test rig and rods jointing the various sensors and end caps on a fuel cladding tube, which is charged with fuel pellets and component parts. Thus, we designed and fabricated the precision welding system consisting of an orbital TIG welder, a low-pressure chamber, and a high-pressure chamber. Using this system, the performance tests were performed with the round and seal spot welds for each welding condition. This paper describes not only the contents for the fabrication of precision TIG welding system but also some results from weld tests using the low-pressure and high-pressure chambers to verify the performance of this system. The TIG welding system was developed to manufacture the nuclear fuel test rig and rods. It has been configured to be able to weld the nuclear fuel test rigs and rods by applying the TIG welder using a low-pressure chamber and a high-pressure chamber. The performance tests using this system were performed with the round and seal spot welds for the welding conditions. The soundness of the orbital TIG welding system was confirmed through performance tests in the low-pressure and high-pressure chambers.

  8. Development of TIG Welding System for a Nuclear Fuel Test Rig

    International Nuclear Information System (INIS)

    Joung, Changyoung; Ahn, Sungho; Hong, Jintae; Kim, Kahye

    2013-01-01

    The welding process is one of the most important among the instrumentation processes of the nuclear fuel test rig and rods. To manufacture the nuclear fuel test rig, a precision welding system needs to be fabricated to develop various welding technologies of the fuel test rig and rods jointing the various sensors and end caps on a fuel cladding tube, which is charged with fuel pellets and component parts. Thus, we designed and fabricated the precision welding system consisting of an orbital TIG welder, a low-pressure chamber, and a high-pressure chamber. Using this system, the performance tests were performed with the round and seal spot welds for each welding condition. This paper describes not only the contents for the fabrication of precision TIG welding system but also some results from weld tests using the low-pressure and high-pressure chambers to verify the performance of this system. The TIG welding system was developed to manufacture the nuclear fuel test rig and rods. It has been configured to be able to weld the nuclear fuel test rigs and rods by applying the TIG welder using a low-pressure chamber and a high-pressure chamber. The performance tests using this system were performed with the round and seal spot welds for the welding conditions. The soundness of the orbital TIG welding system was confirmed through performance tests in the low-pressure and high-pressure chambers

  9. Reptile Toll-like receptor 5 unveils adaptive evolution of bacterial flagellin recognition

    NARCIS (Netherlands)

    Voogdt, Carlos G P|info:eu-repo/dai/nl/413535169; Bouwman, Lieneke I|info:eu-repo/dai/nl/341590797; Kik, Marja J L|info:eu-repo/dai/nl/080432565; Wagenaar, Jaap A|info:eu-repo/dai/nl/126613354; van Putten, Jos P M|info:eu-repo/dai/nl/069916527

    2016-01-01

    Toll-like receptors (TLR) are ancient innate immune receptors crucial for immune homeostasis and protection against infection. TLRs are present in mammals, birds, amphibians and fish but have not been functionally characterized in reptiles despite the central position of this animal class in

  10. Molecular cloning and transcriptional analysis of a NPY receptor-like in common Chinese cuttlefish Sepiella japonica

    Science.gov (United States)

    Yang, Jingwen; Xu, Yuchao; Xu, Ke; Ping, Hongling; Shi, Huilai; Lü, Zhenming; Wu, Changwen; Wang, Tianming

    2017-08-01

    Neuropeptide Y (NPY) has a pivotal role in the regulation of many physiological processes. In this study, the gene encoding a NPY receptor-like from the common Chinese cuttlefish Sepiella japonica (SjNPYR-like) was identified and characterized. The full-length SjNPYR-like cDNA was cloned containing a 492-bp of 5' untranslated region (UTR), 1 182 bp open reading frame (ORF) encoding a protein of 393 amino acid residues, and 228 bp of 3' UTR. The putative protein was predicted to have a molecular weight of 45.54 kDa and an isoelectric point (pI) of 8.13. By informatic analyses, SjNPYR-like was identified as belonging to the class A G protein coupled receptor (GPCR) family (the rhodopsin-type). The amino acid sequence contained 12 potential phosphorylation sites and five predicted N-linked glycosylation sites. Multiple sequence alignment and 3D structure modeling were conducted to clarify SjNPYR bioinformatics characteristics. Phylogenetic analysis identifies it as an NPYR with identity of 33% to Lymnaea stagnalis NPFR. Transmembrane properties of SjNPYR-like were demonstrated in vitro using HEK293 cells and the pEGFP-N1 plasmid. Relative quantification of SjNPYR-like mRNA level confirmed a high level expression and broad distribution of SjNPYR - like in various tissues of female S. japonica. In addition, the transcriptional profile of SjNPYR - like in the brain, liver, and ovary during gonadal development was analyzed. The results provide basic understanding on the molecular characteristics of SjNPYR-like and its potentially physical functions.

  11. Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice.

    Science.gov (United States)

    Li, Xia; Risbrough, Victoria B; Cates-Gatto, Chelsea; Kaczanowska, Katarzyna; Finn, M G; Roberts, Amanda J; Markou, Athina

    2013-07-01

    γ-Aminobutyric acid B (GABAB) receptor activation is a potential therapeutic approach for the treatment of drug addiction, pain, anxiety, and depression. However, full agonists of this receptor induce side-effects, such as sedation, muscle relaxation, tolerance, and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptor may have similar therapeutic effects as agonists with superior side-effect profiles. The present study behaviorally characterized N-([1R,2R,4S]-bicyclo[2.2.1]hept-2-yl)-2-methyl-5-(4-[trifluoromethyl]phenyl)-4-pyrimidinamine (BHF177), a GABAB receptor PAM, in mouse models of anxiety-like behavior, learning and memory. In addition, the effects of BHF177 were compared with the agonist baclofen. Unlike the anxiolytic chlordiazepoxide, baclofen (0.5, 1.5, and 2.5 mg/kg, intraperitoneally) and BHF177 (10, 20, and 40 mg/kg, orally) had no effect on anxiety-like behavior in the elevated plus maze, light/dark box, or Vogel conflict test. Baclofen increased punished drinking in the Vogel conflict test, but this effect may be attributable to the analgesic actions of baclofen. At the highest dose tested (2.5 mg/kg), baclofen-treated mice exhibited sedation-like effects (i.e., reduced locomotor activity) across many of the tests, whereas BHF177-treated mice exhibited no sedation-like effects. BHF177 exhibited pro-convulsion properties only in mice, but not in rats, indicating that this effect may be species-specific. At doses that were not sedative or pro-convulsant, baclofen and BHF177 had no selective effects on fear memory retrieval in contextual and cued fear conditioning or spatial learning and memory in the Barnes maze. These data suggest that BHF177 has little sedative activity, no anxiolytic-like profile, and minimal impairment of learning and memory in mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. iNR-PhysChem: a sequence-based predictor for identifying nuclear receptors and their subfamilies via physical-chemical property matrix.

    Directory of Open Access Journals (Sweden)

    Xuan Xiao

    Full Text Available Nuclear receptors (NRs form a family of ligand-activated transcription factors that regulate a wide variety of biological processes, such as homeostasis, reproduction, development, and metabolism. Human genome contains 48 genes encoding NRs. These receptors have become one of the most important targets for therapeutic drug development. According to their different action mechanisms or functions, NRs have been classified into seven subfamilies. With the avalanche of protein sequences generated in the postgenomic age, we are facing the following challenging problems. Given an uncharacterized protein sequence, how can we identify whether it is a nuclear receptor? If it is, what subfamily it belongs to? To address these problems, we developed a predictor called iNR-PhysChem in which the protein samples were expressed by a novel mode of pseudo amino acid composition (PseAAC whose components were derived from a physical-chemical matrix via a series of auto-covariance and cross-covariance transformations. It was observed that the overall success rate achieved by iNR-PhysChem was over 98% in identifying NRs or non-NRs, and over 92% in identifying NRs among the following seven subfamilies: NR1--thyroid hormone like, NR2--HNF4-like, NR3--estrogen like, NR4--nerve growth factor IB-like, NR5--fushi tarazu-F1 like, NR6--germ cell nuclear factor like, and NR0--knirps like. These rates were derived by the jackknife tests on a stringent benchmark dataset in which none of protein sequences included has ≥60% pairwise sequence identity to any other in a same subset. As a user-friendly web-server, iNR-PhysChem is freely accessible to the public at either http://www.jci-bioinfo.cn/iNR-PhysChem or http://icpr.jci.edu.cn/bioinfo/iNR-PhysChem. Also a step-by-step guide is provided on how to use the web-server to get the desired results without the need to follow the complicated mathematics involved in developing the predictor. It is anticipated that iNR-PhysChem may

  13. Re-rigging Othering: Subversive Infantilisation in Contemporary Bosnian-Herzegovinian Prose

    Directory of Open Access Journals (Sweden)

    Fedja Borčak

    2014-12-01

    Full Text Available In this article I put forward the concept of subversive infantilisation to designate a phenomenon in contemporary Bosnian literature, which by using a certain kind of childish outlook on the world undermines paternalistic and balkanist Western discourse on Bosnia and Herzegovina. By analysing primarily the portrayal of the role of mass media in a few literary texts, principally books by Nenad Veličkovié and Miljenko Jergovié, I highlight the way in which these texts 're-rig' and by means of irony and exaggeration illuminate the problematic logic inherent in the subject position from which one represents the other. Textual characteristics of subversive infantilisation are contextualised further and seen as a discursive continuation of experiences of the 1990s war in Bosnia and Herzegovina.

  14. Intra-abdominal recurrence of colorectal cancer detected by radioimmunoguided surgery (RIGS system)

    International Nuclear Information System (INIS)

    Sardi, A.; Workman, M.; Mojzisik, C.; Hinkle, G.; Nieroda, C.; Martin, E.W. Jr.

    1989-01-01

    Since 1986, 32 patients with metastatic colorectal cancer have undergone second-look radioimmunoguided surgery (RIGS system). The primary tumor was located in the right and transverse colon in 11 patients, left and sigmoid colon in 16, and rectum in five. The carcinoembryonic antigen level was elevated in 30 patients (94%); all patients underwent a computed tomographic scan of the abdomen and pelvis. The overall sensitivity of the computed tomographic scan was 41% (abdomen other than liver, 27%; liver, 58%; and pelvis, 22%). The RIGS system identified recurrent tumor in 81% of the patients. The most common site of metastasis was the liver (41%), independent of the primary location. Local/regional recurrences alone accounted for 40% of all recurrences. In six patients (18%), recurrent tumor was found only with the RIGS system. The RIGS system is more dependable in localizing clinically obscure metastases than other methods, and carcinoembryonic antigen testing remains the most accurate preoperative method to indicate suspected recurrences

  15. Anti-tumor Activity of Toll-Like Receptor 7 Agonists

    Directory of Open Access Journals (Sweden)

    Huju Chi

    2017-05-01

    Full Text Available Toll-like receptors (TLRs are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity. The activated TLRs not only induce inflammatory responses, but also elicit the development of antigen specific immunity. TLR7, a member of TLR family, is an intracellular receptor expressed on the membrane of endosomes. TLR7 can be triggered not only by ssRNA during viral infections, but also by immune modifiers that share a similar structure to nucleosides. Its powerful immune stimulatory action can be potentially used in the anti-tumor therapy. This article reviewed the anti-tumor activity and mechanism of TLR7 agonists that are frequently applied in preclinical and clinical investigations, and mainly focused on small synthetic molecules, including imiquimod, resiquimod, gardiquimod, and 852A, etc.

  16. Reptile Toll-like receptor 5 unveils adaptive evolution of bacterial flagellin recognition

    NARCIS (Netherlands)

    Voogdt, Carlos G.P.; Bouwman, Lieneke I.; Kik, Marja J.L.; Wagenaar, Jaap A.; Putten, Van Jos P.M.

    2016-01-01

    Toll-like receptors (TLR) are ancient innate immune receptors crucial for immune homeostasis and protection against infection. TLRs are present in mammals, birds, amphibians and fish but have not been functionally characterized in reptiles despite the central position of this animal class in

  17. Computer aided extractor design for the RIG 10 high intensity ion source

    International Nuclear Information System (INIS)

    Tanzer, F.; Haeuser, J.; Eppel, D.

    1980-01-01

    The paper discusses recent progress of the rf-ion source RIG 10, and describes a computer code for the simulation of the ion trajectories. The RIG 10 is designed for current densities of some 300 mA/cm 2 , and will be used for the production of neutral. (orig.)

  18. IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling.

    Directory of Open Access Journals (Sweden)

    Helen M Lazear

    2013-01-01

    Full Text Available Although the transcription factors IRF-3 and IRF-7 are considered master regulators of type I interferon (IFN induction and IFN stimulated gene (ISG expression, Irf3(-/-×Irf7(-/- double knockout (DKO myeloid dendritic cells (mDC produce relatively normal levels of IFN-β after viral infection. We generated Irf3(-/-×Irf5(-/-×Irf7(-/- triple knockout (TKO mice to test whether IRF-5 was the source of the residual induction of IFN-β and ISGs in mDCs. In pathogenesis studies with two unrelated positive-sense RNA viruses (West Nile virus (WNV and murine norovirus, TKO mice succumbed at rates greater than DKO mice and equal to or approaching those of mice lacking the type I IFN receptor (Ifnar(-/-. In ex vivo studies, after WNV infection or exposure to Toll-like receptor agonists, TKO mDCs failed to produce IFN-β or express ISGs. In contrast, this response was sustained in TKO macrophages following WNV infection. To define IRF-regulated gene signatures, we performed microarray analysis on WNV-infected mDC from wild type (WT, DKO, TKO, or Ifnar(-/- mice, as well as from mice lacking the RIG-I like receptor adaptor protein MAVS. Whereas the gene induction pattern in DKO mDC was similar to WT cells, remarkably, almost no ISG induction was detected in TKO or Mavs(-/- mDC. The relative equivalence of TKO and Mavs(-/- responses suggested that MAVS dominantly regulates ISG induction in mDC. Moreover, we showed that MAVS-dependent induction of ISGs can occur through an IRF-5-dependent yet IRF-3 and IRF-7-independent pathway. Our results establish IRF-3, -5, and -7 as the key transcription factors responsible for mediating the type I IFN and ISG response in mDC during WNV infection and suggest a novel signaling link between MAVS and IRF-5.

  19. DMPD: Toll-like receptor 9 in murine lupus: more friend than foe! [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18241699 Toll-like receptor 9 in murine lupus: more friend than foe! Yu P, Musette ...us: more friend than foe! PubmedID 18241699 Title Toll-like receptor 9 in murine lupus...P, Peng SL. Immunobiology. 2008;213(2):151-7. Epub 2007 Sep 21. (.png) (.svg) (.html) (.csml) Show Toll-like receptor 9 in murine lup

  20. Anxiolytic-Like Effects of Increased Ghrelin Receptor Signaling in the Amygdala

    DEFF Research Database (Denmark)

    Jensen, Morten; Ratner, Cecilia; Rudenko, Olga

    2016-01-01

    BACKGROUND: Besides the well-known effects of ghrelin on adiposity and food intake regulation, the ghrelin system has been shown to regulate aspects of behavior including anxiety and stress. However, the effect of virus-mediated overexpression of the ghrelin receptor in the amygdala has...... not previously been addressed directly. METHOD: First, we examined the acute effect of peripheral ghrelin administration on anxiety- and depression-like behavior using the open field, elevated plus maze, forced swim and tail suspension tests. Next, we examined the effect of peripheral ghrelin administration...... and ghrelin receptor deficiency on stress in a familiar and social environment using the Intellicage system. Importantly, we also used a novel approach to study ghrelin receptor signaling in the brain by overexpressing the ghrelin receptor in the amygdala. We examined the effect of ghrelin receptor...

  1. Purification of the active C5a receptor from human polymorphonuclear leukocytes as a receptor - G sub i complex

    Energy Technology Data Exchange (ETDEWEB)

    Rollins, T.E.; Siciliano, S.; Kobayashi, S.; Cianciarulo, D.N.; Bonilla-Argudo, V.; Collier, K.; Springer, M.S. (Merck Sharp and Dohme Research Lab., Rahway, NJ (United States))

    1991-02-01

    The authors have isolated, in an active state, the C5a receptor from human polymorphonuclear leukocytes. The purification was achieved in a single step using a C5a affinity column in which the C5a molecule was coupled to the resin through its N terminus. The purified receptor, like the crude solubilized molecule, exhibited a single class of high-affinity binding sites with a K{sub d} of 30 pM. Further, the binding of C5a retained its sensitivity to guanine nucleotides, implying that the purified receptor contained a guanine nucleotide-binding protein (G protein). SDS/PAGE revealed the presence of three polypeptides with molecular masses of 42, 40, and 36 kDa, which were determined to be the C5a-binding subunit and the {alpha} and {beta} subunits of G{sub i}, respectively. The 36- and 40-kDa polypeptides were identified by immunoblotting and by the ability of pertussis toxin to ADP-ribosylate the 40-kDa molecule. These results confirm their earlier hypothesis that the receptor exists as a complex with a G protein in the presence or absence of C5a. The tight coupling between the receptor and G protein should make possible the identification of the G protein(s) involved in the transduction pathways used by C5a to produce its many biological effects.

  2. The neuroprotective effects of intramuscular insulin-like growth factor-I treatment in brain ischemic rats.

    Directory of Open Access Journals (Sweden)

    Heng-Chih Chang

    Full Text Available Brain ischemia leads to muscle inactivity-induced atrophy and may exacerbate motor function deficits. Intramuscular insulin-like growth factor I (IGF-I injection has been shown to alleviate the brain ischemia-induced muscle atrophy and thus improve the motor function. Motor function is normally gauged by the integrity and coordination of the central nervous system and peripheral muscles. Whether brain ischemic regions are adaptively changed by the intramuscular IGF-I injection is not well understood. In this study, the effect of intramuscular IGF-I injection was examined on the central nervous system of brain ischemic rats. Rats were divided into 4 groups: sham control, brain ischemia control, brain ischemia with IGF-I treatment, and brain ischemia with IGF-I plus IGF-I receptor inhibitor treatment. Brain ischemia was induced by right middle cerebral artery occlusion. IGF-I and an IGF-1 receptor inhibitor were injected into the affected calf and anterior tibialis muscles of the treated rats for 4 times. There was an interval of 2 days between each injection. Motor function was examined and measured at the 24 hours and 7 days following a brain ischemia. The affected hind-limb muscles, sciatic nerve, lumbar spinal cord, and motor cortex were collected for examination after euthanizing the rats. IGF-I expression in the central nervous system and affected muscles were significantly decreased after brain ischemia. Intramuscular IGF-I injection increased the IGF-I expression in the affected muscles, sciatic nerve, lumbar spinal cord, and motor cortex. It also increased the p-Akt expression in the affected motor cortex. Furthermore, intramuscular IGF-I injection decreased the neuronal apoptosis and improved the motor function. However, co-administration of the IGF-I receptor inhibitor eliminated these effects. Intramuscular IGF-I injection after brain ischemia attenuated or reversed the decrease of IGF-I in both central and peripheral tissues, and

  3. Small Molecule Drug Discovery at the Glucagon-Like Peptide-1 Receptor

    Directory of Open Access Journals (Sweden)

    Francis S. Willard

    2012-01-01

    Full Text Available The therapeutic success of peptide glucagon-like peptide-1 (GLP-1 receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of “ligand bias” and “probe dependency” for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery.

  4. Mutation of I696 and W697 in the TRP box of vanilloid receptor subtype I modulates allosteric channel activation.

    Science.gov (United States)

    Gregorio-Teruel, Lucia; Valente, Pierluigi; González-Ros, José Manuel; Fernández-Ballester, Gregorio; Ferrer-Montiel, Antonio

    2014-03-01

    The transient receptor potential vanilloid receptor subtype I (TRPV1) channel acts as a polymodal sensory receptor gated by chemical and physical stimuli. Like other TRP channels, TRPV1 contains in its C terminus a short, conserved domain called the TRP box, which is necessary for channel gating. Substitution of two TRP box residues-I696 and W697-with Ala markedly affects TRPV1's response to all activating stimuli, which indicates that these two residues play a crucial role in channel gating. We systematically replaced I696 and W697 with 18 native l-amino acids (excluding cysteine) and evaluated the effect on voltage- and capsaicin-dependent gating. Mutation of I696 decreased channel activation by either voltage or capsaicin; furthermore, gating was only observed with substitution of hydrophobic amino acids. Substitution of W697 with any of the 18 amino acids abolished gating in response to depolarization alone, shifting the threshold to unreachable voltages, but not capsaicin-mediated gating. Moreover, vanilloid-activated responses of W697X mutants showed voltage-dependent gating along with a strong voltage-independent component. Analysis of the data using an allosteric model of activation indicates that mutation of I696 and W697 primarily affects the allosteric coupling constants of the ligand and voltage sensors to the channel pore. Together, our findings substantiate the notion that inter- and/or intrasubunit interactions at the level of the TRP box are critical for efficient coupling of stimulus sensing and gate opening. Perturbation of these interactions markedly reduces the efficacy and potency of the activating stimuli. Furthermore, our results identify these interactions as potential sites for pharmacological intervention.

  5. Negative Regulation of Interferon-β Production by Alternative Splicing of Tumor Necrosis Factor Receptor-Associated Factor 3 in Ducks

    Directory of Open Access Journals (Sweden)

    Xiaoqin Wei

    2018-03-01

    Full Text Available Tumor necrosis factor receptor-associated factor 3 (TRAF3, an intracellular signal transducer, is identified as an important component of Toll-like receptors and RIG-I-like receptors induced type I interferon (IFN signaling pathways. Previous studies have clarified TRAF3 function in mammals, but little is known about the role of TRAF3 in ducks. Here, we cloned and characterized the full-length duck TRAF3 (duTRAF3 gene and an alternatively spliced isoform of duTRAF3 (duTRAF3-S lacking the fragment encoding amino acids 217–319, from duck embryo fibroblasts (DEFs. We found that duTRAF3 and duTRAF3-S played different roles in regulating IFN-β production in DEFs. duTRAF3 through its TRAF domain interacted with duMAVS or duTRIF, leading to the production of IFN-β. However, duTRAF3-S, containing the TRAF domain, was unable to bind duMAVS or duTRIF due to the intramolecular binding between the N- and C-terminal of duTRAF3-S that blocked the function of its TRAF domain. Further analysis identified that duTRAF3-S competed with duTRAF3 itself for binding to duTRAF3, perturbing duTRAF3 self-association, which impaired the assembly of duTRAF3-duMAVS/duTRIF complex, ultimately resulted in a reduced production of IFN-β. These findings suggest that duTRAF3 is an important regulator of duck innate immune signaling and reveal a novel mechanism for the negative regulation of IFN-β production via changing the formation of the homo-oligomerization of wild molecules, implying a novel regulatory role of truncated proteins.

  6. Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials.

