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Sample records for specific receptor-type guanylyl

  1. Goat activin receptor type IIB knockdown by muscle specific promoter driven artificial microRNAs.

    Science.gov (United States)

    Patel, Amrutlal K; Shah, Ravi K; Patel, Utsav A; Tripathi, Ajai K; Joshi, Chaitanya G

    2014-10-10

    Activin receptor type IIB (ACVR2B) is a transmembrane receptor which mediates signaling of TGF beta superfamily ligands known to function in regulation of muscle mass, embryonic development and reproduction. ACVR2B antagonism has shown to enhance the muscle growth in several disease and transgenic models. Here, we show ACVR2B knockdown by RNA interference using muscle creatine kinase (MCK) promoter driven artificial microRNAs (amiRNAs). Among the various promoter elements tested, the ∼1.26 kb MCK promoter region showed maximum transcriptional activity in goat myoblasts cells. We observed up to 20% silencing in non-myogenic 293T cells and up to 32% silencing in myogenic goat myoblasts by MCK directed amiRNAs by transient transfection. Goat myoblasts stably integrated with MCK directed amiRNAs showed merely 8% silencing in proliferating myoblasts which was increased to 34% upon induction of differentiation at transcript level whereas up to 57% silencing at protein level. Knockdown of ACVR2B by 5'-UTR derived amiRNAs resulted in decreased SMAD2/3 signaling, increased expression of myogenic regulatory factors (MRFs) and enhanced proliferation and differentiation of myoblasts. Unexpectedly, knockdown of ACVR2B by 3'-UTR derived amiRNAs resulted in increased SMAD2/3 signaling, reduced expression of MRFs and suppression of myogenesis. Our study offers muscle specific knockdown of ACVR2B as a potential strategy to enhance muscle mass in the farm animal species. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. The specific monomer/dimer equilibrium of the corticotropin-releasing factor receptor type 1 is established in the endoplasmic reticulum.

    Science.gov (United States)

    Teichmann, Anke; Gibert, Arthur; Lampe, André; Grzesik, Paul; Rutz, Claudia; Furkert, Jens; Schmoranzer, Jan; Krause, Gerd; Wiesner, Burkhard; Schülein, Ralf

    2014-08-29

    G protein-coupled receptors (GPCRs) represent the most important drug targets. Although the smallest functional unit of a GPCR is a monomer, it became clear in the past decades that the vast majority of the receptors form dimers. Only very recently, however, data were presented that some receptors may in fact be expressed as a mixture of monomers and dimers and that the interaction of the receptor protomers is dynamic. To date, equilibrium measurements were restricted to the plasma membrane due to experimental limitations. We have addressed the question as to where this equilibrium is established for the corticotropin-releasing factor receptor type 1. By developing a novel approach to analyze single molecule fluorescence cross-correlation spectroscopy data for intracellular membrane compartments, we show that the corticotropin-releasing factor receptor type 1 has a specific monomer/dimer equilibrium that is already established in the endoplasmic reticulum (ER). It remains constant at the plasma membrane even following receptor activation. Moreover, we demonstrate for seven additional GPCRs that they are expressed in specific but substantially different monomer/dimer ratios. Although it is well known that proteins may dimerize in the ER in principle, our data show that the ER is also able to establish the specific monomer/dimer ratios of GPCRs, which sheds new light on the functions of this compartment. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Cell and receptor type-specific alterations in markers of GABA neurotransmission in the prefrontal cortex of subjects with schizophrenia.

    Science.gov (United States)

    Lewis, David A; Hashimoto, Takanori; Morris, Harvey M

    2008-10-01

    Impairments in cognitive control, such as those involved in working memory, are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC) in individuals with schizophrenia. This dysfunction appears to result, at least in part, from abnormalities in GABA-mediated neurotransmission. In this paper, we review recent findings indicating that the altered DLPFC circuitry in subjects with schizophrenia reflects changes in the expression of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission. Specifically, using a combination of methods, we found that subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding presynaptic regulators of GABA neurotransmission, neuropeptide markers of specific subpopulations of GABA neurons, and certain subunits of the GABA(A) receptor. In particular, alterations in the expression of the neuropeptide somatostatin suggested that GABA neurotransmission is impaired in the Martinotti subset of GABA neurons that target the dendrites of pyramidal cells. In contrast, none of the GABA-related transcripts assessed to date were altered in the DLPFC of monkeys chronically exposed to antipsychotic medications, suggesting that the effects observed in the human studies reflect the disease process and not its treatment. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia may be attributable to altered GABA neurotransmission in specific DLPFC microcircuits.

  4. Characterization of two unusual guanylyl cyclases from Dictyostelium

    NARCIS (Netherlands)

    Roelofs, Jeroen; Haastert, Peter J.M. van

    2002-01-01

    Guanylyl cyclase A (GCA) and soluble guanylyl cyclase (sGC) encode GCs in Dictyostelium and have a topology similar to 12-transmembrane and soluble adenylyl cyclase, respectively. We demonstrate that all detectable GC activity is lost in a cell line in which both genes have been inactivated. Cell

  5. Inferring biological functions of guanylyl cyclases with computational methods

    KAUST Repository

    Alquraishi, May Majed; Meier, Stuart Kurt

    2013-01-01

    A number of studies have shown that functionally related genes are often co-expressed and that computational based co-expression analysis can be used to accurately identify functional relationships between genes and by inference, their encoded proteins. Here we describe how a computational based co-expression analysis can be used to link the function of a specific gene of interest to a defined cellular response. Using a worked example we demonstrate how this methodology is used to link the function of the Arabidopsis Wall-Associated Kinase-Like 10 gene, which encodes a functional guanylyl cyclase, to host responses to pathogens. © Springer Science+Business Media New York 2013.

  6. Inferring biological functions of guanylyl cyclases with computational methods

    KAUST Repository

    Alquraishi, May Majed

    2013-09-03

    A number of studies have shown that functionally related genes are often co-expressed and that computational based co-expression analysis can be used to accurately identify functional relationships between genes and by inference, their encoded proteins. Here we describe how a computational based co-expression analysis can be used to link the function of a specific gene of interest to a defined cellular response. Using a worked example we demonstrate how this methodology is used to link the function of the Arabidopsis Wall-Associated Kinase-Like 10 gene, which encodes a functional guanylyl cyclase, to host responses to pathogens. © Springer Science+Business Media New York 2013.

  7. The arabidopsis wall associated kinase-like 10 gene encodes a functional guanylyl cyclase and is co-expressed with pathogen defense related genes

    KAUST Repository

    Meier, Stuart; Ruzvidzo, Oziniel; Morse, Monique; Donaldson, Lara; Kwezi, Lusisizwe; Gehring, Christoph A

    2010-01-01

    Background: Second messengers have a key role in linking environmental stimuli to physiological responses. One such messenger, guanosine 3?,5?-cyclic monophosphate (cGMP), has long been known to be an essential signaling molecule in many different physiological processes in higher plants, including biotic stress responses. To date, however, the guanylyl cyclase (GC) enzymes that catalyze the formation of cGMP from GTP have largely remained elusive in higher plants. Principal Findings: We have identified an Arabidopsis receptor type wall associated kinase-like molecule (AtWAKL10) as a candidate GC and provide experimental evidence to show that the intracellular domain of AtWAKL10431-700 can generate cGMP in vitro. Further, we also demonstrate that the molecule has kinase activity indicating that AtWAKL10 is a twin-domain catalytic protein. A co-expression and stimulus-specific expression analysis revealed that AtWAKL10 is consistently coexpressed with well characterized pathogen defense related genes and along with these genes is induced early and sharply in response to a range of pathogens and their elicitors. Conclusions: We demonstrate that AtWAKL10 is a twin-domain, kinase-GC signaling molecule that may function in biotic stress responses that are critically dependent on the second messenger cGMP. © 2010 Meier et al.

  8. The arabidopsis wall associated kinase-like 10 gene encodes a functional guanylyl cyclase and is co-expressed with pathogen defense related genes

    KAUST Repository

    Meier, Stuart

    2010-01-26

    Background: Second messengers have a key role in linking environmental stimuli to physiological responses. One such messenger, guanosine 3?,5?-cyclic monophosphate (cGMP), has long been known to be an essential signaling molecule in many different physiological processes in higher plants, including biotic stress responses. To date, however, the guanylyl cyclase (GC) enzymes that catalyze the formation of cGMP from GTP have largely remained elusive in higher plants. Principal Findings: We have identified an Arabidopsis receptor type wall associated kinase-like molecule (AtWAKL10) as a candidate GC and provide experimental evidence to show that the intracellular domain of AtWAKL10431-700 can generate cGMP in vitro. Further, we also demonstrate that the molecule has kinase activity indicating that AtWAKL10 is a twin-domain catalytic protein. A co-expression and stimulus-specific expression analysis revealed that AtWAKL10 is consistently coexpressed with well characterized pathogen defense related genes and along with these genes is induced early and sharply in response to a range of pathogens and their elicitors. Conclusions: We demonstrate that AtWAKL10 is a twin-domain, kinase-GC signaling molecule that may function in biotic stress responses that are critically dependent on the second messenger cGMP. © 2010 Meier et al.

  9. Generation of a Novel T Cell Specific Interleukin-1 Receptor Type 1 Conditional Knock Out Mouse Reveals Intrinsic Defects in Survival, Expansion and Cytokine Production of CD4 T Cells.

    Directory of Open Access Journals (Sweden)

    Ilgiz A Mufazalov

    Full Text Available Interleukin-1 (IL-1 plays a crucial role in numerous inflammatory diseases via action on its only known signaling IL-1 receptor type 1 (IL-1R1. To investigate the role of IL-1 signaling in selected cell types, we generated a new mouse strain in which exon 5 of the Il1r1 gene is flanked by loxP sites. Crossing of these mice with CD4-Cre transgenic mice resulted in IL-1R1 loss of function specifically in T cells. These mice, termed IL-1R1ΔT, displayed normal development under steady state conditions. Importantly, isolated CD4 positive T cells retained their capacity to differentiate toward Th1 or Th17 cell lineages in vitro, and strongly proliferated in cultures supplemented with either anti-CD3/CD28 or Concanavalin A, but, as predicted, were completely unresponsive to IL-1β administration. Furthermore, IL-1R1ΔT mice were protected from gut inflammation in the anti-CD3 treatment model, due to dramatically reduced frequencies and absolute numbers of IL-17A and interferon (IFN-γ producing cells. Taken together, our data shows the necessity of intact IL-1 signaling for survival and expansion of CD4 T cells that were developed in an otherwise IL-1 sufficient environment.

  10. A chimeric receptor of the insulin-like growth factor receptor type 1 (IGFR1) and a single chain antibody specific to myelin oligodendrocyte glycoprotein activates the IGF1R signalling cascade in CG4 oligodendrocyte progenitors.

    Science.gov (United States)

    Annenkov, Alexander; Rigby, Anne; Amor, Sandra; Zhou, Dun; Yousaf, Nasim; Hemmer, Bernhard; Chernajovsky, Yuti

    2011-08-01

    In order to generate neural stem cells with increased ability to survive after transplantation in brain parenchyma we developed a chimeric receptor (ChR) that binds to myelin oligodendrocyte glycoprotein (MOG) via its ectodomain and activates the insulin-like growth factor receptor type 1 ‎‎(IGF1R) signalling cascade. Activation of this pro-survival pathway in response to ligand broadly available in the brain might increase neuroregenerative potential of transplanted precursors. The ChR was produced by fusing a MOG-specific single ‎chain antibody with the extracellular boundary of the IGF1R transmembrane segment. The ChR is expressed on the cellular surface, predominantly as a monomer, and is not N-glycosylated. To show MOG-dependent functionality of the ChR, neuroblastoma cells B104 expressing this ChR were stimulated with monolayers of cells expressing recombinant MOG. The ChR undergoes MOG-dependent tyrosine phosphorylation and homodimerisation. It promotes insulin and IGF-independent growth of the oligodendrocyte progenitor cell line CG4. The proposed mode of the ChR activation is by MOG-induced dimerisation which promotes kinase domain transphosphorylation, by-passing the requirement of conformation changes known to be important for IGF1R activation. Another ChR, which contains a segment of the β-chain ectodomain, was produced in an attempt to recapitulate some of these conformational changes, but proved non-functional. 2011 Elsevier B.V. All rights reserved.

  11. A chimeric receptor of the insulin-like growth factor receptor type 1 (IGFR1) and a single chain antibody specific to myelin oligodendrocyte glycoprotein activates the IGF1R signalling cascade in CG4 oligodendrocyte progenitors

    NARCIS (Netherlands)

    Annenkov, A.; Rigby, A.; Amor, S.; Zhou, D.M.; Yousaf, N.; Hemmer, B.; Chernajovsky, Y.

    2011-01-01

    In order to generate neural stem cells with increased ability to survive after transplantation in brain parenchyma we developed a chimeric receptor (ChR) that binds to myelin oligodendrocyte glycoprotein (MOG) via its ectodomain and activates the insulin-like growth factor receptor type 1 (IGF1R)

  12. The guanylyl cyclase family at Y2K.

    Science.gov (United States)

    Wedel, B; Garbers, D

    2001-01-01

    During the 1980s the purification, cloning, and expression of various forms of guanylyl cyclase (GC) revealed that they served as receptors for extracellular signals. Seven membrane forms, which presumably exist as homodimers, and four subunits of apparent heterodimers (commonly referred to as the soluble forms) are known, but in animals such as nematodes, much larger numbers of GCs are expressed. The number of transmembrane segments (none, one, or multiple) divide the GC family into three groups. Those with no or one transmembrane segment bind nitric oxide/carbon monoxide (NO/CO) or peptides. There are no known ligands for the multiple transmembrane segment class of GCs. Mutational and structural analyses support a model where catalysis requires a shared substrate binding site between the subunits, whether homomeric or heteromeric in nature. Because some cyclases or cyclase ligand genes lack specific GC inhibitors, disruption of either has been used to define the functions of individual cyclases, as well as to define human genetic disease counterparts.

  13. Degeneration of the olfactory guanylyl cyclase D gene during primate evolution.

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    Janet M Young

    2007-09-01

    Full Text Available The mammalian olfactory system consists of several subsystems that detect specific sets of chemical cues and underlie a variety of behavioral responses. Within the main olfactory epithelium at least three distinct types of chemosensory neurons can be defined by their expression of unique sets of signal transduction components. In rodents, one set of neurons expresses the olfactory-specific guanylyl cyclase (GC-D gene (Gucy2d, guanylyl cyclase 2d and other cell-type specific molecules. GC-D-positive neurons project their axons to a small group of atypical "necklace" glomeruli in the olfactory bulb, some of which are activated in response to suckling in neonatal rodents and to atmospheric CO2 in adult mice. Because GC-D is a pseudogene in humans, signaling through this system appears to have been lost at some point in primate evolution.Here we used a combination of bioinformatic analysis of trace-archive and genome-assembly data and sequencing of PCR-amplified genomic DNA to determine when during primate evolution the functional gene was lost. Our analysis reveals that GC-D is a pseudogene in a large number of primate species, including apes, Old World and New World monkeys and tarsier. In contrast, the gene appears intact and has evolved under purifying selection in mouse, rat, dog, lemur and bushbaby.These data suggest that signaling through GC-D-expressing cells was probably compromised more than 40 million years ago, prior to the divergence of New World monkeys from Old World monkeys and apes, and thus cannot be involved in chemosensation in most primates.

  14. Localization of a guanylyl cyclase to chemosensory cilia requires the novel ciliary MYND domain protein DAF-25.

    Directory of Open Access Journals (Sweden)

    Victor L Jensen

    2010-11-01

    Full Text Available In harsh conditions, Caenorhabditis elegans arrests development to enter a non-aging, resistant diapause state called the dauer larva. Olfactory sensation modulates the TGF-β and insulin signaling pathways to control this developmental decision. Four mutant alleles of daf-25 (abnormal DAuer Formation were isolated from screens for mutants exhibiting constitutive dauer formation and found to be defective in olfaction. The daf-25 dauer phenotype is suppressed by daf-10/IFT122 mutations (which disrupt ciliogenesis, but not by daf-6/PTCHD3 mutations (which prevent environmental exposure of sensory cilia, implying that DAF-25 functions in the cilia themselves. daf-25 encodes the C. elegans ortholog of mammalian Ankmy2, a MYND domain protein of unknown function. Disruption of DAF-25, which localizes to sensory cilia, produces no apparent cilia structure anomalies, as determined by light and electron microscopy. Hinting at its potential function, the dauer phenotype, epistatic order, and expression profile of daf-25 are similar to daf-11, which encodes a cilium-localized guanylyl cyclase. Indeed, we demonstrate that DAF-25 is required for proper DAF-11 ciliary localization. Furthermore, the functional interaction is evolutionarily conserved, as mouse Ankmy2 interacts with guanylyl cyclase GC1 from ciliary photoreceptors. The interaction may be specific because daf-25 mutants have normally-localized OSM-9/TRPV4, TAX-4/CNGA1, CHE-2/IFT80, CHE-11/IFT140, CHE-13/IFT57, BBS-8, OSM-5/IFT88, and XBX-1/D2LIC in the cilia. Intraflagellar transport (IFT (required to build cilia is not defective in daf-25 mutants, although the ciliary localization of DAF-25 itself is influenced in che-11 mutants, which are defective in retrograde IFT. In summary, we have discovered a novel ciliary protein that plays an important role in cGMP signaling by localizing a guanylyl cyclase to the sensory organelle.

  15. Chimeric opioid peptides: Tools for identifying opioid receptor types

    International Nuclear Information System (INIS)

    Xie, G.; Miyajima, A.; Yokota, T.; Arai, K.; Goldstein, A.

    1990-01-01

    The authors synthesized several chimeric [125J-labelled] peptides in which the N-terminal nine residues of dynorphin-32, a peptide selective for the κ opioid receptor, were replaced by opioid peptides selective for other opioid receptor types. Each chimeric peptide retained the high affinity and type selectivity characteristic of its N-terminal sequence. The common C-terminal two-thirds of the chimeric peptides served as an epitope recognized by the same monoclonal antibody. When bound to receptors on a cell surface or membrane preparation, these peptides could still bind specifically to the monoclonal antibody. These chimeric peptides should be useful for isolating μ, δ, and κ opioid receptors and for identifying opioid receptors on transfected cells in expression cloning procedures. The general approach using chimeric peptides should be applicable to other peptide receptors

  16. The Arabidopsis thaliana proteome harbors undiscovered multi-domain molecules with functional guanylyl cyclase catalytic centers

    KAUST Repository

    Wong, Aloysius Tze; Gehring, Christoph A

    2013-01-01

    plants, guanylyl cyclases (GCs), enzymes that generate cGMP from guanosine-5'-triphosphate (GTP) have remained elusive until recently. GC search motifs constructed from the alignment of known GCs catalytic centers form vertebrates and lower eukaryotes

  17. Guanylyl cyclase C in colorectal cancer: susceptibility gene and potential therapeutic target.

    Science.gov (United States)

    Lin, Jieru E; Li, Peng; Pitari, Giovanni M; Schulz, Stephanie; Waldman, Scott A

    2009-05-01

    Colorectal cancer is one of the leading causes of tumor-related morbidity and mortality worldwide. While mechanisms underlying this disease have been elucidated over the past two decades, these molecular insights have failed to translate into efficacious therapy. The oncogenomic view of cancer suggests that terminal transformation reflects the sequential corruption of signal transduction circuits regulating key homeostatic mechanisms, whose multiplicity underlies the therapeutic resistance of most tumors to interventions targeting individual pathways. Conversely, the paucity of mechanistic insights into proximal pathophysiological processes that initiate and amplify oncogenic circuits preceding accumulation of mutations and transformation impedes development of effective prevention and therapy. In that context, guanylyl cyclase C (GCC), the intestinal receptor for the paracrine hormones guanylin and uroguanylin, whose early loss characterizes colorectal transformation, has emerged as a component of lineage-specific homeostatic programs organizing spatiotemporal patterning along the crypt-surface axis. Dysregulation of GCC signaling, reflecting hormone loss, promotes tumorigenesis through reprogramming of replicative and bioenergetic circuits and genomic instability. Compensatory upregulation of GCC in response to hormone loss provides a unique translational opportunity for prevention and treatment of colorectal tumors by hormone-replacement therapy.

  18. Metabotropic glutamate receptor type 1 autoimmunity

    Science.gov (United States)

    Lopez-Chiriboga, A. Sebastian; Komorowski, Lars; Kümpfel, Tania; Probst, Christian; Hinson, Shannon R.; Pittock, Sean J.