    Science.gov (United States)

    Rodon, Jordi; DeSantos, Victoria; Ferry, Robert Jean; Kurzrock, Razelle

    2008-09-01

    The insulin-like growth factor-I receptor (IGF-IR) was first cloned in 1986. Since then, intense work has defined classic phosphorelays activated via the IGF-IR, which regulate cell proliferation, apoptosis, motility, and fate. The understanding of the roles of hormones in cancer and the growth hormone-IGF-IGF-binding protein axis specifically has yield to a second wave of development: the design of specific inhibitors that interrupt the signaling associated with this axis. The ability to manipulate these pathways holds not only significant therapeutic implications but also increase the chance of deeper insight about the role of the axis in carcinogenesis and metastasis. Nowadays, >25 molecules with the same goal are at different stages of development. Here, we review the clinical and preclinical experience with the two most-investigated strategies, tyrosine kinase inhibitors and monoclonal antibodies, and the advantages and disadvantages of each strategy, as well as other alternatives and possible drug combinations. We also review the biomarkers explored in the first clinical trials, the strategies that have been explored thus far, and the clinical trials that are going to explore their role in cancer treatment.

  7. Structure-Function Analysis of Cf-9, a Receptor-Like Protein with Extracytoplasmic Leucine-Rich Repeats

    NARCIS (Netherlands)

    Hoorn, van der R.A.L.; Wulff, B.B.H.; Rivas, S.; Durrant, M.C.; Ploeg, van der A.; Wit, de P.J.G.M.; Jones, J.D.G.

    2005-01-01

    The tomato (Lycopersicon pimpinellifolium) resistance protein Cf-9 belongs to a large class of plant proteins with extracytoplasmic Leu-rich repeats (eLRRs). eLRR proteins play key roles in plant defense and development, mainly as receptor-like proteins or receptor-like kinases, conferring

  8. Modelling and simulation of dynamic wheel-rail interaction using a roller rig

    International Nuclear Information System (INIS)

    Anyakwo, A; Pislaru, C; Ball, A; Gu, F

    2012-01-01

    The interaction between the wheel and rail greatly influences the dynamic response of railway vehicles on the track. A roller rig facility can be used to study and monitor real time parameters that influence wheel-rail interaction such as wear, adhesion, friction and corrugation without actual field tests being carried out. This paper presents the development of the mathematical models for full scale roller rig and 1/5 scale roller rig and the wear prediction model based on KTH wear function. The simulated critical speed for the 1/5 scale roller rig is about one-fifth of the critical speed for the full scale model so the simulated results compare well with the theory related to wheel-rail contact and dynamics. Also the differences between the simulated rolling radii for the full scale model with and without wear function are analysed. This paper presents the initial stage of a large scale research project where the influence of wear on the wheel-rail performance will be studied in more depth.

  9. DMPD: The role of Toll-like receptors and Nod proteins in bacterial infection. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15476921 The role of Toll-like receptors and Nod proteins in bacterial infection. P...of Toll-like receptors and Nod proteins in bacterial infection. PubmedID 15476921 Title The role of Toll-like receptors and Nod prote...ins in bacterial infection. Authors Philpott DJ, Girardi

  10. Excessive D1 Dopamine Receptor Activation in the Dorsal Striatum Promotes Autistic-Like Behaviors.

    Science.gov (United States)

    Lee, Yunjin; Kim, Hannah; Kim, Ji-Eun; Park, Jin-Young; Choi, Juli; Lee, Jung-Eun; Lee, Eun-Hwa; Han, Pyung-Lim

    2018-07-01

    The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.

  11. Real-time trafficking and signaling of the glucagon-like peptide-1 receptor

    DEFF Research Database (Denmark)

    Roed, Sarah Noerklit; Wismann, Pernille; Underwood, Christina Rye

    2014-01-01

    The glucagon-like peptide-1 incretin receptor (GLP-1R) of family B G protein-coupled receptors (GPCRs) is a major drug target in type-2-diabetes due to its regulatory effect on post-prandial blood-glucose levels. The mechanism(s) controlling GLP-1R mediated signaling are far from fully understood....... A fundamental mechanism controlling the signaling capacity of GPCRs is the post-endocytic trafficking of receptors between recycling and degradative fates. Here, we combined microscopy with novel real-time assays to monitor both receptor trafficking and signaling in living cells. We find that the human GLP-1R...

  12. Betaxolol, a selective β1-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats

    Science.gov (United States)

    Rudoy, C.A.; Van Bockstaele, E.J.

    2007-01-01

    Background Anxiety has been indicated as one of the main symptoms of the cocaine withdrawal syndrome in human addicts and severe anxiety during withdrawal may potentially contribute to relapse. As alterations in noradrenergic transmission in limbic areas underlie withdrawal symptomatology for many drugs of abuse, the present study sought to determine the effect of cocaine withdrawal on β-adrenergic receptor (β1 and β2) expression in the amygdala. Methods Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that β1–adrenergic receptor, but not β2–adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with betaxolol, a highly selective β1–adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 hours following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 hours following the last betaxolol injection. Following behavioral testing, betaxolol effects on β1-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal. Results Animals treated with betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline

  13. Activation of temperature-sensitive TRPV1-like receptors in ARC POMC neurons reduces food intake.

    Directory of Open Access Journals (Sweden)

    Jae Hoon Jeong

    2018-04-01

    Full Text Available Proopiomelanocortin (POMC neurons in the arcuate nucleus of the hypothalamus (ARC respond to numerous hormonal and neural signals, resulting in changes in food intake. Here, we demonstrate that ARC POMC neurons express capsaicin-sensitive transient receptor potential vanilloid 1 receptor (TRPV1-like receptors. To show expression of TRPV1-like receptors in ARC POMC neurons, we use single-cell reverse transcription-polymerase chain reaction (RT-PCR, immunohistochemistry, electrophysiology, TRPV1 knock-out (KO, and TRPV1-Cre knock-in mice. A small elevation of temperature in the physiological range is enough to depolarize ARC POMC neurons. This depolarization is blocked by the TRPV1 receptor antagonist and by Trpv1 gene knockdown. Capsaicin-induced activation reduces food intake that is abolished by a melanocortin receptor antagonist. To selectively stimulate TRPV1-like receptor-expressing ARC POMC neurons in the ARC, we generate an adeno-associated virus serotype 5 (AAV5 carrying a Cre-dependent channelrhodopsin-2 (ChR2-enhanced yellow fluorescent protein (eYFP expression cassette under the control of the two neuronal POMC enhancers (nPEs. Optogenetic stimulation of TRPV1-like receptor-expressing POMC neurons decreases food intake. Hypothalamic temperature is rapidly elevated and reaches to approximately 39 °C during treadmill running. This elevation is associated with a reduction in food intake. Knockdown of the Trpv1 gene exclusively in ARC POMC neurons blocks the feeding inhibition produced by increased hypothalamic temperature. Taken together, our findings identify a melanocortinergic circuit that links acute elevations in hypothalamic temperature with acute reductions in food intake.

  14. Activation of toll-like receptors 2 and 4 by gram-negative periodontal bacteria

    NARCIS (Netherlands)

    Kikkert, R.; Laine, M. L.; Aarden, L. A.; van Winkelhoff, A. J.

    2007-01-01

    BACKGROUND/AIMS: Periodontitis is a chronic infectious disease associated with a gram-negative subgingival microflora. Bacterial components stimulate, among other receptors, Toll-like receptor (TLR) 2 and/or TLR4. Accumulating evidence indicates that both qualitatively and quantitatively distinct

  15. Dopamine D₂-Like Receptors and Behavioral Economics of Food Reinforcement.

    Science.gov (United States)

    Soto, Paul L; Hiranita, Takato; Xu, Ming; Hursh, Steven R; Grandy, David K; Katz, Jonathan L

    2016-03-01

    Previous studies suggest dopamine (DA) D2-like receptor involvement in the reinforcing effects of food. To determine contributions of the three D2-like receptor subtypes, knockout (KO) mice completely lacking DA D2, D3, or D4 receptors (D2R, D3R, or D4R KO mice) and their wild-type (WT) littermates were exposed to a series of fixed-ratio (FR) food-reinforcement schedules in two contexts: an open economy with additional food provided outside the experimental setting and a closed economy with all food earned within the experimental setting. A behavioral economic model was used to quantify reinforcer effectiveness with food pellets obtained as a function of price (FR schedule value) plotted to assess elasticity of demand. Under both economies, as price increased, food pellets obtained decreased more rapidly (ie, food demand was more elastic) in DA D2R KO mice compared with WT littermates. Extinction of responding was studied in two contexts: by eliminating food deliveries and by delivering food independently of responding. A hyperbolic model quantified rates of extinction. Extinction in DA D2R KO mice occurred less rapidly compared with WT mice in both contexts. Elasticity of food demand was higher in DA D4R KO than WT mice in the open, but not closed, economy. Extinction of responding in DA D4R KO mice was not different from that in WT littermates in either context. No differences in elasticity of food demand or extinction rate were obtained in D3R KO mice and WT littermates. These results indicate that the D2R is the primary DA D2-like receptor subtype mediating the reinforcing effectiveness of food.

  16. Soluble TNF-Alpha-Receptors I Are Prognostic Markers in TIPS-Treated Patients with Cirrhosis and Portal Hypertension

    DEFF Research Database (Denmark)

    Trebicka, Jonel; Krag, Aleksander; Gansweid, Stefan

    2013-01-01

    TNFα levels are increased in liver cirrhosis even in the absence of infection, most likely owing to a continuous endotoxin influx into the portal blood. Soluble TNFα receptors (sTNFR type I and II) reflect release of the short-lived TNFα, because they are cleaved from the cells after binding...

  17. DMPD: Signaling to NF-kappaB by Toll-like receptors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available l Med. 2007 Nov;13(11):460-9. Epub 2007 Oct 29. (.png) (.svg) (.html) (.csml) Show Signaling to NF-kappaB by Toll-like receptors. Pub...medID 18029230 Title Signaling to NF-kappaB by Toll-like receptors. Authors Kawai T

  18. Insulin-like growth factor-I treatment of children with Laron syndrome (primary growth hormone insensitivity).

    Science.gov (United States)

    Laron, Zvi

    2008-03-01

    Laron syndrome (LS, congenital primary GH insensitivity) is caused by deletions or mutations in the GH receptor gene, resulting in an inability to generate insulin-like growth factor-I (IGF-I). If untreated, the deficiency of IGF-I results in severe dwarfism, as well as skeletal and muscular underdevelopment. The only treatment is the daily administration of recombinant IGF-I. This review summarizes the present experience by several groups worldwide. The main conclusions are: A. The one or two injections regimen result in the same growth velocity; B. The growth velocity obtained with IGF-I administration is smaller than that observed with hGH in children with congenital isolated GH deficiency; C. Overdosage of IGF-I causes a series of adverse effects which can be avoided by carefully monitoring the serum IGF-I and GH levels.

  19. Wythenshawe boiler rig. Thirty years of support to the UK nuclear power industry

    International Nuclear Information System (INIS)

    Rudge, Andy; Woolsey, Ian S.; Moore, Andrew

    2010-01-01

    The Wythenshawe Boiler Rig in Manchester, UK, recently celebrated thirty years of operation in support of the UK nuclear power industry. The Boiler Rig, owned by EDF Energy and operated on EDF Energy's behalf by Serco plc, is a full scale once-through boiler test facility for the investigation of chemistry and corrosion related topics. This paper presents an overview of the design and operation of the Boiler Rig together with some of the technical highlights from its thirty years of operation, many of which have relevance to power plant operations beyond those plants for which the work was performed. (orig.)

  20. Stress-life relation of the rolling-contact fatigue spin rig

    Science.gov (United States)

    Butler, Robert H; Carter, Thomas L

    1957-01-01

    The rolling-contact fatigue spin rig was used to test groups of SAE 52100 9.16-inch-diameter balls lubricated with a mineral oil at 600,000-, 675,000-, and 750,000-psi maximum Hertz stress. Cylinders of AISI M-1 vacuum and commercial melts and MV-1 (AISI M-50) were used as race specimens. Stress-life exponents produced agree closely with values accepted in industry. The type of failure obtained in the spin rig was similar to the subsurface fatigue spells found in bearings.

  1. Insulin-like growth factor I and II in 14 animal species and man as determined by three radioligand assays and two bioassays

    Energy Technology Data Exchange (ETDEWEB)

    Zangger, I.; Zapf, J.; Froesch, E.R.

    1987-01-01

    Insulin-like growth factor I and II (IGF I and II) were determined by five different assays in human serum, in the sera of ten mammalian species and in chicken, turtle, and frog serum. Sera of all tested mammals contain two different IGFs corresponding to human immunoreactive IGF I and receptor reactive IGF II. Receptor reactive IGF II of most animal species does not show significant cross-reactivity in the RIA for human IGF II. IGF activity was also detected in sera of non-mammals, such as chicken and turtles, but not in frog serum. The IGF values obtained with the different assay system corresponded rather well: there is a good correlation between the values obtained in the protein binding and the fat cell assay, and between the results of the latter assays and the sum of immunoreactive IGF I and receptor reative IGF II. The results suggest that those regions in the IGF I and II molecules which are responsible for reactivity with the type I IGF and the insulin receptor have not essentially changed during evolution. Similarly, the C-region, which mainly determines the immunological properties of IGFs, appears to have remained relatively constant in the IGF I, but not in the IGF II molecule.

  2. Novel receptor-like protein kinases induced by Erwinia carotovora and short oligogalacturonides in potato.

    Science.gov (United States)

    Montesano, M; Kõiv, V; Mäe, A; Palva, E T

    2001-11-01

    summary Identification of potato genes responsive to cell wall-degrading enzymes of Erwinia carotovora resulted in the isolation of cDNA clones for four related receptor-like protein kinases. One of the putative serine-threonine protein kinases might have arisen through alternative splicing. These potato receptor-like kinases (PRK1-4) were highly equivalent (91-99%), most likely constituting a family of related receptors. All PRKs and four other plant RLKs share in their extracellular domain a conserved bi-modular pattern of cysteine repeats distinct from that in previously characterized plant RLKs, suggesting that they represent a new class of receptors. The corresponding genes were rapidly induced by E. carotovora culture filtrate (CF), both in the leaves and tubers of potato. Furthermore, the genes were transiently induced by short oligogalacturonides. The structural identity of PRKs and their induction pattern suggested that they constitute part of the early response of potato to E. carotovora infection.

  3. Insulin-like growth factor (IGF)-I binding to a cell membrane associated IGF binding protein-3 acid-labile subunit complex in human anterior pituitary gland

    NARCIS (Netherlands)

    Wilczak, N; Kuhl, N; Chesik, D; Geerts, A; Luiten, P; De Keyser, J

    The binding characteristics of [(125) I]insulin-like growth factor (IGF)-I were studied in human brain and pituitary gland. Competition binding studies with DES(1-3)IGF-I and R-3 -IGF-I, which display high affinity for the IGF-I receptor and low affinity for IGF binding proteins (IGFBPs), were

  4. Interleukin-17A and Toll-Like Receptor 3 Ligand Poly(I:C Synergistically Induced Neutrophil Chemoattractant Production by Bronchial Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Hirotaka Matsuzaki

    Full Text Available Chronic inflammatory airway diseases, such as bronchial asthma and chronic obstructive pulmonary disease, are common respiratory disorders worldwide. Exacerbations of these diseases are frequent and worsen patients' respiratory condition and overall health. However, the mechanisms of exacerbation have not been fully elucidated. Recently, it was reported that interleukin (IL-17A might play an important role in neutrophilic inflammation, which is characteristic of such exacerbations, through increased production of neutrophil chemoattractants. Therefore, we hypothesized that IL-17A was involved in the pathogenesis of acute exacerbation, due to viral infection in chronic inflammatory airway diseases. In this study, we assessed chemokine production by bronchial epithelial cells and investigated the underlying mechanisms. Comprehensive chemokine analysis showed that, compared with poly(I:C alone, co-stimulation of BEAS-2B cells with IL-17A and poly(I:C strongly induced production of such neutrophil chemoattractants as CXC chemokine ligand (CXCL8, growth-related oncogene (GRO, and CXCL1. Co-stimulation synergistically induced CXCL8 and CXCL1 mRNA and protein production by BEAS-2B cells and normal human bronchial epithelial cells. Poly(I:C induced chemokine expression by BEAS-2B cells mainly via Toll-like receptor 3/TIR-domain-containing adapter-inducing interferon-β-mediated signals. The co-stimulation with IL-17A and poly(I:C markedly activated the p38 and extracellular-signal-regulated kinase 1/2 pathway, compared with poly(I:C, although there was little change in nuclear factor-κB translocation into the nucleus or the transcriptional activities of nuclear factor-κB and activator protein 1. IL-17A promoted stabilization of CXCL8 mRNA in BEAS-2B cells treated with poly(I:C. In conclusion, IL-17A appears to be involved in the pathogenesis of chronic inflammatory airway disease exacerbation, due to viral infection by promoting release of neutrophil

  5. Toll-like receptor-4 (TLR-4) expression on polymorphonuclear ...

    African Journals Online (AJOL)

    To establish a foundation for further researches on the improvement of polymorphonuclear neutrophil leukocytes (PMN) functions in dairy cow during perinatal period, the counting of PMN, as well as the mRNA and protein expression of toll-like receptor-4 (TLR-4) on PMN was studied during this critical period.

  6. Physiology and Emerging Biochemistry of the Glucagon-Like Peptide-1 Receptor

    Directory of Open Access Journals (Sweden)

    Francis S. Willard

    2012-01-01

    Full Text Available The glucagon-like peptide-1 (GLP-1 receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM. Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic roles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the foundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines for patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved in ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques are being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic level. These efforts should better inform three-dimensional modeling of the GLP-1 receptor that will help inspire more rational approaches to identify and optimize small molecule agonists or allosteric modulators targeting the GLP-1 receptor. This article reviews GLP-1 receptor physiology with an emphasis on GLP-1 induced signaling mechanisms in order to highlight new molecular strategies that help determine desired pharmacologic characteristics for guiding development of future nonpeptide GLP-1 receptor activators.

  7. Synthesis of the possible receptor Ligand [125I]-spiperone for D2-dopamine receptor and in-vivo biodistribution

    International Nuclear Information System (INIS)

    Amin, A.M.; Shoukry, M.; Abd EL-Bary, A.

    2009-01-01

    The spiperone is a selective D2-dopamine receptor antagonist radioiodination of spiperone is of interest for dopamine (DA) receptor studies both in vivo and in vitro. The labeling of spiperone with iodine-125 was extremely done in a neutral ph 7, using chloramine-T as oxidizing agent via heating the reaction mixture at 70 C (degree) for 10 - 15 minutes producing radiochemical yield of 97 %. In vivo biodistribution studies showed that the initial brain uptake correlated fairly well with the brain uptake index and that the kinetics of the radioactivity specifically bound to the striatum were strongly influenced by the dopamine receptor binding affinity of the compound. The brain uptake of 125 I-Spiperone was high and equal to 3.5, 3.25,2.75 and 1.7 % per gram tissue at 5, 30, 60 and 120 minutes post injection, respectively. 125 I-Spiperone binds with high affinity to dopamine receptors in vivo. Specific binding is about 65% of the total binding as is displaced stereo-specifically by clozapine. 125 I-spiperone may prove to be a useful ligand in studies examining D2-dopamine receptors. Furthermore iodinated spiperone may be useful in radioreceptor assays of neuroleptic drug levels and, in a 123 I-labeled form, for imaging of dopamine receptors, in vivo, using single photon tomography.

  8. A Built for Purpose Micro-Hole Coiled Tubing Rig (MCTR)

    Energy Technology Data Exchange (ETDEWEB)

    Bart Patton

    2007-09-30

    This report will serve as the final report on the work performed from the contract period October 2005 thru April 2007. The project 'A Built for Purpose Microhole Coiled Tubing Rig (MCTR)' purpose was to upgrade an existing state-of-the-art Coiled Tubing Drilling Rig to a Microhole Coiled Tubing Rig (MCTR) capable of meeting the specifications and tasks of the Department of Energy. The individual tasks outlined to meet the Department of Energy's specifications are: (1) Concept and development of lubricator and tool deployment system; (2) Concept and development of process control and data acquisition; (3) Concept and development of safety and efficiency improvements; and (4) Final unit integration and testing. The end result of the MCTR upgrade has produced a unit capable of meeting the following requirements: (1) Capable of handling 1-inch through 2-3/8-inch coiled tubing (Currently dressed for 2-3/8-inch coiled tubing and capable of running up to 3-1/2-inch coiled tubing); (2) Capable of drilling and casing surface, intermediate, production and liner hole intervals; (3) Capable of drilling with coiled tubing and has all controls and installation piping for a top drive; (4) Rig is capable of running 7-5/8-inch range 2 casing; and (5) Capable of drilling 5,000 ft true vertical depth (TVD) and 6,000 ft true measured depth (TMD).

  9. Tachykinin-Related Peptides Share a G Protein-Coupled Receptor with Ion Transport Peptide-Like in the Silkworm Bombyx mori.

    Directory of Open Access Journals (Sweden)

    Chiaki Nagai-Okatani

    Full Text Available Recently, we identified an orphan Bombyx mori neuropeptide G protein-coupled receptor (BNGR-A24 as an ion transport peptide-like (ITPL receptor. BNGR-A24 belongs to the same clade as BNGR-A32 and -A33, which were recently identified as natalisin receptors. Since these three BNGRs share high similarities with known receptors for tachykinin-related peptides (TRPs, we examined whether these BNGRs can function as physiological receptors for five endogenous B. mori TRPs (TK-1-5. In a heterologous expression system, BNGR-A24 acted as a receptor for all five TRPs. In contrast, BNGR-A32 responded only to TK-5, and BNGR-A33 did not respond to any of the TRPs. These findings are consistent with recent studies on the ligand preferences for B. mori natalisins. Furthermore, we evaluated whether the binding of ITPL and TRPs to BNGR-A24 is competitive by using a Ca2+ imaging assay. Concomitant addition of a TRP receptor antagonist, spantide I, reduced the responses of BNGR-A24 not only to TK-4 but also to ITPL. The results of a binding assay using fluorescent-labeled BNGR-A24 and ligands demonstrated that the binding of ITPL to BNGR-A24 was inhibited by TK-4 as well as by spantide I, and vice versa. In addition, the ITPL-induced increase in cGMP levels of BNGR-A24-expressing BmN cells was suppressed by the addition of excess TK-4 or spantide I. The intracellular levels of cAMP and cGMP, as second messenger candidates of the TRP signaling, were not altered by the five TRPs, suggesting that these peptides act via different signaling pathways from cAMP and cGMP signaling at least in BmN cells. Taken together, the present findings suggest that ITPL and TRPs are endogenous orthosteric ligands of BNGR-A24 that may activate discrete signaling pathways. This receptor, which shares orthosteric ligands, may constitute an important model for studying ligand-biased signaling.

  10. Ligand binding and activation mechanism og the glucagon-like peptide-1 receptor

    DEFF Research Database (Denmark)

    Underwood, Christina Rye

    GLP-1R interacts with receptor agonists. The thesis includes four studies, which investigate different aspects of these interactions. The first study elucidates GLP-1 binding to the extracellular domain of GLP-1R (ECD) (Study I), whereas the second study identifies receptor domains important for small...

  11. Bycatch in 36 and 40 mm PA Turkish twin rigged beam trawl codends

    African Journals Online (AJOL)

    The Turkish twin rigged beam trawl which has two identical nets rigged side by side on the same beam targets mainly the Parapenaeus longirostris, although some bycatch fish species have also become target species. Thus, landings of the shrimp beam trawling fleet also include some commercially valuable fishes.

  12. Freon Rig design for performing to heat transfer experiments for nuclear reactors fuel bundles

    International Nuclear Information System (INIS)

    Flores, L.F.V.

    1981-01-01

    The main features of a Freon Rig design for performing to heat transfer experiments for PWR and BWR fuel bundles, are presented. The project is based on a Freon Rig pressurized at 30 bar with a flow rate up to 80 m 3 /h. The maximum power fed to test sections is of about 420 KW D.C. The rig was designed to use scaling techniques wich would enable a fluid of low latente heat to be used in place of water, thereby reducing the cost of testes. (Author) [pt

  13. Role of toll like receptors in bacterial and viral diseases – A ...

    African Journals Online (AJOL)

    Avishek Das

    2017-05-20

    May 20, 2017 ... Cellular Immunology Laboratory, Department of Zoology, University of North ... Background: Toll like receptors are key-receptors of the innate immune ...... Triggering TLR7 in mice induces immune activation and lymphoid.

  14. Role of insulin-like growth factor-I receptor (IGF-IR) in survival kinetics and radioresistance of mouse embryo fibroblasts in a hypoxic environment

    International Nuclear Information System (INIS)

    Okochi, Kiyoshi

    2002-01-01

    The role of insulin-like growth factor-I receptor (IGF-IR) in survival kinetics and radioresistance of fibroblasts in a severely hypoxic environment (partial oxygen pressure of less than 3 mmHg) was analyzed, in both low and high cell-density conditions. Mouse embryonic fibroblasts R(-), with a targeted disruption of the IGF-IR gene, and R(+) cells, derived from R(-) cells stably transfected with a plasmid containing a human IGF-IR cDNA, were used for this purpose. Survival time in hypoxia was longer in R(+) cells than R(-) cells, which correlated with highly elevated expression of caspase 3-like activity in R(-) cells, but not with HIF-Iα expression. Under euoxia, R(+) cells were more radioresistant, by a factor of 1.9, than R(-) cells. Under hypoxia, R(+) cells became more radioresistant, with an oxygen-enhancement ratio (OER) of 2.7, than R(-) cells, with an OER of 1.5, in a low cell density. However, unexpected hyper-radiosensitivity in hypoxia was observed for both R(+) and R(-) cells in a high cell density, which further increased with incubation time in hypoxia following X-irradiation. The hyper-radiosensitivity was more pronounced for R(-) cells. The result thus implies that IGF-IR may be an important target molecule for radioresistant tumors in radiotherapy. (author)

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

    Science.gov (United States)

    Khorooshi, Reza; Wlodarczyk, Agnieszka; Asgari, Nasrin; Owens, Trevor

    2013-09-01

    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 the formation of neuromyelitis optica lesions. Immunoglobulin G from a neuromyelitis optica patient was injected intracerebrally with human complement to type I interferon receptor deficient and wildtype mice. Loss of aquaporin-4 and glial fibrillary acidic protein was reduced in type I interferon receptor deficient mice brain. Our findings suggest that type I interferon signaling contributes to neuromyelitis optica pathogenesis. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Synthesis and evaluation of peptide and nucleic acid based Toll-like receptor ligands

    NARCIS (Netherlands)

    Weterings, Josephus Johannes

    2008-01-01

    Toll-like receptors (TLRs) are receptors that continuously scour their direct surroundings for pathogen associated molecular patterns (PAMPs) of bacterial, viral or fungal origin. TLRs can be found at cells that play a role in the immune system. Binding of the TLR with its corresponding ligand

  17. Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88.

    Science.gov (United States)

    Dunne, Aisling; Ejdeback, Mikael; Ludidi, Phumzile L; O'Neill, Luke A J; Gay, Nicholas J

    2003-10-17

    The Toll/interleukin 1 receptor (TIR) domain is a region found in the cytoplasmic tails of members of the Toll-like receptor/interleukin-1 receptor superfamily. The domain is essential for signaling and is also found in the adaptor proteins Mal (MyD88 adaptor-like) and MyD88, which function to couple activation of the receptor to downstream signaling components. Experimental structures of two Toll/interleukin 1 receptor domains reveal a alpha-beta-fold similar to that of the bacterial chemotaxis protein CheY, and other evidence suggests that the adaptors can make heterotypic interactions with both the receptors and themselves. Here we show that the purified TIR domains of Mal and MyD88 can form stable heterodimers and also that Mal homodimers and oligomers are dissociated in the presence of ATP. To identify structural features that may contribute to the formation of signaling complexes, we produced models of the TIR domains from human Toll-like receptor 4 (TLR4), Mal, and MyD88. We found that although the overall fold is conserved the electrostatic surface potentials are quite distinct. Docking studies of the models suggest that Mal and MyD88 bind to different regions in TLRs 2 and 4, a finding consistent with a cooperative role of the two adaptors in signaling. Mal and MyD88 are predicted to interact at a third non-overlapping site, suggesting that the receptor and adaptors may form heterotetrameric complexes. The theoretical model of the interactions is supported by experimental data from glutathione S-transferase pull-downs and co-immunoprecipitations. Neither theoretical nor experimental data suggest a direct role for the conserved proline in the BB-loop in the association of TLR4, Mal, and MyD88. Finally we show a sequence relationship between the Drosophila protein Tube and Mal that may indicate a functional equivalence of these two adaptors in the Drosophila and vertebrate Toll pathways.

  18. Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor.

    Science.gov (United States)

    Chaki, Shigeyuki; Hirota, Shiho; Funakoshi, Takeo; Suzuki, Yoshiko; Suetake, Sayoko; Okubo, Taketoshi; Ishii, Takaaki; Nakazato, Atsuro; Okuyama, Shigeru

    2003-02-01

    We investigated the effects of a novel melanocortin-4 (MC4) receptor antagonist,1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine (MCL0129) on anxiety and depression in various rodent models. MCL0129 inhibited [(125)I][Nle(4)-D-Phe(7)]-alpha-melanocyte-stimulating hormone (alpha-MSH) binding to MC4 receptor with a K(i) value of 7.9 nM, without showing affinity for MC1 and MC3 receptors. MCL0129 at 1 microM had no apparent affinity for other receptors, transporters, and ion channels related to anxiety and depression except for a moderate affinity for the sigma(1) receptor, serotonin transporter, and alpha(1)-adrenoceptor, which means that MCL0129 is selective for the MC4 receptor. MCL0129 attenuated the alpha-MSH-increased cAMP formation in COS-1 cells expressing the MC4 receptor, whereas MCL0129 did not affect basal cAMP levels, thereby indicating that MCL0129 acts as an antagonist at the MC4 receptor. Swim stress markedly induced anxiogenic-like effects in both the light/dark exploration task in mice and the elevated plus-maze task in rats, and MCL0129 reversed the stress-induced anxiogenic-like effects. Under nonstress conditions, MCL0129 prolonged time spent in the light area in the light/dark exploration task and suppressed marble-burying behavior. MCL0129 shortened immobility time in the forced swim test and reduced the number of escape failures in inescapable shocks in the learned helplessness test, thus indicating an antidepressant potential. In contrast, MCL0129 had negligible effects on spontaneous locomotor activity, Rotarod performance, and hexobarbital-induced anesthesia. These observations indicate that MCL0129 is a potent and selective MC4 antagonist with anxiolytic- and antidepressant-like activities in various rodent models. MC4 receptor antagonists may prove effective for treating subjects with stress-related disorders such as depression and/or anxiety.

  19. Rig automation: where it's been and where it's going

    Energy Technology Data Exchange (ETDEWEB)

    Rinaldi, R.

    1982-06-01

    For over 30 years dreamers, tinkerers and engineers have attempted to automate various drilling functions. Now this effort is paying off, and a partially automated rig is no longer a curiosity. Fully automated and computerized rigs are on the way. For the contractor this means higher productivity, but more maintenance and training responsibilities.

  20. The Winfrith horizontal impact rig

    International Nuclear Information System (INIS)

    Barr, P.

    1985-12-01

    The Horizontal Impact Rig has been designed to allow studies of the impact of radioactive material transport containers and their associated transport vehicles and impact limiters, using large scale models, and to allow physically large missiles to be projected for studying the impact behaviour of metal and concrete structures. It provides an adequately rigid support structure for impact experiments with targets of large dimensions. Details of its design, instrumentation, performance prediction and construction are given. (U.K.)

  1. Paternal HLA-C and Maternal Killer-Cell Immunoglobulin-Like Receptor Genotypes in the Development of Autism.

    Science.gov (United States)

    Gamliel, Moriya; Anderson, Karen L; Ebstein, Richard P; Yirmiya, Nurit; Mankuta, David

    2016-01-01

    Killer-cell immunoglobulin-like receptors (KIRs) are a family of cell surface proteins found on natural killer cells, which are components of the innate immune system. KIRs recognize MHC class I proteins, mainly HLA-C and are further divided into two groups: short-tailed 2/3DS activating receptors and long-tailed 2/3DL inhibitory receptors. Based on the Barker Hypothesis, the origins of illness can be traced back to embryonic development in the uterus, and since KIR:HLA interaction figures prominently in the maternal-fetal interface, we investigated whether specific KIR:HLA combinations may be found in autism spectrum disorders (ASD) children compared with their healthy parents. This study enrolled 49 ASD children from different Israeli families, and their healthy parents. Among the parents, a higher frequency of HLA-C2 allotypes was found in the fathers, while its corresponding ligand 2DS1 was found in higher percentage in the maternal group. However, such skewing in KIR:HLA frequencies did not appear in the ASD children. Additionally, analysis of "overall activation" indicated higher activation in maternal than in paternal cohorts.

  2. Characterization of cardiac adenosine receptors using N6-phenyladenosines and a new radioligand, [125I]-(m-aminophenyl)adenosine

    International Nuclear Information System (INIS)

    Kwatra, M.M.; Hosey, M.M.; Green, R.

    1986-01-01

    The chick heart contains adenosine receptors with characteristics similar to the R adenosine receptors found in the CNS. They have synthesized several N 6 -phenyladenosines and tested their potencies for inhibiting the binding of [ 125 I](p-aminobenzyl)adenosine {[ 125 I]ABA) to chick heart membranes. Of the 12 compounds tested, N 6 -(p-aminobenzyl) adenosine (ABA) was the least potent (IC 50 ∼ 40 nM) while N 6 -(m-nitrophenyl)adenosine(MNPA) was the most potent (IC 50 ∼ 1 nM). The IC 50 of N 6 -(m-aminophenyl)adenosine(MAPA) was greater than that of N 6 -phenyladenosine(PA) while that of MNPA was less than that of PA. The effects of these electron-releasing (-NH 2 ) and electron-withdrawing (-NO 2 ) groups along with data obtained with other phenyl-substituted N 6 -phenyladenosines suggest that the electron density of the N 6 -nitrogen may affect the affinities of these compounds for the cardiac adenosine receptor. MAPA can be iodinated to produce a new ligand, [ 125 I]MAPA. This iodination, like that of ABA, increases the affinity of the compound and produces a ligand with good affinity and low nonspecific binding suitable for studies on tissues with low concentrations of adenosine receptors

  3. Development of a low cost test rig for standalone WECS subject to electrical faults.

    Science.gov (United States)

    Himani; Dahiya, Ratna

    2016-11-01

    In this paper, a contribution to the development of low-cost wind turbine (WT) test rig for stator fault diagnosis of wind turbine generator is proposed. The test rig is developed using a 2.5kW, 1750 RPM DC motor coupled to a 1.5kW, 1500 RPM self-excited induction generator interfaced with a WT mathematical model in LabVIEW. The performance of the test rig is benchmarked with already proven wind turbine test rigs. In order to detect the stator faults using non-stationary signals in self-excited induction generator, an online fault diagnostic technique of DWT-based multi-resolution analysis is proposed. It has been experimentally proven that for varying wind conditions wavelet decomposition allows good differentiation between faulty and healthy conditions leading to an effective diagnostic procedure for wind turbine condition monitoring. Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.

  4. TECHNICAL FEATURES OF RIGGED YACHT BY CATEGORIES AND CLASSES

    Directory of Open Access Journals (Sweden)

    Svitlana Yeroshkina

    2016-06-01

    Full Text Available The article is directed on the deeply meaningful scientific study and structural analysis of the technical features of the rigged world modern yachts to pass sailing regattas in different navigation areas. The complete classification of sailing boats in it’s world classes was done for olympic, international, national regattas. It was done the technical indicators of yachting racing classes. The economic analysis material selection sails for yachts are directed of different types of races. In it’s scientific article is made economic calculation of operating cost of the boat and it was done the analysis of cost saving yachts in european / ukrainian marinas.Key words: yachting, rigged yacht, racing, classes of yachts. JEL: L 92

  5. The Role of Toll Like Receptors in Pregnancy

    Directory of Open Access Journals (Sweden)

    Elham Amirchaghmaghi

    2013-09-01

    Full Text Available For many years, the innate immunity was of less interest than the adaptive immunity because it was perceived to have secondary importance in the functionality of the immune system. During the past decades, with the advancement of knowledge about innate immune system, interest in innate immunity has grown dramatically and thus its function has been extensively studied. Innate immunity plays fundamental roles in the initiation and induction of adaptive immune responses. It consists of several cells and receptors including natural killer (NK cells, macrophages (MQs, dendritic cells (DCs and pattern recognition receptors (PRRs. Two decades ago, Toll like receptors (TLRs family was known as one of the important PRRs with unique functions especially in protection against invading pathogens. Since the female reproductive tract has access to the outside environment and has a unique interaction with different pathogens whether invading microorganisms or normal flora, allogenic sperm and semi allogenic fetus, it has an essential need for effective immune responses. It has therefore been suggested that TLRs may play important roles in the immune regulation of the female reproductive tract. In addition, it has been demonstrated that immune disturbance may be responsible for some adverse pregnancy outcomes such as preeclampsia (PE, recurrent spontaneous abortion (RSA and intrauterine growth restriction (IUGR. Our focus in this review is to show the importance of TLRs in pregnancy with emphasis on the expression of these receptors in different tissues related to pregnancy.

  6. Structure-based drug design approach to target toll-like receptor ...

    African Journals Online (AJOL)

    Toll-like receptor (TLR) signaling pathways are the first line of defence against many microbial organisms. The question of how TLRs recognize endogenous ligands remains controversial. Several studies have shown that TLRs are implicated in the pathogenesis of autoimmune diseases such as systemic lupus ...

  7. Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test.

    Science.gov (United States)

    Filho, Carlos B; Del Fabbro, Lucian; de Gomes, Marcelo G; Goes, André T R; Souza, Leandro C; Boeira, Silvana P; Jesse, Cristiano R

    2013-01-05

    The opioid system has been implicated as a contributing factor for major depression and is thought to play a role in the mechanism of action of antidepressants. This study investigated the involvement of the opioid system in the antidepressant-like effect of hesperidin in the mouse forced swimming test. Our results demonstrate that hesperidin (0.1, 0.3 and 1 mg/kg; intraperitoneal) decreased the immobility time in the forced swimming test without affecting locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) in the forced swimming test was prevented by pretreating mice with naloxone (1 mg/kg, a nonselective opioid receptor antagonist) and 2-(3,4-dichlorophenyl)-Nmethyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl] acetamide (DIPPA (1 mg/kg), a selective κ-opioid receptor antagonist), but not with naloxone methiodide (1 mg/kg, a peripherally acting opioid receptor antagonist), naltrindole (3 mg/kg, a selective δ-opioid receptor antagonist), clocinnamox (1 mg/kg, a selective μ-opioid receptor antagonist) or caffeine (3 mg/kg, a nonselective adenosine receptor antagonist). In addition, a sub-effective dose of hesperidin (0.01 mg/kg) produced a synergistic antidepressant-like effect in the forced swimming test when combined with a sub-effective dose of morphine (1 mg/kg). The antidepressant-like effect of hesperidin in the forced swimming test on mice was dependent on its interaction with the κ-opioid receptor, but not with the δ-opioid, μ-opioid or adenosinergic receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders. Published by Elsevier B.V.

  8. Eigenfunction expansions and scattering theory in rigged Hilbert spaces

    Energy Technology Data Exchange (ETDEWEB)

    Gomez-Cubillo, F [Dpt. de Analisis Matematico, Universidad de Valladolid. Facultad de Ciencias, 47011 Valladolid (Spain)], E-mail: fgcubill@am.uva.es

    2008-08-15

    The work reviews some mathematical aspects of spectral properties, eigenfunction expansions and scattering theory in rigged Hilbert spaces, laying emphasis on Lippmann-Schwinger equations and Schroedinger operators.

  9. The D299G/T399I Toll-like receptor 4 variant associates with body and liver fat: results from the TULIP and METSIM Studies.

    Directory of Open Access Journals (Sweden)

    Peter Weyrich

    Full Text Available BACKGROUND: Toll-like-receptor 4 (TLR is discussed to provide a molecular link between obesity, inflammation and insulin resistance. Genetic studies with replications in non-diabetic individuals in regard to their fat distribution or insulin resistance according to their carrier status of a common toll-like receptor 4 (TLR4 variant (TLR4(D299G/T399I are still lacking. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cross-sectional analysis in individuals phenotyped for prediabetic traits as body fat composition (including magnetic resonance imaging, blood glucose levels and insulin resistance (oral glucose tolerance testing, euglycemic hyperinsulinemic clamp, according to TLR4 genotype determined by candidate SNP analyses (rs4986790. We analyzed N = 1482 non-diabetic individuals from the TÜF/TULIP cohort (South Germany, aged 39±13 y, BMI 28.5±7.9, mean±SD and N = 5327 non-diabetic participants of the METSIM study (Finland, males aged 58±6 y, BMI 26.8±3.8 for replication purposes. German TLR4(D299G/T399I carriers had a significantly increased body fat (XG in rs4986790: +6.98%, p = 0.03, dominant model, adjusted for age, gender and decreased insulin sensitivity (XG: -15.3%, Matsuda model, p = 0.04; XG: -20.6%, p = 0.016, clamp; both dominant models adjusted for age, gender, body fat. In addition, both liver fat (AG: +49.7%; p = 0.002 and visceral adipose tissue (AG: +8.2%; p = 0.047, both adjusted for age, gender, body fat were significantly increased in rs4986790 minor allele carriers, and the effect on liver fat remained significant also after additional adjustment for visceral fat (p = 0.014. The analysis in METSIM confirmed increased body fat content in association with the rare G allele in rs4986790 (AG: +1.26%, GG: +11.0%; p = 0.010, additive model, adjusted for age and showed a non-significant trend towards decreased insulin sensitivity (AG: -0.99%, GG: -10.62%. CONCLUSIONS/SIGNIFICANCE: TLR4(D299G

  10. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    International Nuclear Information System (INIS)

    Waser, Beatrice; Reubi, Jean Claude

    2014-01-01

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the 125 iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer 125 I-GLP-1(7-36)amide. Receptor autoradiography studies with 125 I-GLP-1(7-36)amide agonist or 125 I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist 125 I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer 125 I-GLP-1(7-36)amide. For comparison, 125 I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with 125 I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  11. DMPD: Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways inmacrophage activation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17502339 Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways inmacrophage...May 14. (.png) (.svg) (.html) (.csml) Show Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways inmacrophage...T, Toll-like receptor, and ITAM-dependent pathways inmacrophage activation. Authors Hu X, Chen J, Wang L, Iv

  12. Research on control system of truck-mounted rig for coalbed methane

    Directory of Open Access Journals (Sweden)

    Wang Hejian

    2018-01-01

    Full Text Available The coal-bed methane (CBM as a kind energy is clean and efficient, also it can become a security risk in mining process if it could not get out of the coal seam. In view of the current large-scale exploitation of coal-bed methane resources, the development of drilling rig for CBM drilling is needed. The parameters and structures were introduced in the paper. The rig uses a highly integrated approach that integrates the required functions on the chassis of the vehicle to meet the needs of rapid installation and transportation. Drilling control system uses hydraulic control and electro-hydraulic control dual control mode, can achieve short-range and remote control operations. The control system include security circuits and electric control system. Through the field trial, it is shown that the rig can meet the construction of the majority of coalbed methane drilling in the country and the performance is stable and the operation is simple.

  13. NOD-Like Receptors: A Tail from Plants to Mammals Through Invertebrates.

    Science.gov (United States)

    Pontillo, Alessandra; Crovella, Sergio

    2017-01-01

    NOD Like Receptors (NLRs) are the most abundant cytoplasmic immune receptors in plants and animals and they similarly act sensing pathogen invasion and activating immune response. Despite the fact that plant and mammals NLRs share homology.; with some protein structure differences.; for signalling pathway.; divergent evolution of the receptors has been hypothesized. Next generation genome sequencing has contributed to the description of NLRs in phyla others than plants and mammals and leads to new knowledge about NLRs evolution along phylogeny. Full comprehension of NLR-mediated immune response in plant could contribute to the understanding of animal NLRs physiology and/or pathology. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Immunolocalization of a tachykinin-receptor-like protein in the central nervous system of Locusta migratoria migratorioides and neobellieria bullata.

    Science.gov (United States)

    Veelaert, D; Oonk, H B; Vanden Eynde, G; Torfs, H; Meloen, R H; Schoofs, L; Parmentier, M; De Loof, A; Vanden Broeck, J

    1999-05-10

    Antisera raised against two distinct peptide regions of the Drosophila neurokinin-like receptor NKD were used to immunolocalize tachykinin-receptor-like proteins in the central nervous system of two insect species: the African migratory locust, Locusta migratoria, and the gray fleshfly, Neobellieria bullata. The resulting immunopositive staining patterns were identical for both antisera. Moreover, a very similar distribution of the immunoreactive material was observed in fleshflies and locusts. Immunoreactivity was found in nerve terminals of the retrocerebral complex, suggesting a presynaptic localization of the receptor in this part of the brain. Cell bodies were stained in the subesophageal ganglion: an anterior group of four larger cells and a posterior group of about 20 cells. These cells have axons projecting into the contralateral nervus corporis allati (NCA) II, bypassing the corpus allatum and projecting through the NCA I into the storage part of the corpus cardiacum. In the glandular part of the corpus cardiacum, the glandular adipokinetic hormone-producing cells did not show any immunopositive staining. In the locust, additional immunopositive staining was observed in internolaterally located neurons of the tritocerebrum and in important integrative parts of the neuropil such as the central body and the mushroom bodies.

  15. A calibration rig for multi-component internal strain gauge balance using the new design-of-experiment (DOE) approach

    Science.gov (United States)

    Nouri, N. M.; Mostafapour, K.; Kamran, M.

    2018-02-01

    In a closed water-tunnel circuit, the multi-component strain gauge force and moment sensor (also known as balance) are generally used to measure hydrodynamic forces and moments acting on scaled models. These balances are periodically calibrated by static loading. Their performance and accuracy depend significantly on the rig and the method of calibration. In this research, a new calibration rig was designed and constructed to calibrate multi-component internal strain gauge balances. The calibration rig has six degrees of freedom and six different component-loading structures that can be applied separately and synchronously. The system was designed based on the applicability of formal experimental design techniques, using gravity for balance loading and balance positioning and alignment relative to gravity. To evaluate the calibration rig, a six-component internal balance developed by Iran University of Science and Technology was calibrated using response surface methodology. According to the results, calibration rig met all design criteria. This rig provides the means by which various methods of formal experimental design techniques can be implemented. The simplicity of the rig saves time and money in the design of experiments and in balance calibration while simultaneously increasing the accuracy of these activities.