    2016-01-01

    Objective: To describe retrospectively the clinical associations of immunoglobulin G (IgG) targeting metabotropic glutamate receptor 1 (mGluR1-IgG). Methods: Specimens of 9 patients evaluated on a service basis in the Mayo Clinic Neuroimmunology Laboratory by tissue-based immunofluorescence assay (IFA) yielded a robust, synaptic immunostaining pattern consistent with mGluR1-IgG (serum, 9; CSF, 2 available). Transfected HEK293 cell-based assay (CBA) confirmed mGluR1 specificity in all 11 specimens. A further 2 patients were detected in Germany primarily by CBA. Results: The median symptom onset age for the 11 patients was 58 years (range 33–81 years); 6 were male. All 9 Mayo Clinic patients had subacute onset of cerebellar ataxia, 4 had dysgeusia, 1 had psychiatric symptoms, and 1 had cognitive impairment. All were evaluated for malignancy, but only 1 was affected (cutaneous T-cell lymphoma). One developed ataxia post–herpes zoster infection. Head MRIs were generally atrophic or normal-appearing, and CSF was inflammatory in just 1 of 5 tested, though mGluR1-IgG was detected in both specimens submitted. Five patients improved (attributable to immunotherapy in 4, spontaneously in 1), 3 stabilized (attributable to immunotherapy in 2, cancer therapy in 1), and 1 progressively declined (untreated). The 2 German patients had ataxia, but fulfilled multiple sclerosis diagnostic criteria (1 relapsing-remitting, 1 progressive). However, both had histories of hematologic malignancy (acute lymphocytic leukemia and mantle cell lymphoma), and had mGluR1-IgG detected in serum by CBA (weakly positive on tissue-based IFA). Conclusions: mGluR1 autoimmunity represents a treatable form of cerebellar ataxia. Dysgeusia may be a diagnostic clue. Paraneoplastic, parainfectious, or idiopathic causes may occur. PMID:26888994

  19. cCMP, cUMP, cTMP, cIMP and cXMP as possible second messengers: development of a hypothesis based on studies with soluble guanylyl cyclase α(1)β(1).

    Science.gov (United States)

    Beste, Kerstin Y; Seifert, Roland

    2013-02-01

    Adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate are second messengers that regulate multiple physiological functions. The existence of additional cyclic nucleotides in mammalian cells was postulated many years ago, but technical problems hampered development of the field. Using highly specific and sensitive mass spectrometry methods, soluble guanylyl cyclase has recently been shown to catalyze the formation of several cyclic nucleotides in vitro. This minireview discusses the broad substrate-specificity of soluble guanylyl cyclase and the possible second messenger roles of cyclic nucleotides other than adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate. We hope that this article stimulates productive and critical research in an area that has been neglected for many years.

  20. The plant natriuretic peptide receptor is a guanylyl cyclase and enables cGMP-dependent signaling

    KAUST Repository

    Turek, Ilona

    2016-03-05

    The functional homologues of vertebrate natriuretic peptides (NPs), the plant natriuretic peptides (PNPs), are a novel class of peptidic hormones that signal via guanosine 3′,5′-cyclic monophosphate (cGMP) and systemically affect plant salt and water balance and responses to biotrophic plant pathogens. Although there is increasing understanding of the complex roles of PNPs in plant responses at the systems level, little is known about the underlying signaling mechanisms. Here we report isolation and identification of a novel Leucine-Rich Repeat (LRR) protein that directly interacts with A. thaliana PNP, AtPNP-A. In vitro binding studies revealed that the Arabidopsis AtPNP-A binds specifically to the LRR protein, termed AtPNP-R1, and the active region of AtPNP-A is sufficient for the interaction to occur. Importantly, the cytosolic part of the AtPNP-R1, much like in some vertebrate NP receptors, harbors a catalytic center diagnostic for guanylyl cyclases and the recombinant AtPNP-R1 is capable of catalyzing the conversion of guanosine triphosphate to cGMP. In addition, we show that AtPNP-A causes rapid increases of cGMP levels in wild type (WT) leaf tissue while this response is significantly reduced in the atpnp-r1 mutants. AtPNP-A also causes cGMP-dependent net water uptake into WT protoplasts, and hence volume increases, whereas responses of the protoplasts from the receptor mutant are impaired. Taken together, our results suggest that the identified LRR protein is an AtPNP-A receptor essential for the PNP-dependent regulation of ion and water homeostasis in plants and that PNP- and vertebrate NP-receptors and their signaling mechanisms share surprising similarities. © 2016 Springer Science+Business Media Dordrecht

  1. Corruption of homeostatic mechanisms in the guanylyl cyclase C signaling pathway underlying colorectal tumorigenesis.

    Science.gov (United States)

    Li, Peng; Waldman, Scott A

    2010-08-01

    Colon cancer, the second leading cause of cancer-related mortality worldwide, originates from the malignant transformation of intestinal epithelial cells. The intestinal epithelium undergoes a highly organized process of rapid regeneration along the crypt-villus axis, characterized by proliferation, migration, differentiation and apoptosis, whose coordination is essential to maintaining the mucosal barrier. Disruption of these homeostatic processes predisposes cells to mutations in tumor suppressors or oncogenes, whose dysfunction provides transformed cells an evolutionary growth advantage. While sequences of genetic mutations at different stages along the neoplastic continuum have been established, little is known of the events initiating tumorigenesis prior to adenomatous polyposis coli (APC) mutations. Here, we examine a role for the corruption of homeostasis induced by silencing novel tumor suppressors, including the intestine-specific transcription factor CDX2 and its gene target guanylyl cyclase C (GCC), as early events predisposing cells to mutations in APC and other sequential genes that initiate colorectal cancer. CDX2 and GCC maintain homeostatic regeneration in the intestine by restricting cell proliferation, promoting cell maturation and adhesion, regulating cell migration and defending the intestinal barrier and genomic integrity. Elimination of CDX2 or GCC promotes intestinal tumor initiation and growth in aged mice, mice carrying APC mutations or mice exposed to carcinogens. The roles of CDX2 and GCC in suppressing intestinal tumorigenesis, universal disruption in their signaling through silencing of hormones driving GCC, and the uniform overexpression of GCC by tumors underscore the potential value of oral replacement with GCC ligands as targeted prevention and therapy for colorectal cancer.

  2. Chimeric opioid peptides: tools for identifying opioid receptor types.

    OpenAIRE

    Xie, G X; Miyajima, A; Yokota, T; Arai, K; Goldstein, A

    1990-01-01

    We synthesized several chimeric peptides in which the N-terminal nine residues of dynorphin-32, a peptide selective for the kappa opioid receptor, were replaced by opioid peptides selective for other opioid receptor types. Each chimeric peptide retained the high affinity and type selectivity characteristic of its N-terminal sequence. The common C-terminal two-thirds of the chimeric peptides served as an epitope recognized by the same monoclonal antibody. When bound to receptors on a cell surf...

  3. Clathrin-dependent internalization, signaling, and metabolic processing of guanylyl cyclase/natriuretic peptide receptor-A.

    Science.gov (United States)

    Somanna, Naveen K; Mani, Indra; Tripathi, Satyabha; Pandey, Kailash N

    2018-04-01

    Cardiac hormones, atrial and brain natriuretic peptides (ANP and BNP), have pivotal roles in renal hemodynamics, neuroendocrine signaling, blood pressure regulation, and cardiovascular homeostasis. Binding of ANP and BNP to the guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) induces rapid internalization and trafficking of the receptor via endolysosomal compartments, with concurrent generation of cGMP. However, the mechanisms of the endocytotic processes of NPRA are not well understood. The present study, using 125 I-ANP binding assay and confocal microscopy, examined the function of dynamin in the internalization of NPRA in stably transfected human embryonic kidney-293 (HEK-293) cells. Treatment of recombinant HEK-293 cells with ANP time-dependently accelerated the internalization of receptor from the cell surface to the cell interior. However, the internalization of ligand-receptor complexes of NPRA was drastically decreased by the specific inhibitors of clathrin- and dynamin-dependent receptor internalization, almost 85% by monodansylcadaverine, 80% by chlorpromazine, and 90% by mutant dynamin, which are specific blockers of endocytic vesicle formation. Visualizing the internalization of NPRA and enhanced GFP-tagged NPRA in HEK-293 cells by confocal microscopy demonstrated the formation of endocytic vesicles after 5 min of ANP treatment; this effect was blocked by the inhibitors of clathrin and by mutant dynamin construct. Our results suggest that NPRA undergoes internalization via clathrin-mediated endocytosis as part of its normal itinerary, including trafficking, signaling, and metabolic degradation.

  4. Hypoxic Vasospasm Mediated by cIMP: When Soluble Guanylyl Cyclase Turns Bad.

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    Gao, Yuansheng; Chen, Zhengju; Leung, Susan W S; Vanhoutte, Paul M

    2015-06-01

    In a number of isolated blood vessel types, hypoxia causes an acute contraction that is dependent on the presence of nitric oxide and activation of soluble guanylyl cyclase. It is more pronounced when the preparations are constricted and is therefore termed hypoxic augmentation of vasoconstriction. This hypoxic response is accompanied by increases in the intracellular level of inosine 5'-triphosphate and in the synthesis of inosine 3',5'-cyclic monophosphate (cIMP) by soluble guanylyl cyclase. The administration of exogenous cIMP or inosine 5'-triphosphate causes augmented vasoconstriction to hypoxia. Furthermore, the vasoconstriction evoked by hypoxia and cIMP is associated with increased activity of Rho kinase (ROCK), indicating that cIMP may mediate the hypoxic effect by sensitizing the myofilaments to Ca through ROCK. Hypoxia is implicated in exaggerated vasoconstriction in the pathogenesis of coronary artery disease, myocardial infarction, hypertension, and stroke. The newly found role of cIMP may help to identify unique therapeutic targets for certain cardiovascular disorders.

  5. Simvastatin enhances bone morphogenetic protein receptor type II expression

    International Nuclear Information System (INIS)

    Hu Hong; Sung, Arthur; Zhao, Guohua; Shi, Lingfang; Qiu Daoming; Nishimura, Toshihiko; Kao, Peter N.

    2006-01-01

    Statins confer therapeutic benefits in systemic and pulmonary vascular diseases. Bone morphogenetic protein (BMP) receptors serve essential signaling functions in cardiovascular development and skeletal morphogenesis. Mutations in BMP receptor type II (BMPR2) are associated with human familial and idiopathic pulmonary arterial hypertension, and pathologic neointimal proliferation of vascular endothelial and smooth muscle cells within small pulmonary arteries. In severe experimental pulmonary hypertension, simvastatin reversed disease and conferred a 100% survival advantage. Here, modulation of BMPR2 gene expression by simvastatin is characterized in human embryonic kidney (HEK) 293T, pulmonary artery smooth muscle, and lung microvascular endothelial cells (HLMVECs). A 1.4 kb BMPR2 promoter containing Egr-1 binding sites confers reporter gene activation in 293T cells which is partially inhibited by simvastatin. Simvastatin enhances steady-state BMPR2 mRNA and protein expression in HLMVEC, through posttranscriptional mRNA stabilization. Simvastatin induction of BMPR2 expression may improve BMP-BMPR2 signaling thereby enhancing endothelial differentiation and function

  6. Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging

    Directory of Open Access Journals (Sweden)

    Ahmed Haider

    2016-07-01

    Full Text Available Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well characterized. The cannabinoid receptor type 1 (CB1 is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2 in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based 11C-labeled PET ligands designated [11C]AAT-015 and [11C]AAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki values of 3.3 ± 0.5 nM (CB2 and 1.0 ± 0.2 µM (CB1 for AAT-015. AAT-778 showed similar Ki values of 4.3 ± 0.7 nM (CB2 and 1.1 ± 0.1 µM (CB1. Radiosynthesis was carried out under basic conditions using [11C]iodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 - 449 GBq/µmol for both tracers. In order to demonstrate CB2 specificity of [11C]AAT-015 and [11C]AAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, [11C]AAT-015 was administered to healthy rats via tail

  7. Immediate and Catastrophic Antibody-Mediated Rejection in a Lung Transplant Recipient With Anti-Angiotensin II Receptor Type 1 and Anti-Endothelin-1 Receptor Type A Antibodies.

    Science.gov (United States)

    Cozzi, E; Calabrese, F; Schiavon, M; Feltracco, P; Seveso, M; Carollo, C; Loy, M; Cardillo, M; Rea, F

    2017-02-01

    Preexisting donor-specific anti-HLA antibodies (DSAs) have been associated with reduced survival of lung allografts. However, antibodies with specificities other than HLA may have a detrimental role on the lung transplant outcome. A young man with cystic fibrosis underwent lung transplantation with organs from a suitable deceased donor. At the time of transplantation, there were no anti-HLA DSAs. During surgery, the patient developed a severe and intractable pulmonary hypertension associated with right ventriular dysfunction, which required arteriovenous extracorporeal membrane oxygenation. After a brief period of clinical improvement, a rapid deterioration in hemodynamics led to the patient's death on postoperative day 5. Postmortem studies showed that lung specimens taken at the end of surgery were compatible with antibody-mediated rejection (AMR), while terminal samples evidenced diffuse capillaritis, blood extravasation, edema, and microthrombi, with foci of acute cellular rejection (A3). Immunological investigations demonstrated the presence of preexisting antibodies against the endothelin-1 receptor type A (ET A R) and the angiotensin II receptor type 1 (AT 1 R), two of the most potent vasoconstrictors reported to date, whose levels slightly rose after transplantation. These data suggest that preexisting anti-ET A R and anti-AT 1 R antibodies may have contributed to the onset of AMR and to the catastrophic clinical course of this patient. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  8. High density and ligand affinity confer ultrasensitive signal detection by a guanylyl cyclase chemoreceptor

    Science.gov (United States)

    Pichlo, Magdalena; Bungert-Plümke, Stefanie; Weyand, Ingo; Seifert, Reinhard; Bönigk, Wolfgang; Strünker, Timo; Kashikar, Nachiket Dilip; Goodwin, Normann; Müller, Astrid; Körschen, Heinz G.; Collienne, Ursel; Pelzer, Patric; Van, Qui; Enderlein, Jörg; Klemm, Clementine; Krause, Eberhard; Trötschel, Christian; Poetsch, Ansgar; Kremmer, Elisabeth

    2014-01-01

    Guanylyl cyclases (GCs), which synthesize the messenger cyclic guanosine 3′,5′-monophosphate, control several sensory functions, such as phototransduction, chemosensation, and thermosensation, in many species from worms to mammals. The GC chemoreceptor in sea urchin sperm can decode chemoattractant concentrations with single-molecule sensitivity. The molecular and cellular underpinnings of such ultrasensitivity are not known for any eukaryotic chemoreceptor. In this paper, we show that an exquisitely high density of 3 × 105 GC chemoreceptors and subnanomolar ligand affinity provide a high ligand-capture efficacy and render sperm perfect absorbers. The GC activity is terminated within 150 ms by dephosphorylation steps of the receptor, which provides a means for precise control of the GC lifetime and which reduces “molecule noise.” Compared with other ultrasensitive sensory systems, the 10-fold signal amplification by the GC receptor is surprisingly low. The hallmarks of this signaling mechanism provide a blueprint for chemical sensing in small compartments, such as olfactory cilia, insect antennae, or even synaptic boutons. PMID:25135936

  9. Biased activity of soluble guanylyl cyclase: the Janus face of thymoquinone.

    Science.gov (United States)

    Detremmerie, Charlotte; Vanhoutte, Paul M; Leung, Susan

    2017-07-01

    The natural compound thymoquinone, extracted from Nigella sativa (black cumin), is widely used in humans for its anti-oxidative properties. Thymoquinone is known for its acute endothelium-independent vasodilator effects in isolated rat aortae and pulmonary arteries, depending in part on activation of adenosine triphosphate-sensitive potassium channels and inhibition of voltage-dependent calcium channels. The compound also improves endothelial dysfunction in mesenteric arteries of ageing rodents and in aortae of rabbits treated with pyrogallol, by inhibiting oxidative stress. Serendipitously, thymoquinone was found to augment contractions in isolated arteries with endothelium of both rats and pigs. The endothelium-dependent augmentation it causes counterintuitively depends on biased activation of soluble guanylyl cyclase (sGC) producing inosine 3',5'-cyclic monophosphate (cyclic IMP) rather than guanosine 3',5'-cyclic monophosphate. This phenomenon shows a striking mechanistic similarity to the hypoxic augmentation previously observed in porcine coronary arteries. The cyclic IMP preferentially produced under thymoquinone exposure causes an increased contractility of arterial smooth muscle by interfering with calcium homeostasis. This brief review summarizes the vascular pharmacology of thymoquinone, focussing in particular on how the compound causes endothelium-dependent contractions by biasing the activity of sGC.

  10. Biased activity of soluble guanylyl cyclase: the Janus face of thymoquinone

    Directory of Open Access Journals (Sweden)

    Charlotte Detremmerie

    2017-07-01

    Full Text Available The natural compound thymoquinone, extracted from Nigella sativa (black cumin, is widely used in humans for its anti-oxidative properties. Thymoquinone is known for its acute endothelium-independent vasodilator effects in isolated rat aortae and pulmonary arteries, depending in part on activation of adenosine triphosphate-sensitive potassium channels and inhibition of voltage-dependent calcium channels. The compound also improves endothelial dysfunction in mesenteric arteries of ageing rodents and in aortae of rabbits treated with pyrogallol, by inhibiting oxidative stress. Serendipitously, thymoquinone was found to augment contractions in isolated arteries with endothelium of both rats and pigs. The endothelium-dependent augmentation it causes counterintuitively depends on biased activation of soluble guanylyl cyclase (sGC producing inosine 3ʹ,5ʹ-cyclic monophosphate (cyclic IMP rather than guanosine 3ʹ,5ʹ-cyclic monophosphate. This phenomenon shows a striking mechanistic similarity to the hypoxic augmentation previously observed in porcine coronary arteries. The cyclic IMP preferentially produced under thymoquinone exposure causes an increased contractility of arterial smooth muscle by interfering with calcium homeostasis. This brief review summarizes the vascular pharmacology of thymoquinone, focussing in particular on how the compound causes endothelium-dependent contractions by biasing the activity of sGC.

  11. Mapping Soluble Guanylyl Cyclase and Protein Disulfide Isomerase Regions of Interaction.

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    Erin J Heckler

    Full Text Available Soluble guanylyl cyclase (sGC is a heterodimeric nitric oxide (NO receptor that produces cyclic GMP. This signaling mechanism is a key component in the cardiovascular system. NO binds to heme in the β subunit and stimulates the catalytic conversion of GTP to cGMP several hundred fold. Several endogenous factors have been identified that modulate sGC function in vitro and in vivo. In previous work, we determined that protein disulfide isomerase (PDI interacts with sGC in a redox-dependent manner in vitro and that PDI inhibited NO-stimulated activity in cells. To our knowledge, this was the first report of a physical interaction between sGC and a thiol-redox protein. To characterize this interaction between sGC and PDI, we first identified peptide linkages between sGC and PDI, using a lysine cross-linking reagent and recently developed mass spectrometry analysis. Together with Flag-immunoprecipitation using sGC domain deletions, wild-type (WT and mutated PDI, regions of sGC involved in this interaction were identified. The observed data were further explored with computational modeling to gain insight into the interaction mechanism between sGC and oxidized PDI. Our results indicate that PDI interacts preferentially with the catalytic domain of sGC, thus providing a mechanism for PDI inhibition of sGC. A model in which PDI interacts with either the α or the β catalytic domain is proposed.

  12. Loss of guanylyl cyclase C (GCC signaling leads to dysfunctional intestinal barrier.

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    Xiaonan Han

    2011-01-01

    Full Text Available Guanylyl Cyclase C (GCC signaling via uroguanylin (UGN and guanylin activation is a critical mediator of intestinal fluid homeostasis, intestinal cell proliferation/apoptosis, and tumorigenesis. As a mechanism for some of these effects, we hypothesized that GCC signaling mediates regulation of intestinal barrier function.Paracellular permeability of intestinal segments was assessed in wild type (WT and GCC deficient (GCC-/- mice with and without lipopolysaccharide (LPS challenge, as well as in UGN deficient (UGN-/- mice. IFNγ and myosin light chain kinase (MLCK levels were determined by real time PCR. Expression of tight junction proteins (TJPs, phosphorylation of myosin II regulatory light chain (MLC, and STAT1 activation were examined in intestinal epithelial cells (IECs and intestinal mucosa. The permeability of Caco-2 and HT-29 IEC monolayers, grown on Transwell filters was determined in the absence and presence of GCC RNA interference (RNAi. We found that intestinal permeability was increased in GCC-/- and UGN-/- mice compared to WT, accompanied by increased IFNγ levels, MLCK and STAT1 activation in IECs. LPS challenge promotes greater IFNγ and STAT1 activation in IECs of GCC-/- mice compared to WT mice. Claudin-2 and JAM-A expression were reduced in GCC deficient intestine; the level of phosphorylated MLC in IECs was significantly increased in GCC-/- and UGN-/- mice compared to WT. GCC knockdown induced MLC phosphorylation, increased permeability in IEC monolayers under basal conditions, and enhanced TNFα and IFNγ-induced monolayer hyperpermeability.GCC signaling plays a protective role in the integrity of the intestinal mucosal barrier by regulating MLCK activation and TJ disassembly. GCC signaling activation may therefore represent a novel mechanism in maintaining the small bowel barrier in response to injury.

  13. Evaluation of the specificity of antibodies raised against cannabinoid receptor type 2 in the mouse retina

    DEFF Research Database (Denmark)

    Cécyre, Bruno; Thomas, Sébastien; Ptito, Maurice

    2014-01-01

    Cannabinoid receptors (CB1R and CB2R) are among the most abundant G protein-coupled receptors in the central nervous system. The endocannabinoid system is an attractive therapeutic target for immune system modulation and peripheral pain management. While CB1R is distributed in the nervous system......, CB2R has traditionally been associated to the immune system. This dogma is currently a subject of debate since the discovery of CB2R expression in neurons using antibody-based methods. The localization of CB2R in the central nervous system (CNS) could have a significant impact on drug development...... because it would mean that in addition to its effects on the peripheral pain pathway, CB2R could also mediate some central effects of cannabinoids. In an attempt to clarify the debate over CB2R expression in the CNS, we tested several commercially or academically produced CB2R antibodies using Western...

  14. FRET-based localization of fluorescent protein insertions within the ryanodine receptor type 1.

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    Shweta A Raina

    Full Text Available Fluorescent protein (FP insertions have often been used to localize primary structure elements in mid-resolution 3D cryo electron microscopic (EM maps of large protein complexes. However, little is known as to the precise spatial relationship between the location of the fused FP and its insertion site within a larger protein. To gain insights into these structural considerations, Förster resonance energy transfer (FRET measurements were used to localize green fluorescent protein (GFP insertions within the ryanodine receptor type 1 (RyR1, a large intracellular Ca(2+ release channel that plays a key role in skeletal muscle excitation contraction coupling. A series of full-length His-tagged GFP-RyR1 fusion constructs were created, expressed in human embryonic kidney (HEK-293T cells and then complexed with Cy3NTA, a His-tag specific FRET acceptor. FRET efficiency values measured from each GFP donor to Cy3NTA bound to each His tag acceptor site were converted into intermolecular distances and the positions of each inserted GFP were then triangulated relative to a previously published X-ray crystal structure of a 559 amino acid RyR1 fragment. We observed that the chromophoric centers of fluorescent proteins inserted into RyR1 can be located as far as 45 Å from their insertion sites and that the fused proteins can also be located in internal cavities within RyR1. These findings should prove useful in interpreting structural results obtained in cryo EM maps using fusions of small fluorescent proteins. More accurate point-to-point distance information may be obtained using complementary orthogonal labeling systems that rely on fluorescent probes that bind directly to amino acid side chains.

  15. The Arabidopsis thaliana proteome harbors undiscovered multi-domain molecules with functional guanylyl cyclase catalytic centers

    KAUST Repository

    Wong, Aloysius Tze

    2013-07-08

    Background: Second messengers link external cues to complex physiological responses. One such messenger, 3\\',5\\'-cyclic guanosine monophosphate (cGMP), has been shown to play a key role in many physiological responses in plants. However, in higher plants, guanylyl cyclases (GCs), enzymes that generate cGMP from guanosine-5\\'-triphosphate (GTP) have remained elusive until recently. GC search motifs constructed from the alignment of known GCs catalytic centers form vertebrates and lower eukaryotes have led to the identification of a number of plant GCs that have been characterized in vitro and in vivo.Presentation of the hypothesis.Recently characterized GCs in Arabidopsis thaliana contributed to the development of search parameters that can identify novel candidate GCs in plants. We hypothesize that there are still a substantial number (> 40) of multi-domain molecules with potentially functional GC catalytic centers in plants that remain to be discovered and characterized. Testing the hypothesis. The hypothesis can be tested, firstly, by computational methods constructing 3D models of selected GC candidates using available crystal structures as templates. Homology modeling must include substrate docking that can provide support for the structural feasibility of the GC catalytic centers in those candidates. Secondly, recombinant peptides containing the GC domain need to be tested in in vitro GC assays such as the enzyme-linked immune-sorbent assay (ELISA) and/or in mass spectrometry based cGMP assays. In addition, quantification of in vivo cGMP transients with fluorescent cGMP-reporter assays in wild-type or selected mutants will help to elucidate the biological role of novel GCs.Implications of the hypothesis.If it turns out that plants do harbor a large number of functional GC domains as part of multi-domain enzymes, then major new insights will be gained into the complex signal transduction pathways that link cGMP to fundamental processes such as ion transport

  16. The soluble guanylyl cyclase activator bay 58-2667 selectively limits cardiomyocyte hypertrophy.

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    Jennifer C Irvine

    Full Text Available Although evidence now suggests cGMP is a negative regulator of cardiac hypertrophy, the direct consequences of the soluble guanylyl cyclase (sGC activator BAY 58-2667 on cardiac remodeling, independent of changes in hemodynamic load, has not been investigated. In the present study, we tested the hypothesis that the NO(•-independent sGC activator BAY 58-2667 inhibits cardiomyocyte hypertrophy in vitro. Concomitant impact of BAY 58-2667 on cardiac fibroblast proliferation, and insights into potential mechanisms of action, were also sought. Results were compared to the sGC stimulator BAY 41-2272.Neonatal rat cardiomyocytes were incubated with endothelin-1 (ET(1, 60nmol/L in the presence and absence of BAY 41-2272 and BAY 58-2667 (0.01-0.3 µmol/L. Hypertrophic responses and its triggers, as well as cGMP signaling, were determined. The impact of both sGC ligands on basal and stimulated cardiac fibroblast proliferation in vitro was also determined.We now demonstrate that BAY 58-2667 (0.01-0.3 µmol/L elicited concentration-dependent antihypertrophic actions, inhibiting ET(1-mediated increases in cardiomyocyte 2D area and de novo protein synthesis, as well as suppressing ET(1-induced cardiomyocyte superoxide generation. This was accompanied by potent increases in cardiomyocyte cGMP accumulation and activity of its downstream signal, vasodilator-stimulated phosphoprotein (VASP, without elevating cardiomyocyte cAMP. In contrast, submicromolar concentrations of BAY 58-2667 had no effect on basal or stimulated cardiac fibroblast proliferation. Indeed, only at concentrations ≥10 µmol/L was inhibition of cardiac fibrosis seen in vitro. The effects of BAY 58-2667 in both cell types were mimicked by BAY 41-2272.Our results demonstrate that BAY 58-2667 elicits protective, cardiomyocyte-selective effects in vitro. These actions are associated with sGC activation and are evident in the absence of confounding hemodynamic factors, at low (submicromolar

  17. Impact of the NO-Sensitive Guanylyl Cyclase 1 and 2 on Renal Blood Flow and Systemic Blood Pressure in Mice.

    Science.gov (United States)

    Mergia, Evanthia; Thieme, Manuel; Hoch, Henning; Daniil, Georgios; Hering, Lydia; Yakoub, Mina; Scherbaum, Christina Rebecca; Rump, Lars Christian; Koesling, Doris; Stegbauer, Johannes

    2018-03-23

    Nitric oxide (NO) modulates renal blood flow (RBF) and kidney function and is involved in blood pressure (BP) regulation predominantly via stimulation of the NO-sensitive guanylyl cyclase (NO-GC), existing in two isoforms, NO-GC1 and NO-GC2. Here, we used isoform-specific knockout (KO) mice and investigated their contribution to renal hemodynamics under normotensive and angiotensin II-induced hypertensive conditions. Stimulation of the NO-GCs by S -nitrosoglutathione (GSNO) reduced BP in normotensive and hypertensive wildtype (WT) and NO-GC2-KO mice more efficiently than in NO-GC1-KO. NO-induced increase of RBF in normotensive mice did not differ between the genotypes, but the respective increase under hypertensive conditions was impaired in NO-GC1-KO. Similarly, inhibition of endogenous NO increased BP and reduced RBF to a lesser extent in NO-GC1-KO than in NO-GC2-KO. These findings indicate NO-GC1 as a target of NO to normalize RBF in hypertension. As these effects were not completely abolished in NO-GC1-KO and renal cyclic guanosine monophosphate (cGMP) levels were decreased in both NO-GC1-KO and NO-GC2-KO, the results suggest an additional contribution of NO-GC2. Hence, NO-GC1 plays a predominant role in the regulation of BP and RBF, especially in hypertension. However, renal NO-GC2 appears to compensate the loss of NO-GC1, and is able to regulate renal hemodynamics under physiological conditions.

  18. Gaseous ligand selectivity of the H-NOX sensor protein from Shewanella oneidensis and comparison to those of other bacterial H-NOXs and soluble guanylyl cyclase.

    Science.gov (United States)

    Wu, Gang; Liu, Wen; Berka, Vladimir; Tsai, Ah-Lim

    2017-09-01

    To delineate the commonalities and differences in gaseous ligand discrimination among the heme-based sensors with Heme Nitric oxide/OXygen binding protein (H-NOX) scaffold, the binding kinetic parameters for gaseous ligands NO, CO, and O 2 , including K D , k on , and k off , of Shewanella oneidensis H-NOX (So H-NOX) were characterized in detail in this study and compared to those of previously characterized H-NOXs from Clostridium botulinum (Cb H-NOX), Nostoc sp. (Ns H-NOX), Thermoanaerobacter tengcongensis (Tt H-NOX), Vibrio cholera (Vc H-NOX), and human soluble guanylyl cyclase (sGC), an H-NOX analogue. The K D (NO) and K D (CO) of each bacterial H-NOX or sGC follow the "sliding scale rule"; the affinities of the bacterial H-NOXs for NO and CO vary in a small range but stronger than those of sGC by at least two orders of magnitude. On the other hand, each bacterial H-NOX exhibits different characters in the stability of its 6c NO complex, reactivity with secondary NO, stability of oxyferrous heme and autoxidation to ferric heme. A facile access channel for gaseous ligands is also identified, implying that ligand access has only minimal effect on gaseous ligand selectivity of H-NOXs or sGC. This comparative study of the binding parameters of the bacterial H-NOXs and sGC provides a basis to guide future new structural and functional studies of each specific heme sensor with the H-NOX protein fold. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  19. Immunohistochemistry detected and localized cannabinoid receptor type 2 in bovine fetal pancreas at late gestation

    Directory of Open Access Journals (Sweden)

    Cecilia Dall'Aglio

    2017-03-01

    Full Text Available At present, data on the endocannabinoid system expression and distribution in the pancreatic gland appear scarce and controversial as descriptions are limited to humans and laboratory animals. Since the bovine pancreas is very similar to the human in endocrine portion development and control, studies on the fetal gland could prove to be very interesting, as an abnormal maternal condition during late pregnancy may be a predisposing trigger for adult metabolic disorders. The present investigation studied cannabinoid receptor type 2 presence and distribution in the bovine fetal pancreas towards the end of gestation. Histological analyses revealed numerous endocrinal cell clusters or islets which were distributed among exocrine adenomeri in connectival tissue. Immunohistochemistry showed that endocrine-islets contained some CB2-positive cells with a very peculiar localization that is a few primarily localized at the edges of islets and some of them also scattered in the center of the cluster. Characteristically, also the epithelium of the excretory ducts and the smooth muscle layers of the smaller arteries, in the interlobular glandular septa, tested positive for the CB2 endocannabinoid receptor. Conse - quently, the endocannabinoid system, via the cannabinoid receptor type 2, was hypothesized to play a major role in controlling pancreas function from normal fetal development to correct metabolic functioning in adulthood.

  20. 17 beta-estradiol modifies nitric oxide-sensitive guanylyl cyclase expression and down-regulates its activity in rat anterior pituitary gland.

    Science.gov (United States)

    Cabilla, Jimena P; Díaz, María del Carmen; Machiavelli, Leticia I; Poliandri, Ariel H; Quinteros, Fernanda A; Lasaga, Mercedes; Duvilanski, Beatriz H

    2006-09-01

    Previous studies showed that 17 beta-estradiol (17 beta-E2) regulates the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP pathway in many tissues. Evidence from our laboratory indicates that 17 beta-E2 disrupts the inhibitory effect of NO on prolactin release, decreasing sGC activity and affecting the cGMP pathway in anterior pituitary gland of adult ovariectomized and estrogenized rats. To ascertain the mechanisms by which 17 beta-E2 affects sGC activity, we investigated the in vivo and in vitro effects of 17 beta-E2 on sGC protein and mRNA expression in anterior pituitary gland from immature female rats. In the present work, we showed that 17 beta-E2 acute treatment exerted opposite effects on the two sGC subunits, increasing alpha1 and decreasing beta1 subunit protein and mRNA expression. This action on sGC protein expression was maximal 6-9 h after 17 beta-E2 administration. 17beta-E2 also caused the same effect on mRNA expression at earlier times. Concomitantly, 17 beta-E2 dramatically decreased sGC activity 6 and 9 h after injection. These effects were specific of 17 beta-E2, because they were not observed with the administration of other steroids such as progesterone and 17 alpha-estradiol. This inhibitory action of 17beta-E2 on sGC also required the activation of estrogen receptor (ER), because treatment with the pure ER antagonist ICI 182,780 completely blocked 17 beta-E2 action. 17 beta-E2 acute treatment caused the same effects on pituitary cells in culture. These results suggest that 17 beta-E2 exerts an acute inhibitory effect on sGC in anterior pituitary gland by down-regulating sGC beta 1 subunit and sGC activity in a specific, ER-dependent manner.

  1. Catalytically Active Guanylyl Cyclase B Requires Endoplasmic Reticulum-mediated Glycosylation, and Mutations That Inhibit This Process Cause Dwarfism.

    Science.gov (United States)

    Dickey, Deborah M; Edmund, Aaron B; Otto, Neil M; Chaffee, Thomas S; Robinson, Jerid W; Potter, Lincoln R

    2016-05-20

    C-type natriuretic peptide activation of guanylyl cyclase B (GC-B), also known as natriuretic peptide receptor B or NPR2, stimulates long bone growth, and missense mutations in GC-B cause dwarfism. Four such mutants (L658F, Y708C, R776W, and G959A) bound (125)I-C-type natriuretic peptide on the surface of cells but failed to synthesize cGMP in membrane GC assays. Immunofluorescence microscopy also indicated that the mutant receptors were on the cell surface. All mutant proteins were dephosphorylated and incompletely glycosylated, but dephosphorylation did not explain the inactivation because the mutations inactivated a "constitutively phosphorylated" enzyme. Tunicamycin inhibition of glycosylation in the endoplasmic reticulum or mutation of the Asn-24 glycosylation site decreased GC activity, but neither inhibition of glycosylation in the Golgi by N-acetylglucosaminyltransferase I gene inactivation nor PNGase F deglycosylation of fully processed GC-B reduced GC activity. We conclude that endoplasmic reticulum-mediated glycosylation is required for the formation of an active catalytic, but not ligand-binding domain, and that mutations that inhibit this process cause dwarfism. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Identification of residues in the heme domain of soluble guanylyl cyclase that are important for basal and stimulated catalytic activity.

    Directory of Open Access Journals (Sweden)

    Padmamalini Baskaran

    Full Text Available Nitric oxide signals through activation of soluble guanylyl cyclase (sGC, a heme-containing heterodimer. NO binds to the heme domain located in the N-terminal part of the β subunit of sGC resulting in increased production of cGMP in the catalytic domain located at the C-terminal part of sGC. Little is known about the mechanism by which the NO signaling is propagated from the receptor domain (heme domain to the effector domain (catalytic domain, in particular events subsequent to the breakage of the bond between the heme iron and Histidine 105 (H105 of the β subunit. Our modeling of the heme-binding domain as well as previous homologous heme domain structures in different states point to two regions that could be critical for propagation of the NO activation signal. Structure-based mutational analysis of these regions revealed that residues T110 and R116 in the αF helix-β1 strand, and residues I41 and R40 in the αB-αC loop mediate propagation of activation between the heme domain and the catalytic domain. Biochemical analysis of these heme mutants allows refinement of the map of the residues that are critical for heme stability and propagation of the NO/YC-1 activation signal in sGC.

  3. The fibrate gemfibrozil is a NO- and haem-independent activator of soluble guanylyl cyclase: in vitro studies.

    Science.gov (United States)

    Sharina, I G; Sobolevsky, M; Papakyriakou, A; Rukoyatkina, N; Spyroulias, G A; Gambaryan, S; Martin, E

    2015-05-01

    Fibrates are a class of drugs widely used to treat dyslipidaemias. They regulate lipid metabolism and act as PPARα agonists. Clinical trials demonstrate that besides changes in lipid profiles, fibrates decrease the incidence of cardiovascular events, with gemfibrozil exhibiting the most pronounced benefit. This study aims to characterize the effect of gemfibrozil on the activity and function of soluble guanylyl cyclase (sGC), the key mediator of NO signalling. High-throughput screening of a drug library identified gemfibrozil as a direct sGC activator. Activation of sGC is unique to gemfibrozil and is not shared by other fibrates. Gemfibrozil activated purified sGC, induced endothelium-independent relaxation of aortic rings and inhibited platelet aggregation. Gemfibrozil-dependent activation was absent when the sGC haem domain was deleted, but was significantly enhanced when sGC haem was lacking or oxidized. Oxidation of sGC haem enhanced the vasoactive and anti-platelet effects of gemfibrozil. Gemfibrozil competed with the haem-independent sGC activators ataciguat and cinaciguat. Computational modelling predicted that gemfibrozil occupies the space of the haem group and interacts with residues crucial for haem stabilization. This is consistent with structure-activity data which revealed an absolute requirement for gemfibrozil's carboxyl group. These data suggest that in addition to altered lipid and lipoprotein state, the cardiovascular preventive benefits of gemfibrozil may derive from direct activation and protection of sGC function. A sGC-directed action may explain the more pronounced cardiovascular benefit of gemfibrozil observed over other fibrates and some of the described side effects of gemfibrozil. © 2014 The British Pharmacological Society.

  4. C-X-C Chemokine Receptor Type 4 Plays a Crucial Role in Mediating Oxidative Stress-Induced Podocyte Injury.

    Science.gov (United States)

    Mo, Hongyan; Wu, Qinyu; Miao, Jinhua; Luo, Congwei; Hong, Xue; Wang, Yongping; Tang, Lan; Hou, Fan Fan; Liu, Youhua; Zhou, Lili

    2017-08-20

    Oxidative stress plays a role in mediating podocyte injury and proteinuria. However, the underlying mechanism remains poorly understood. In this study, we investigated the potential role of C-X-C chemokine receptor type 4 (CXCR4), the receptor for stromal cell-derived factor 1α (SDF-1α), in mediating oxidative stress-induced podocyte injury. In mouse model of adriamycin nephropathy (ADR), CXCR4 expression was significantly induced in podocytes as early as 3 days. This was accompanied by an increased upregulation of oxidative stress in podocyte, as demonstrated by malondialdehyde assay, nitrotyrosine staining and secretion of 8-hydroxy-2'-deoxyguanosine in urine, and induction of NOX2 and NOX4, major subunits of NADPH oxidase. CXCR4 was also induced in human kidney biopsies with proteinuric kidney diseases and colocalized with advanced oxidation protein products (AOPPs), an established oxidative stress trigger. Using cultured podocytes and mouse model, we found that AOPPs induced significant loss of podocyte marker Wilms tumor 1 (WT1), nephrin, and podocalyxin, accompanied by upregulation of desmin both in vitro and in vivo. Furthermore, AOPPs worsened proteinuria and aggravated glomerulosclerosis in ADR. These effects were associated with marked activation of SDF-1α/CXCR4 axis in podocytes. Administration of AMD3100, a specific inhibitor of CXCR4, reduced proteinuria and ameliorated podocyte dysfunction and renal fibrosis triggered by AOPPs in mice. In glomerular miniorgan culture, AOPPs also induced CXCR4 expression and downregulated nephrin and WT1. Innovation and Conclusion: These results suggest that chemokine receptor CXCR4 plays a crucial role in mediating oxidative stress-induced podocyte injury, proteinuria, and renal fibrosis. CXCR4 could be a new target for mitigating podocyte injury, proteinuria, and glomerular sclerosis in proteinuric chronic kidney disease. Antioxid. Redox Signal. 27, 345-362.