  16. Group I mGlu receptors potentiate synaptosomal [3H]glutamate release independently of exogenously applied arachidonic acid

    International Nuclear Information System (INIS)

    Reid, M.E.; Toms, N.J.; Bedingfield, J.S.; Roberts, P.J.

    1999-01-01

    In the current study, we have characterized group I metabotropic glutamate (mGlu) receptor enhancement of 4-aminopyridine (4AP)-evoked [ 3 H]glutamate release from rat cerebrocortical synaptosomes. The broad spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD, 10 μM) increased 4AP-evoked [ 3 H]glutamate release (143.32±2.73% control) only in the presence of exogenously applied arachidonic acid; an effect reversed by the inclusion of bovine serum albumin (BSA, fatty acid free). In contrast, the selective group I mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) potentiated (EC 50 =1.60±0.25 μM; E max =147.61±10.96% control) 4AP-evoked [ 3 H]glutamate release, in the absence of arachidonic acid. This potentiation could be abolished by either the selective mGlu 1 receptor antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA, 1 mM) or the selective PKC inhibitor (Ro 31-8220, 10 μM) and was BSA-insensitive. The selective mGlu 5 receptor agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG, 300μM) was without effect. DHPG (100 μM) also potentiated both 30 mM and 50 mM K + -evoked [ 3 H]glutamate release (121.60±12.77% and 121.50±4.45% control, respectively). DHPG (100 μM) failed to influence both 4AP-stimulated 45 Ca 2+ influx and 50 mM K + -induced changes in synaptosomal membrane potential. Possible group I mGlu receptor suppression of tonic adenosine A 1 receptor, group II/III mGlu receptors or GABA B receptor activity is unlikely since 4AP-evoked [ 3 H]glutamate release was insensitive to the selective inhibitory receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine, (R,S)-α-cyclopropyl-4-phosphonophenylglycine or CGP55845A, respectively. These data suggest an 'mGlu 1 receptor-like' receptor potentiates [ 3 H]glutamate release from cerebrocortical synaptosomes in the absence of exogenously applied arachidonic acid. This PKC dependent effect is unlikely to be via modulation of synaptosomal membrane

  17. Toll-like receptor and associated regulators in pneumonia and sepsis

    NARCIS (Netherlands)

    Blok, D.C.

    2015-01-01

    Humanity struggles against micro-organism invasion on a daily basis. Innate immunity is part of the first line of defense when it comes to preventing infection, signaling a perceived health threat and eliminating microbes before they can cause harm. Toll-like receptors (TLRs) and other pattern

  18. (-)[125I]-iodopindolol, a new highly selective radioiodinated beta-adrenergic receptor antagonist: measurement of beta-receptors on intact rat astrocytoma cells

    International Nuclear Information System (INIS)

    Barovsky, K.; Brooker, G.

    1980-01-01

    (-)-Pindolol, one of the most potent beta-adrenergic receptor antagonists, was radioiodinated using chloramine-T oxidation of carrier-free Na 125I and separated from unreacted pindolol to yield 2200 Ci/mmole (-)-[125I]-iodopindolol ((-)-[125I]-IPin). Mass and ultraviolet spectra confirmed that the iodination occurred on the indole ring, presumably at the 3 position. The binding of radiolabeled (-)-[125I]-IPin to beta-adrenergic receptors has been studied using intact C6 rat astrocytoma cells (2B subclone) grown in monolayer cultures. Binding of (-)[125IPin was saturable with time and concentration. Using 13 pM (-)-[125I]IPin, binding equilibrium was reached in 90 min at 21-22 degrees C. The reverse rate constant was 0.026 min-1 at 21 0 C. Specific binding (expressed as 1 microM(-)-propranolol displaceable counts) of (-)-[125I]-IPin was 95% of total binding. Scatchard analysis of (-)-[125I]-I]Pin binding revealed approximately 4300 receptors/cell and a dissociation constant of 30 pM. This was in excellent agreement with the kinetically determined dissociation constant of 35 pM. Displacement by propranolol and isoproterenol showed that (-)-[125I]-IPin binding sites were pharmacologically and stereospecifically selective. These results indicate that (-)-[125I]-IPin, a pure (-)-stereoisomer, high specific activity radioligand, selectively binds to beta-adrenergic receptors in whole cells with a high percentage of specific binding and should therefore be useful in the study and measurement of cellular beta-adrenergic receptors

  19. Development of a test rig and its application for validation and reliability testing of safety-critical software

    Energy Technology Data Exchange (ETDEWEB)

    Thai, N D; McDonald, A M [Atomic Energy of Canada Ltd., Mississauga, ON (Canada)

    1996-12-31

    This paper describes a versatile test rig developed by AECL for functional testing of safety-critical software used in the process trip computers of the Wolsong CANDU stations. The description covers the hardware and software aspects of the test rig, the test language and its interpreter, and other major testing software utilities such as the test oracle, sampler and profiler. The paper also discusses the application of the rig in the final stages of testing of the process trip computer software, namely validation and reliability tests. It shows how random test cases are generated, test scripts prepared and automatically run on the test rig. The versatility of the rig is further demonstrated in other types of testing such as sub-system tests, verification of the test oracle, testing of newly-developed test script, self-test and calibration. (author). 5 tabs., 10 figs.

  20. Development of a test rig and its application for validation and reliability testing of safety-critical software

    International Nuclear Information System (INIS)

    Thai, N.D.; McDonald, A.M.

    1995-01-01

    This paper describes a versatile test rig developed by AECL for functional testing of safety-critical software used in the process trip computers of the Wolsong CANDU stations. The description covers the hardware and software aspects of the test rig, the test language and its interpreter, and other major testing software utilities such as the test oracle, sampler and profiler. The paper also discusses the application of the rig in the final stages of testing of the process trip computer software, namely validation and reliability tests. It shows how random test cases are generated, test scripts prepared and automatically run on the test rig. The versatility of the rig is further demonstrated in other types of testing such as sub-system tests, verification of the test oracle, testing of newly-developed test script, self-test and calibration. (author). 5 tabs., 10 figs

  1. Technical specification for IR rig manufacture

    Energy Technology Data Exchange (ETDEWEB)

    Han Hyon Soo; Cho, W. K.; Kim, S. D.; Park, U. J.; Hong, S. B.; Yoo, K. M

    2000-10-01

    IR Rig is one of the equipments are required in HANARO core for a radioisotope target. The various conditions like high radiation, high heat, rapid flow and vibration may cause swelling, Brittleness and acceleration of corrosion in HANARO core. These specific problems can be prevented and the safety of such equipment are prerequisite as well as durableness and surveillance. Therefore, the selection of material has to be made on the basis of small cross-section area, low energy emission by the gamma ray due to the absorption of neutron and short half life. The body is consist of aluminum and Inconel-750 was used for the internal spring(coil) which is known to be durable. The whole production process including the purchase of accessory, mechanical processing, welding and assembly was carried out according to the standard procedure to meet the requirement. A design, manufacture, utilization of reactor core and the other relevant uses were fit to class ''T'' to certify the whole process as general. And design, fabrication, analytical test, materials and accessory were carried out based on the ASME, ASTM, ANSI, AWS, JIS and KS standard.

  2. Toll-like receptors as therapeutic targets in cystic fibrosis.

    LENUS (Irish Health Repository)

    Greene, Catherine M

    2008-12-01

    Background: Toll-like receptors (TLRs) are pattern recognition receptors that act as a first-line of defence in the innate immune response by recognising and responding to conserved molecular patterns in microbial factors and endogenous danger signals. Cystic fibrosis (CF)-affected airways represent a milieu potentially rich in TLR agonists and the chronic inflammatory phenotype evident in CF airway epithelial cells is probably due in large part to activation of TLRs. Objective\\/methods: To examine the prospects of developing novel therapies for CF by targeting TLRs. We outline the expression and function of TLRs and explore the therapeutic potential of naturally-occurring and synthetic TLR inhibitors for CF. Results\\/conclusion: Modulation of TLRs has therapeutic potential for the inflammatory lung manifestations of CF.

  3. AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA

    Directory of Open Access Journals (Sweden)

    Yuki Nakaya

    2017-07-01

    Full Text Available Cytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs that stimulate the induction of interferons (IFNs and other cytokines, leading to autoimmune disease. Cyclic GMP-AMP synthase is one PRR that senses retrotransposon DNA, activating type I IFN responses through the stimulator of IFN genes (STING. Absent in melanoma 2 (AIM2-like receptors (ALRs have also been implicated in these pathways. Here we show that the mouse ALR IFI205 senses cytosolic retrotransposon DNA independently of cyclic GMP-AMP production. AIM2 antagonizes IFI205-mediated IFN induction activity by sequestering it from STING. We also found that the complement of genes located in the ALR locus in C57BL/6 and AIM2 knockout mice are different and unique, which has implications for interpretation of the sensing of pathogens in different mouse strains. Our data suggest that members of the ALR family are critical to the host IFN response to endogenous DNA.

  4. Human blood-brain barrier insulin-like growth factor receptor

    International Nuclear Information System (INIS)

    Duffy, K.R.; Pardridge, W.M.; Rosenfeld, R.G.

    1988-01-01

    Insulin-like growth factor (IGF)-1 and IGF-2, may be important regulatory molecules in the CNS. Possible origins of IGFs in brain include either de novo synthesis or transport of circulating IGFs from blood into brain via receptor mediated transcytosis mechanisms at the brain capillary endothelial wall, ie, the blood-brain barrier (BBB). In the present studies, isolated human brain capillaries are used as an in vitro model system of the human BBB and the characteristics of IGF-1 or IGF-2 binding to this preparation were assessed. The total binding of IGF-2 at 37 degrees C exceeded 130% per mg protein and was threefold greater than the total binding for IGF-1. However, at 37 degrees C nonsaturable binding equaled total binding, suggesting that endocytosis is rate limiting at physiologic temperatures. Binding studies performed at 4 degrees C slowed endocytosis to a greater extent than membrane binding, and specific binding of either IGF-1 or IGF-2 was detectable. Scatchard plots for either peptide were linear and the molar dissociation constant of IGF-1 and IGF-2 binding was 2.1 +/- 0.4 and 1.1 +/- 0.1 nmol/L, respectively. Superphysiologic concentrations of porcine insulin inhibited the binding of both IGF-1 (ED50 = 2 micrograms/mL) and IGF-2 (ED50 = 0.5 microgram/mL). Affinity cross linking of 125 I-IGF-1, 125 I-IGF-2, and 125 I-insulin to isolated human brain capillaries was performed using disuccinimidylsuberate (DSS). These studies revealed a 141 kd binding site for both IGF-1 and IGF-2, and a 133 kd binding site for insulin

  5. Association study of the estrogen receptor I gene (ESR1) in anorexia nervosa and eating disorders: No replication found

    NARCIS (Netherlands)

    Slof-Op 't Landt, M.C.T.; van Furth, E.F.; Meulenbelt, I.; Bartels, M.; Slagboom, P.E.; Boomsma, D.I.

    2014-01-01

    Objective The female preponderance and onset around puberty in the majority of eating disorders (EDs) suggest that sex hormones, like estrogens, may be involved in the onset of these disorders. An eight-SNP haplotype at the estrogen receptor I (ESR1) gene was found to be associated with anorexia

  6. γ-Preprotachykinin-(72-92)-peptide amide: An endogenous preprotachykinin I gene-derived peptide that preferentially binds to neurokinin-2 receptors

    International Nuclear Information System (INIS)

    Dam, T.V.; Takeda, Y.; Krause, J.E.; Escher, E.; Quirion, R.

    1990-01-01

    The presence of N-terminally extended forms of neurokinin A has recently been reported in the mammalian brain. Among them, gamma-preprotachykinin-(72-92)-peptide amide [gamma-PPT-(72-92)-NH2], a peptide derived by posttranslational processing of gamma-preprotachykinin, is most prominent. We report here that this peptide most likely acts on neurokinin-2 receptor sites since neurokinin A (a putative neurokinin-2 agonist) and gamma-PPT-(72-92)-NH2 are potent competitors of 125I-labeled gamma-PPT-(72-92)-NH2 binding whereas selective neurokinin-1 and -3 agonists are not. Moreover, the distribution of 125I-labeled gamma-PPT-(72-92)-NH2 and 125I-labeled neurokinin A binding sites are very similar in rat brain. On the other hand, 125I-labeled Bolton-Hunter-substance P (a neurokinin-1 ligand) and 125I-labeled Bolton-Hunter-eledoisin (a neurokinin-3 ligand) binding sites are differentially located in this tissue. Thus, it appears that gamma-PPT-(72-92)-NH2 binds to neurokinin-2 receptors and should be considered as a putative endogenous ligand for this receptor class

  7. Toll-Like Receptors and Myocardial Inflammation

    Directory of Open Access Journals (Sweden)

    Yan Feng

    2011-01-01

    Full Text Available Toll-like receptors (TLRs are a member of the innate immune system. TLRs detect invading pathogens through the pathogen-associated molecular patterns (PAMPs recognition and play an essential role in the host defense. TLRs can also sense a large number of endogenous molecules with the damage-associated molecular patterns (DAMPs that are produced under various injurious conditions. Animal studies of the last decade have demonstrated that TLR signaling contributes to the pathogenesis of the critical cardiac conditions, where myocardial inflammation plays a prominent role, such as ischemic myocardial injury, myocarditis, and septic cardiomyopathy. This paper reviews the animal data on (1 TLRs, TLR ligands, and the signal transduction system and (2 the important role of TLR signaling in these critical cardiac conditions.

  8. Dopamine D2-Like Receptors and Behavioral Economics of Food Reinforcement

    Science.gov (United States)

    Soto, Paul L; Hiranita, Takato; Xu, Ming; Hursh, Steven R; Grandy, David K; Katz, Jonathan L

    2016-01-01

    Previous studies suggest dopamine (DA) D2-like receptor involvement in the reinforcing effects of food. To determine contributions of the three D2-like receptor subtypes, knockout (KO) mice completely lacking DA D2, D3, or D4 receptors (D2R, D3R, or D4R KO mice) and their wild-type (WT) littermates were exposed to a series of fixed-ratio (FR) food-reinforcement schedules in two contexts: an open economy with additional food provided outside the experimental setting and a closed economy with all food earned within the experimental setting. A behavioral economic model was used to quantify reinforcer effectiveness with food pellets obtained as a function of price (FR schedule value) plotted to assess elasticity of demand. Under both economies, as price increased, food pellets obtained decreased more rapidly (ie, food demand was more elastic) in DA D2R KO mice compared with WT littermates. Extinction of responding was studied in two contexts: by eliminating food deliveries and by delivering food independently of responding. A hyperbolic model quantified rates of extinction. Extinction in DA D2R KO mice occurred less rapidly compared with WT mice in both contexts. Elasticity of food demand was higher in DA D4R KO than WT mice in the open, but not closed, economy. Extinction of responding in DA D4R KO mice was not different from that in WT littermates in either context. No differences in elasticity of food demand or extinction rate were obtained in D3R KO mice and WT littermates. These results indicate that the D2R is the primary DA D2-like receptor subtype mediating the reinforcing effectiveness of food. PMID:26205210

  9. The Hydraulic Test Report for Non-instrumented Irradiation Test Rig of DUO-Cooled Annular Pellet

    International Nuclear Information System (INIS)

    Kim, Dae Ho; Lee, Kang Hee; Shin, Chang Hwan; Yang, Yong Sik; Kim, Sun Ki; Bang, Je Geon; Song, Kun Woo

    2007-08-01

    This report presents the results of pressure drop test and vibration test for non-instrumented rig of Advanced PWR DUO-Fuel Annular Pellet which were designed and fabricated by KAERI. From the pressure drop test results, it is noted that the flow velocity across the non-instrumented rig of Advanced PWR DUO-Fuel Annular Pellet corresponding to the pressure drop of 200 kPa is measured to be about 8.30 kg/sec. Vibration frequency results for the non-instrumented rig at the pump spin frequency ranges from 19.0 to 32.0 Hz, RMS(Root Mean Square) displacement for the non-instrumented rig of Advanced PWR DUO-Fuel Annular Pellet is less than 7.25 m, and the maximum displacement is less than 31.27 μm. This test was performed at the FIVPET facility

  10. Role of toll like receptors in bacterial and viral diseases – A systemic ...

    African Journals Online (AJOL)

    Background: Toll like receptors are key-receptors of the innate immune system, but their role against bacterial and viral infections are yet to be understood. Aim: The present study is aimed to investigate the diversity and frequency distribution of 10 TLR genes among typhoid fever and HIV+ patients. In this study, 44 samples ...

  11. Differential expression of toll-like receptors in patients with irritable bowel syndrome.

    LENUS (Irish Health Repository)

    Brint, Elizabeth K

    2011-02-01

    The pathogenesis of irritable bowel syndrome (IBS) is poorly understood. One contributory factor may be low-grade mucosal inflammation, perhaps initiated by the microbiota. Toll-like receptors (TLRs) are a family of pathogen-recognition receptors of the innate immune system. The aim of this study was to evaluate the potential involvement of TLRs in IBS to further understand the involvement of the innate immune system in this complex disorder.

  12. 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

    the Toll-like receptor 3 (TLR3)-mediated and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated signaling pathway. We also found that SVV is sensitive to IFN-β. These findings increase our understanding of the interaction between SVV and host innate immunity. Copyright © 2017 American Society for Microbiology.

  13. Receptor-like protein-tyrosine phosphatase alpha specifically inhibits insulin-increased prolactin gene expression

    DEFF Research Database (Denmark)

    Jacob, K K; Sap, J; Stanley, F M

    1998-01-01

    A physiologically relevant response to insulin, stimulation of prolactin promoter activity in GH4 pituitary cells, was used as an assay to study the specificity of protein-tyrosine phosphatase function. Receptor-like protein-tyrosine phosphatase alpha (RPTPalpha) blocks the effect of insulin...... is specific by two criteria. A number of potential RPTPalpha targets were ruled out by finding (a) that they are not affected or (b) that they are not on the pathway to insulin-increased prolactin-CAT activity. The negative effect of RPTPalpha on insulin activation of the prolactin promoter is not due...... to reduced phosphorylation or kinase activity of the insulin receptor or to reduced phosphorylation of insulin receptor substrate-1 or Shc. Inhibitor studies suggest that insulin-increased prolactin gene expression is mediated by a Ras-like GTPase but is not mitogen-activated protein kinase dependent...

  14. A reciprocating pin-on-plate test-rig for studying friction materials for holding brakes

    DEFF Research Database (Denmark)

    Poulios, Konstantinos; Drago, Nicola; Klit, Peder

    2014-01-01

    -on-plate test-rig for studying the evolution of wear by monitoring the pin height reduction using Eddy-current proximity sensors is presented. Moreover, a new mechanism for recording the friction force is suggested. Apart from the design of the test-rig, friction force and wear rate measurements for two...

  15. Resonances, scattering theory and rigged Hilbert spaces

    International Nuclear Information System (INIS)

    Parravicini, G.; Gorini, V.; Sudarshan, E.C.G.

    1979-01-01

    The problem of decaying states and resonances is examined within the framework of scattering theory in a rigged Hilbert space formalism. The stationary free, in, and out eigenvectors of formal scattering theory, which have a rigorous setting in rigged Hilbert space, are considered to be analytic functions of the energy eigenvalue. The value of these analytic functions at any point of regularity, real or complex, is an eigenvector with eigenvalue equal to the position of the point. The poles of the eigenvector families give origin to other eigenvectors of the Hamiltonian; the singularities of the out eigenvector family are the same as those of the continued S matrix, so that resonances are seen as eigenvectors of the Hamiltonian with eigenvalue equal to their location in the complex energy plane. Cauchy theorem then provides for expansions in terms of complete sets of eigenvectors with complex eigenvalues of the Hamiltonian. Applying such expansions to the survival amplitude of a decaying state, one finds that resonances give discrete contributions with purely exponential time behavior; the background is of course present, but explicitly separated. The resolvent of the Hamiltonian, restricted to the nuclear space appearing in the rigged Hilbert space, can be continued across the absolutely continuous spectrum; the singularities of the continuation are the same as those of the out eigenvectors. The free, in and out eigenvectors with complex eigenvalues and those corresponding to resonances can be approximated by physical vectors in the Hilbert space, as plane waves can. The need for having some further physical information in addition to the specification of the total Hamiltonian is apparent in the proposed framework. The formalism is applied to the Lee-Friedrichs model. 48 references

  16. Injury Rates on New and Old Technology Oil and Gas Rigs Operated by the Largest United States Onshore Drilling Contractor

    Science.gov (United States)

    Blackley, David J.; Retzer, Kyla D.; Hubler, Warren G.; Hill, Ryan D.; Laney, A. Scott

    2015-01-01

    Background Occupational fatality rates among oil and gas extraction industry and specifically among drilling contractor workers are high compared to the U.S. all-industry average. There is scant literature focused on non-fatal injuries among drilling contractors, some of which have introduced engineering controls to improve rig efficiency and reduce injury risk. Methods We compared injury rates on new and old technology rigs operated by the largest U.S. drilling contractor during 2003–2012, stratifying by job type and grouping outcomes by injury severity and body part affected. Results Six hundred seventy-one injuries were recorded over 77.4 million person-hours. The rate on new rigs was 66% of that on old rigs. Roughnecks had lower injury rates on new rigs, largely through reduced limb injury rates. New rigs had lower rates in each non-fatal injury severity category. Conclusions For this company, new technology rigs appear to provide a safer environment for roughnecks. Future studies could include data from additional companies. PMID:25164118

  17. Injury rates on new and old technology oil and gas rigs operated by the largest United States onshore drilling contractor.

    Science.gov (United States)

    Blackley, David J; Retzer, Kyla D; Hubler, Warren G; Hill, Ryan D; Laney, A Scott

    2014-10-01

    Occupational fatality rates among oil and gas extraction industry and specifically among drilling contractor workers are high compared to the U.S. all-industry average. There is scant literature focused on non-fatal injuries among drilling contractors, some of which have introduced engineering controls to improve rig efficiency and reduce injury risk. We compared injury rates on new and old technology rigs operated by the largest U.S. drilling contractor during 2003-2012, stratifying by job type and grouping outcomes by injury severity and body part affected. Six hundred seventy-one injuries were recorded over 77.4 million person-hours. The rate on new rigs was 66% of that on old rigs. Roughnecks had lower injury rates on new rigs, largely through reduced limb injury rates. New rigs had lower rates in each non-fatal injury severity category. For this company, new technology rigs appear to provide a safer environment for roughnecks. Future studies could include data from additional companies. © 2014 Wiley Periodicals, Inc.

  18. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

    2014-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  19. The immunohistochemical expression of calcitonin receptor-like receptor (CRLR) in human gliomas.