  5. Expression and Regulation of Corticotropin-Releasing Factor Receptor Type 2 beta in Developing and Mature Mouse Skeletal Muscle

    NARCIS (Netherlands)

    Kuperman, Yael; Issler, Orna; Vaughan, Joan; Bilezikjian, Louise; Vale, Wylie; Chen, Alon

    Corticotropin-releasing factor receptor type 2 (CRFR2) is highly expressed in skeletal muscle (SM) tissue where it is suggested to inhibit interactions between insulin signaling pathway components affecting whole-body glucose homeostasis. However, little is known about factors regulating SM CRFR2

  6. Pharmacological benefits of selective modulation of cannabinoid receptor type 2 (CB2) in experimental Alzheimer's disease.

    Science.gov (United States)

    Jayant, Shalini; Sharma, Brij Mohan; Bansal, Rani; Sharma, Bhupesh

    2016-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that pervasively affects the population across the world. Currently, there is no effective treatment available for this and existing drugs merely slow the progression of cognitive function decline. Thus, massive effort is required to find an intended therapeutic target to overcome this condition. The present study has been framed to investigate the ameliorative role of selective modulator of cannabinoid receptor type 2 (CB2), 1-phenylisatin in experimental AD condition. We have induced experimental AD in mice by using two induction models viz., intracerebroventricular (i.c.v.) administration of streptozotocin (STZ) and aluminum trichloride (AlCl3)+d-galactose. Morris water maze (MWM) and attentional set shifting test (ASST) were used to assess learning and memory. Hematoxylin-eosin and Congo red staining were used to examine the structural variation in brain. Brain oxidative stress (thiobarbituric acid reactive substance and glutathione), nitric oxide levels (nitrites/nitrates), acetyl cholinesterase activity, myeloperoxidase and calcium levels were also estimated. i.c.v. STZ as well as AlCl3+d-galactose have impaired spatial and reversal learning with executive functioning, increased brain oxidative and nitrosative stress, cholinergic activity, inflammation and calcium levels. Furthermore, these agents have also enhanced the burden of Aβ plaque in the brain. Treatment with 1-phenylisatin and donepezil attenuated i.c.v. STZ as well as AlCl3+d-galactose induced impairment of learning-memory, brain biochemistry and brain damage. Hence, this study concludes that CB2 receptor modulation can be a potential therapeutic target for the management of AD. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Geographical distribution of complement receptor type 1 variants and their associated disease risk.

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    Thaisa Lucas Sandri

    Full Text Available Pathogens exert selective pressure which may lead to substantial changes in host immune responses. The human complement receptor type 1 (CR1 is an innate immune recognition glycoprotein that regulates the activation of the complement pathway and removes opsonized immune complexes. CR1 genetic variants in exon 29 have been associated with expression levels, C1q or C3b binding and increased susceptibility to several infectious diseases. Five distinct CR1 nucleotide substitutions determine the Knops blood group phenotypes, namely Kna/b, McCa/b, Sl1/Sl2, Sl4/Sl5 and KCAM+/-.CR1 variants were genotyped by direct sequencing in a cohort of 441 healthy individuals from Brazil, Vietnam, India, Republic of Congo and Ghana.The distribution of the CR1 alleles, genotypes and haplotypes differed significantly among geographical settings (p≤0.001. CR1 variants rs17047660A/G (McCa/b and rs17047661A/G (Sl1/Sl2 were exclusively observed to be polymorphic in African populations compared to the groups from Asia and South-America, strongly suggesting that these two SNPs may be subjected to selection. This is further substantiated by a high linkage disequilibrium between the two variants in the Congolese and Ghanaian populations. A total of nine CR1 haplotypes were observed. The CR1*AGAATA haplotype was found more frequently among the Brazilian and Vietnamese study groups; the CR1*AGAATG haplotype was frequent in the Indian and Vietnamese populations, while the CR1*AGAGTG haplotype was frequent among Congolese and Ghanaian individuals.The African populations included in this study might have a selective advantage conferred to immune genes involved in pathogen recognition and signaling, possibly contributing to disease susceptibility or resistance.

  8. Fluorescent fusion proteins of soluble guanylyl cyclase indicate proximity of the heme nitric oxide domain and catalytic domain.

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    Tobias Haase

    Full Text Available BACKGROUND: To examine the structural organisation of heterodimeric soluble guanylyl cyclase (sGC Förster resonance energy transfer (FRET was measured between fluorescent proteins fused to the amino- and carboxy-terminal ends of the sGC beta1 and alpha subunits. METHODOLOGY/PRINCIPAL FINDINGS: Cyan fluorescent protein (CFP was used as FRET donor and yellow fluorescent protein (YFP as FRET acceptor. After generation of recombinant baculovirus, fluorescent-tagged sGC subunits were co-expressed in Sf9 cells. Fluorescent variants of sGC were analyzed in vitro in cytosolic fractions by sensitized emission FRET. Co-expression of the amino-terminally tagged alpha subunits with the carboxy-terminally tagged beta1 subunit resulted in an enzyme complex that showed a FRET efficiency of 10% similar to fluorescent proteins separated by a helix of only 48 amino acids. Because these findings indicated that the amino-terminus of the alpha subunits is close to the carboxy-terminus of the beta1 subunit we constructed fusion proteins where both subunits are connected by a fluorescent protein. The resulting constructs were not only fluorescent, they also showed preserved enzyme activity and regulation by NO. CONCLUSIONS/SIGNIFICANCE: Based on the ability of an amino-terminal fragment of the beta1 subunit to inhibit activity of an heterodimer consisting only of the catalytic domains (alphacatbetacat, Winger and Marletta (Biochemistry 2005, 44:4083-90 have proposed a direct interaction of the amino-terminal region of beta1 with the catalytic domains. In support of such a concept of "trans" regulation of sGC activity by the H-NOX domains our results indicate that the domains within sGC are organized in a way that allows for direct interaction of the amino-terminal regulatory domains with the carboxy-terminal catalytic region. In addition, we constructed "fluorescent-conjoined" sGC's by fusion of the alpha amino-terminus to the beta1 carboxy-terminus leading to a

  9. Ca 2+ signaling by plant Arabidopsis thaliana Pep peptides depends on AtPepR1, a receptor with guanylyl cyclase activity, and cGMP-activated Ca 2+ channels

    KAUST Repository

    Qia, Zhi; Verma, Rajeev K.; Gehring, Christoph A; Yamaguchi, Yube; Zhao, Yichen; Ryan, Clarence A.; Berkowitz, Gerald A.

    2010-01-01

    receptor- like kinase receptor AtPepR1 has guanylyl cyclase activity, generating cGMP from GTP, and that cGMP can activate CNGC2- dependent cytosolic Ca 2+ elevation. AtPep-dependent expression of pathogen-defense genes (PDF1.2, MPK3, and WRKY33

  10. Cell and Receptor Type-Specific Alterations in Markers of GABA Neurotransmission in the Prefrontal Cortex of Subjects with Schizophrenia

    OpenAIRE

    Lewis, David A.; Hashimoto, Takanori; Morris, Harvey M.

    2008-01-01

    Impairments in cognitive control, such as those involved in working memory, are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC) in individuals with schizophrenia. This dysfunction appears to result, at least in part, from abnormalities in GABA-mediated neurotransmission. In this paper, we review recent findings indicating that the altered DLPFC circuitry in subjects with schizophrenia reflects changes in the expression of genes that encode selective presynaptic and p...

  11. Isolation of lymphocyte membrane complement receptor type two (the C3d receptor) and preparation of receptor-specific antibody.

    OpenAIRE

    Lambris, J D; Dobson, N J; Ross, G D

    1981-01-01

    A glycoprotein binding complement component C3d was isolated from media used for culture of Raji human lymphoblastoid cells. Analysis by sodium dodecyl sulfate/polyacrylamide gel electrophoresis and gas/liquid chromatography indicated that the C3d-binding glycoprotein consisted of a single polypeptide chain with extensive intrachain disulfide bonds, a molecular weight of 72,000, and several different bound carbohydrates. Several lines of evidence indicated that this medium-derived C3d-binding...

  12. Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist.

    Science.gov (United States)

    Steiner, Michel A; Gatfield, John; Brisbare-Roch, Catherine; Dietrich, Hendrik; Treiber, Alexander; Jenck, Francois; Boss, Christoph

    2013-06-01

    Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type 1 (OXR-1) and 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that is orally available, penetrates the brain, and decreases fear, compulsive behaviors and autonomic stress reactions in rats. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta

    DEFF Research Database (Denmark)

    Yan, Zhen Cheng; Liu, Dao Yan; Zhang, Li Li

    2007-01-01

    Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-delta (PPAR-delta)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow...... or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p...

  14. Heterodimerization with the β1 subunit directs the α2 subunit of nitric oxide-sensitive guanylyl cyclase to calcium-insensitive cell-cell contacts in HEK293 cells: Interaction with Lin7a.

    Science.gov (United States)

    Hochheiser, Julia; Haase, Tobias; Busker, Mareike; Sömmer, Anne; Kreienkamp, Hans-Jürgen; Behrends, Sönke

    2016-12-15

    Nitric oxide-sensitive guanylyl cyclase is a heterodimeric enzyme consisting of an α and a β subunit. Two different α subunits (α 1 and α 2 ) give rise to two heterodimeric enzymes α 1 /β 1 and α 2 /β 1 . Both coexist in a wide range of tissues including blood vessels and the lung, but expression of the α 2 /β 1 form is generally much lower and approaches levels similar to the α 1 /β 1 form in the brain only. In the present paper, we show that the α 2 /β 1 form interacts with Lin7a in mouse brain synaptosomes based on co-precipitation analysis. In HEK293 cells, we found that the overexpressed α 2 /β 1 form, but not the α 1 /β 1 form is directed to calcium-insensitive cell-cell contacts. The isolated PDZ binding motif of an amino-terminally truncated α 2 subunit was sufficient for cell-cell contact localization. For the full length α 2 subunit with the PDZ binding motif this was only the case in the heterodimer configuration with the β 1 subunit, but not as isolated α 2 subunit. We conclude that the PDZ binding motif of the α 2 subunit is only accessible in the heterodimer conformation of the mature nitric oxide-sensitive enzyme. Interaction with Lin7a, a small scaffold protein important for synaptic function and cell polarity, can direct this complex to nectin based cell-cell contacts via MPP3 in HEK293 cells. We conclude that heterodimerization is a prerequisite for further protein-protein interactions that direct the α 2 /β 1 form to strategic sites of the cell membrane with adjacent neighbouring cells. Drugs increasing the nitric oxide-sensitivity of this specific form may be particularly effective. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Protein tyrosine phosphatase receptor type R deficient mice exhibit increased exploration in a new environment and impaired novel object recognition memory

    NARCIS (Netherlands)

    Erkens, M.; Bakker, B.; Duijn, L.M. van; Hendriks, W.J.A.J.; Zee, C.E.E.M. van der

    2014-01-01

    Mouse gene Ptprr encodes multiple protein tyrosine phosphatase receptor type R (PTPRR) isoforms that negatively regulate mitogen-activated protein kinase (MAPK) signaling pathways. In the mouse brain, PTPRR proteins are expressed in cerebellum, olfactory bulb, hippocampus, amygdala and perirhinal

  16. Different serotonin receptor types participate in 5-hydroxytryptophan-induced gonadotropins and prolactin release in the female infantile rat.

    Science.gov (United States)

    Lacau-Mengido, I M; Libertun, C; Becú-Villalobos, D

    1996-05-01

    Serotonin (5-HT) receptors can be classified into at least three, possibly up to seven, classes of receptors. They comprise the 5-HT1, 5-HT2, and 5-HT3 classes, the "uncloned' 5-HT4 receptor and the recombinant receptors 5-ht5, 5-ht6 and 5-ht7. We investigated the role of different serotonin receptor types in a neuroendocrine response to the activation of the serotonergic system. Female immature rats were chosen as an experimental model as it has been shown that during the 3rd week of life, and not at later developmental stages, 5-hydroxytryptophan (5-HTP, a serotonin precursor) induces gonadotropin release in females and not in males. Besides, at this age, serotonin releases prolactin in both sexes. 5-HTP (50 mg/kg) released prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as expected. Ketanserin (5-HT2A antagonist) and methysergide (5-HT2C antagonist) blocked 5-HTP-induced prolactin release, but did not block the LH or FSH responses. Ondansetron (5-HT3 receptor antagonist) did not modify prolactin response to 5-HTP, whereas it blocked 5-HTP-induced LH and FSH release. Propranolol (5-HT1 and beta-adrenergic antagonist) blocked prolactin, LH and FSH release induced by 5-HTP. The 5-HT2C agonist 1-(3-chlorophenyl)piperazine dihydrochloride released prolactin, without modifying LH or FSH release. Methyl-quipazine and phenylbiguanide (5-HT3 agonists) increased both LH and FSH levels, without altering prolactin secretion. The present experiments indicate that serotonin acting at the 5-HT3 receptor mediates LH and FSH release in infantile female rats, whereas 5-HT2C or 2A receptor types participate in the release of prolactin at this age. 5-HT1 receptor type may be involved in the release of the three hormones, though a beta-adrenergic component of the response cannot be discarded.

  17. The Pseudo signal peptide of the corticotropin-releasing factor receptor type 2A prevents receptor oligomerization.

    Science.gov (United States)

    Teichmann, Anke; Rutz, Claudia; Kreuchwig, Annika; Krause, Gerd; Wiesner, Burkhard; Schülein, Ralf

    2012-08-03

    N-terminal signal peptides mediate the interaction of native proteins with the translocon complex of the endoplasmic reticulum membrane and are cleaved off during early protein biogenesis. The corticotropin-releasing factor receptor type 2a (CRF(2(a))R) possesses an N-terminal pseudo signal peptide, which represents a so far unique domain within the large protein family of G protein-coupled receptors (GPCRs). In contrast to a conventional signal peptide, the pseudo signal peptide remains uncleaved and consequently forms a hydrophobic extension at the N terminus of the receptor. The functional consequence of the presence of the pseudo signal peptide is not understood. Here, we have analyzed the significance of this domain for receptor dimerization/oligomerization in detail. To this end, we took the CRF(2(a))R and the homologous corticotropin-releasing factor receptor type 1 (CRF(1)R) possessing a conventional cleaved signal peptide and conducted signal peptide exchange experiments. Using single cell and single molecule imaging methods (fluorescence resonance energy transfer and fluorescence cross-correlation spectroscopy, respectively) as well as biochemical experiments, we obtained two novel findings; we could show that (i) the CRF(2(a))R is expressed exclusively as a monomer, and (ii) the presence of the pseudo signal peptide prevents its oligomerization. Thus, we have identified a novel functional domain within the GPCR protein family, which plays a role in receptor oligomerization and which may be useful to study the functional significance of this process in general.

  18. Role of Nitric Oxide, Nitric Oxide Synthase, Soluble Guanylyl Cyclase, and cGMP-Dependent Protein Kinase I in Mouse Stem Cell Cardiac Development

    Directory of Open Access Journals (Sweden)

    Valentina Spinelli

    2016-01-01

    Full Text Available Introduction and Aim. Nitric oxide (NO can trigger cardiac differentiation of embryonic stem cells (ESCs, indicating a cardiogenic function of the NO synthetizing enzyme(s (NOS. However, the involvement of the NO/NOS downstream effectors soluble guanylyl cyclase (sGC and cGMP activated protein kinase I (PKG-I is less defined. Therefore, we assess the involvement of the entire NO/NOS/sGC/PKG-I pathway during cardiac differentiation process. Methods. Mouse ESCs were differentiated toward cardiac lineages by hanging drop methodology for 21 days. NOS/sGC/PKG-I pathway was studied quantifying genes, proteins, enzymatic activities, and effects of inhibition during differentiation. Percentages of beating embryoid bodies (mEBs were evaluated as an index of cardiogenesis. Results and Discussion. Genes and protein expression of enzymes were increased during differentiation with distinctive kinetics and proteins possessed their enzymatic functions. Exogenous administered NO accelerated whereas the blockade of PKG-I strongly slowed cardiogenesis. sGC inhibition was effective only at early stages and NOS blockade ineffective. Of NOS/sGC/PKG-I pathway, PKG-I seems to play the prominent role in cardiac maturation. Conclusion. We concluded that exogenous administered NO and other pharmacological strategies able to increase the activity of PKG-I provide new tools to investigate and promote differentiation of cardiogenic precursors.

  19. Nitric oxide-soluble guanylyl cyclase-cyclic GMP signaling in the striatum: New targets for the treatment of Parkinson's disease?

    Directory of Open Access Journals (Sweden)

    Anthony R West

    2011-06-01

    Full Text Available Striatal nitric oxide (NO-producing interneurons play an important role in the regulation of corticostriatal synaptic transmission and motor behavior. Striatal NO synthesis is driven by concurrent activation of NMDA and dopamine (DA D1 receptors. NO diffuses into the dendrites of medium-sized spiny neurons (MSNs which contain high levels of NO receptors called soluble guanylyl cyclases (sGC. NO-mediated activation of sGC leads to the synthesis of the second messenger cGMP. In the intact striatum, transient elevations in intracellular cGMP primarily act to increase neuronal excitability and to facilitate glutamatergic corticostriatal transmission. NO-cGMP signaling also functionally opposes the inhibitory effects of DA D2 receptor activation on corticostriatal transmission. Not surprisingly, abnormal striatal NO-sGC-cGMP signaling becomes apparent following striatal DA depletion, an alteration thought to contribute to pathophysiological changes observed in basal ganglia circuits in Parkinson’s disease (PD. Here, we discuss recent developments in the field which have shed light on the role of NO-sGC-cGMP signaling pathways in basal ganglia dysfunction and motor symptoms associated with PD and L-DOPA-induced dyskinesias.

  20. Optogenetic manipulation of cGMP in cells and animals by the tightly light-regulated guanylyl-cyclase opsin CyclOp.

    Science.gov (United States)

    Gao, Shiqiang; Nagpal, Jatin; Schneider, Martin W; Kozjak-Pavlovic, Vera; Nagel, Georg; Gottschalk, Alexander

    2015-09-08

    Cyclic GMP (cGMP) signalling regulates multiple biological functions through activation of protein kinase G and cyclic nucleotide-gated (CNG) channels. In sensory neurons, cGMP permits signal modulation, amplification and encoding, before depolarization. Here we implement a guanylyl cyclase rhodopsin from Blastocladiella emersonii as a new optogenetic tool (BeCyclOp), enabling rapid light-triggered cGMP increase in heterologous cells (Xenopus oocytes, HEK293T cells) and in Caenorhabditis elegans. Among five different fungal CyclOps, exhibiting unusual eight transmembrane topologies and cytosolic N-termini, BeCyclOp is the superior optogenetic tool (light/dark activity ratio: 5,000; no cAMP production; turnover (20 °C) ∼17 cGMP s(-1)). Via co-expressed CNG channels (OLF in oocytes, TAX-2/4 in C. elegans muscle), BeCyclOp photoactivation induces a rapid conductance increase and depolarization at very low light intensities. In O2/CO2 sensory neurons of C. elegans, BeCyclOp activation evokes behavioural responses consistent with their normal sensory function. BeCyclOp therefore enables precise and rapid optogenetic manipulation of cGMP levels in cells and animals.

  1. Neomycin is a platelet-derived growth factor (PDGF) antagonist that allows discrimination of PDGF alpha- and beta-receptor signals in cells expressing both receptor types.

    Science.gov (United States)

    Vassbotn, F S; Ostman, A; Siegbahn, A; Holmsen, H; Heldin, C H

    1992-08-05

    The aminoglycoside neomycin has recently been found to affect certain platelet-derived growth factor (PDGF) responses in C3H/10T1/2 C18 fibroblasts. Using porcine aortic endothelial cells transfected with PDGF alpha- or beta-receptors, we explored the possibility that neomycin interferes with the interaction between the different PDGF isoforms and their receptors. We found that neomycin (5 mM) inhibited the binding of 125I-PDGF-BB to the alpha-receptor with only partial effect on the binding of 125I-PDGF-AA; in contrast, the binding of 125I-PDGF-BB to the beta-receptor was not affected by the aminoglycoside. Scatchard analyses showed that neomycin (5 mM) decreased the number of binding sites for PDGF-BB on alpha-receptor-expressing cells by 87%. Together with cross-competition studies with 125I-labeled PDGF homodimers, the effect of neomycin indicates that PDGF-AA and PDGF-BB bind to both common and unique structures on the PDGF alpha-receptor. Neomycin specifically inhibited the autophosphorylation of the alpha-receptor by PDGF-BB, with less effect on the phosphorylation induced by PDGF-AA and no effect on the phosphorylation of the beta-receptor by PDGF-BB. Thus, neomycin is a PDGF isoform- and receptor-specific antagonist that provides a possibility to compare the signal transduction pathways of alpha- and beta-receptors in cells expressing both receptor types. This approach was used to show that activation of PDGF beta-receptors by PDGF-BB mediated a chemotactic response in human fibroblasts, whereas activation of alpha-receptors by the same ligand inhibited chemotaxis.

  2. Cannabinoid receptor type-1: breaking the dogmas [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Arnau Busquets Garcia

    2016-05-01

    Full Text Available The endocannabinoid system (ECS is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids, and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB1. In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells and intracellular compartments (e.g., mitochondria. Interestingly, cellular and molecular effects are differentially mediated by CB1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons. Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.

  3. Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer.

    Science.gov (United States)

    Takahashi, Satoru; Uemura, Hiroji; Seeni, Azman; Tang, Mingxi; Komiya, Masami; Long, Ne; Ishiguro, Hitoshi; Kubota, Yoshinobu; Shirai, Tomoyuki

    2012-10-01

    With the limited strategies for curative treatment of castration-resistant prostate cancer (CRPC), public interest has focused on the potential prevention of prostate cancer. Recent studies have demonstrated that an angiotensin II receptor blocker (ARB) has the potential to decrease serum prostate-specific antigen (PSA) level and improve performance status in CRPC patients. These facts prompted us to investigate the direct effects of ARBs on prostate cancer growth and progression. Transgenic rat for adenocarcinoma of prostate (TRAP) model established in our laboratory was used. TRAP rats of 3 weeks of age received ARB (telmisartan or candesartan) at the concentration of 2 or 10 mg/kg/day in drinking water for 12 weeks. In vitro analyses for cell growth, ubiquitylation or reporter gene assay were performed using LNCaP cells. We found that both telmisartan and candesartan attenuated prostate carcinogenesis in TRAP rats by augmentation of apoptosis resulting from activation of caspases, inactivation of p38 MAPK and down-regulation of the androgen receptor (AR). Further, microarray analysis demonstrated up-regulation of estrogen receptor β (ERβ) by ARB treatment. In both parental and androgen-independent LNCaP cells, ARB inhibited both cell growth and AR-mediated transcriptional activity. ARB also exerted a mild additional effect on AR-mediated transcriptional activation by the ERβ up-regulation. An intervention study revealed that PSA progression was prolonged in prostate cancer patients given an ARB compared with placebo control. These data provide a new concept that ARBs are promising potential chemopreventive and chemotherapeutic agents for prostate cancer. Copyright © 2012 Wiley Periodicals, Inc.

  4. Expression of receptor-type protein tyrosine phosphatase in developing and adult renal vasculature.

    Directory of Open Access Journals (Sweden)

    Keiko Takahashi

    Full Text Available Renal vascular development is a coordinated process that requires ordered endothelial cell proliferation, migration, intercellular adhesion, and morphogenesis. In recent decades, studies have defined the pivotal role of endothelial receptor tyrosine kinases (RPTKs in the development and maintenance of renal vasculature. However, the expression and the role of receptor tyrosine phosphatases (RPTPs in renal endothelium are poorly understood, though coupled and counterbalancing roles of RPTKs and RPTPs are well defined in other systems. In this study, we evaluated the promoter activity and immunolocalization of two endothelial RPTPs, VE-PTP and PTPμ, in developing and adult renal vasculature using the heterozygous LacZ knock-in mice and specific antibodies. In adult kidneys, both VE-PTP and PTPμ were expressed in the endothelium of arterial, glomerular, and medullary vessels, while their expression was highly limited in peritubular capillaries and venous endothelium. VE-PTP and PTPμ promoter activity was also observed in medullary tubular segments in adult kidneys. In embryonic (E12.5, E13.5, E15.5, E17.5 and postnatal (P0, P3, P7 kidneys, these RPTPs were expressed in ingrowing renal arteries, developing glomerular microvasculature (as early as the S-shaped stage, and medullary vessels. Their expression became more evident as the vasculatures matured. Peritubular capillary expression of VE-PTP was also noted in embryonic and postnatal kidneys. Compared to VE-PTP, PTPμ immunoreactivity was relatively limited in embryonic and neonatal renal vasculature and evident immunoreactivity was observed from the P3 stage. These findings indicate 1 VE-PTP and PTPμ are expressed in endothelium of arterial, glomerular, and medullary renal vasculature, 2 their expression increases as renal vascular development proceeds, suggesting that these RPTPs play a role in maturation and maintenance of these vasculatures, and 3 peritubular capillary VE-PTP expression

  5. Metabotropic glutamate receptor type 1 autoimmunity: Clinical features and treatment outcomes.

    Science.gov (United States)

    Lopez-Chiriboga, A Sebastian; Komorowski, Lars; Kümpfel, Tania; Probst, Christian; Hinson, Shannon R; Pittock, Sean J; McKeon, Andrew

    2016-03-15

    To describe retrospectively the clinical associations of immunoglobulin G (IgG) targeting metabotropic glutamate receptor 1 (mGluR1-IgG). Specimens of 9 patients evaluated on a service basis in the Mayo Clinic Neuroimmunology Laboratory by tissue-based immunofluorescence assay (IFA) yielded a robust, synaptic immunostaining pattern consistent with mGluR1-IgG (serum, 9; CSF, 2 available). Transfected HEK293 cell-based assay (CBA) confirmed mGluR1 specificity in all 11 specimens. A further 2 patients were detected in Germany primarily by CBA. The median symptom onset age for the 11 patients was 58 years (range 33-81 years); 6 were male. All 9 Mayo Clinic patients had subacute onset of cerebellar ataxia, 4 had dysgeusia, 1 had psychiatric symptoms, and 1 had cognitive impairment. All were evaluated for malignancy, but only 1 was affected (cutaneous T-cell lymphoma). One developed ataxia post-herpes zoster infection. Head MRIs were generally atrophic or normal-appearing, and CSF was inflammatory in just 1 of 5 tested, though mGluR1-IgG was detected in both specimens submitted. Five patients improved (attributable to immunotherapy in 4, spontaneously in 1), 3 stabilized (attributable to immunotherapy in 2, cancer therapy in 1), and 1 progressively declined (untreated). The 2 German patients had ataxia, but fulfilled multiple sclerosis diagnostic criteria (1 relapsing-remitting, 1 progressive). However, both had histories of hematologic malignancy (acute lymphocytic leukemia and mantle cell lymphoma), and had mGluR1-IgG detected in serum by CBA (weakly positive on tissue-based IFA). mGluR1 autoimmunity represents a treatable form of cerebellar ataxia. Dysgeusia may be a diagnostic clue. Paraneoplastic, parainfectious, or idiopathic causes may occur. © 2016 American Academy of Neurology.

  6. Spontaneous complement activation on human B cells results in localized membrane depolarization and the clustering of complement receptor type 2 and C3 fragments

    DEFF Research Database (Denmark)

    Løbner, Morten; Leslie, Robert G Q; Prodinger, Wolfgang M

    2009-01-01

    While our previous studies have demonstrated that complement activation induced by complement receptors type 2 (CR2/CD21) and 1 (CR1/CD35) results in C3-fragment deposition and membrane attack complex (MAC) formation in human B cells, the consequences of these events for B-cell functions remain u...

  7. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on (9)-tetrahydrocannabinol challenge tests

    NARCIS (Netherlands)

    Guan, Zheng; Klumpers, Linda E.; Oyetayo, Olubukayo-Opeyemi; Heuberger, Jules; van Gerven, Joop M. A.; Stevens, Jasper

    Aim: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of

  8. Interleukin-1 receptor type I gene-deficient mice are less susceptible to Staphylococcus epidermidis biomaterial-associated infection than are wild-type mice

    NARCIS (Netherlands)

    Boelens, J. J.; van der Poll, T.; Zaat, S. A.; Murk, J. L.; Weening, J. J.; Dankert, J.

    2000-01-01

    Elevated concentrations of interleukin-1 (IL-1) were found in tissue surrounding biomaterials infected with Staphylococcus epidermidis. To determine the role of IL-1 in biomaterial-associated infection (BAI), IL-1 receptor type I-deficient (IL-1R(-/-)) and wild-type mice received subcutaneous

  9. Conditional expression of the dominant-negative TGF-β receptor type II elicits lingual epithelial hyperplasia in transgenic mice.

    Science.gov (United States)

    Li, Feng; Zhou, Mingliang

    2013-05-01

    The transforming growth factor-β (TGF-β) signaling pathway is generally believed to be a potent inhibitor of proliferation. However, many epithelia lacking the essential Tgfbr2 gene still maintain normal tissue homeostasis. Here, transgenic mice expressing rtTA from the human keratin 14 (K14) promoter were used to generate an inducible dominant-negative TGF-β receptor type II (Tgfbr2) mutant model, which allowed us to distinguish between the primary and secondary effects of TGF-β signaling disruption by Doxycycline treatment in K14+ epithelial stem cells. We showed that in mice lacking TGF-β signaling in K14+ cells, invasive carcinomas developed on the ventral surface of the tip of the tongue, while filiform papillae on the dorsal surface showed different pathological changes from the tip to the posterior of the tongue. In addition, acetylation levels of histone H4 and histone H3 rapidly increased, while pMAPK activity was enhanced and Jagged2 inactivated in lingual epithelia after disruption of TGF-β signaling. Our results contribute to the understanding of TGF-β signaling in regulating homeostasis and carcinogenesis in lingual epithelia. Copyright © 2013 Wiley Periodicals, Inc.

  10. Interactions between environmental factors and melatonin receptor type 1A polymorphism in relation to oral cancer susceptibility and clinicopathologic development.

    Directory of Open Access Journals (Sweden)

    Feng-Yan Lin

    Full Text Available The purpose of this study was to explore the combined effect of melatonin receptor type 1A (MTNR1A gene polymorphisms and exposure to environmental carcinogens on the susceptibility and clinicopathological characteristics of oral cancer.Three polymorphisms of the MTNR1A gene from 618 patients with oral cancer and 560 non-cancer controls were analyzed by real-time polymerase chain reaction (PCR. The CTA haplotype of the studied MTNR1A polymorphisms (rs2119882, rs13140012, rs6553010 was related to a higher risk of oral cancer. Moreover, MTNR1A gene polymorphisms exhibited synergistic effects of environmental factors (betel quid and tobacco use on the susceptibility of oral cancer. Finally, oral-cancer patients with betel quid-chewing habit who had T/T allele of MTNR1A rs13140012 were at higher risk for developing an advanced clinical stage and lymph node metastasis.These results support gene-environment interactions of MTNR1A polymorphisms with smoking and betel quid-chewing habits possibly altering oral-cancer susceptibility and metastasis.

  11. Receptor-type Protein Tyrosine Phosphatase β Regulates Met Phosphorylation and Function in Head and Neck Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Yiru Xu

    2012-11-01

    Full Text Available Head and neck squamous cell carcinoma (HNSCC is the sixth most common cancer and has a high rate of mortality. Emerging evidence indicates that hepatocyte growth factor receptor (or Met pathway plays a pivotal role in HNSCC metastasis and resistance to chemotherapy. Met function is dependent on tyrosine phosphorylation that is under direct control by receptor-type protein tyrosine phosphatase β (RPTP-β. We report here that RPTP-β expression is significantly downregulated in HNSCC cells derived from metastatic tumors compared to subject-matched cells from primary tumors. Knockdown of endogenous RPTP-β in HNSCC cells from primary tumor potentiated Met tyrosine phosphorylation, downstream mitogen-activated protein (MAP kinase pathway activation, cell migration, and invasion. Conversely, restoration of RPTP-β expression in cells from matched metastatic tumor decreased Met tyrosine phosphorylation and downstream functions. Furthermore, we observed that six of eight HNSCC tumors had reduced levels of RPTP-β protein in comparison with normal oral tissues. Collectively, the results demonstrate the importance of RPTP-β in tumor biology of HNSCC through direct dephosphorylation of Met and regulation of downstream signal transduction pathways. Reduced RPTP-β levels, with or without Met overexpression, could promote Met activation in HNSCC tumors.

  12. Membrane Estrogen Receptor-α Interacts with Metabotropic Glutamate Receptor Type 1a to Mobilize Intracellular Calcium in Hypothalamic Astrocytes

    Science.gov (United States)

    Kuo, John; Hariri, Omid R.; Bondar, Galyna; Ogi, Julie; Micevych, Paul

    2009-01-01

    Estradiol, acting on a membrane-associated estrogen receptor-α (mERα), induces an increase in free cytoplasmic calcium concentration ([Ca2+]i) needed for progesterone synthesis in hypothalamic astrocytes. To determine whether rapid estradiol signaling involves an interaction of mERα with metabotropic glutamate receptor type 1a (mGluR1a), changes in [Ca2+]i were monitored with the calcium indicator, Fluo-4 AM, in primary cultures of female postpubertal hypothalamic astrocytes. 17β-Estradiol over a range of 1 nm to 100 nm induced a maximal increase in [Ca2+]i flux measured as a change in relative fluorescence [ΔF Ca2+ = 615 ± 36 to 641 ± 47 relative fluorescent units (RFU)], whereas 0.1 nm of estradiol stimulated a moderate [Ca2+]i increase (275 ± 16 RFU). The rapid estradiol-induced [Ca2+]i flux was blocked with 1 μm of the estrogen receptor antagonist ICI 182,780 (635 ± 24 vs. 102 ± 11 RFU, P estradiol-induced membrane signaling in astrocytes. PMID:18948402

  13. Kaempferol inhibits fibroblast collagen synthesis, proliferation and activation in hypertrophic scar via targeting TGF-β receptor type I.

    Science.gov (United States)

    Li, Hongwei; Yang, Liu; Zhang, Yuebing; Gao, Zhigang

    2016-10-01

    Hypertrophic scar (HPS) formation is a debilitating condition that results in pain, esthetic symptom and loss of tissue function. So far, no satisfactory therapeutic approach has been available for HPS treatment. In this study, we discovered that a natural small molecule, kaempferol, could significantly inhibit HPS formation in a mechanical load-induced mouse model. Our results also demonstrated that kaempferol remarkably attenuated collagen synthesis, proliferation and activation of fibroblasts in vitro and in vivo. Western blot analysis further revealed that kaempferol significantly down-regulated Smad2 and Smad3 phosphorylation in a dose-dependent manner. At last, we found that such bioactivity of kaempferol which resulted from the inhibition of TGF-β1/Smads signaling was induced by the selective binding of kaempferol to TGF-β receptor type I (TGFβRI). These findings suggest that kaempferol could be developed into a promising agent for the treatment of HPS or other fibroproliferative disorders. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  14. Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-δ

    International Nuclear Information System (INIS)

    Yan Zhencheng; Liu Daoyan; Zhang Lili; Shen Chenyi; Ma Qunli; Cao Tingbing; Wang Lijuan; Nie Hai; Zidek, Walter; Tepel, Martin; Zhu Zhiming

    2007-01-01

    Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-δ (PPAR-δ)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p < 0.05). Adipocyte hypertrophy induced by high-fat diet was accompanied by increased CB1 expression in adipose tissue, whereas exercise significantly reduced CB1 expression (each p < 0.05). CB1 receptor expression and adipocyte differentiation were directly regulated by PPAR-δ. Adipocyte hypertrophy induced by high-fat diet was accompanied by reduced PPAR-δ. Furthermore, selective silencing of PPAR-δ by RNA interference in 3T3-L1-preadipocyte cells significantly increased CB1 expression from 1.00 ± 0.06 (n = 3) to 1.91 ± 0.06 (n = 3; p < 0.01) and increased adipocyte differentiation, whereas adenovirus-mediated overexpression of PPAR-δ significantly reduced CB1 expression to 0.39 ± 0.03 (n = 3; p < 0.01) and reduced adipocyte differentiation. In the presence of the CB1 antagonist rimonabant adipocyte differentiation in stimulated 3T3 L1 preadipocyte cells was significantly reduced. The study indicates that high-fat diet-induced hypertrophy of adipocytes is associated with increased CB1 receptor expression which is directly regulated by PPAR-δ. Both CB1 and PPAR-δ are intimately involved in therapeutic interventions against a most important cardiovascular risk factor

  15. Nitric oxide-sensitive guanylyl cyclase is differentially regulated by nuclear and non-nuclear estrogen pathways in anterior pituitary gland.

    Directory of Open Access Journals (Sweden)

    Jimena P Cabilla

    Full Text Available 17β-estradiol (E2 regulates hormonal release as well as proliferation and cell death in the pituitary. The main nitric oxide receptor, nitric oxide sensitive- or soluble guanylyl cyclase (sGC, is a heterodimer composed of two subunits, α and β, that catalyses cGMP formation. α1β1 is the most abundant and widely expressed heterodimer, showing the greater activity. Previously we have shown that E2 decreased sGC activity but exerts opposite effects on sGC subunits increasing α1 and decreasing β1 mRNA and protein levels. In the present work we investigate the mechanisms by which E2 differentially regulates sGC subunits' expression on rat anterior pituitary gland. Experiments were performed on primary cultures of anterior pituitary cells from adult female Wistar rats at random stages of estrous cycle. After 6 h of E2 treatment, α1 mRNA and protein expression is increased while β1 levels are down-regulated. E2 effects on sGC expression are partially dependent on de novo transcription while de novo translation is fully required. E2 treatment decreased HuR mRNA stabilization factor and increased AUF1 p37 mRNA destabilization factor. E2-elicited β1 mRNA decrease correlates with a mRNA destabilization environment in the anterior pituitary gland. On the other hand, after 6 h of treatment, E2-BSA (1 nM and E2-dendrimer conjugate (EDC, 1 nM were unable to modify α1 or β1 mRNA levels, showing that nuclear receptor is involved in E2 actions. However, at earlier times (3 h, 1 nM EDC causes a transient decrease of α1 in a PI3k-dependent fashion. Our results show for the first time that E2 is able to exert opposite actions in the anterior pituitary gland, depending on the activation of classical or non-classical pathways. Thus, E2 can also modify sGC expression through membrane-initiated signals bringing to light a new point of regulation in NO/sGC pathway.

  16. Nitric oxide-sensitive guanylyl cyclase is differentially regulated by nuclear and non-nuclear estrogen pathways in anterior pituitary gland.

    Science.gov (United States)

    Cabilla, Jimena P; Nudler, Silvana I; Ronchetti, Sonia A; Quinteros, Fernanda A; Lasaga, Mercedes; Duvilanski, Beatriz H

    2011-01-01

    17β-estradiol (E2) regulates hormonal release as well as proliferation and cell death in the pituitary. The main nitric oxide receptor, nitric oxide sensitive- or soluble guanylyl cyclase (sGC), is a heterodimer composed of two subunits, α and β, that catalyses cGMP formation. α1β1 is the most abundant and widely expressed heterodimer, showing the greater activity. Previously we have shown that E2 decreased sGC activity but exerts opposite effects on sGC subunits increasing α1 and decreasing β1 mRNA and protein levels. In the present work we investigate the mechanisms by which E2 differentially regulates sGC subunits' expression on rat anterior pituitary gland. Experiments were performed on primary cultures of anterior pituitary cells from adult female Wistar rats at random stages of estrous cycle. After 6 h of E2 treatment, α1 mRNA and protein expression is increased while β1 levels are down-regulated. E2 effects on sGC expression are partially dependent on de novo transcription while de novo translation is fully required. E2 treatment decreased HuR mRNA stabilization factor and increased AUF1 p37 mRNA destabilization factor. E2-elicited β1 mRNA decrease correlates with a mRNA destabilization environment in the anterior pituitary gland. On the other hand, after 6 h of treatment, E2-BSA (1 nM) and E2-dendrimer conjugate (EDC, 1 nM) were unable to modify α1 or β1 mRNA levels, showing that nuclear receptor is involved in E2 actions. However, at earlier times (3 h), 1 nM EDC causes a transient decrease of α1 in a PI3k-dependent fashion. Our results show for the first time that E2 is able to exert opposite actions in the anterior pituitary gland, depending on the activation of classical or non-classical pathways. Thus, E2 can also modify sGC expression through membrane-initiated signals bringing to light a new point of regulation in NO/sGC pathway. © 2011 Cabilla et al.

  17. rse, a novel receptor-type tyrosine kinase with homology to Axl/Ufo, is expressed at high levels in the brain.