    Science.gov (United States)

    Benes, L; Kappus, C; McGregor, G P; Bertalanffy, H; Mennel, H D; Hagner, S

    2004-02-01

    Gliomas are the most common primary tumours of the central nervous system and exhibit rapid growth that is associated with neovascularisation. Adrenomedullin is an important tumour survival factor in human carcinogenesis. It has growth promoting effects on gliomas, and blockade of its actions has been experimentally shown to reduce the growth of glioma tissues and cell lines. There is some evidence that the calcitonin receptor-like receptor (CRLR) mediates the tumorigenic actions of adrenomedullin. To determine whether CRLR is expressed in human gliomas and the probable cellular targets of adrenomedullin. Biopsies from 95 human gliomas of varying grade were processed for immunohistochemical analysis using a previously developed and characterised antibody to CRLR. All tumour specimens were positive for CRLR. As previously found in normal peripheral tissues, CRLR immunostaining was particularly intense in the endothelial cells. This was evident in all the various vascular conformations that were observed, and which are typical of gliomas. In addition, clear immunostaining of tumour cells with astrocyte morphology was observed. These were preferentially localised around vessels. This study has shown for the first time that the CRLR protein is present in human glioma tissue. The expression of the receptor in endothelial cells and in astrocytic tumour cells is consistent with the evidence that its endogenous ligand, adrenomedullin, may influence glioma growth by means of both direct mitogenic and indirect angiogenic effects. CRLR may be a valuable target for effective therapeutic intervention in these malignant tumours.

  20. The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Andersen, Maibritt B; Fink-Jensen, Anders; Peacock, Linda

    2003-01-01

    Xanomeline is a muscarinic M(1)/M(4) preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects ...

  1. The Design and Manufacturing Report of Plug Type Non-Instrumented Rig for Irradiation Test in HANARO OR Hole

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dae Ho; Bang, Je Geon; Lim, Ik Sung; Kim, Sun Ki; Yang, Yong Sik; Song, Kun Woo

    2008-09-15

    This project is developed the plug type non-instrumented irradiation test rig of the advanced nuclear fuel in HANARO for pursuit advanced performance in High Performance Fuel Technology Development as a part Nuclear Mid and Long-term R and D Program. This irradiation rig was confirmed the integrity and HANARO core compatibility by the optimum design and the thermal hydraulic out-pile test in FIVPET. The characteristic of plug type non-instrument rig is to possible irradiation test of variable in-pile condition and reduced the wastes for reusable as function. This plug type non-instrumented rig was satisfied the quality assurance requirements and written out the end of manufacturing report. This plug type non-instrumented rig is adopt to the irradiation test for nuclear fuel irradiation test in HANARO OR hole.

  2. [Association of polymorphisms in toll-like receptor genes with atopic dermatitis in the Republic of Bashkortostan].

    Science.gov (United States)

    Gimalova, G F; Karunas, A S; Fedorova, Iu Iu; Gumennaia, É R; Levasheva, S V; Khismatullina, Z R; Prans, E; Koks, S; Étkina, É I; Khusnutdinova, É K

    2014-01-01

    Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease developing as a result of the interaction between genetic predisposition and environmental factors. Considerable role in allergic diseases development is played by polymorphisms of genes of pattern-recognition receptors (PRR) which are capable of recognizing conservative standard molecular structures (patterns) unique for large pathogen groups. In this study polymorphic variants of PRR genes--Toll-like receptors (TLR1, TLR2, TLR4, TLR5, TLR6, TLR9, TLR10), NOD-like receptors (NOD1, NOD2), lipopolysaccharide receptor CD14 gene, and C11orf30 and LRRC32 genes, located in 11q13.5 region, have been investigated in AD patients and control subjects from the Republic of Bashkortostan. An association of TLR1 (rs5743571 and rs5743604), TLR6 (rs5743794) and TLR10 (rs11466617) with AD was found. Our results confirm an important role of the innate immune system in the pathogenesis of AD and the significance of polymorphisms within the Toll-like receptor 2 subfamily genes in AD development.

  3. Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability

    Science.gov (United States)

    Beckley, Ethan H.; Scibelli, Angela C.; Finn, Deborah A.

    2010-01-01

    Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone’s GABAA receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression. PMID:21163582

  4. Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability.

    Science.gov (United States)

    Beckley, Ethan H; Scibelli, Angela C; Finn, Deborah A

    2011-07-01

    Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone's GABA(A) receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression. Copyright © 2010 Elsevier Ltd. All rights reserved.

  5. Rotavirus nonstructural protein 1 antagonizes innate immune response by interacting with retinoic acid inducible gene I

    Directory of Open Access Journals (Sweden)

    Qin Lan

    2011-12-01

    Full Text Available Abstract Background The nonstructural protein 1 (NSP1 of rotavirus has been reported to block interferon (IFN signaling by mediating proteasome-dependent degradation of IFN-regulatory factors (IRFs and (or the β-transducin repeat containing protein (β-TrCP. However, in addition to these targets, NSP1 may subvert innate immune responses via other mechanisms. Results The NSP1 of rotavirus OSU strain as well as the IRF3 binding domain truncated NSP1 of rotavirus SA11 strain are unable to degrade IRFs, but can still inhibit host IFN response, indicating that NSP1 may target alternative host factor(s other than IRFs. Overexpression of NSP1 can block IFN-β promoter activation induced by the retinoic acid inducible gene I (RIG-I, but does not inhibit IFN-β activation induced by the mitochondrial antiviral-signaling protein (MAVS, indicating that NSP1 may target RIG-I. Immunoprecipitation experiments show that NSP1 interacts with RIG-I independent of IRF3 binding domain. In addition, NSP1 induces down-regulation of RIG-I in a proteasome-independent way. Conclusions Our findings demonstrate that inhibition of RIG-I mediated type I IFN responses by NSP1 may contribute to the immune evasion of rotavirus.

  6. Olfactory Receptor Database: a sensory chemoreceptor resource

    OpenAIRE

    Skoufos, Emmanouil; Marenco, Luis; Nadkarni, Prakash M.; Miller, Perry L.; Shepherd, Gordon M.

    2000-01-01

    The Olfactory Receptor Database (ORDB) is a WWW-accessible database that has been expanded from an olfactory receptor resource to a chemoreceptor resource. It stores data on six classes of G-protein-coupled sensory chemoreceptors: (i) olfactory receptor-like proteins, (ii) vomeronasal receptors, (iii) insect olfactory receptors, (iv) worm chemoreceptors, (v) taste papilla receptors and (vi) fungal pheromone receptors. A complementary database of the ligands of these receptors (OdorDB) has bee...

  7. Dansyl-PQRamide, a putative antagonist of NPFF receptors, reduces anxiety-like behavior of ethanol withdrawal in a plus-maze test in rats.

    Science.gov (United States)

    Kotlinska, Jolanta; Pachuta, Agnieszka; Bochenski, Marcin; Silberring, Jerzy

    2009-06-01

    Much evidence indicates that endogenous opioid peptides are involved in effects caused by ethanol. The aim of the present study was to determine whether dansyl-PQR amide, a putative antagonist of receptors for an anti-opioid peptide-neuropeptide FF (NPFF) could affect anxiety-like behavior measured during withdrawal from acute-, and chronic ethanol administration in the elevated plus maze test in rats. Our study indicated that intracerebroventricular (i.c.v.) administration of dansyl-PQRamide (2.4 and 4.8 nmol) reversed anxiety-like behavior measured as a percent time spent in the open arms, and a percent open arm entries onto the open arms in the elevated plus-maze test in rats. These effects were inhibited by NPFF (10 and/or 20 nmol, i.c.v.) in the experiments performed during withdrawal from acute- and chronic ethanol administration. During withdrawal from acute ethanol, naloxone (1mg/kg, i.p.), a nonselective opioid receptor antagonist, attenuated only an increased percent time spent in the open arms induced by dansyl-PQR amide (4.8 nmol). Dansyl-PQR amide, NPFF and naloxone given alone to naive rats did not have influence on spontaneous locomotor activity of animals. Furthermore, NPFF potentiated anxiety-like behavior during withdrawal from chronic, but not acute, ethanol administration in rats. Our data suggest that NPFF system is involved in regulation of affective symptoms of ethanol withdrawal. It seems that involvement of the NPFF system in ethanol withdrawal anxiety-like behavior is associated with regulation of the opioid system activity.

  8. Novel drugs targeting Toll-like receptors for antiviral therapy.

    Science.gov (United States)

    Patel, Mira C; Shirey, Kari Ann; Pletneva, Lioubov M; Boukhvalova, Marina S; Garzino-Demo, Alfredo; Vogel, Stefanie N; Blanco, Jorge Cg

    2014-09-01

    Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved 'pathogen-associated molecular patterns' of invading microbes, including viruses. The activation of TLRs establishes antiviral innate immune responses and coordinates the development of long-lasting adaptive immunity in order to control viral pathogenesis. However, microbe-induced damage to host tissues may release 'danger-associated molecular patterns' that also activate TLRs, leading to an overexuberant inflammatory response and, ultimately, to tissue damage. Thus, TLRs have proven to be promising targets as therapeutics for the treatment of viral infections that result in inflammatory damage or as adjuvants in order to enhance the efficacy of vaccines. Here, we explore recent advances in TLR biology with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy.

  9. Polymorphism of glucagon-like peptide-1 receptor gene (rs1042044 ...

    African Journals Online (AJOL)

    Previous investigations indicated that glucagon-like peptide-1 (GLP-1) played important roles in bone turnover via GLP-1 receptors (GLP1Rs) in postmenopausal state. Furthermore, polymorphisms in GLP1R gene were suggested to affect the function of GLP1Rs and be associated with many diseases. However, the ...

  10. Expression analysis of the Toll-like receptor and TIR domain adaptor families of zebrafish.

    NARCIS (Netherlands)

    Meijer, A.H.; Krens, SF Gabby; Rodriguez, IA Medina; He, S; Bitter, W.; Snaar-Jagalska, B Ewa; Spaink, H.P.

    2004-01-01

    The zebrafish genomic sequence database was analysed for the presence of genes encoding members of the Toll-like receptors (TLR) and interleukin receptors (IL-R) and associated adaptor proteins containing a TIR domain. The resulting predictions show the presence of one or more counterparts for the

  11. Characterization of glucagon-like peptide-1 receptor-binding determinants.

    Science.gov (United States)

    Xiao, Q; Jeng, W; Wheeler, M B

    2000-12-01

    Glucagon-like peptide 1 (GLP-1) is a potent insulinotropic hormone currently under study as a therapeutic agent for type 2 diabetes. Since an understanding of the molecular mechanisms leading to high-affinity receptor (R) binding and activation may facilitate the development of more potent GLP-1R agonists, we have localized specific regions of GLP-1R required for binding. The purified N-terminal fragment (hereafter referred to as NT) of the GLP-1R produced in either insect (Sf9) or mammalian (COS-7) cells was shown to bind GLP-1. The physical interaction of NT with GLP-1 was first demonstrated by cross-linking ((125)I-GLP-1/NT complex band at approximately 28 kDa) and secondly by attachment to Ni(2+)-NTA beads. The GLP-1R NT protein attached to beads bound GLP-1, but with lower affinity (inhibitory concentration (IC(50)): 4.5 x 10(-7) M) than wild-type (WT) GLP-1R (IC(50): 5.2 x 10(-9)M). The low affinity of GLP-1R NT suggested that other receptor domains may contribute to GLP-1 binding. This was supported by studies using chimeric glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptors. GIP(1-151)/GLP-1R, but not GIP(1-222)/GLP-1R, exhibited specific GLP-1 binding and GLP-1-induced cAMP production, suggesting that the region encompassing transmembrane (TM) domain 1 through to TM3 was required for binding. Since it was hypothesized that certain charged or polar amino acids in this region might be involved in binding, these residues (TM2-TM3) were analyzed by substitution mutagenesis. Five mutants (K197A, D198A, K202A, D215A, R227A) displayed remarkably reduced binding affinity. These studies indicate that the NT domain of the GLP-1R is able to bind GLP-1, but charged residues concentrated at the distal TM2/extracellular loop-1 (EC1) interface (K197, D198, K202) and in EC1 (D215 and R227) probably contribute to the binding determinants of the GLP-1R.

  12. [123I]epidepride binding to cerebellar dopamine D2/D3 receptors is displaceable: implications for the use of cerebellum as a reference region

    DEFF Research Database (Denmark)

    Pinborg, Lars H; Videbaek, Charlotte; Ziebell, Morten

    2007-01-01

    The low density of cerebellar dopamine D(2)/D(3) receptors provides the basis for using the cerebellum as a representation of free- and non-specifically bound radioligand in positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies. With the development...... of ultra high-affinity dopamine D(2)/D(3) ligands like [(123)I]epidepride, [(18)F]fallypride, and [(11)C]FLB-457, quantification of extrastriatal low density receptor populations including the cerebellum is possible with important implications for calculation of binding parameters. [(123)I...... [(123)I]epidepride binding to dopamine D(2)/D(3) receptors in the cerebellum. Using the cerebellum as a representation of free and non-specifically bound radioligand and neglecting the specifically bound component may lead to results that erroneously imply that antipsychotic drugs bind to extrastriatal...

  13. The structural basis for endotoxin-induced allosteric regulation of the Toll-like receptor 4 (TLR4) innate immune receptor.

    Science.gov (United States)

    Paramo, Teresa; Piggot, Thomas J; Bryant, Clare E; Bond, Peter J

    2013-12-20

    As part of the innate immune system, Toll-like receptor 4 (TLR4) recognizes bacterial cell surface lipopolysaccharide (LPS) by forming a complex with a lipid-binding co-receptor, MD-2. In the presence of agonist, TLR4·MD-2 dimerizes to form an active receptor complex, leading to initiation of intracellular inflammatory signals. TLR4 is of great biomedical interest, but its pharmacological manipulation is complicated because even subtle variations in the structure of LPS can profoundly impact the resultant immunological response. Here, we use atomically detailed molecular simulations to gain insights into the nature of the molecular signaling mechanism. We first demonstrate that MD-2 is extraordinarily flexible. The "clamshell-like" motions of its β-cup fold enable it to sensitively match the volume of its hydrophobic cavity to the size and shape of the bound lipid moiety. We show that MD-2 allosterically transmits this conformational plasticity, in a ligand-dependent manner, to a phenylalanine residue (Phe-126) at the cavity mouth previously implicated in TLR4 activation. Remarkably, within the receptor complex, we observe spontaneous transitions between active and inactive signaling states of Phe-126, and we confirm that Phe-126 is indeed the "molecular switch" in endotoxic signaling.

  14. Mach 0.3 Burner Rig Facility at the NASA Glenn Materials Research Laboratory

    Science.gov (United States)

    Fox, Dennis S.; Miller, Robert A.; Zhu, Dongming; Perez, Michael; Cuy, Michael D.; Robinson, R. Craig

    2011-01-01

    This Technical Memorandum presents the current capabilities of the state-of-the-art Mach 0.3 Burner Rig Facility. It is used for materials research including oxidation, corrosion, erosion and impact. Consisting of seven computer controlled jet-fueled combustors in individual test cells, these relatively small rigs burn just 2 to 3 gal of jet fuel per hour. The rigs are used as an efficient means of subjecting potential aircraft engine/airframe advanced materials to the high temperatures, high velocities and thermal cycling closely approximating actual operating environments. Materials of various geometries and compositions can be evaluated at temperatures from 700 to 2400 F. Tests are conducted not only on bare superalloys and ceramics, but also to study the behavior and durability of protective coatings applied to those materials.

  15. Avr4 promotes Cf-4 receptor-like protein association with the BAK1/SERK3 receptor-like kinase to initiate receptor endocytosis and plant immunity.

    Science.gov (United States)

    Postma, Jelle; Liebrand, Thomas W H; Bi, Guozhi; Evrard, Alexandre; Bye, Ruby R; Mbengue, Malick; Kuhn, Hannah; Joosten, Matthieu H A J; Robatzek, Silke

    2016-04-01

    The first layer of plant immunity is activated by cell surface receptor-like kinases (RLKs) and proteins (RLPs) that detect infectious pathogens. Constitutive interaction with the SUPPRESSOR OF BIR1 (SOBIR1) RLK contributes to RLP stability and kinase activity. As RLK activation requires transphosphorylation with a second associated RLK, it remains elusive how RLPs initiate downstream signaling. We employed live-cell imaging, gene silencing and coimmunoprecipitation to investigate the requirement of associated kinases for functioning and ligand-induced subcellular trafficking of Cf RLPs that mediate immunity of tomato against Cladosporium fulvum. Our research shows that after elicitation with matching effector ligands Avr4 and Avr9, BRI1-ASSOCIATED KINASE 1/SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3 (BAK1/SERK3) associates with Cf-4 and Cf-9. BAK1/SERK3 is required for the effector-triggered hypersensitive response and resistance of tomato against C. fulvum. Furthermore, Cf-4 interacts with SOBIR1 at the plasma membrane and is recruited to late endosomes upon Avr4 trigger, also depending on BAK1/SERK3. These observations indicate that RLP-mediated resistance and endocytosis require ligand-induced recruitment of BAK1/SERK3, reminiscent of BAK1/SERK3 interaction and subcellular fate of the FLAGELLIN SENSING 2 (FLS2) RLK. This reveals that diverse classes of cell surface immune receptors share common requirements for initiation of resistance and endocytosis. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  16. Antipsychotic-like effect of the muscarinic acetylcholine receptor agonist BuTAC in non-human primates

    DEFF Research Database (Denmark)

    Andersen, Maibritt B; Croy, Carrie Hughes; Dencker, Ditte

    2015-01-01

    Cholinergic, muscarinic receptor agonists exhibit functional dopamine antagonism and muscarinic receptors have been suggested as possible future targets for the treatment of schizophrenia and drug abuse. The muscarinic ligand (5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane...... (BuTAC) exhibits high affinity for muscarinic receptors with no or substantially less affinity for a large number of other receptors and binding sites, including the dopamine receptors and the dopamine transporter. In the present study, we wanted to examine the possible antipsychotic-like effects...

  17. Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I

    DEFF Research Database (Denmark)

    Orskov, C; Poulsen, Steen Seier; Møller, M

    1996-01-01

    -labeled GLP-I. The specificity of the binding was tested by co-injection of excess amounts of unlabeled GLP-I. Using light microscopical autoradiography of rat brain sections, we found specific 125I-GLP-I binding exclusively in the subfornical organ and the area postrema. This binding was abolished when...... an excess amount of unlabeled GLP-I was co-injected with the labeled GLP-I. We conclude that cells in the subfornical organ and the area postrema could be responsive to blood-borne GLP-I. The observed binding of peripherally administered GLP-I to the subfornical organ and the area postrema, which both have...

  18. Ebselen has lithium-like effects on central 5-HT2A receptor function.

    Science.gov (United States)

    Antoniadou, I; Kouskou, M; Arsiwala, T; Singh, N; Vasudevan, S R; Fowler, T; Cadirci, E; Churchill, G C; Sharp, T

    2018-02-27

    Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in G q protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here we investigated both ebselen and lithium in models of the 5-HT 2A receptor, a G q protein coupled receptor implicated in lithium's actions. 5-HT 2A receptor function was modelled in mice by measuring the behavioural (head-twitches) and cortical immediate early gene (IEG; Arc, c-fos and Erg2 mRNA) responses to 5-HT 2A receptor agonist administration. Ebselen and lithium were administered either acutely or chronically prior to assessment of 5-HT 2A receptor function. Given the SSRI augmenting action of lithium and 5-HT 2A antagonists, ebselen was also tested for this action by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments. Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT 2A receptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690,330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen increased regional brain 5-HT synthesis and enhanced the increase in extracellular 5-HT induced by citalopram. The current data demonstrate lithium-mimetic effects of ebselen in different experimental models of 5-HT 2A receptor function, likely mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorder, including as an antidepressant augmenting agent. This article is protected by copyright. All rights reserved.

  19. Study of NSILA-s (nonsuppressible insulin-like activity soluble in acid ethanol) by a new radio-receptor assay

    International Nuclear Information System (INIS)

    Megyeri, K.

    1977-01-01

    The insulin-like activity nonsuppressible with insulin-antibodies (NSILA) accounts for 90% of the insulin activity of the blood plasma. A peptid, soluble in acid ethanol, was purified (NSILA-s) and specific NSILA-s receptors were found on the plasma membrane of liver cells. The specificity, kinetics, affinity and pH-optimum of NSILA-s receptors significantly differed from those of insulin-receptors. A new, highly specific radio-receptor assay was developed, applying 125 I NSILA-s and liver cell membranes or lymphocytes. By this means the NSILA-s concentration of blood plasma was determined under normal and pathological (hypoglycaemizing tumours, hypopituritarism, acromegaly, anorexia nervosa, etc.) conditions. It is concluded that, 90% of the NSILA-s concentration of blood plasma is bound. In cases of hypoglycaemizing tumours increased NSILA-s activity was demonstrated both in blood serum and in the extracts of the tumour-tissue. Pharmacological doses of growth hormon (GH) increased plasma NSILA-s concentration, however, in the case of stimulation- and inhibition-tests carried out in normal patients, no unambiguous relationship could be demonstrated between plasma GH- and NSILA-s-levels. (L.E.)

  20. Test Rig for Valves of Digital Displacement Machines

    DEFF Research Database (Denmark)

    Nørgård, Christian; Christensen, Jeppe Haals; Bech, Michael Møller

    2017-01-01

    A test rig for the valves of digital displacement machines has been developed at Aalborg University. It is composed of a commercial radial piston machine, which has been modified to facilitate Digital Displacement operation for a single piston. Prototype valves have been optimized, designed and m...

  1. Toll-like receptors and cancer: MYD88 mutation and inflammation

    Directory of Open Access Journals (Sweden)

    James Q Wang

    2014-07-01

    Full Text Available Pattern recognition receptors (PRRs expressed on immune cells are crucial for the early detection of invading pathogens, in initiating early innate immune response and in orchestrating the adaptive immune response. PRRs are activated by specific pathogen-associated molecular patterns (PAMPs that are present in pathogenic microbes or nucleic acids of viruses or bacteria. However, inappropriate activation of these PRRs, such as the Toll-like receptors (TLRs, due to genetic lesions or chronic inflammation has been demonstrated to be a major cause of many haematological malignancies. Gain-of-function mutations in the TLR adaptor protein MYD88 found in 39% of the activated B cell type of diffuse large B cell lymphomas (ABC-DLBCL and almost 100% of Waldenström’s macroglobulinemia (WM further highlight the involvement of TLRs in these malignancies. MYD88 mutations result in the chronic activation of TLR signalling pathways, thus the constitutive activation of the transcription factor NFκB to promote cell survival and proliferation. These recent insights into TLR pathway driven malignancies warrant the need for a better understanding of TLRs in cancers and the development of novel anti-cancer therapies targeting TLRs. This review focuses on Toll-like receptors function and signalling in normal or inflammatory conditions, and how mutations can also hijack the TLR signalling pathways to give rise to cancer. Lastly, we discuss how potential therapeutic agents could be used to restore normal responses to TLRs and have long lasting anti-tumour effects.

  2. A Concerted Action Of Estradiol And Insulin Like Growth Factor I Underlies Sex Differences In Mood Regulation By Exercise.