    Science.gov (United States)

    Mark, M R; Scadden, D T; Wang, Z; Gu, Q; Goddard, A; Godowski, P J

    1994-04-08

    We have isolated cDNA clones that encode the human and murine forms of a novel receptor-type tyrosine kinase termed Rse. Sequence analysis indicates that human Rse contains 890 amino acids, with an extracellular region composed of two immunoglobulin-like domains followed by two fibronectin type III domains. Murine Rse contains 880 amino acids and shares 90% amino acid identity with its human counterpart. Rse is structurally similar to the receptor-type tyrosine kinase Axl/Ufo, and the two proteins have 35 and 63% sequence identity in their extracellular and intracellular domains, respectively. To study the synthesis and activation of this putative receptor-type tyrosine kinase, we constructed a version of Rse (termed gD-Rse, where gD represents glycoprotein D) that contains an NH2-terminal epitope tag. NIH3T3 cells were engineered to express gD-Rse, which could be detected at the cell surface by fluorescence-activated cell sorting. Moreover, gD-Rse was rapidly phosphorylated on tyrosine residues upon incubation of the cells with an antibody directed against the epitope tag, suggesting that rse encodes an active tyrosine kinase. In the human tissues we examined, the highest level of expression of rse mRNA was observed in the brain; rse mRNA was also detected in the premegakaryocytopoietic cell lines CMK11-5 and Dami. The gene for rse was localized to human chromosome 15.

  18. The expression of a novel receptor-type tyrosine phosphatase suggests a role in morphogenesis and plasticity of the nervous system

    DEFF Research Database (Denmark)

    Canoll, P D; Barnea, G; Levy, J B

    1993-01-01

    Analysis of the localization of receptor-type protein tyrosine phosphatase-beta (RPTP-beta) by in situ hybridization and immunocytochemistry indicates that it is predominantly expressed in the developing central nervous system (CNS). RPTP-beta is highly expressed in radial glia and other forms....... In the adult, high levels of RPTP-beta are seen in regions of the brain where there is continued neurogenesis and neurite outgrowth. The spatial and temporal patterns of RPTP-beta expression suggest that this receptor phosphatase plays a role in morphogenesis and plasticity of the nervous system....

  19. Anatomical and histological profile of bronchus-associated lymphoid tissue and localization of melatonin receptor types (Mel 1a and Mel 1b) in the lung-associated immune system of a tropical bird, Perdicula asiatica.

    Science.gov (United States)

    Kumar Kharwar, Rajesh; Haldar, Chandana

    2011-05-01

    The histological distribution of the lung-associated immune system (LAIS) and the expressional pattern of melatonin receptors are still unknown in birds. The aim of the present study was to determine the localization of the bronchus-associated lymphoid tissue (BALT nodule) in a tropical bird, the Indian jungle bush quail, Perdicula asiatica. We also demonstrate the expression of melatonin receptor types (Mel(1a) and Mel(1b)) in order to propose an immunomodulatory role of melatonin in LAIS. Localization of melatonin receptors in the lung of the Indian jungle bush quail, P. asiatica was supported immunohistochemically and by Western blot analysis using specific antibodies for those receptors. Immunolocalization for Mel(1b) receptor was noted in the bronchial region of the lungs, in finger-like projections of mucosal foldings, in lymphocytes in the BALT nodule as well as in free form. In contrast, immunolocalization for Mel(1a) receptor was noted in various areas of the lung instead of in the bronchial region. Western blot analysis showed a single band at 37 and 39kDa for Mel(1a) and Mel(1b) receptors, respectively, with the latter showing higher expression. The results demonstrate a well-developed LAIS and region-specific distribution of melatonin receptors in the lung and provide evidence for a possible functional role for melatonin in the LAIS of birds. Copyright © 2010 Elsevier GmbH. All rights reserved.

  20. Genetic polymorphisms in bone morphogenetic protein receptor type IA gene predisposes individuals to ossification of the posterior longitudinal ligament of the cervical spine via the smad signaling pathway.

    Science.gov (United States)

    Wang, Hao; Jin, Weitao; Li, Haibin

    2018-02-20

    The present study investigated the molecular mechanisms underlying the 4A > C and -349C > T single nucleotide polymorphisms (SNPs) in bone morphogenetic protein receptor type IA (BMPR-IA) gene, which significantly associated with the occurrence and the extent of ossification of the posterior longitudinal ligament (OPLL) in the cervical spine. The SNPs in BMPR-IA gene were genotyped, and the association with the occurrence and severity of OPLL were evaluated in 356 OPLL patients and 617 non-OPLL controls. In stably transfected mouse embryonic mesenchymal stem cells (C3H10T1/2), the expression levels of the BMPR-IA gene and Smad4 protein as well as phosphorylated Smad1/5/8 were detected by Western blotting. In addition, the alkaline phosphatase (ALP) and osteocalcin (OC) activity of osteogenesis specificity protein was assessed using the ALP quantitation and osteocalcin radioimmunoassay kit, respectively. The 4A > C and the -349C > T polymorphisms of BMPR-IA gene were significantly associated with the development of OPLL in the cervical spine. The C allele type in 4A > C polymorphism significantly increases the occurrence and the extent of OPLL. The T allele type in -349C > T polymorphism significantly increases the susceptibility to OPLL, but not the extent of OPLL. The current results further validate our previous observations. The expression levels of BMPR-IA gene were significantly increased in pcDNA3.1/BMPR-IA (mutation type, MT -349C > T; MT 4A > C; MT -349C > T and 4A > C) vector-transfected C3H10T1/2 cells compared to the wild type (WT) vector-transfected cells. The levels of phosphorylated Smad1/5/8 and ALP activity were significantly increased in pcDNA3.1/BMPR-IA (MT -349C > T) vector-transfected C3H10T1/2 cells compared to the WT vector-transfected cells. However, no significant differences were observed in the protein levels of phosphorylated Smad1/5/8 and the ALP activity between MT A/C and WT vector

  1. On the Emerging Role of the Taste Receptor Type 1 (T1R Family of Nutrient-Sensors in the Musculoskeletal System

    Directory of Open Access Journals (Sweden)

    Shoichiro Kokabu

    2017-03-01

    Full Text Available The special sense of taste guides and guards food intake and is essential for body maintenance. Salty and sour tastes are sensed via ion channels or gated ion channels while G protein-coupled receptors (GPCRs of the taste receptor type 1 (T1R family sense sweet and umami tastes and GPCRs of the taste receptor type 2 (T2R family sense bitter tastes. T1R and T2R receptors share similar downstream signaling pathways that result in the stimulation of phospholipase-C-β2. The T1R family includes three members that form heterodimeric complexes to recognize either amino acids or sweet molecules such as glucose. Although these functions were originally described in gustatory tissue, T1R family members are expressed in numerous non-gustatory tissues and are now viewed as nutrient sensors that play important roles in monitoring global glucose and amino acid status. Here, we highlight emerging evidence detailing the function of T1R family members in the musculoskeletal system and review these findings in the context of the musculoskeletal diseases sarcopenia and osteoporosis, which are major public health problems among the elderly that affect locomotion, activities of daily living, and quality of life. These studies raise the possibility that T1R family member function may be modulated for therapeutic benefit.

  2. Discovery of novel, potent and low-toxicity angiotensin II receptor type 1 (AT1) blockers: Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazoles with a chiral center.

    Science.gov (United States)

    Han, Xiao-Feng; He, Xing; Wang, Miao; Xu, Di; Hao, Li-Ping; Liang, Ai-Hua; Zhang, Jun; Zhou, Zhi-Ming

    2015-10-20

    Novel angiotensin II receptor type 1 (AT1) blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center were designed and synthesized as the first step to develop new antihypertensive agents and understand their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [(125)I] Sar(1) Ile(8)-Ang II, which was specifically bound to human AT1 receptor. Radioligand binding assays revealed nanomolar affinity in several compounds under study. The IC50 values of nine ligands were higher than those of Losartan. The screening of decreased blood pressure in spontaneous hypertensive rats displayed that compound 8S (IC₅₀ = 5.0 nM) was equipotent with Losartan, whereas compounds 13R (IC₅₀ = 7.3 nM), 14R (IC₅₀ = 6.3 nM), and 14S (IC₅₀ = 3.5 nM) were slightly ahead of Losartan, and the most significant activity was demonstrated by compound 8R (IC₅₀ = 1.1 nM). Candidate 8R was identified for its excellent efficacy in antihypertension and fairly low toxicity based on plasma analyses, toxicology studies, and chronic oral tests. Finally, compound 8R exhibited strong and multiple interactions with target active sites of the theoretical AT1 receptor model in docking study. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  3. A new monoclonal antibody detects downregulation of protein tyrosine phosphatase receptor type γ in chronic myeloid leukemia patients

    Directory of Open Access Journals (Sweden)

    Marzia Vezzalini

    2017-06-01

    Full Text Available Abstract Background Protein tyrosine phosphatase receptor gamma (PTPRG is a ubiquitously expressed member of the protein tyrosine phosphatase family known to act as a tumor suppressor gene in many different neoplasms with mechanisms of inactivation including mutations and methylation of CpG islands in the promoter region. Although a critical role in human hematopoiesis and an oncosuppressor role in chronic myeloid leukemia (CML have been reported, only one polyclonal antibody (named chPTPRG has been described as capable of recognizing the native antigen of this phosphatase by flow cytometry. Protein biomarkers of CML have not yet found applications in the clinic, and in this study, we have analyzed a group of newly diagnosed CML patients before and after treatment. The aim of this work was to characterize and exploit a newly developed murine monoclonal antibody specific for the PTPRG extracellular domain (named TPγ B9-2 to better define PTPRG protein downregulation in CML patients. Methods TPγ B9-2 specifically recognizes PTPRG (both human and murine by flow cytometry, western blotting, immunoprecipitation, and immunohistochemistry. Results Co-localization experiments performed with both anti-PTPRG antibodies identified the presence of isoforms and confirmed protein downregulation at diagnosis in the Philadelphia-positive myeloid lineage (including CD34+/CD38bright/dim cells. After effective tyrosine kinase inhibitor (TKI treatment, its expression recovered in tandem with the return of Philadelphia-negative hematopoiesis. Of note, PTPRG mRNA levels remain unchanged in tyrosine kinase inhibitors (TKI non-responder patients, confirming that downregulation selectively occurs in primary CML cells. Conclusions The availability of this unique antibody permits its evaluation for clinical application including the support for diagnosis and follow-up of these disorders. Evaluation of PTPRG as a potential therapeutic target is also facilitated by the

  4. [Role of angiotensin II receptor type 2 in predicting biochemical recurrence in the treatment of prostate cancer].

    Science.gov (United States)

    Chibichyan, M B; Kogan, M I; Chernogubova, E A; Pavlenko, I A; Matishov, D G

    2016-12-01

    To identify markers for predicting aggressive forms of prostate cancer. The study retrospectively evaluated expression of angiotensin II type 2 receptors (AT2-R) in prostate needle biopsy tissue from patients with and without biochemical recurrence after combined hormone and radiation therapy. The study findings showed that low expression of AT2-R in prostate tissue was associated with a high risk of biochemical recurrence. The data on the nature of AT2-R expression in prostate tissue of prostate cancer patients may be considered as a tool for predicting biochemical recurrence after combined hormone and radiation therapy. The test has a sensitivity of 87.5% and specificity of 85.71%.

  5. Spatial distribution of cannabinoid receptor type 1 (CB1 in normal canine central and peripheral nervous system.

    Directory of Open Access Journals (Sweden)

    Jessica Freundt-Revilla

    Full Text Available The endocannabinoid system is a regulatory pathway consisting of two main types of cannabinoid receptors (CB1 and CB2 and their endogenous ligands, the endocannabinoids. The CB1 receptor is highly expressed in the central and peripheral nervous systems (PNS in mammalians and is involved in neuromodulatory functions. Since endocannabinoids were shown to be elevated in cerebrospinal fluid of epileptic dogs, knowledge about the species specific CB receptor expression in the nervous system is required. Therefore, we assessed the spatial distribution of CB1 receptors in the normal canine CNS and PNS. Immunohistochemistry of several regions of the brain, spinal cord and peripheral nerves from a healthy four-week-old puppy, three six-month-old dogs, and one ten-year-old dog revealed strong dot-like immunoreactivity in the neuropil of the cerebral cortex, Cornu Ammonis (CA and dentate gyrus of the hippocampus, midbrain, cerebellum, medulla oblongata and grey matter of the spinal cord. Dense CB1 expression was found in fibres of the globus pallidus and substantia nigra surrounding immunonegative neurons. Astrocytes were constantly positive in all examined regions. CB1 labelled neurons and satellite cells of the dorsal root ganglia, and myelinating Schwann cells in the PNS. These results demonstrate for the first time the spatial distribution of CB1 receptors in the healthy canine CNS and PNS. These results can be used as a basis for further studies aiming to elucidate the physiological consequences of this particular anatomical and cellular distribution.

  6. The association of metabotropic glutamate receptor type 5 with the neuronal Ca2+-binding protein 2 modulates receptor function.

    Science.gov (United States)

    Canela, Laia; Fernández-Dueñas, Víctor; Albergaria, Catarina; Watanabe, Masahiko; Lluís, Carme; Mallol, Josefa; Canela, Enric I; Franco, Rafael; Luján, Rafael; Ciruela, Francisco

    2009-10-01

    Metabotropic glutamate (mGlu) receptors mediate in part the CNS effects of glutamate. These receptors interact with a large array of intracellular proteins in which the final role is to regulate receptor function. Here, using co-immunoprecipitation and pull-down experiments we showed a close and specific interaction between mGlu(5) receptor and NECAB2 in both transfected human embryonic kidney cells and rat hippocampus. Interestingly, in pull-down experiments increasing concentrations of calcium drastically reduced the ability of these two proteins to interact, suggesting that NECAB2 binds to mGlu(5) receptor in a calcium-regulated manner. Immunoelectron microscopy detection of NECAB2 and mGlu(5) receptor in the rat hippocampal formation indicated that both proteins are codistributed in the same subcellular compartment of pyramidal cells. In addition, the NECAB2/mGlu(5) receptor interaction regulated mGlu(5b)-mediated activation of both inositol phosphate accumulation and the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. Overall, these findings indicate that NECAB2 by its physical interaction with mGlu(5b) receptor modulates receptor function.

  7. The Gyc76C Receptor Guanylyl Cyclase and the Foraging cGMP-Dependent Kinase Regulate Extracellular Matrix Organization and BMP Signaling in the Developing Wing of Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Justin Schleede

    2015-10-01

    Full Text Available The developing crossveins of the wing of Drosophila melanogaster are specified by long-range BMP signaling and are especially sensitive to loss of extracellular modulators of BMP signaling such as the Chordin homolog Short gastrulation (Sog. However, the role of the extracellular matrix in BMP signaling and Sog activity in the crossveins has been poorly explored. Using a genetic mosaic screen for mutations that disrupt BMP signaling and posterior crossvein development, we identify Gyc76C, a member of the receptor guanylyl cyclase family that includes mammalian natriuretic peptide receptors. We show that Gyc76C and the soluble cGMP-dependent kinase Foraging, likely linked by cGMP, are necessary for normal refinement and maintenance of long-range BMP signaling in the posterior crossvein. This does not occur through cell-autonomous crosstalk between cGMP and BMP signal transduction, but likely through altered extracellular activity of Sog. We identify a novel pathway leading from Gyc76C to the organization of the wing extracellular matrix by matrix metalloproteinases, and show that both the extracellular matrix and BMP signaling effects are largely mediated by changes in the activity of matrix metalloproteinases. We discuss parallels and differences between this pathway and other examples of cGMP activity in both Drosophila melanogaster and mammalian cells and tissues.

  8. The Gyc76C Receptor Guanylyl Cyclase and the Foraging cGMP-Dependent Kinase Regulate Extracellular Matrix Organization and BMP Signaling in the Developing Wing of Drosophila melanogaster.

    Science.gov (United States)

    Schleede, Justin; Blair, Seth S

    2015-10-01

    The developing crossveins of the wing of Drosophila melanogaster are specified by long-range BMP signaling and are especially sensitive to loss of extracellular modulators of BMP signaling such as the Chordin homolog Short gastrulation (Sog). However, the role of the extracellular matrix in BMP signaling and Sog activity in the crossveins has been poorly explored. Using a genetic mosaic screen for mutations that disrupt BMP signaling and posterior crossvein development, we identify Gyc76C, a member of the receptor guanylyl cyclase family that includes mammalian natriuretic peptide receptors. We show that Gyc76C and the soluble cGMP-dependent kinase Foraging, likely linked by cGMP, are necessary for normal refinement and maintenance of long-range BMP signaling in the posterior crossvein. This does not occur through cell-autonomous crosstalk between cGMP and BMP signal transduction, but likely through altered extracellular activity of Sog. We identify a novel pathway leading from Gyc76C to the organization of the wing extracellular matrix by matrix metalloproteinases, and show that both the extracellular matrix and BMP signaling effects are largely mediated by changes in the activity of matrix metalloproteinases. We discuss parallels and differences between this pathway and other examples of cGMP activity in both Drosophila melanogaster and mammalian cells and tissues.

  9. Rearing-environment-dependent hippocampal local field potential differences in wild-type and inositol trisphosphate receptor type 2 knockout mice.

    Science.gov (United States)

    Tanaka, Mika; Wang, Xiaowen; Mikoshiba, Katsuhiko; Hirase, Hajime; Shinohara, Yoshiaki

    2017-10-15

    Mice reared in an enriched environment are demonstrated to have larger hippocampal gamma oscillations than those reared in isolation, thereby confirming previous observations in rats. To test whether astrocytic Ca 2+ surges are involved in this experience-dependent LFP pattern modulation, we used inositol trisphosphate receptor type 2 (IP 3 R2)-knockout (KO) mice, in which IP 3 /Ca 2+ signalling in astrocytes is largely diminished. We found that this experience-dependent gamma power alteration persists in the KO mice. Interestingly, hippocampal ripple events, the synchronized events critical for memory consolidation, are reduced in magnitude and frequency by both isolated rearing and IP 3 R2 deficiency. Rearing in an enriched environment (ENR) is known to enhance cognitive and memory abilities in rodents, whereas social isolation (ISO) induces depression-like behaviour. The hippocampus has been documented to undergo morphological and functional changes depending on these rearing environments. For example, rearing condition during juvenility alters CA1 stratum radiatum gamma oscillation power in rats. In the present study, hippocampal CA1 local field potentials (LFP) were recorded from bilateral CA1 in urethane-anaesthetized mice that were reared in either an ENR or ISO condition. Similar to previous findings in rats, gamma oscillation power during theta states was higher in the ENR group. Ripple events that occur during non-theta periods in the CA1 stratum pyramidale also had longer intervals in ISO mice. Because astrocytic Ca 2+ elevations play a key role in synaptic plasticity, we next tested whether these changes in LFP are also expressed in inositol trisphosphate receptor type 2 (IP 3 R2)-knockout (KO) mice, in which astrocytic Ca 2+ elevations are largely diminished. We found that the gamma power was also higher in IP 3 R2-KO-ENR mice compared to IP 3 R2-KO-ISO mice, suggesting that the rearing-environment-dependent gamma power alteration does not necessarily

  10. Coordinate expression of activating Fc gamma receptors I and III and inhibiting Fc gamma receptor type II in the determination of joint inflammation and cartilage destruction during immune complex-mediated arthritis.

    NARCIS (Netherlands)

    Nabbe, K.C.A.M.; Blom, A.B.; Holthuysen, A.E.M.; Boross, P.; Roth, J.; Verbeek, S.; Lent, P.L.E.M. van; Berg, W.B. van den

    2003-01-01

    OBJECTIVE: To study the role of the activating Fc gamma receptor types I and III (Fc gamma RI and Fc gamma RIII, respectively) and the inhibiting Fc gamma receptor II (Fc gamma RII) in inflammation and in various aspects of cartilage destruction during arthritis that is solely induced by immune

  11. Heritability of Transforming Growth Factor-β1 and Tumor Necrosis Factor-Receptor Type 1 Expression and Vitamin D Levels in Healthy Adolescent Twins.