    Science.gov (United States)

    Munive, Victor; Santi, Andrea; Torres-Aleman, Ignacio

    2016-05-12

    Mood homeostasis present sexually dimorphic traits which may explain sex differences in the incidence of mood disorders. We explored whether diverse behavioral-setting components of mood may be differentially regulated in males and females by exercise, a known modulator of mood. We found that exercise decreases anxiety only in males. Conversely, exercise enhanced resilience to stress and physical arousal, two other important components of mood, only in females. Because exercise increases brain input of circulating insulin-like growth factor I (IGF-I), a potent modulator of mood, we explored whether sex-specific actions of exercise on mood homeostasis relate to changes in brain IGF-I input. We found that exercise increased hippocampal IGF-I levels only in cycling females. Underlying mechanism involved activation of estrogen (E2) receptors in brain vessels that led to increased uptake of serum IGF-I as E2 was found to stimulate IGF-I uptake in brain endothelial cells. Indeed, modulatory effects of exercise on mood were absent in female mice with low serum IGF-I levels or after either ovariectomy or administration of an E2 receptor antagonist. These results suggest that sex-specific brain IGF-I responses to physiological stimuli such as exercise contribute to dimorphic mood homeostasis that may explain sex differences in affective disorders.

  3. Identification and characterization of alpha 1 adrenergic receptors in the canine prostate using [125I]-Heat

    International Nuclear Information System (INIS)

    Lepor, H.; Baumann, M.; Shapiro, E.

    1987-01-01

    We have recently utilized radioligand receptor binding methods to characterize muscarinic cholinergic and alpha adrenergic receptors in human prostate adenomas. The primary advantages of radioligand receptor binding methods are that neurotransmitter receptor density is quantitated, the affinity of unlabelled drugs for receptor sites is determined, and receptors can be localized using autoradiography on slide-mounted tissue sections. Recently, [ 125 I]-Heat, a selective and high affinity ligand with high specific activity (2200 Ci/mmole) has been used to characterize alpha 1 adrenergic receptors in the brain. In this study alpha 1 adrenergic receptors in the dog prostate were characterized using [ 125 I]-Heat. The Scatchard plots were linear indicating homogeneity of [ 125 I]-Heat binding sites. The mean alpha 1 adrenergic receptor density determined from these Scatchard plots was 0.61 +/- 0.07 fmol/mg. wet wt. +/- S.E.M. The binding of [ 125 I]-Heat to canine prostate alpha 1 adrenergic binding sites was of high affinity (Kd = 86 +/- 19 pM). Steady state conditions were reached following an incubation interval of 30 minutes and specific binding and tissue concentration were linear within the range of tissue concentrations assayed. The specificity of [ 125 I]-Heat for alpha 1 adrenergic binding sites was confirmed by competitive displacement assays using unlabelled clonidine and prazosin. Retrospective analysis of the saturation experiments demonstrated that Bmax can be accurately calculated by determining specific [ 125 I]-Heat binding at a single ligand concentration. [ 125 I]-Heat is an ideal ligand for studying alpha 1 adrenergic receptors in the prostate and its favorable properties should facilitate the autoradiographic localization of alpha 1 adrenergic receptors in the prostate

  4. Design and Demonstration of a Test-Rig for Static Performance-Studies of Permanent Magnet Couplings

    DEFF Research Database (Denmark)

    Högberg, Stig; Jensen, Bogi Bech; Bendixen, Flemming Buus

    2013-01-01

    The design and construction of an easy-to-use test-rig for permanent magnet couplings is presented. Static torque of permanent magnet couplings as a function of angular displacement is measured of permanent magnet couplings through an semi-automated test system. The test-rig is capable of measuring...

  5. Antipsychotic-like effect of the muscarinic acetylcholine receptor agonist BuTAC in non-human primates.

    Directory of Open Access Journals (Sweden)

    Maibritt B Andersen

    Full Text Available Cholinergic, muscarinic receptor agonists exhibit functional dopamine antagonism and muscarinic receptors have been suggested as possible future targets for the treatment of schizophrenia and drug abuse. The muscarinic ligand (5R,6R-6-(3-butylthio-1,2,5-thiadiazol-4-yl-1-azabicyclo[3.2.1]octane (BuTAC exhibits high affinity for muscarinic receptors with no or substantially less affinity for a large number of other receptors and binding sites, including the dopamine receptors and the dopamine transporter. In the present study, we wanted to examine the possible antipsychotic-like effects of BuTAC in primates. To this end, we investigated the effects of BuTAC on d-amphetamine-induced behaviour in antipsychotic-naive Cebus paella monkeys. Possible adverse events of BuTAC, were evaluated in the same monkeys as well as in monkeys sensitized to antipsychotic-induced extrapyramidal side effects. The present data suggests that, the muscarinic receptor ligand BuTAC exhibits antipsychotic-like behaviour in primates. The behavioural data of BuTAC as well as the new biochemical data further substantiate the rationale for the use of muscarinic M1/M2/M4-preferring receptor agonists as novel pharmacological tools in the treatment of schizophrenia.

  6. Toll-like receptors in the pathogenesis of human B cell malignancies

    NARCIS (Netherlands)

    Isaza-Correa, Johana M.; Liang, Zheng; van den Berg, Anke; Diepstra, Arjan; Visser, Lydia

    2014-01-01

    Toll-like receptors (TLRs) are important players in B-cell activation, maturation and memory and may be involved in the pathogenesis of B-cell lymphomas. Accumulating studies show differential expression in this heterogeneous group of cancers. Stimulation with TLR specific ligands, or agonists of

  7. A novel test rig to investigate under-platform damper dynamics

    Science.gov (United States)

    Botto, Daniele; Umer, Muhammad

    2018-02-01

    In the field of turbomachinery, vibration amplitude is often reduced by dissipating the kinetic energy of the blades with devices that utilize dry friction. Under-platform dampers, for example, are often placed in the underside of two consecutive turbine blades. Dampers are kept in contact with the under-platform of the respective blades by means of the centrifugal force. If the damper is well designed, vibration of blades instigate a relative motion between the under-platform and the damper. A friction force, that is a non-conservative force, arises in the contact and partly dissipates the vibration energy. Several contact models are available in the literature to simulate the contact between the damper and the under-platform. However, the actual dynamics of the blade-damper interaction have not fully understood yet. Several test rigs have been previously developed to experimentally investigate the performance of under-platform dampers. The majority of these experimental setups aim to evaluate the overall damper efficiency in terms of reduction in response amplitude of the blade for a given exciting force that simulates the aerodynamic loads. Unfortunately, the experimental data acquired on the blade dynamics do not provide enough information to understand the damper dynamics. Therefore, the uncertainty on the damper behavior remains a big issue. In this work, a novel experimental test rig has been developed to extensively investigate the damper dynamic behavior. A single replaceable blade is clamped in the rig with a specific clamping device. With this device the blade root is pressed against a groove machined in the test rig. The pushing force is controllable and measurable, to better simulate the actual centrifugal load acting on the blade. Two dampers, one on each side of the blade, are in contact with the blade under-platforms and with platforms on force measuring supports. These supports have been specifically designed to measure the contact forces on the

  8. A dimer of the Toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins.

    Directory of Open Access Journals (Sweden)

    Ricardo Núñez Miguel

    2007-08-01

    Full Text Available The Toll-like receptor 4 (TLR4 is a class I transmembrane receptor expressed on the surface of immune system cells. TLR4 is activated by exposure to lipopolysaccharides derived from the outer membrane of Gram negative bacteria and forms part of the innate immune response in mammals. Like other class 1 receptors, TLR4 is activated by ligand induced dimerization, and recent studies suggest that this causes concerted conformational changes in the receptor leading to self association of the cytoplasmic Toll/Interleukin 1 receptor (TIR signalling domain. This homodimerization event is proposed to provide a new scaffold that is able to bind downstream signalling adaptor proteins. TLR4 uses two different sets of adaptors; TRAM and TRIF, and Mal and MyD88. These adaptor pairs couple two distinct signalling pathways leading to the activation of interferon response factor 3 (IRF-3 and nuclear factor kappaB (NFkappaB respectively. In this paper we have generated a structural model of the TLR4 TIR dimer and used molecular docking to probe for potential sites of interaction between the receptor homodimer and the adaptor molecules. Remarkably, both the Mal and TRAM adaptors are strongly predicted to bind at two symmetry-related sites at the homodimer interface. This model of TLR4 activation is supported by extensive functional studies involving site directed mutagenesis, inhibition by cell permeable peptides and stable protein phosphorylation of receptor and adaptor TIR domains. Our results also suggest a molecular mechanism for two recent findings, the caspase 1 dependence of Mal signalling and the protective effects conferred by the Mal polymorphism Ser180Leu.

  9. DMPD: Innate recognition of lipopolysaccharide by Toll-like receptor 4-MD-2. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15051069 Innate recognition of lipopolysaccharide by Toll-like receptor 4-MD-2. Miy...ake K. Trends Microbiol. 2004 Apr;12(4):186-92. (.png) (.svg) (.html) (.csml) Show Innate recognition of lip...opolysaccharide by Toll-like receptor 4-MD-2. PubmedID 15051069 Title Innate recognition of lipopolysacchari

  10. Insulin-like growth factor I/somatomedin C: a potent inducer of oligodendrocyte development

    International Nuclear Information System (INIS)

    McMorris, F.A.; Smith, T.M.; DeSalvo, S.; Furlanetto, R.W.

    1986-01-01

    Cell cultures established from cerebrum of 1-day-old rats were used to investigate hormonal regulation of the development of oligodendrocytes, which synthesize myelin in the central nervous system. The number of oligodendrocytes that developed was preferentially increased by insulin, or by insulin-like growth factor I (IGF-I), also known as somatomedin C. High concentrations of insulin were required for substantial induction of oligodendrocyte development, whereas only 3.3 ng of IGF-I per ml was needed for a 2-fold increase in oligodendrocyte numbers. At an IGF-I concentration of 100 ng/ml, oligodendrocyte numbers were increased 6-fold in cultures grown in the presence of 10% fetal bovine serum, or up to 60-fold in cultures maintained in serum-free medium. IGF-I produced less than a 2-fold increase in the number of nonoligodendroglial cells in the same cultures. Type I IGF receptors were identified on oligodendrocytes and on a putative oligodendrocyte precursor cell population identified by using mouse monoclonal antibody A2B5. Radioligand binding assays were done. These results indicate that IGF-I is a potent inducer of oligodendrocyte development and suggest a possible mechanism based on IGF deficiency for the hypomyelination that results from early postnatal malnutrition

  11. Cloning of low dose radiation induced gene RIG1 by RACE based on non-cloned cDNA library

    International Nuclear Information System (INIS)

    Luo Ying; Sui Jianli; Tie Yi; Zhang Yuanping; Zhou Pingkun; Sun Zhixian

    2001-01-01

    Objective: To obtain full-length cDNA of radiation induced new gene RIG1 based on its EST fragment. Methods: Based on non-cloned cDNA library, enhanced nested RACE PCR and biotin-avidin labelled probe for magnetic bead purification was used to obtain full-length cDNA of RIG1. Results: About 1 kb of 3' end of RIG1 gene was successfully cloned by this set of methods and cloning of RIG1 5' end is proceeding well. Conclusion: The result is consistent with the design of experiment. This set of protocol is useful for cloning of full-length gene based on EST fragment

  12. A Study on the Dynamic Analysis of the Nuclear Fuel Test Rig Using 1-Way Fluid-Structure Coupled Analysis

    International Nuclear Information System (INIS)

    Yang, Tae-Ho; Hong, Jin-Tae; Ahn, Sung-Ho; Joung, Chang-Young; Heo, Sung-Ho; Jang, Seo-Yun

    2015-01-01

    1-way fluid-structure coupled analysis is used to estimate the dynamic characteristic of the fuel test rig. the motion at the bottom of the test rig is confirmed. The maximum deformation of the test rig is 0.11 mm. The structural integrity of the test rig is performed by using the comparison with the Von-mises stress of the analysis and yield stress of the material. It is evaluated that the motion at the bottom of the test rig is able to cause other structural problem. Using the 2-way fluid-structural coupled analysis, the structural integrity of the test rig will be performed in further paper. The cooling water with specific flow rate was flowed in the nuclear fuel test rig. The structural integrity of the test rig was affected by the vibration. The fluid-induced vibration test had to be performed to obtain the amplitude of the vibration on the structure. Various test systems was developed. Flow-induced vibration and pressure drop experimental tester was developed in Korea Atomic Energy Research Institute. The vibration test with high fluid flow rate was difficult by the tester. To generate the nuclear fuel test environment, coolant flow simulation system was developed. The scaled nuclear fuel test was able to be performed by the simulation system. The mock-up model of the test rig was used in the simulation system. The mock-up model in the simulation system was manufactured with scaled down full model. In this paper, the fluid induced vibration characteristic of the full model in the nuclear fuel test is studied. The hydraulic pressure on the velocity of the fluid was calculated. The static structure analysis was performed by using the pressure. The structural integrity was assessed using the results of the analysis

  13. Toll-like receptor 7-mediated enhancement of contextual fear memory in mice.

    Science.gov (United States)

    Kubo, Yasunori; Yanagawa, Yoshiki; Matsumoto, Machiko; Hiraide, Sachiko; Kobayashi, Masanobu; Togashi, Hiroko

    2012-10-01

    Toll-like receptor (TLR) 7 recognizes viral single-stranded RNA and triggers production of the type I interferons (IFNs) IFN-α and IFN-β. Imiquimod, a synthetic TLR7 ligand, induces production of type I IFNs and is used clinically as an antiviral and antitumor drug. In the present study, we examined the effect of imiquimod on conditioned and innate fear behaviors in mice. Imiquimod was administered 2, 4, or 15 h before contextual fear conditioning. Imiquimod treatment 4 or 15 h before fear conditioning significantly enhanced context-dependent freezing behavior. This imiquimod-induced enhancement of fear-related behaviors was observed 120 h after fear conditioning. In contrast, imiquimod failed to enhance context-dependent freezing behavior in TLR7 knockout mice. Imiquimod had no significant effect on pain threshold or on innate fear-related behavior, as measured by the elevated plus-maze. The levels of type I IFN mRNA in the brain were significantly increased at 2 h after imiquimod treatment. Imiquimod also increased interleukin (IL)-1β mRNA expression in the brain at 4 h following administration, while mRNA expression of F4/80, a macrophage marker, was unaffected by imiquimod treatment. Our findings suggest that TLR7-mediated signaling enhances contextual fear memory in mice, possibly by inducing the expression of type I IFNs and IL-1β in the brain. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Rotavirus activates lymphocytes from non-obese diabetic mice by triggering toll-like receptor 7 signaling and interferon production in plasmacytoid dendritic cells.

    Directory of Open Access Journals (Sweden)

    Jessica A Pane

    2014-03-01

    Full Text Available It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I

  15. Rotavirus Activates Lymphocytes from Non-Obese Diabetic Mice by Triggering Toll-Like Receptor 7 Signaling and Interferon Production in Plasmacytoid Dendritic Cells

    Science.gov (United States)

    Pane, Jessica A.; Webster, Nicole L.; Coulson, Barbara S.

    2014-01-01

    It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD) mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV) accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I interferon

  16. Knowing your friends and foes--plant receptor-like kinases as initiators of symbiosis or defence.

    Science.gov (United States)

    Antolín-Llovera, Meritxell; Petutsching, Elena Kristin; Ried, Martina Katharina; Lipka, Volker; Nürnberger, Thorsten; Robatzek, Silke; Parniske, Martin

    2014-12-01

    The decision between defence and symbiosis signalling in plants involves alternative and modular plasma membrane-localized receptor complexes. A critical step in their activation is ligand-induced homo- or hetero-oligomerization of leucine-rich repeat (LRR)- and/or lysin motif (LysM) receptor-like kinases (RLKs). In defence signalling, receptor complexes form upon binding of pathogen-associated molecular patterns (PAMPs), including the bacterial flagellin-derived peptide flg22, or chitin. Similar mechanisms are likely to operate during the perception of microbial symbiont-derived (lipo)-chitooligosaccharides. The structurally related chitin-oligomer ligands chitooctaose and chitotetraose trigger defence and symbiosis signalling, respectively, and their discrimination involves closely related, if not identical, LysM-RLKs. This illustrates the demand for and the challenges imposed on decision mechanisms that ensure appropriate signal initiation. Appropriate signalling critically depends on abundance and localization of RLKs at the cell surface. This is regulated by internalization, which also provides a mechanism for the removal of activated signalling RLKs. Abundance of the malectin-like domain (MLD)-LRR-RLK Symbiosis Receptor-like Kinase (SYMRK) is additionally controlled by cleavage of its modular ectodomain, which generates a truncated and rapidly degraded RLK fragment. This review explores LRR- and LysM-mediated signalling, the involvement of MLD-LRR-RLKs in symbiosis and defence, and the role of endocytosis in RLK function. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  17. [Significance of Toll-like receptors in the pathophysiology of surgical sepsis].

    LENUS (Irish Health Repository)

    Romics, Laszlo Jr

    2012-02-03

    The discovery of Toll-like receptors has substantially changed our knowledge of pathogen recognition. 11 Toll-like receptors have so far been described in humans. These recognize distinct pathogen associated molecular patterns, as well as endogenous ligands and small molecular synthetic compounds. TLRs have a multifunctional role in pathogen-triggered immune responses and represent an important connection between the "innate" and "adaptive" immunity. The role of the TLRs in the recognition of pathogens renders them a key figure in the activation of the immune response during surgical sepsis. However, emerging evidence points to a fundamental role in tumorigenesis, transplantation, wound healing, atherogenesis and inflammatory bowel disease. The aim hence was to review experimental data pertaining to the activation of TLR signalling pathways in conditions associated with surgical sepsis. A systematic review of the literature was undertaken by searching the MEDLINE database for the period 1966-2004 without language restriction. The paper also analyses the possible therapeutic utilization of the TLR signalling pathways in surgical sepsis.

  18. Role of toll like receptors in bacterial and viral diseases – A ...

    African Journals Online (AJOL)

    Avishek Das

    2017-05-20

    May 20, 2017 ... Background: Toll like receptors are key-receptors of the innate immune system, but their role against bacterial and viral infections are yet to be understood. Aim: The present study is aimed to investigate the diversity and frequency distribution of 10 TLR genes among typhoid fever and HIV+ patients. In this ...

  19. Combating Drug Abuse by Targeting Toll-Like Receptor 4 (TLR)

    Science.gov (United States)

    2015-12-01

    the treatment of addiction . 2. Keywords Drug reward Addiction Opioid Morphine Heroine Cocaine Dopamine Mesolimbic dopamine pathway...there is some other less selective explanation for this phenomenon. Current pharmacological treatments for opioid addiction /abuse tend to be only...toll like receptor 4 in both opioid and cocaine reward / reinforcement. In addition it has successfully documented the potential of (+)naltrexone (a

  20. Activation of toll-like receptors and dendritic cells by a broad range of bacterial molecules

    NARCIS (Netherlands)

    Boele, L.C.L.; Bajramovic, J.J.; Vries, A.M.M.B.C. de; Voskamp-Visser, I.A.I.; Kaman, W.E.; Kleij, D. van der

    2009-01-01

    Activation of pattern recognition receptors such as Toll-like receptors (TLRs) by pathogens leads to activation and maturation of dendritic cells (DC), which orchestrate the development of the adaptive immune response. To create an overview of the effects of a broad range of pathogenic bacteria,

  1. Forkhead box A1 (FOXA1) is a key mediator of insulin-like growth factor I (IGF-I) activity.

    Science.gov (United States)

    Potter, Adam S; Casa, Angelo J; Lee, Adrian V

    2012-01-01

    The insulin-like growth factor receptor (IGF-IR) has been implicated in a number of human tumors, including breast cancer. Data from human breast tumors has demonstrated that IGF-IR is over-expressed and hyper-phosphorylated. Additionally, microarray analysis has shown that IGF-I treatment of MCF7 cells leads to a gene signature comprised of induced and repressed genes, which correlated with luminal B tumors. FOXA1, a forkhead family transcription factor, has been shown to be crucial for mammary ductal morphogenesis, similar to IGF-IR, and expressed at high levels in luminal subtype B breast tumors. Here, we investigated the relationship between FOXA1 and IGF-I action in breast cancer cells. We show that genes regulated by IGF-I are enriched for FOXA1 binding sites, and knock down of FOXA1 blocked the ability of IGF-I to regulate gene expression. IGF-I treatment of MCF7 cells increased the half-life of FOXA1 protein and this increase in half-life appeared to be dependent on canonical IGF-I signal transduction through both MAPK and AKT pathways. Finally, knock down of FOXA1 led to a decreased ability of IGF-I to induce proliferation and protect against apoptosis. Together, these results demonstrate that IGF-I can increase the stability of FOXA1 protein expression and place it as a critical mediator of IGF-I regulation of gene expression and IGF-I-mediated biological responses. Copyright © 2011 Wiley Periodicals, Inc.

  2. Expression of insulin-like growth factor-1 and insulin-like growth factor-1 receptors in EL4 lymphoma cells overexpressing growth hormone.

    Science.gov (United States)

    Weigent, Douglas A; Arnold, Robyn E

    2005-03-01

    Almost all of the previous studies with growth hormone (GH) have been done with exogenously supplied GH and, therefore, involve actions of the hormone through its receptor. However, the actions of endogenous or lymphocyte GH are still unclear. In a previous study, we showed that overexpression of GH (GHo) in a lymphoid cell line resulted in protection of the cells to apoptosis mediated by nitric oxide (NO). In the present study, we show that the protection from apoptosis could be transferred to control cells with culture fluids obtained from GHo cells and blocked by antibodies to the insulin-like growth factor-1 (IGF-1) or antibodies to the IGF-1-receptor (IGF-1R). Northern and Western blot analysis detected significantly higher levels of IGF-1 in cells overexpressing GH. An increase in the expression of the IGF-1R in GHo cells was also detected by Western blot analysis, (125)I-IGF-1 binding and analysis of IGF-1R promoter luciferase constructs. Transfection of GHo cells with a dominant negative IGF-1R mutant construct blocked the generation of NO and activation of Akt seen in GHo cells compared to vector alone control EL4 cells. The results suggest that one of the consequences of the overexpression of GH, in cells lacking the GH receptor, is an increase in the expression of IGF-1 and the IGF-1R which mediate the protection of EL4 lymphoma cells from apoptosis.

  3. (125I)Iodoazidococaine, a photoaffinity label for the haloperidol-sensitive sigma receptor

    International Nuclear Information System (INIS)

    Kahoun, J.R.; Ruoho, A.E.