    Science.gov (United States)

    Mills, Natalie T; Wright, Margie J; Henders, Anjali K; Eyles, Darryl W; Baune, Bernhard T; McGrath, John J; Byrne, Enda M; Hansell, Narelle K; Birosova, Eva; Scott, James G; Martin, Nicholas G; Montgomery, Grant W; Wray, Naomi R; Vinkhuyzen, Anna A E

    2015-02-01

    Cytokines and vitamin D both have a role in modulating the immune system, and are also potentially useful biomarkers in mental illnesses such as major depressive disorder (MDD) and schizophrenia. Studying the variability of cytokines and vitamin D in a healthy population sample may add to understanding the association between these biomarkers and mental illness. To assess genetic and environmental contributions to variation in circulating levels of cytokines and vitamin D (25-hydroxy vitamin D: 25(OH)D3), we analyzed data from a healthy adolescent twin cohort (mean age 16.2 years; standard deviation 0.25). Plasma cytokine measures were available for 400 individuals (85 MZ, 115 DZ pairs), dried blood spot sample vitamin D measures were available for 378 individuals (70 MZ, 118 DZ pairs). Heritability estimates were moderate but significant for the cytokines transforming growth factor-β1 (TGF-β1), 0.57 (95% CI 0.26-0.80) and tumor necrosis factor-receptor type 1 (TNFR1), 0.50 (95% CI 0.11-0.63) respectively. Measures of 25(OH)D3 were within normal range and heritability was estimated to be high (0.86, 95% CI 0.61-0.94). Assays of other cytokines did not generate meaningful results. These potential biomarkers may be useful in mental illness, with further research warranted in larger sample sizes. They may be particularly important in adolescents with mental illness where diagnostic uncertainty poses a significant clinical challenge.

  12. No association between the protein tyrosine phosphatase, receptor-type, Z Polypeptide 1 (PTPRZ1) gene and schizophrenia in the Japanese population.

    Science.gov (United States)

    Ito, Yoshihito; Yamada, Shinnosuke; Takahashi, Nagahide; Saito, Shinichi; Yoshimi, Akira; Inada, Toshiya; Noda, Yukihiro; Ozaki, Norio

    2008-10-05

    NRG1-ERBB signaling influences the risk for schizophrenia pathology. A recent study has reported that MAGI1, MAGI2, and protein tyrosine phosphatase, receptor-type, Z polypeptide 1 (PTPRZ1; located on 7q31.3) gene products regulate the NRG1-ERBB4 signaling pathway, and PTPRZ1 is associated with schizophrenia in a Caucasian population. By applying a gene-based association concept, we analyzed any association between PTPRZ1 tagging SNPs and schizophrenia in the Japanese population (576 schizophrenics and 768 controls). After linkage disequilibrium analysis, 29 single nucleotide polymorphisms (SNPs) were genotyped using a 5'-exonuclease allelic discrimination assay. We found a significant association of one tagging SNP in a genotype-wise analysis (P = 0.007); however, this might be resulted from type I error due to multiple testing (P = 0.17 after SNPSpD correction). No association was observed between schizophrenic patients and controls in either allelic, genotypic, or haplotypic analyses. Our results therefore suggest that PTPRZ1 is unlikely to be related to the development of schizophrenia in the Japanese population.

  13. Endothelial microparticle formation by angiotensin II is mediated via Ang II receptor type I/NADPH oxidase/ Rho kinase pathways targeted to lipid rafts.

    Science.gov (United States)

    Burger, Dylan; Montezano, Augusto C; Nishigaki, Nobuhiro; He, Ying; Carter, Anthony; Touyz, Rhian M

    2011-08-01

    Circulating microparticles are increased in cardiovascular disease and may themselves promote oxidative stress and inflammation. Molecular mechanisms underlying their formation and signaling are unclear. We investigated the role of reactive oxygen species (ROS), Rho kinase, and lipid rafts in microparticle formation and examined their functional significance in endothelial cells (ECs). Microparticle formation from angiotensin II (Ang II)-stimulated ECs and apolipoprotein E(-/-) mice was assessed by annexin V or by CD144 staining and electron microscopy. Ang II promoted microparticle formation and increased EC O(2)(-) generation and Rho kinase activity. Ang II-stimulated effects were inhibited by irbesartan (Ang II receptor type I blocker) and fasudil (Rho kinase inhibitor). Methyl-β-cyclodextrin and nystatin, which disrupt lipid rafts/caveolae, blocked microparticle release. Functional responses, assessed in microparticle-stimulated ECs, revealed increased O(2)(-) production, enhanced vascular cell adhesion molecule/platelet-EC adhesion molecule expression, and augmented macrophage adhesion. Inhibition of epidermal growth factor receptor blocked the prooxidative and proinflammatory effects of microparticles. In vitro observations were confirmed in apolipoprotein E(-/-) mice, which displayed vascular inflammation and high levels of circulating endothelial microparticles, effects that were reduced by apocynin. We demonstrated direct actions of Ang II on endothelial microparticle release, mediated through NADPH oxidase, ROS, and Rho kinase targeted to lipid rafts. Microparticles themselves stimulated endothelial ROS formation and inflammatory responses. Our findings suggest a feedforward system whereby Ang II promotes EC injury through its own endothelial-derived microparticles.

  14. Ca 2+ signaling by plant Arabidopsis thaliana Pep peptides depends on AtPepR1, a receptor with guanylyl cyclase activity, and cGMP-activated Ca 2+ channels

    KAUST Repository

    Qia, Zhi

    2010-11-18

    A family of peptide signaling molecules (AtPeps) and their plasma membrane receptor AtPepR1 are known to act in pathogendefense signaling cascades in plants. Little is currently known about the molecular mechanisms that link these signaling peptides and their receptor, a leucine-rich repeat receptor-like kinase, to downstream pathogen-defense responses. We identify some cellular activities of these molecules that provide the context for a model for their action in signaling cascades. AtPeps activate plasma membrane inwardly conducting Ca 2+ permeable channels in mesophyll cells, resulting in cytosolic Ca 2+ elevation. This activity is dependent on their receptor as well as a cyclic nucleotide-gated channel (CNGC2). We also show that the leucine-rich repeat receptor- like kinase receptor AtPepR1 has guanylyl cyclase activity, generating cGMP from GTP, and that cGMP can activate CNGC2- dependent cytosolic Ca 2+ elevation. AtPep-dependent expression of pathogen-defense genes (PDF1.2, MPK3, and WRKY33) is mediated by the Ca 2+ signaling pathway associated with AtPep peptides and their receptor. The work presented here indicates that extracellular AtPeps, which can act as danger-associated molecular patterns, signal by interaction with their receptor, AtPepR1, a plasma membrane protein that can generate cGMP. Downstream from AtPep and AtPepR1 in a signaling cascade, the cGMP-activated channel CNGC2 is involved in AtPep- and AtPepR1-dependent inward Ca 2+ conductance and resulting cytosolic Ca 2+ elevation. The signaling cascade initiated by AtPeps leads to expression of pathogen- defense genes in a Ca 2+-dependent manner.

  15. G-231A and G+70C polymorphisms of endothelin receptor type-A gene could affect the psoriasis area and severity index score and endothelin 1 levels

    Directory of Open Access Journals (Sweden)

    Gökhan Okan

    2015-01-01

    Full Text Available Background: The etiopathogenesis of psoriasis has not been clearly elucidated although the role of chronic inflammation, imbalance between pro- and anti-inflammatory cytokines, and many immunological events have been established. Endothelin 1 (EDN1 and endothelin receptor type-A (EDNRA are implicated in the inflammatory process. The relationships between EDN1 and EDNRA polymorphisms with several diseases have been found. Aims and Objectives: This study examined the possible association of EDN1 (G5665T and T-1370G and EDNRA (G-231A and G + 70C single nucleotide polymorphisms (SNPs with the occurence of psoriasis, and evaluated the relationship between genotypes and clinical/laboratory manifestation of psoriasis. Materials and Methods: We analyzed genotype and allele distributions of the above-mentioned polymorphisms in 151 patients with psoriasis and 152 healthy controls by real-time PCR combined with melting curve analysis. Results: We did not find significant differences in the genotype and allele distributions of EDN1 T-1370G, EDNRA G-231A, and EDNRA G+70C polymorphisms between patients with psoriasis and healthy controls. Psoriasis area and severity index (PASI score of EDNRA -231 polymorphic A allele carrying subjects (AA and AA + AG was higher than that of wild homozygotes (P = 0.044 and P = 0.027, respectively. In addition, EDN1 levels in EDNRA+70 polymorphic C allele carriers (CC + CG were elevated when compared with GG genotype; however, the difference was at borderline significance (P = 0.05. Conclusion: Although there were no associations between studied polymorphisms and psoriasis susceptibility, the PASI score and EDN1 levels seem to be affected by EDNRA G-231A and G + 70C polymorphisms.

  16. Chronic Blockade of Brain Endothelin Receptor Type-A (ETA Reduces Blood Pressure and Prevents Catecholaminergic Overactivity in the Right Olfactory Bulb of DOCA-Salt Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Luis R. Cassinotti

    2018-02-01

    Full Text Available Overactivity of the sympathetic nervous system and central endothelins (ETs are involved in the development of hypertension. Besides the well-known brain structures involved in the regulation of blood pressure like the hypothalamus or locus coeruleus, evidence suggests that the olfactory bulb (OB also modulates cardiovascular function. In the present study, we evaluated the interaction between the endothelinergic and catecholaminergic systems in the OB of deoxycorticosterone acetate (DOCA-salt hypertensive rats. Following brain ET receptor type A (ETA blockade by BQ610 (selective antagonist, transcriptional, traductional, and post-traductional changes in tyrosine hydroxylase (TH were assessed in the OB of normotensive and DOCA-salt hypertensive rats. Time course variations in systolic blood pressure and heart rate were also registered. Results showed that ETA blockade dose dependently reduced blood pressure in hypertensive rats, but it did not change heart rate. It also prevented the increase in TH activity and expression (mRNA and protein in the right OB of hypertensive animals. However, ETA blockade did not affect hemodynamics or TH in normotensive animals. Present results support that brain ETA are not involved in blood pressure regulation in normal rats, but they significantly contribute to chronic blood pressure elevation in hypertensive animals. Changes in TH activity and expression were observed in the right but not in the left OB, supporting functional asymmetry, in line with previous studies regarding cardiovascular regulation. Present findings provide further evidence on the role of ETs in the regulation of catecholaminergic activity and the contribution of the right OB to DOCA-salt hypertension.

  17. IL-1RI (Interleukin-1 Receptor Type I Signalling is Essential for Host Defence and Hemichannel Activity During Acute Central Nervous System Bacterial Infection

    Directory of Open Access Journals (Sweden)

    Juan Xiong

    2012-03-01

    Full Text Available Staphylococcus aureus is a common aetiological agent of bacterial brain abscesses. We have previously established that a considerable IL-1 (interleukin-1 response is elicited immediately following S. aureus infection, where the cytokine can exert pleiotropic effects on glial activation and blood–brain barrier permeability. To assess the combined actions of IL-1α and IL-1β during CNS (central nervous system infection, host defence responses were evaluated in IL-1RI (IL-1 receptor type I KO (knockout animals. IL-1RI KO mice were exquisitely sensitive to intracerebral S. aureus infection, as demonstrated by enhanced mortality rates and bacterial burdens within the first 24 h following pathogen exposure compared with WT (wild-type animals. Loss of IL-1RI signalling also dampened the expression of select cytokines and chemokines, concomitant with significant reductions in neutrophil and macrophage infiltrates into the brain. In addition, the opening of astrocyte hemichannels during acute infection was shown to be dependent on IL-1RI activity. Collectively, these results demonstrate that IL-1RI signalling plays a pivotal role in the genesis of immune responses during the acute stage of brain abscess development through S. aureus containment, inflammatory mediator production, peripheral immune cell recruitment, and regulation of astrocyte hemichannel activity. Taken in the context of previous studies with MyD88 (myeloid differentiation primary response gene 88 and TLR2 (Toll-like receptor 2 KO animals, the current report advances our understanding of MyD88-dependent cascades and implicates IL-1RI signalling as a major antimicrobial effector pathway during acute brain-abscess formation.

  18. Lack of evidence from studies of soluble protein fragments that Knops blood group polymorphisms in complement receptor-type 1 are driven by malaria.

    Directory of Open Access Journals (Sweden)

    Patience B Tetteh-Quarcoo

    Full Text Available Complement receptor-type 1 (CR1, CD35 is the immune-adherence receptor, a complement regulator, and an erythroid receptor for Plasmodium falciparum during merozoite invasion and subsequent rosette formation involving parasitized and non-infected erythrocytes. The non-uniform geographical distribution of Knops blood group CR1 alleles Sl1/2 and McC(a/b may result from selective pressures exerted by differential exposure to infectious hazards. Here, four variant short recombinant versions of CR1 were produced and analyzed, focusing on complement control protein modules (CCPs 15-25 of its ectodomain. These eleven modules encompass a region (CCPs 15-17 key to rosetting, opsonin recognition and complement regulation, as well as the Knops blood group polymorphisms in CCPs 24-25. All four CR1 15-25 variants were monomeric and had similar axial ratios. Modules 21 and 22, despite their double-length inter-modular linker, did not lie side-by-side so as to stabilize a bent-back architecture that would facilitate cooperation between key functional modules and Knops blood group antigens. Indeed, the four CR1 15-25 variants had virtually indistinguishable affinities for immobilized complement fragments C3b (K(D = 0.8-1.1 µM and C4b (K(D = 5.0-5.3 µM. They were all equally good co-factors for factor I-catalysed cleavage of C3b and C4b, and they bound equally within a narrow affinity range, to immobilized C1q. No differences between the variants were observed in assays for inhibition of erythrocyte invasion by P. falciparum or for rosette disruption. Neither differences in complement-regulatory functionality, nor interactions with P. falciparum proteins tested here, appear to have driven the non-uniform geographic distribution of these alleles.

  19. Chronic Blockade of Brain Endothelin Receptor Type-A (ETA) Reduces Blood Pressure and Prevents Catecholaminergic Overactivity in the Right Olfactory Bulb of DOCA-Salt Hypertensive Rats.

    Science.gov (United States)

    Cassinotti, Luis R; Guil, María J; Schöller, Mercedes I; Navarro, Mónica P; Bianciotti, Liliana G; Vatta, Marcelo S

    2018-02-27

    Overactivity of the sympathetic nervous system and central endothelins (ETs) are involved in the development of hypertension. Besides the well-known brain structures involved in the regulation of blood pressure like the hypothalamus or locus coeruleus, evidence suggests that the olfactory bulb (OB) also modulates cardiovascular function. In the present study, we evaluated the interaction between the endothelinergic and catecholaminergic systems in the OB of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Following brain ET receptor type A (ET A ) blockade by BQ610 (selective antagonist), transcriptional, traductional, and post-traductional changes in tyrosine hydroxylase (TH) were assessed in the OB of normotensive and DOCA-salt hypertensive rats. Time course variations in systolic blood pressure and heart rate were also registered. Results showed that ET A blockade dose dependently reduced blood pressure in hypertensive rats, but it did not change heart rate. It also prevented the increase in TH activity and expression (mRNA and protein) in the right OB of hypertensive animals. However, ET A blockade did not affect hemodynamics or TH in normotensive animals. Present results support that brain ET A are not involved in blood pressure regulation in normal rats, but they significantly contribute to chronic blood pressure elevation in hypertensive animals. Changes in TH activity and expression were observed in the right but not in the left OB, supporting functional asymmetry, in line with previous studies regarding cardiovascular regulation. Present findings provide further evidence on the role of ETs in the regulation of catecholaminergic activity and the contribution of the right OB to DOCA-salt hypertension.

  20. Corticotropin-Releasing Hormone Receptor Type 1 (CRHR1 Clustering with MAGUKs Is Mediated via Its C-Terminal PDZ Binding Motif.

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    Julia Bender

    Full Text Available The corticotropin-releasing hormone receptor type 1 (CRHR1 plays an important role in orchestrating neuroendocrine, behavioral, and autonomic responses to stress. To identify molecules capable of directly modulating CRHR1 signaling, we performed a yeast-two-hybrid screen using the C-terminal intracellular tail of the receptor as bait. We identified several members of the membrane-associated guanylate kinase (MAGUK family: postsynaptic density protein 95 (PSD95, synapse-associated protein 97 (SAP97, SAP102 and membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2. CRHR1 is co-expressed with the identified MAGUKs and with the additionally investigated PSD93 in neurons of the adult mouse brain and in primary hippocampal neurons, supporting the probability of a physiological interaction in vivo. The C-terminal PDZ (PSD-95, discs large, zona occludens 1 binding motif of CRHR1 is essential for its physical interaction with MAGUKs, as revealed by the CRHR1-STAVA mutant, which harbors a functionally impaired PDZ binding motif. The imitation of a phosphorylation at Thr413 within the PDZ binding motif also disrupted the interaction with MAGUKs. In contrast, distinct PDZ domains within the identified MAGUKs are involved in the interactions. Expression of CRHR1 in primary neurons demonstrated its localization throughout the neuronal plasma membrane, including the excitatory post synapse, where the receptor co-localized with PSD95 and SAP97. The co-expression of CRHR1 and respective interacting MAGUKs in HEK293 cells resulted in a clustered subcellular co-localization which required an intact PDZ binding motif. In conclusion, our study characterized the PDZ binding motif-mediated interaction of CRHR1 with multiple MAGUKs, which directly affects receptor function.

  1. The role of complement receptors type 1 (CR1, CD35) and 2 (CR2, CD21) in promoting C3 fragment deposition and membrane attack complex formation on normal peripheral human B cells

    DEFF Research Database (Denmark)

    Nielsen, Claus Henrik; Pedersen, Morten Løbner; Marquart, Hanne Vibeke Hansen

    2002-01-01

    Normal human B lymphocytes are known to activate the alternative pathway (AP) of complement, leading to C3-fragment deposition and membrane attack complex (MAC) formation. The process is mediated via complement receptor type 2 (CR2, CD21), with complement receptor type 1 (CR1, CD35) playing...... a subsidiary role. In this study, we examine the relative contributions of CR1 and CR2 to the deposition of C3 fragments and MAC on B lymphocytes under circumstances where all complement pathways are operational. C3-fragment deposition and MAC formation were assessed on human peripheral B lymphocytes...... in the presence of 30% autologous serum. Blocking the CR2 ligand-binding site with monoclonal antibody (mAb) FE8 resulted in significant reduction (37.9+/-11.9%) in C3-fragment deposition, whereas MAC formation was only marginally affected (12.1+/-22.2% reduction). Blocking the CR1 binding-site resulted...

  2. Characterization of the human Activin-A receptor type II-like kinase 1 (ACVRL1 promoter and its regulation by Sp1

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    Botella Luisa M

    2010-06-01

    Full Text Available Abstract Background Activin receptor-like kinase 1 (ALK1 is a Transforming Growth Factor-β (TGF-β receptor type I, mainly expressed in endothelial cells that plays a pivotal role in vascular remodelling and angiogenesis. Mutations in the ALK1 gene (ACVRL1 give rise to Hereditary Haemorrhagic Telangiectasia, a dominant autosomal vascular dysplasia caused by a haploinsufficiency mechanism. In spite of its patho-physiological relevance, little is known about the transcriptional regulation of ACVRL1. Here, we have studied the different origins of ACVRL1 transcription, we have analyzed in silico its 5'-proximal promoter sequence and we have characterized the role of Sp1 in the transcriptional regulation of ACVRL1. Results We have performed a 5'Rapid Amplification of cDNA Ends (5'RACE of ACVRL1 transcripts, finding two new transcriptional origins, upstream of the one previously described, that give rise to a new exon undiscovered to date. The 5'-proximal promoter region of ACVRL1 (-1,035/+210 was analyzed in silico, finding that it lacks TATA/CAAT boxes, but contains a remarkably high number of GC-rich Sp1 consensus sites. In cells lacking Sp1, ACVRL1 promoter reporters did not present any significant transcriptional activity, whereas increasing concentrations of Sp1 triggered a dose-dependent stimulation of its transcription. Moreover, silencing Sp1 in HEK293T cells resulted in a marked decrease of ACVRL1 transcriptional activity. Chromatin immunoprecipitation assays demonstrated multiple Sp1 binding sites along the proximal promoter region of ACVRL1 in endothelial cells. Furthermore, demethylation of CpG islands, led to an increase in ACVRL1 transcription, whereas in vitro hypermethylation resulted in the abolishment of Sp1-dependent transcriptional activation of ACVRL1. Conclusions Our results describe two new transcriptional start sites in ACVRL1 gene, and indicate that Sp1 is a key regulator of ACVRL1 transcription, providing new insights into

  3. Calcium-Dependent Energetics of Calmodulin Domain Interactions with Regulatory Regions of the Ryanodine Receptor Type 1 (RyR1)

    Science.gov (United States)

    Newman, Rhonda A.; Sorensen, Brenda R.; Kilpatrick, Adina M.; Shea, Madeline A.