    1992-01-01

    A carrier-free radioiodinated cocaine photoaffinity label, (-)-3-( 125 I)iodo-4-azidococaine [( 125 I)IACoc], has been synthesized and used as a probe for cocaine-binding proteins. Photoaffinity labeling with 0.5 nM ( 125 I)IACoc resulted in selective derivatization of a 26-kDa polypeptide with the pharmacology of a sigma receptor in membranes derived from whole rat brain, rat liver, and human placenta. ( 125 I)IACoc labeling of the 26-kDa polypeptide was also inhibited by 10 μM imipramine, amitriptyline, fluoxetine, benztropine, and tetrabenazine. The size of the ( 125 I)I-ACoc-labeled proteins is consistent with the size of proteins photolabeled in guinea pig brain and liver membranes by using the sigma photolabel azido-[ 3 H]DTG. Kinetic analysis of ( 125 I)IACoc binding to rat liver microsomes revealed two sites with K d values of 19 and 126 pM, respectively. The presence or absence of proteolytic inhibitors during membrane preparation did not alter the size of the photolabeled sigma receptor, indicating that the 26-kDa polypeptide was not derived from a larger protein. In summary, ( 125 I)IACoc is a potent and highly specific photoaffinity label for the haloperidol-sensitive sigma receptor and will be useful for its biochemical and molecular characterization

  4. Ligands, cell-based models, and readouts required for Toll-like receptor action.

    LENUS (Irish Health Repository)

    Dellacasagrande, Jerome

    2012-02-01

    This chapter details the tools that are available to study Toll-like receptor (TLR) biology in vitro. This includes ligands, host cells, and readouts. The use of modified TLRs to circumvent some technical problems is also discussed.

  5. Autoradiographic localization of substance P receptors using 125I substance P

    International Nuclear Information System (INIS)

    Shults, C.W.; Quirion, R.; Jensen, R.T.; Moody, T.W.; O'Donohue, T.L.; Chase, T.N.

    1982-01-01

    This paper describes a method for localization of substance P receptors in the rat central nervous system using 125 I labeled substance P in an autoradiographic procedure. Particularly high densities of substance P receptors were observed in the olfactory bulb, dentate gyrus, amygdala, superior colliculus, and locus coeruleus. Surprisingly low densities of substance P receptors were found in the substantia nigra pars reticulata, a region which contains high concentrations of substance P

  6. Toll-Like Receptors in the Pathogenesis of Autoimmune Diseases

    Science.gov (United States)

    Mohammad Hosseini, Akbar; Majidi, Jafar; Baradaran, Behzad; Yousefi, Mehdi

    2015-01-01

    Human Toll-like receptors (TLRs) are a family of transmembrane receptors, which play a key role in both innate and adaptive immune responses. Beside of recognizing specific molecular patterns that associated with different types of pathogens, TLRs may also detect a number of self-proteins and endogenous nucleic acids. Activating TLRs lead to the heightened expression of various inflammatory genes, which have a protective role against infection. Data rising predominantly from human patients and animal models of autoimmune disease indicate that, inappropriate triggering of TLR pathways by exogenous or endogenous ligands may cause the initiation and/or perpetuation of autoimmune reactions and tissue damage. Given their important role in infectious and non-infectious disease process, TLRs and its signaling pathways emerge as appealing targets for therapeutics. In this review, we demonstrate how TLRs pathways could be involved in autoimmune disorders and their therapeutic application. PMID:26793605

  7. CONCENTRIC TUBE-FOULING RIG FOR INVESTIGATION OF FOULING DEPOSIT FORMATION FROM PASTEURISER OF VISCOUS FOOD LIQUID

    Directory of Open Access Journals (Sweden)

    N. I. KHALID

    2013-02-01

    Full Text Available This paper reports the work on developing concentric tube-fouling rig, a new fouling deposit monitoring device. This device can detect and quantify the level of fouling deposit formation. It can also functioning as sampler for fouling deposit study, which can be attached at any food processing equipment. The design is initiated with conceptual design. The rig is designed with inner diameter of 7 cm and with tube length of 37 cm. A spiral insert with 34.5 cm length and with 5.4 cm diameter is fitted inside the tube to ensure the fluid flows around the tube. In this work, the rig is attached to the lab-scale concentric tube-pasteurizer to test its effectiveness and to collect a fouling sample after pasteurization of pink guava puree. Temperature changes are recorded during the pasteurization and the data is used to plot the heat transfer profile. Thickness of the fouling deposit is also measured. The trends for thickness, heat resistance profile and heat transfer profile for concentric tube-fouling rig matched the trends obtained from lab-scale concentric tube-pasteurizer very well. The findings from this work have shown a good potential of this rig however there is a limitation with spiral insert, which is discussed in this paper.

  8. Group I mGlu receptors potentiate synaptosomal [{sup 3}H]glutamate release independently of exogenously applied arachidonic acid

    Energy Technology Data Exchange (ETDEWEB)

    Reid, M.E.; Toms, N.J.; Bedingfield, J.S.; Roberts, P.J. [Department of Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD (United Kingdom)

    1999-04-01

    In the current study, we have characterized group I metabotropic glutamate (mGlu) receptor enhancement of 4-aminopyridine (4AP)-evoked [{sup 3}H]glutamate release from rat cerebrocortical synaptosomes. The broad spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD, 10 {mu}M) increased 4AP-evoked [{sup 3}H]glutamate release (143.32{+-}2.73% control) only in the presence of exogenously applied arachidonic acid; an effect reversed by the inclusion of bovine serum albumin (BSA, fatty acid free). In contrast, the selective group I mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) potentiated (EC{sub 50}=1.60{+-}0.25 {mu}M; E{sub max}=147.61{+-}10.96% control) 4AP-evoked [{sup 3}H]glutamate release, in the absence of arachidonic acid. This potentiation could be abolished by either the selective mGlu{sub 1} receptor antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA, 1 mM) or the selective PKC inhibitor (Ro 31-8220, 10 {mu}M) and was BSA-insensitive. The selective mGlu{sub 5} receptor agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG, 300{mu}M) was without effect. DHPG (100 {mu}M) also potentiated both 30 mM and 50 mM K{sup +}-evoked [{sup 3}H]glutamate release (121.60{+-}12.77% and 121.50{+-}4.45% control, respectively). DHPG (100 {mu}M) failed to influence both 4AP-stimulated {sup 45}Ca{sup 2+} influx and 50 mM K{sup +}-induced changes in synaptosomal membrane potential. Possible group I mGlu receptor suppression of tonic adenosine A{sub 1} receptor, group II/III mGlu receptors or GABA{sub B} receptor activity is unlikely since 4AP-evoked [{sup 3}H]glutamate release was insensitive to the selective inhibitory receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine, (R,S)-{alpha}-cyclopropyl-4-phosphonophenylglycine or CGP55845A, respectively. These data suggest an 'mGlu{sub 1} receptor-like' receptor potentiates [{sup 3}H]glutamate release from cerebrocortical synaptosomes in the absence of

  9. Analysis of 125I-[Tyr3] octreotide receptors of NCI-H466 cell line

    International Nuclear Information System (INIS)

    Sun Junjie; Fan Wo; Xu Yujie; Zhang Youjiu; Zhu Ran

    2002-01-01

    Objective: To study the affinity of small cell lung carcinoma to [Tyr 3 ] octreotide (TOC). Methods: Taking 125 I-[Tyr 3 ] octreotide (labeled by chloramine-T method), as the ligand, small cell lung carcinoma NCI-H466 cell line was inspected for the receptor-binding points and affinity constant. Results: The radio-chemical purity of 125 I-TOC purified through sephadex G-10 was higher than 95%. Receptor analysis study showed that the expression of somatostatin receptors on NCI-H446 cells was numerous (Bmax = 1.17 x 10 5 /cell) with strong affinity to 125 I-TOC (Kd = 0.56 nM). Conclusion: Labeled TOC could be used for small cell lung carcinoma receptor imaging and radio-pharmaceutical therapy

  10. Dopamine1 receptors in rat kidneys identified with 125I-Sch 23982

    International Nuclear Information System (INIS)

    Felder, R.A.; Jose, P.A.

    1988-01-01

    Dopamine1 receptors were studied in rat kidney using the selective dopamine1 antagonist 125I-labeled Sch 23982. The specific binding of 125I-Sch 23982 (defined by 5 microM Sch 23390) to renal cortical homogenates incubated at room temperature was rapid, saturable with time and ligand concentration, and reversible. Analysis of Rosenthal plots revealed a single class of receptors with an apparent dissociation constant of 12.2 +/- 1.9 nM and maximum receptor density of 1.03 +/- 0.15 pmol/mg protein (n = 6). However, competition experiments with the dopamine1 antagonist Sch 23390 revealed a low- and high-affinity binding site with inhibition constants of 1 x 10(-6) and 1 x 10(-8) M, respectively. The competition experiments were also indicative of dopamine1 receptors with stereoselectivity noted for dopamine1 but not for dopamine2 antagonists. The inhibition constants for dopamine1 antagonists and agonists were two orders of magnitude greater in renal cortical than striatal homogenates. Different buffers affected striatal but not renal cortical binding. Autoradiographic studies revealed 125I-Sch 23982 binding in renal cortical but not medullary tissue. These studies confirm the presence of dopamine1 receptors in the cortex of the rat kidney

  11. Morphine-induced internalization of the L83I mutant of the rat μ-opioid receptor.

    Science.gov (United States)

    Cooke, A E; Oldfield, S; Krasel, C; Mundell, S J; Henderson, G; Kelly, E

    2015-01-01

    Naturally occurring single-nucleotide polymorphisms (SNPs) within GPCRs can result in alterations in various pharmacological parameters. Understanding the regulation and function of endocytic trafficking of the μ-opioid receptor (MOP receptor) is of great importance given its implication in the development of opioid tolerance. This study has compared the agonist-dependent trafficking and signalling of L83I, the rat orthologue of a naturally occurring variant of the MOP receptor. Cell surface elisa, confocal microscopy and immunoprecipitation assays were used to characterize the trafficking properties of the MOP-L83I variant in comparison with the wild-type receptor in HEK 293 cells. Functional assays were used to compare the ability of the L83I variant to signal to several downstream pathways. Morphine-induced internalization of the L83I MOP receptor was markedly increased in comparison with the wild-type receptor. The altered trafficking of this variant was found to be specific to morphine and was both G-protein receptor kinase- and dynamin-dependent. The enhanced internalization of L83I variant in response to morphine was not due to increased phosphorylation of serine 375, arrestin association or an increased ability to signal. These results suggest that morphine promotes a specific conformation of the L83I variant that makes it more liable to internalize in response to morphine, unlike the wild-type receptor that undergoes significantly less morphine-stimulated internalization, providing an example of a ligand-selective biased receptor. The presence of this SNP within an individual may consequently affect the development of tolerance and analgesic responses. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British Pharmacological Society.

  12. SPET imaging of central muscarinic receptors with (R,R)[123I]-I-QNB: methodological considerations

    International Nuclear Information System (INIS)

    Norbury, R.; Travis, M.J.; Erlandsson, K.; Waddington, W.; Owens, J.; Ell, P.J.; Murphy, D.G.

    2004-01-01

    Investigations on the effect of normal healthy ageing on the muscarinic system have shown conflicting results. Also, in vivo determination of muscarinic receptor binding has been hampered by a lack of subtype selective ligands and differences in methods used for quantification of receptor densities. Recent in vitro and in vivo work with the muscarinic antagonist (R,R)-I-QNB indicates this ligand has selectivity for m 1 and m 4 muscarinic receptor subtypes. Therefore, we used (R,R)[ 123 I]-I-QNB and single photon emission tomography to study brain m 1 and m 4 muscarinic receptors in 25 healthy female subjects (11 younger subjects, age range 26-32 years and 14 older subjects, age range 57-82 years). Our aims were to ascertain the viability of tracer administration and imaging within the same day, and to evaluate whether normalization to whole brain, compared to normalization to cerebellum, could alter the clinical interpretation of results. Images were analyzed using the simplified reference tissue model and by two ratio methods: normalization to whole brain and normalization to cerebellum. Significant correlations were observed between kinetic analysis and normalization to cerebellum, but not to whole brain. Both the kinetic analysis and normalization to cerebellum showed age-related reductions in muscarinic binding in frontal, orbitofrontal, and parietal regions. Normalization to whole brain, however, failed to detect age-related changes in any region. Here we show that, for this radiotracer, normalizing to a region of negligible specific binding (cerebellum) significantly improves sensitivity when compared to global normalization

  13. Electronic temperature control and measurements reactor fuel rig circuits

    Energy Technology Data Exchange (ETDEWEB)

    Glowacki, S W

    1980-01-01

    The electronic circuits of two digital temperature meters developed for the thermocouple of Ni-NiCr type are described. The output thermocouple signal as converted by means of voltage-to-freguency converter. The frequency is measured by a digital scaler controled by quartz generator signals. One of the described meter is coupled with digital temperature controler which drives the power stage of the reactor rig heater. The internal rig temperature is measured by the thermocouple providing the input signal to the mentioned voltage-to-frequency converter, that means the circuits work in the negative feedback loop. The converter frequency-to-voltage ratio is automatically adjusted to match to thermocouple sensitivity changes in the course of the temperature variations. The accuracy of measuring system is of order of +- 1degC for thermocouple temperature changes from 523 K up to 973 K (50degC up to 700degC).

  14. Genetic polymorphisms and protein structures in growth hormone, growth hormone receptor, ghrelin, insulin-like growth factor 1 and leptin in Mehraban sheep.

    Science.gov (United States)

    Bahrami, A; Behzadi, Sh; Miraei-Ashtiani, S R; Roh, S-G; Katoh, K

    2013-09-15

    The somatotropic axis, the control system for growth hormone (GH) secretion and its endogenous factors involved in the regulation of metabolism and energy partitioning, has promising potentials for producing economically valuable traits in farm animals. Here we investigated single nucleotide polymorphisms (SNPs) of the genes of factors involved in the somatotropic axis for growth hormone (GH1), growth hormone receptor (GHR), ghrelin (GHRL), insulin-like growth factor 1 (IGF-I) and leptin (LEP), using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods in 452 individual Mehraban sheep. A nonradioactive method to allow SSCP detection was used for genomic DNA and PCR amplification of six fragments: exons 4 and 5 of GH1; exon 10 of GH receptor (GHR); exon 1 of ghrelin (GHRL); exon 1 of insulin-like growth factor-I (IGF-I), and exon 3 of leptin (LEP). Polymorphisms were detected in five of the six PCR products. Two electrophoretic patterns were detected for GH1 exon 4. Five conformational patterns were detected for GH1 exon 5 and LEP exon 3, and three for IGF-I exon 1. Only GHR and GHRL were monomorphic. Changes in protein structures due to variable SNPs were also analyzed. The results suggest that Mehraban sheep, a major breed that is important for the animal industry in Middle East countries, has high genetic variability, opening interesting prospects for future selection programs and preservation strategies. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. The Thermal-hydraulic Performance Test Report for the Non-instrumented Irradiation Test Rig of Annular Fuel

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dae Ho; Lee, Kang Hee; Shin, Chang Hwan

    2008-09-15

    This report presents the results of pressure drop test, vibration test and endurance test for the non-instrumented rig using the irradiation test in HANARO of the double cooled annular fuel which were designed and fabricated by KAERI. From the out-pile thermal hydraulic tests, corresponding to the pressure drop of 200 kPa is measured to be about 9.72 kg/sec. Vibration frequency for the non-instrumented rig ranges from 5.0 to 10.7 kg/s. RMS(Root Mean Square) displacement for non-instrumented rig is less than 11.73 m, and the maximum displacement is less than 54.87m. The flow rate for endurance test were 10.5 kg/s, which was 110% of 9.72 kg/s. And the endurance test was carried out for 3 days. The test results found not to the wear and satisfied to the limits of pressure drop, flow rate, vibration and wear in the non-instrumented rig. This test was performed at the FIVPET facility.

  16. Proteolysis of MDA5 and IPS-1 is not required for inhibition of the type I IFN response by poliovirus.

    Science.gov (United States)

    Kotla, Swathi; Gustin, Kurt E

    2015-10-06

    The type I interferon (IFN) response is a critical component of the innate immune response to infection by RNA viruses and is initiated via recognition of viral nucleic acids by RIG-like receptors (RLR). Engagement of these receptors in the cytoplasm initiates a signal transduction pathway leading to activation of the transcription factors NF-κB, ATF-2 and IRF-3 that coordinately upregulate transcription of type I IFN genes, such as that encoding IFN-β. In this study the impact of poliovirus infection on the type I interferon response has been examined. The type I IFN response was assessed by measuring IFN-β mRNA levels using qRT-PCR and normalizing to levels of β-actin mRNA. The status of host factors involved in activation of the type I IFN response was examined by immunoblot, immunofluorescence microcopy and qRT-PCR. The results show that poliovirus infection results in induction of very low levels of IFN-β mRNA despite clear activation of NF-κB and ATF-2. In contrast, analysis of IRF-3 revealed no transcriptional induction of an IRF-3-responsive promoter or homodimerization of IRF-3 indicating it is not activated in poliovirus-infected cells. Exposure of poliovirus-infected cells to poly(I:C) results in lower levels of IFN-β mRNA synthesis and IRF-3 activation compared to mock-infected cells. Analysis of MDA-5 and IPS-1 revealed that these components of the RLR pathway were largely intact at times when the type I IFN response was suppressed. Collectively, these results demonstrate that poliovirus infection actively suppresses the host type I interferon response by blocking activation of IRF-3 and suggests that this is not mediated by cleavage of MDA-5 or IPS-1.

  17. Origin and diversification of leucine-rich repeat receptor-like protein kinase (LRR-RLK) genes in plants

    OpenAIRE

    Liu, Ping-Li; Du, Liang; Huang, Yuan; Gao, Shu-Min; Yu, Meng

    2017-01-01

    Background Leucine-rich repeat receptor-like protein kinases (LRR-RLKs) are the largest group of receptor-like kinases in plants and play crucial roles in development and stress responses. The evolutionary relationships among LRR-RLK genes have been investigated in flowering plants; however, no comprehensive studies have been performed for these genes in more ancestral groups. The subfamily classification of LRR-RLK genes in plants, the evolutionary history and driving force for the evolution...

  18. MECHANISMS OF ANTIINFECTIOUS FUNCTIONS OF INNATE IMMUNITY: ROLE OF TOLL-LIKE RECEPTORS

    Directory of Open Access Journals (Sweden)

    S. I. Suskov

    2012-01-01

    Full Text Available This review describes the main role of toll-like receptors of innate immunity for pathogen recognition; signaling; production of inflammatory response. Also Interrelation of innate and adaptive Immunity in conditions of pathology and organ transplantation were considered. 

  19. IL-1 receptor-antagonist (IL-1Ra) knockout mice show anxiety-like behavior by aging.

    Science.gov (United States)

    Wakabayashi, Chisato; Numakawa, Tadahiro; Odaka, Haruki; Ooshima, Yoshiko; Kiyama, Yuji; Manabe, Toshiya; Kunugi, Hiroshi; Iwakura, Yoichiro

    2015-07-10

    Interleukin 1 (IL-1) plays a critical role in stress responses, and its mRNA is induced in the brain by restraint stress. Previously, we reported that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lacked IL-1Ra molecules that antagonize the IL-1 receptor, showed anti-depression-like behavior via adrenergic modulation at the age of 8 weeks. Here, we report that IL-1Ra KO mice display an anxiety-like phenotype that is induced spontaneously by aging in the elevated plus-maze (EPM) test. This anxiety-like phenotype was improved by the administration of diazepam. The expression of the anxiety-related molecule glucocorticoid receptor (GR) was significantly reduced in 20-week-old but not in 11-week-old IL-1Ra KO mice compared to wild-type (WT) littermates. The expression of the mineralocorticoid receptor (MR) was not altered between IL-1Ra KO mice and WT littermates at either 11 or 20 weeks old. Analysis of monoamine concentration in the hippocampus revealed that tryptophan, the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), and the dopamine metabolite homovanillic acid (HVA) were significantly increased in 20-week-old IL-1Ra KO mice compared to littermate WT mice. These findings strongly suggest that the anxiety-like behavior observed in older mice was caused by the complicated alteration of monoamine metabolism and/or GR expression in the hippocampus. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Binding specificity of Bacillus thuringiensis Cry1Aa for purified, native Bombyx mori aminopeptidase N and cadherin-like receptors

    Directory of Open Access Journals (Sweden)

    Jenkins Jeremy L

    2001-10-01

    Full Text Available Abstract Background To better understand the molecular interactions of Bt toxins with non-target insects, we have examined the real-time binding specificity and affinity of Cry1 toxins to native silkworm (Bombyx mori midgut receptors. Previous studies on B. mori receptors utilized brush border membrane vesicles or purifed receptors in blot-type assays. Results The Bombyx mori (silkworm aminopeptidase N (APN and cadherin-like receptors for Bacillus thuringiensis insecticidal Cry1Aa toxin were purified and their real-time binding affinities for Cry toxins were examined by surface plasmon resonance. Cry1Ab and Cry1Ac toxins did not bind to the immobilized native receptors, correlating with their low toxicities. Cry1Aa displayed moderate affinity for B. mori APN (75 nM, and unusually tight binding to the cadherin-like receptor (2.6 nM, which results from slow dissociation rates. The binding of a hybrid toxin (Aa/Aa/Ac was identical to Cry1Aa. Conclusions These results indicate domain II of Cry1Aa is essential for binding to native B. mori receptors and for toxicity. Moreover, the high-affinity binding of Cry1Aa to native cadherin-like receptor emphasizes the importance of this receptor class for Bt toxin research.

  1. Binding specificity of Bacillus thuringiensis Cry1Aa for purified, native Bombyx mori aminopeptidase N and cadherin-like receptors

    Science.gov (United States)

    Jenkins, Jeremy L; Dean, Donald H

    2001-01-01

    Background To better understand the molecular interactions of Bt toxins with non-target insects, we have examined the real-time binding specificity and affinity of Cry1 toxins to native silkworm (Bombyx mori) midgut receptors. Previous studies on B. mori receptors utilized brush border membrane vesicles or purifed receptors in blot-type assays. Results The Bombyx mori (silkworm) aminopeptidase N (APN) and cadherin-like receptors for Bacillus thuringiensis insecticidal Cry1Aa toxin were purified and their real-time binding affinities for Cry toxins were examined by surface plasmon resonance. Cry1Ab and Cry1Ac toxins did not bind to the immobilized native receptors, correlating with their low toxicities. Cry1Aa displayed moderate affinity for B. mori APN (75 nM), and unusually tight binding to the cadherin-like receptor (2.6 nM), which results from slow dissociation rates. The binding of a hybrid toxin (Aa/Aa/Ac) was identical to Cry1Aa. Conclusions These results indicate domain II of Cry1Aa is essential for binding to native B. mori receptors and for toxicity. Moreover, the high-affinity binding of Cry1Aa to native cadherin-like receptor emphasizes the importance of this receptor class for Bt toxin research. PMID:11722800

  2. Collisions damage assessment of ships and jack-up rigs

    DEFF Research Database (Denmark)

    Zhang, Shengming; Pedersen, P. Terndrup; Ocakli, Hasan

    2015-01-01

    Ship collision with offshore installations is one of the key concerns in design and assess of platforms performance and safety. This paper presents an analysis on collision energy and structural damage in ship and offshore platform collisions for various collision scenarios. The platform or rig...

  3. G-Protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention.

    Science.gov (United States)

    Conrad, Kirk P

    2016-09-01

    Important roles for G-protein-coupled receptors (GPCRs) have been identified in the maternal physiological adaptations to pregnancy and in the pathogenesis of preeclampsia. On this basis, GPCRs are potential therapeutic targets for preeclampsia. In this review, vasopressin and apelin are initially considered in this context before the focus on the hormone relaxin and its cognate receptor, the relaxin/insulin-like family peptide receptor 1 (RXFP1). Based on both compelling scientific rationale and a promising safety profile, the relaxin ligand-receptor system is comprehensively evaluated as a potential therapeutic endpoint in preeclampsia. The published literature relating to the topic was searched through January 2016 using PubMed. Relaxin is a peptide hormone secreted by the corpus luteum; it circulates in the luteal phase and during pregnancy. Activation of RXFP1 is vasodilatory; thus, relaxin supplementation is expected to at least partly restore the fundamental vasodilatory changes of normal pregnancy, thereby alleviating maternal organ hypoperfusion, which is a major pathogenic manifestation of severe preeclampsia. Specifically, by exploiting its pleiotropic hemodynamic attributes in preeclampsia, relaxin administration is predicted to (i) reverse robust arterial myogenic constriction; (ii) blunt systemic and renal vasoconstriction in response to activation of the angiotensin II receptor, type 1; (iii) mollify the action of endogenous vasoconstrictors on uterine spiral arteries with failed remodeling and retained smooth muscle; (iv) increase arterial compliance; (v) enhance insulin-mediated glucose disposal by promoting skeletal muscle vasodilation and (vi) mobilize and activate bone marrow-derived angiogenic progenitor cells, thereby repairing injured endothelium and improving maternal vascularity in organs such as breast, uterus, pancreas, skin and fat. By exploiting its pleiotropic molecular attributes in preeclampsia, relaxin supplementation is

  4. Insights into the diversity of NOD-like receptors: Identification and expression analysis of NLRC3, NLRC5 and NLRX1 in rainbow trout.

    Science.gov (United States)

    Álvarez, Claudio A; Ramírez-Cepeda, Felipe; Santana, Paula; Torres, Elisa; Cortés, Jimena; Guzmán, Fanny; Schmitt, Paulina; Mercado, Luis

    2017-07-01

    Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are efficient soluble intracellular sensors that activate defense mechanisms against pathogens. In teleost fish, the involvement of NLRs in the immune response is not well understood. However, recent work has evidenced the expression of different NLRs in response to some pathogen associated molecular patterns (PAMPs). In the present work, the cDNA sequence encoding three new NOD-like receptors were identified in Oncorhynchus mykiss, namely OmNLRC3, OmNLRC5 and OmNLRX1. Results showed that their sequences coded for proteins of 1135, 836 and 1010 amino acids, respectively. The deduced protein sequences of all receptors showed characteristic domains of this receptor family, such as leucine rich repeats and NACHT domain. Phylogenetic analysis revealed a high degree of identity with other NOD-like receptors and they are clustered into different families. Transcript expression analysis indicated that OmNLRs are constitutively expressed in liver, spleen, intestine, gill, skin and brain. OmNLR expression was upregulated in kidney and gills from rainbow trout in response to LPS. In order to give new insights into the function of these new NLR members, an in vitro model of immune stimulation was established using the rainbow trout cell line RTgill-W1. Expression analysis revealed that RTgill-W1 overexpressed proinflammatory cytokines in response to LPS and poly I:C alongside with a differential overexpression of OmNLRC3, OmNLRC5 and OmNLRX1. The expression of OmNLRC5 was further verified at the protein level by immunofluorescence. Finally, the effect of the overexpressed cytokines on the OmNLR expression by RTgill-W1 cells was assessed, suggesting a regulatory mechanism on OmNLRC3 expression. Overall, results suggest that O. mykiss NOD-like receptors could play a key role in the defense mechanisms of teleost through PAMP recognition. Future studies will focus on gills which could be related with a key

  5. Micro-pyrolysis of technical lignins in a new modular rig and product analysis by GC-MS/FID and GC x GC-TOFMS/FID

    NARCIS (Netherlands)

    Windt, Michael; Meier, Dietrich; Marsman, Jan Henk; Heeres, Hero Jan; de Koning, Sjaak

    A new offline-pyrolysis rig has been designed to allow multifunctional experiments for preparative and analytical purposes. The system conditions can be set and monitored, e.g. temperature, its gradients and heat flux. Some special features include ( I) high heating rates up to 120 degrees C/s with

  6. iReceptor: A platform for querying and analyzing antibody/B-cell and T-cell receptor repertoire data across federated repositories.

    Science.gov (United States)

    Corrie, Brian D; Marthandan, Nishanth; Zimonja, Bojan; Jaglale, Jerome; Zhou, Yang; Barr, Emily; Knoetze, Nicole; Breden, Frances M W; Christley, Scott; Scott, Jamie K; Cowell, Lindsay G; Breden, Felix

    2018-07-01

    Next-generation sequencing allows the characterization of the adaptive immune receptor repertoire (AIRR) in exquisite detail. These large-scale AIRR-seq data sets have rapidly become critical to vaccine development, understanding the immune response in autoimmune and infectious disease, and monitoring novel therapeutics against cancer. However, at present there is no easy way to compare these AIRR-seq data sets across studies and institutions. The ability to combine and compare information for different disease conditions will greatly enhance the value of AIRR-seq data for improving biomedical research and patient care. The iReceptor Data Integration Platform (gateway.ireceptor.org) provides one implementation of the AIRR Data Commons envisioned by the AIRR Community (airr-community.org), an initiative that is developing protocols to facilitate sharing and comparing AIRR-seq data. The iReceptor Scientific Gateway links distributed (federated) AIRR-seq repositories, allowing sequence searches or metadata queries across multiple studies at multiple institutions, returning sets of sequences fulfilling specific criteria. We present a review of the development of iReceptor, and how it fits in with the general trend toward sharing genomic and health data, and the development of standards for describing and reporting AIRR-seq data. Researchers interested in integrating their repositories of AIRR-seq data into the iReceptor Platform are invited to contact support@ireceptor.org. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Test rig overview for validation and reliability testing of shutdown system software

    International Nuclear Information System (INIS)

    Zhao, M.; McDonald, A.; Dick, P.

    2007-01-01

    The test rig for Validation and Reliability Testing of shutdown system software has been upgraded from the AECL Windows-based test rig previously used for CANDU6 stations. It includes a Virtual Trip Computer, which is a software simulation of the functional specification of the trip computer, and a real-time trip computer simulator in a separate chassis, which is used during the preparation of trip computer test cases before the actual trip computers are available. This allows preparation work for Validation and Reliability Testing to be performed in advance of delivery of actual trip computers to maintain a project schedule. (author)

  8. Performance Analysis of Retrofitted Tribo-Corrosion Test Rig for Monitoring In Situ Oil Conditions

    Directory of Open Access Journals (Sweden)

    Arpith Siddaiah

    2017-09-01

    Full Text Available Oils and lubricants, once extracted after use from a mechanical system, can hardly be reused, and should be refurbished or replaced in most applications. New methods of in situ oil and lubricant efficiency monitoring systems have been introduced for a wide variety of mechanical systems, such as automobiles, aerospace aircrafts, ships, offshore wind turbines, and deep sea oil drilling rigs. These methods utilize electronic sensors to monitor the “byproduct effects” in a mechanical system that are not indicative of the actual remaining lifecycle and reliability of the oils. A reliable oil monitoring system should be able to monitor the wear rate and the corrosion rate of the tribo-pairs due to the inclusion of contaminants. The current study addresses this technological gap, and presents a novel design of a tribo-corrosion test rig for oils used in a dynamic system. A pin-on-disk tribometer test rig retrofitted with a three electrode-potentiostat corrosion monitoring system was used to analyze the corrosion and wear rate of a steel tribo-pair in industrial grade transmission oil. The effectiveness of the retrofitted test rig was analyzed by introducing various concentrations of contaminants in an oil medium that usually leads to a corrosive working environment. The results indicate that the retrofitted test rig can effectively monitor the in situ tribological performance of the oil in a controlled dynamic corrosive environment. It is a useful method to understand the wear–corrosion synergies for further experimental work, and to develop accurate predictive lifecycle assessment and prognostic models. The application of this system is expected to have economic benefits and help reduce the ecological oil waste footprint.

  9. Performance Analysis of Retrofitted Tribo-Corrosion Test Rig for Monitoring In Situ Oil Conditions.

    Science.gov (United States)

    Siddaiah, Arpith; Khan, Zulfiqar Ahmad; Ramachandran, Rahul; Menezes, Pradeep L

    2017-09-28

    Oils and lubricants, once extracted after use from a mechanical system, can hardly be reused, and should be refurbished or replaced in most applications. New methods of in situ oil and lubricant efficiency monitoring systems have been introduced for a wide variety of mechanical systems, such as automobiles, aerospace aircrafts, ships, offshore wind turbines, and deep sea oil drilling rigs. These methods utilize electronic sensors to monitor the "byproduct effects" in a mechanical system that are not indicative of the actual remaining lifecycle and reliability of the oils. A reliable oil monitoring system should be able to monitor the wear rate and the corrosion rate of the tribo-pairs due to the inclusion of contaminants. The current study addresses this technological gap, and presents a novel design of a tribo-corrosion test rig for oils used in a dynamic system. A pin-on-disk tribometer test rig retrofitted with a three electrode-potentiostat corrosion monitoring system was used to analyze the corrosion and wear rate of a steel tribo-pair in industrial grade transmission oil. The effectiveness of the retrofitted test rig was analyzed by introducing various concentrations of contaminants in an oil medium that usually leads to a corrosive working environment. The results indicate that the retrofitted test rig can effectively monitor the in situ tribological performance of the oil in a controlled dynamic corrosive environment. It is a useful method to understand the wear-corrosion synergies for further experimental work, and to develop accurate predictive lifecycle assessment and prognostic models. The application of this system is expected to have economic benefits and help reduce the ecological oil waste footprint.

  10. 78 FR 70326 - Rigging Equipment for Material Handling; Extension of the Office of Management and Budget's (OMB...

    Science.gov (United States)

    2013-11-25

    ...] Rigging Equipment for Material Handling; Extension of the Office of Management and Budget's (OMB) Approval... on Rigging Equipment for Material Handling (29 CFR 1926.251). These paragraphs require affixing... automated or other technological information collection and transmission techniques. III. Proposed Actions...

  11. Joint test rig for tests and calibration of different methods of two-phase mass flow measurement

    International Nuclear Information System (INIS)

    John, H.; Erbacher, F.; Wanner, E.

    1975-01-01

    On behalf of the Federal Ministry of Research and Technology, the Institute of Reactor Components (IRB) has begun building a test rig which will be used for testing and calibrating the methods of measuring non-steady state two-phase mass flows developed by various research agencies. The test rig is designed for the generation of steam-water mixtures of any mixing ratio and a maximum pressure of 160 data. Depending on the mixing ratio, the mass flow will reach a maximum level of 10 to 20 t/h. The conceptual design phase of the test rig has largely been finished, the component ordering phase has begun. (orig.) [de

  12. Involvement of dopamine D2 receptors in addictive-like behaviour for acetaldehyde.

    Science.gov (United States)

    Brancato, Anna; Plescia, Fulvio; Marino, Rosa Anna Maria; Maniaci, Giuseppe; Navarra, Michele; Cannizzaro, Carla

    2014-01-01

    Acetaldehyde, the first metabolite of ethanol, is active in the central nervous system, where it exerts motivational properties. Acetaldehyde is able to induce drinking behaviour in operant-conflict paradigms that resemble the core features of the addictive phenotype: drug-intake acquisition and maintenance, drug-seeking, relapse and drug use despite negative consequences. Since acetaldehyde directly stimulates dopamine neuronal firing in the mesolimbic system, the aim of this study was the investigation of dopamine D2-receptors' role in the onset of the operant drinking behaviour for acetaldehyde in different functional stages, by the administration of two different D2-receptor agonists, quinpirole and ropinirole. Our results show that acetaldehyde was able to induce and maintain a drug-taking behaviour, displaying an escalation during training, and a reinstatement behaviour after 1-week forced abstinence. Acetaldehyde operant drinking behaviour involved D2-receptor signalling: in particular, quinpirole administration at 0.03 mg/kg, induced a significant decrease in the number of lever presses both in extinction and in relapse. Ropinirole, administered at 0.03 mg/kg during extinction, did not produce any modification but, when administered during abstinence, induced a strong decrease in acetaldehyde intake in the following relapse session. Taken together, our data suggest that acetaldehyde exerts its own motivational properties, involving the dopaminergic transmission: indeed, activation of pre-synaptic D2-receptors by quinpirole, during extinction and relapse, negatively affects operant behaviour for acetaldehyde, likely decreasing acetaldehyde-induced dopamine release. The activation of post-synaptic D2-receptors by ropinirole, during abstinence, decreases the motivation to the consecutive reinstatement of acetaldehyde drinking behaviour, likely counteracting the reduction in the dopaminergic tone typical of withdrawal. These data further strengthen the evidence

  13. Involvement of dopamine D2 receptors in addictive-like behaviour for acetaldehyde.

    Directory of Open Access Journals (Sweden)

    Anna Brancato

    Full Text Available Acetaldehyde, the first metabolite of ethanol, is active in the central nervous system, where it exerts motivational properties. Acetaldehyde is able to induce drinking behaviour in operant-conflict paradigms that resemble the core features of the addictive phenotype: drug-intake acquisition and maintenance, drug-seeking, relapse and drug use despite negative consequences. Since acetaldehyde directly stimulates dopamine neuronal firing in the mesolimbic system, the aim of this study was the investigation of dopamine D2-receptors' role in the onset of the operant drinking behaviour for acetaldehyde in different functional stages, by the administration of two different D2-receptor agonists, quinpirole and ropinirole. Our results show that acetaldehyde was able to induce and maintain a drug-taking behaviour, displaying an escalation during training, and a reinstatement behaviour after 1-week forced abstinence. Acetaldehyde operant drinking behaviour involved D2-receptor signalling: in particular, quinpirole administration at 0.03 mg/kg, induced a significant decrease in the number of lever presses both in extinction and in relapse. Ropinirole, administered at 0.03 mg/kg during extinction, did not produce any modification but, when administered during abstinence, induced a strong decrease in acetaldehyde intake in the following relapse session. Taken together, our data suggest that acetaldehyde exerts its own motivational properties, involving the dopaminergic transmission: indeed, activation of pre-synaptic D2-receptors by quinpirole, during extinction and relapse, negatively affects operant behaviour for acetaldehyde, likely decreasing acetaldehyde-induced dopamine release. The activation of post-synaptic D2-receptors by ropinirole, during abstinence, decreases the motivation to the consecutive reinstatement of acetaldehyde drinking behaviour, likely counteracting the reduction in the dopaminergic tone typical of withdrawal. These data further

  14. Identification of potential pathway mediation targets in Toll-like receptor signaling.

    Directory of Open Access Journals (Sweden)

    Fan Li

    2009-02-01

    Full Text Available Recent advances in reconstruction and analytical methods for signaling networks have spurred the development of large-scale models that incorporate fully functional and biologically relevant features. An extended reconstruction of the human Toll-like receptor signaling network is presented herein. This reconstruction contains an extensive complement of kinases, phosphatases, and other associated proteins that mediate the signaling cascade along with a delineation of their associated chemical reactions. A computational framework based on the methods of large-scale convex analysis was developed and applied to this network to characterize input-output relationships. The input-output relationships enabled significant modularization of the network into ten pathways. The analysis identified potential candidates for inhibitory mediation of TLR signaling with respect to their specificity and potency. Subsequently, we were able to identify eight novel inhibition targets through constraint-based modeling methods. The results of this study are expected to yield meaningful avenues for further research in the task of mediating the Toll-like receptor signaling network and its effects.

  15. Estradiol and progesterone regulate the expression of insulin-like growth factor-I receptor and insulin-like growth factor binding protein-2 in the hypothalamus of adult female rats.

    Science.gov (United States)

    Cardona-Gómez, G P; Chowen, J A; Garcia-Segura, L M

    2000-06-05

    Gonadal hormones interact with insulin-like growthfactor-I (IGF-I) to regulate synaptic plasticity during the estrous cycle in the rat mediobasal hypothalamus. It has been proposed that tanycytes, specialized glial cells lining the ventral region of the third ventricle, may regulate the availability of IGF-I to hypothalamic neurons. IGF-I levels in tanycytes fluctuate during the estrous cycle. Furthermore, estrogen administration to ovariectomized rats increases IGF-I levels in tanycytes, while progesterone, injected simultaneously with estrogen, blocks the estrogen-induced increase of IGF-I levels in tanycytes. To test whether hormonal regulation of IGF-I receptor (IGF-IR) and IGF binding protein-2 (IGFBP-2) may be involved in the accumulation of IGF-I in tanycytes, we assessed the effect of ovarian hormones on the levels of these molecules in the mediobasal hypothalamus of adult female rats. Ovariectomized animals were treated with either oil, estrogen, progesterone, or estrogen and progesterone simultaneously and then killed 6 or 24 h later. Some neurons, some astrocytes, and many tanycytes in the mediobasal hypothalamus were found by confocal microscopy to be immunoreactive for IGF-IR. IGFBP-2 immunoreactivity was restricted almost exclusively to tanycytes and ependymal cells and was colocalized with IGF-IR immunoreactivity in tanycytes. By electron microscope immunocytochemistry using colloidal gold labeling, IGF-IR and IGFBP-2 immunoreactivities were observed in the microvilli of tanycytes in the lumen of the third ventricle. IGF-IR and IGFBP-2 immunoreactive levels on the apical surface of tanycytes were significantly decreased by the administration of progesterone, either alone or in the presence of estradiol. IGF-IR levels in the mediobasal hypothalamus, measured by Western blotting, were not significantly affected by the separate administration of estradiol or progesterone to ovariectomized rats. However, the simultaneous administration of both hormones

  16. Systemic blockade of dopamine D2-like receptors increases high-voltage spindles in the globus pallidus and motor cortex of freely moving rats.

    Directory of Open Access Journals (Sweden)

    Chen Yang

    Full Text Available High-voltage spindles (HVSs have been reported to appear spontaneously and widely in the cortical-basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D₁-like receptors or D₂-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1 in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D₂-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D₂-like receptor antagonists. On the contrary, the selective dopamine D₁-like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D₂-like receptors, but not D₁-like receptors, were involved in HVS regulation. This supports the important role of dopamine D₂-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion.

  17. Systemic blockade of dopamine D2-like receptors increases high-voltage spindles in the globus pallidus and motor cortex of freely moving rats.

    Science.gov (United States)

    Yang, Chen; Ge, Shun-Nan; Zhang, Jia-Rui; Chen, Lei; Yan, Zhi-Qiang; Heng, Li-Jun; Zhao, Tian-Zhi; Li, Wei-Xin; Jia, Dong; Zhu, Jun-Ling; Gao, Guo-Dong

    2013-01-01

    High-voltage spindles (HVSs) have been reported to appear spontaneously and widely in the cortical-basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP) and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D₁-like receptors or D₂-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1) in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D₂-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D₂-like receptor antagonists. On the contrary, the selective dopamine D₁-like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D₂-like receptors, but not D₁-like receptors, were involved in HVS regulation. This supports the important role of dopamine D₂-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion.

  18. Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins

    Energy Technology Data Exchange (ETDEWEB)

    Edwards, Megan R.; Liu, Gai; Mire, Chad E.; Sureshchandra, Suhas; Luthra, Priya; Yen, Benjamin; Shabman, Reed S.; Leung, Daisy W.; Messaoudi, Ilhem; Geisbert, Thomas W.; Amarasinghe, Gaya K.; Basler, Christopher F.

    2016-02-11

    Suppression of innate immune responses during filoviral infection contributes to disease severity. Ebola (EBOV) and Marburg (MARV) viruses each encode a VP35 protein that suppresses RIG-I-like receptor signaling and interferon-α/β (IFN-α/β) production by several mechanisms, including direct binding to double stranded RNA (dsRNA). Here, we demonstrate that in cell culture, MARV infection results in a greater upregulation of IFN responses as compared to EBOV infection. This correlates with differences in the efficiencies by which EBOV and MARV VP35s antagonize RIG-I signaling. Furthermore, structural and biochemical studies suggest that differential recognition of RNA elements by the respective VP35 C-terminal IFN inhibitory domain (IID) rather than affinity for RNA by the respective VP35s is critical for this observation. Our studies reveal functional differences in EBOV versus MARV VP35 RNA binding that result in unexpected differences in the host response to deadly viral pathogens.

  19. Collagen Type I as a Ligand for Receptor-Mediated Signaling

    Directory of Open Access Journals (Sweden)

    Iris Boraschi-Diaz

    2017-05-01

    Full Text Available Collagens form the fibrous component of the extracellular matrix in all multi-cellular animals. Collagen type I is the most abundant collagen present in skin, tendons, vasculature, as well as the organic portion of the calcified tissue of bone and teeth. This review focuses on numerous receptors for which collagen acts as a ligand, including integrins, discoidin domain receptors DDR1 and 2, OSCAR, GPVI, G6b-B, and LAIR-1 of the leukocyte receptor complex (LRC and mannose family receptor uPARAP/Endo180. We explore the process of collagen production and self-assembly, as well as its degradation by collagenases and gelatinases in order to predict potential temporal and spatial sites of action of different collagen receptors. While the interactions of the mature collagen matrix with integrins and DDR are well-appreciated, potential signals from immature matrix as well as collagen degradation products are possible but not yet described. The role of multiple collagen receptors in physiological processes and their contribution to pathophysiology of diseases affecting collagen homeostasis require further studies.

  20. Novel receptor-like kinases in cacao contain PR-1 extracellular domains.

    Science.gov (United States)

    Teixeira, Paulo José Pereira Lima; Costa, Gustavo Gilson Lacerda; Fiorin, Gabriel Lorencini; Pereira, Gonçalo Amarante Guimarães; Mondego, Jorge Maurício Costa

    2013-08-01

    Members of the pathogenesis-related protein 1 (PR-1) family are well-known markers of plant defence responses, forming part of the arsenal of the secreted proteins produced on pathogen recognition. Here, we report the identification of two cacao (Theobroma cacao L.) PR-1s that are fused to transmembrane regions and serine/threonine kinase domains, in a manner characteristic of receptor-like kinases (RLKs). These proteins (TcPR-1f and TcPR-1g) were named PR-1 receptor kinases (PR-1RKs). Phylogenetic analysis of RLKs and PR-1 proteins from cacao indicated that PR-1RKs originated from a fusion between sequences encoding PR-1 and the kinase domain of a LecRLK (Lectin Receptor-Like Kinase). Retrotransposition marks surround TcPR-1f, suggesting that retrotransposition was involved in the origin of PR-1RKs. Genes with a similar domain architecture to cacao PR-1RKs were found in rice (Oryza sativa), barrel medic (Medicago truncatula) and a nonphototrophic bacterium (Herpetosiphon aurantiacus). However, their kinase domains differed from those found in LecRLKs, indicating the occurrence of convergent evolution. TcPR-1g expression was up-regulated in the biotrophic stage of witches' broom disease, suggesting a role for PR-1RKs during cacao defence responses. We hypothesize that PR-1RKs transduce a defence signal by interacting with a PR-1 ligand. © 2013 BSPP AND JOHN WILEY & SONS LTD.