    2014-01-01

    Calmodulin (CaM) plays a vital role in calcium homeostasis by allosterically modulating intracellular calcium channels including the homo-tetrameric human Ryanodine Receptor Type 1 (hRyR1). Apo (calcium-free) CaM activates hRyR1 while calcium-saturated CaM inhibits it. Two CaM-binding regions (residues 1975–1999 and 3614–3643) identified in each RyR1 monomer were proposed to allow CaM to bridge adjacent RyR1 subunits. We explored the distinct roles of CaM domains by using fluorescence anisotropy to determine the affinity of CaM1–148 (full-length), CaM1–80 (N-domain) and CaM76–148 (C-domain) for peptides encompassing hRyR1 residues 1975–1999 or 3614–3643. Both CaM1–148 and CaM76–148 associated in a calcium-independent manner with similar affinities for hRyR1(3614–3643)p while CaM1–80 required calcium and bound ~250-fold more weakly. Association of CaM1–148, CaM1–80 and CaM76–148 with hRyR1(1975–1999)p was much less favorable than with hRyR1(3614–3643)p; differences between the two CaM domains were smaller. Equilibrium calcium titrations monitored by steady-state fluorescence demonstrated that both hRyR1 peptides increased the calcium-binding affinity of both CaM domains. These thermodynamic properties support a prior model in which the CaM C-domain associates with RyR1(3614–3643) at low levels of calcium, positioning CaM to rapidly respond to calcium efflux. However, the affinity of the N-domain of CaM for hRyR1(1975–1999)p is insufficient to explain a model in which CaM bridges adjacent RyR1 subunits within the tetramer. This indicates that other protein factors or properties of the tertiary or quaternary structure of hRyR1 contribute to the energetics of CaM-mediated regulation. PMID:25145833

  4. Hexa-histidin tag position influences disulfide structure but not binding behavior of in vitro folded N-terminal domain of rat corticotropin-releasing factor receptor type 2a

    OpenAIRE

    Klose, Jana; Wendt, Norbert; Kubald, Sybille; Krause, Eberhard; Fechner, Klaus; Beyermann, Michael; Bienert, Michael; Rudolph, Rainer; Rothemund, Sven

    2004-01-01

    The oxidative folding, particularly the arrangement of disulfide bonds of recombinant extracellular N-terminal domains of the corticotropin-releasing factor receptor type 2a bearing five cysteines (C2 to C6), was investigated. Depending on the position of a His-tag, two types of disulfide patterns were found. In the case of an N-terminal His-tag, the disulfide bonds C2–C3 and C4–C6 were found, leaving C5 free, whereas the C-terminal position of the His-tag led to the disulfide pattern C2–C5 a...

  5. A randomized, phase II study of the anti-insulin-like growth factor receptor type 1 (IGF-1R) monoclonal antibody robatumumab (SCH 717454) in patients with advanced colorectal cancer

    International Nuclear Information System (INIS)

    Lin, Edward H; Lenz, Heinz-Josef; Saleh, Mansoor N; Mackenzie, Mary J; Knost, James A; Pathiraja, Kumudu; Langdon, Ronald B; Yao, Siu-Long; Lu, Brian D

    2014-01-01

    Overexpression of insulin-like growth factor receptor type 1 (IGF-1R) may promote tumor development and progression in some cancer patients. Our objective was to assess tumor uptake of fluorodeoxyglucose by positron-emission tomography in patients with chemotherapy-refractory colorectal cancer treated with an anti-insulin-like growth factor receptor type 1 (anti-IGF-1R) monoclonal antibody, robatumumab. This was a randomized, open-label study with two periods (P1 and P2). Patients were randomized 3:1 into treatment arms R/R and C/R that received, respectively, one cycle of 0.3 mg/kg robatumumab or one or more cycles of second-line chemotherapy in P1, followed in either case by 10 mg/kg robatumumab biweekly in P2. The primary measure of fluorodeoxyglucose uptake was maximum standardized uptake value (SUV max ). The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUV max (DiSUV) greater than 20% 12–14 days postdose in P2. Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)-defined tumor response and pharmacodynamic measures of target engagement. Among 41 patients who were evaluable for the primary endpoint, seven (17%, 95% CI 7%–32%) had DiSUV greater than 20%. Fifty robatumumab-treated patients were evaluable for RECIST-defined tumor response and six (12%) had stable disease lasting greater than or equal to 7 weeks in P2. Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab, but not 0.3 mg/kg. The most frequently reported adverse events were fatigue/asthenia, nausea, anorexia, and gastrointestinal disturbances. In this study, few patients with chemotherapy-refractory colorectal cancer appeared to benefit from treatment with the IGF-1R antagonist robatumumab

  6. Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration

    OpenAIRE

    McBrayer, Zofeyah L.; Dimova, Jiva; Pisansky, Marc T.; Sun, Mu; Beppu, Hideyuki; Gewirtz, Jonathan C.; O’Connor, Michael B.

    2015-01-01

    To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII) in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not ...

  7. The activation of RhoC in vascular endothelial cells is required for the S1P receptor type 2-induced inhibition of angiogenesis.

    Science.gov (United States)

    Del Galdo, Sabrina; Vettel, Christiane; Heringdorf, Dagmar Meyer Zu; Wieland, Thomas

    2013-12-01

    Sphingosine-1-phosphate (S1P) is a multifunctional phospholipid inducing a variety of cellular responses in endothelial cells (EC). S1P responses are mediated by five G protein coupled receptors of which three types (S1P1R-S1P3R) have been described to be of importance in vascular endothelial cells (EC). Whereas the S1P1R regulates endothelial barrier function by coupling to Gαi and the monomeric GTPase Rac1, the signaling pathways involved in the S1P-induced regulation of angiogenesis are ill defined. We therefore studied the sprouting of human umbilical vein EC (HUVEC) in vitro and analyzed the activation of the RhoGTPases RhoA and RhoC. Physiological relevant concentrations of S1P (100-300nM) induce a moderate activation of RhoA and RhoC. Inhibition or siRNA-mediated depletion of the S1P2R preferentially decreased the activation of RhoC. Both manipulations caused an increase of sprouting in a spheroid based in vitro sprouting assay. Interestingly, a similar increase in sprouting was detected after effective siRNA-mediated knockdown of RhoC. In contrast, the depletion of RhoA had no influence on sprouting. Furthermore, suppression of the activity of G proteins of the Gα12/13 subfamily by adenoviral overexpression of the regulator of G protein signaling domain of LSC as well as siRNA-mediated knockdown of the Rho specific guanine nucleotide exchange factor leukemia associated RhoGEF (LARG) inhibited the S1P-induced activation of RhoC and concomitantly increased sprouting of HUVEC with similar efficacy. We conclude that the angiogenic sprouting of EC is suppressed via the S1P2R subtype. Thus, the increase in basal sprouting can be attributed to blocking of the inhibitory action of autocrine S1P stimulating the S1P2R. This inhibitory pathway involves the activation of RhoC via Gα12/13 and LARG, while the simultaneously occurring activation of RhoA is apparently dispensable here. © 2013.

  8. The Int7G24A variant of transforming growth factor-beta receptor type I is a risk factor for colorectal cancer in the male Spanish population: a case-control study

    International Nuclear Information System (INIS)

    Castillejo, Adela; Guillén-Ponce, Carmen; Carrato, Alfredo; Soto, José-Luís; Mata-Balaguer, Trinidad; Guarinos, Carla; Castillejo, María-Isabel; Martínez-Cantó, Ana; Barberá, Víctor-Manuel; Montenegro, Paola; Ochoa, Enrique; Lázaro, Rafael

    2009-01-01

    The Int7G24A variant of transforming growth factor-beta receptor type I (TGFBR1) has been shown to increase the risk for kidney, ovarian, bladder, lung and breast cancers. Its role in colorectal cancer (CRC) has not been established. The aims of this study were to assess the association of TGFBR1*Int7G24A variant with CRC occurrence, patient age, gender, tumour location and stage. We performed a case-control study with 504 cases of sporadic CRC; and 504 non-cancerous age, gender and ethnically matched controls. Genotyping analysis was performed using allelic discrimination assay by real time PCR. The Int7G24A variant was associated with increased CRC incidence in an additive model of inheritance (P for trend = 0.005). No significant differences were found between Int7G24A genotypes and tumour location or stage. Interestingly, the association of the Int7G24A variant with CRC risk was significant in men (odds ratio 4.10 with 95% confidence intervals 1.41-11.85 for homozygous individuals; P for trend = 0.00023), but not in women. We also observed an increase in susceptibility to CRC for individuals aged less than 70 years. Our data suggest that the Int7G24A variant represents a risk factor for CRC in the male Spanish population

  9. The Int7G24A variant of transforming growth factor-beta receptor type I is a risk factor for colorectal cancer in the male Spanish population: a case-control study

    Directory of Open Access Journals (Sweden)

    Lázaro Rafael

    2009-11-01

    Full Text Available Abstract Background The Int7G24A variant of transforming growth factor-beta receptor type I (TGFBR1 has been shown to increase the risk for kidney, ovarian, bladder, lung and breast cancers. Its role in colorectal cancer (CRC has not been established. The aims of this study were to assess the association of TGFBR1*Int7G24A variant with CRC occurrence, patient age, gender, tumour location and stage. Methods We performed a case-control study with 504 cases of sporadic CRC; and 504 non-cancerous age, gender and ethnically matched controls. Genotyping analysis was performed using allelic discrimination assay by real time PCR. Results The Int7G24A variant was associated with increased CRC incidence in an additive model of inheritance (P for trend = 0.005. No significant differences were found between Int7G24A genotypes and tumour location or stage. Interestingly, the association of the Int7G24A variant with CRC risk was significant in men (odds ratio 4.10 with 95% confidence intervals 1.41-11.85 for homozygous individuals; P for trend = 0.00023, but not in women. We also observed an increase in susceptibility to CRC for individuals aged less than 70 years. Conclusion Our data suggest that the Int7G24A variant represents a risk factor for CRC in the male Spanish population.

  10. Elimination of soluble 123I-labeled aggregates of IgG in patients with systemic lupus erythematosus. Effect of serum IgG and numbers of erythrocyte complement receptor type 1

    International Nuclear Information System (INIS)

    Halma, C.; Breedveld, F.C.; Daha, M.R.; Blok, D.; Evers-Schouten, J.H.; Hermans, J.; Pauwels, E.K.; van Es, L.A.

    1991-01-01

    Using soluble 123 I-labeled aggregates of human IgG ( 123 I-AHIgG) as a probe, we examined the function of the mononuclear phagocyte system in 22 patients with systemic lupus erythematosus (SLE) and 12 healthy controls. In SLE patients, a decreased number of erythrocyte complement receptor type 1 was associated with less binding of 123 I-AHIgG to erythrocytes and a faster initial rate of elimination of 123 I-AHIgG (mean +/- SEM half-maximal clearance time 5.23 +/- 0.2 minutes, versus 6.58 +/- 0.2 minutes in the controls), with possible spillover of the material outside the mononuclear phagocyte system of the liver and spleen. However, multiple regression analysis showed that serum concentrations of IgG were the most important factor predicting the rate of 123 I-AHIgG elimination. IgG concentration may thus reflect immune complex clearance, which in turn, would influence the inflammatory reaction, in SLE

  11. Computer modeling of Cannabinoid receptor type 1

    Directory of Open Access Journals (Sweden)

    Sapundzhi Fatima

    2018-01-01

    Full Text Available Cannabinoid receptors are important class of receptors as they are involved in various physiological processes such as appetite, pain-sensation, mood, and memory. It is important to design receptor-selective ligands in order to treat a particular disorder. The aim of the present study is to model the structure of cannabinoid receptor CB1 and to perform docking between obtained models and known ligands. Two models of CBR1 were prepared with two different methods (Modeller of Chimera and MOE. They were used for docking with GOLD 5.2. It was established a high correlation between inhibitory constant Ki of CB1 cannabinoid ligands and the ChemScore scoring function of GOLD, which concerns both models. This suggests that the models of the CB1 receptors obtained could be used for docking studies and in further investigation and design of new potential, selective and active cannabinoids with the desired effects.

  12. TNF Receptor Type II as an Emerging Drug Target for the Treatment of Cancer, Autoimmune Diseases, and Graft-Versus-Host Disease: Current Perspectives and In Silico Search for Small Molecule Binders

    Directory of Open Access Journals (Sweden)

    Faraz Shaikh

    2018-06-01

    Full Text Available There is now compelling evidence that TNF receptor type II (TNFR2 is predominantly expressed on CD4+Foxp3+ regulatory T cells (Tregs and myeloid-derived suppressor cells (MDSCs, and plays a major role in the expansion and function of Tregs and MDSCs. Consequently, targeting of TNFR2 by either antagonists or agonists may represent a novel strategy in the treatment of cancer and autoimmune diseases, by downregulating or upregulating suppressor cell activity. The advance in the understanding of complex structure of TNFR2 and its binding with TNF at molecular levels offers opportunity for structure-guided drug discovery. This article reviews the current evidences regarding the decisive role of TNFR2 in immunosuppressive function of Tregs and MDSCs, and the current effort to develop novel TNFR2-targeting therapeutic agents in the treatment of cancer, autoimmune diseases, and graft-versus-host disease. To shed light on the potential TNFR2-targeting small molecules, we for the first time performed virtual screening of 400,000 natural compounds against the two TNF-binding sites, regions 3 and 4, of TNFR2. Our result showed that the top hits at region 4 had slightly higher docking energies than those at region 3. Nevertheless, free energy calculation from the TNF–TNFR2 molecular dynamics simulation revealed that the binding strength of TNF in region 3 is only one-tenth of that in region 4. This suggests that region 3 is a potentially more viable binding site to be targeted by small molecules than region 4. Therefore, the effectiveness in targeting region 3 of TNFR2 deserves further investigation.

  13. Genotype-Phenotype Associations of the CD-Associated Single Nucleotide Polymorphism within the Gene Locus Encoding Protein Tyrosine Phosphatase Non-Receptor Type 22 in Patients of the Swiss IBD Cohort.

    Directory of Open Access Journals (Sweden)

    Marianne R Spalinger

    Full Text Available Protein tyrosine phosphatase non-receptor type 22 (PTPN22 plays an important role in immune cell function and intestinal homeostasis. The single nucleotide polymorphism (SNP rs2476601 within the PTPN22 gene locus results in aberrant function of PTPN22 protein and protects from Crohn's disease (CD. Here, we investigated associations of PTPN22 SNP rs2476601 in inflammatory bowel disease (IBD patients in the Swiss IBD Cohort Study (SIBDCS.2'028 SIBDCS patients (1173 CD and 855 ulcerative colitis (UC patients were included. The clinical characteristics were analysed for an association with the presence of the PTPN22 SNP rs2476601 genotypes 'homozygous variant' (AA, 'heterozygous' (GA and 'homozygous wild-type' (GG.13 patients (0.6% were homozygous variant (AA for the PTPN22 polymorphism, 269 (13.3% heterozygous variant (GA and 1'746 (86.1% homozygous wild-type (GG. In CD, AA and GA genotypes were associated with less use of steroids and antibiotics, and reduced prevalence of vitamin D and calcium deficiency. In UC the AA and GA genotype was associated with increased use of azathioprine and anti-TNF antibodies, but significantly less patients with the PTPN22 variant featured malabsorption syndrome (p = 0.026.Our study for the first time addressed how presence of SNP rs2476601 within the PTPN22 gene affects clinical characteristics in IBD-patients. Several factors that correlate with more severe disease were found to be less common in CD patients carrying the A-allele, pointing towards a protective role for this variant in affected CD patients. In UC patients however, we found the opposite trend, suggesting a disease-promoting effect of the A-allele.

  14. Differences in expression of the cancer stem cell marker aldehyde dehydrogenase 1 among estrogen receptor-positive/human epidermal growth factor receptor type 2-negative breast cancer cases with early, late, and no recurrence.

    Science.gov (United States)

    Miyoshi, Yuichiro; Shien, Tadahiko; Ogiya, Akiko; Ishida, Naoko; Yamazaki, Kieko; Horii, Rie; Horimoto, Yoshiya; Masuda, Norikazu; Yasojima, Hiroyuki; Inao, Touko; Osako, Tomofumi; Takahashi, Masato; Tomioka, Nobumoto; Endo, Yumi; Hosoda, Mitsuchika; Doihara, Hiroyoshi; Miyoshi, Shinichiro; Yamashita, Hiroko

    2016-07-02

    The significance of the expression of aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, for predicting the recurrence of estrogen receptor (ER)-positive/human epidermal growth factor receptor type 2 (HER2)-negative breast cancer is still poorly understood. The value of ALDH1 in predicting the time of recurrence remains unknown. In total, 184 patients with early distant recurrence, 134 patients with late distant recurrence, and 321 control patients without recurrence for more than 10 years after starting initial treatment for ER-positive/HER2-negative breast cancer, registered in 9 institutions, were analyzed. We assessed relationships between ALDH1 and other clinicopathological features, and ALDH1 expression was compared among the three groups. The relationship between ALDH1 expression and overall survival after recurrence was also evaluated in each group. The rates of ALDH1 expression positivity (more than 1 %) in the early, late, and no recurrence groups were 18.4 %, 13.4 %, and 8.4 %, respectively. ALDH1 expression correlated significantly with lymph node metastases (p = 0.048) and the Ki-67 labeling index (p factor independently predicting overall survival after the detection of recurrence (adjusted OR 1.451, 95 % CI 0.985-2.085, p = 0.059). Among patients with ER-positive/HER2-negative breast cancer, ALDH1 expression was more common in those with early recurrence, and this expression was found to be associated with a more aggressive breast cancer phenotype than that in the patients without recurrence. Further study is needed to clarify the prognostic significance of the heterogeneity of cancer stem cells and to confirm their role in resistance to chemotherapy.

  15. The effect of chronic stimulation of serotonin receptor type 7 on recognition, passive avoidance memory, hippocampal long-term potentiation, and neuronal apoptosis in the amyloid β protein treated rat.

    Science.gov (United States)

    Shahidi, Siamak; Asl, Sara Soleimani; Komaki, Alireza; Hashemi-Firouzi, Nasrin

    2018-05-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment, neuronal death, and synaptic loss in the hippocampus. Long-term potentiation (LTP), a type of synaptic plasticity, occurs during learning and memory. Serotonin receptor type 7 (5-HTR7) activation is suggested as a possible therapeutic target for AD. The aim of the present study was to examine the effects of chronic treatment with the 5-HTR7 agonist, AS19, on cognitive function, memory, hippocampal plasticity, amyloid beta (Aβ) plaque accumulation, and apoptosis in an adult rat model of AD. AD was induced in rats using Aβ (single 1 μg/μL intracerebroventricular (icv) injection during surgery). The following experimental groups were included: control, sham-operated, Aβ + saline (1 μL icv for 30 days), and Aβ + AS19 (1 μg/μL icv for 30 days) groups. The animals were tested for cognition and memory performance using the novel object recognition and passive avoidance tests, respectively. Next, anesthetized rats were placed in a stereotaxic apparatus for electrode implantation, and field potentials were recorded in the hippocampal dentate gyrus. Lastly, brains were removed and Aβ plaques and neuronal apoptosis were evaluated using Congo red staining and TUNEL assay, respectively. Administration of AS19 in the Aβ rats increased the discrimination index of the novel object recognition test. Furthermore, AS19 treatment decreased time spent in the dark compartment during the passive avoidance test. AS19 also enhanced both the population spike (PS) amplitude and the field excitatory postsynaptic potential (fEPSP) slope evoked potentials of the LTP components. Aβ plaques and neuronal apoptosis were decreased in the AS19-treated Aβ rats. These results indicate that chronic treatment with a 5-HTR7 agonist can prevent Aβ-related impairments in cognition and memory performance by alleviating Aβ plaque accumulation and neuronal apoptosis, hence improving neuronal

  16. Specifying Specification.

    Science.gov (United States)

    Paulo, Norbert

    2016-03-01

    This paper tackles the accusation that applied ethics is no serious academic enterprise because it lacks theoretical bracing. It does so in two steps. In the first step I introduce and discuss a highly acclaimed method to guarantee stability in ethical theories: Henry Richardson's specification. The discussion shows how seriously ethicists take the stability of the connection between the foundational parts of their theories and their further development as well as their "application" to particular problems or cases. A detailed scrutiny of specification leads to the second step, where I use insights from legal theory to inform the debate around stability from that point of view. This view reveals some of specification's limitations. I suggest that, once specification is sufficiently specified, it appears astonishingly similar to deduction as used in legal theory. Legal theory also provides valuable insight into the functional range of deduction and its relation to other forms of reasoning. This leads to a richer understanding of stability in normative theories and to a smart division of labor between deduction and other forms of reasoning. The comparison to legal theory thereby provides a framework for how different methods such as specification, deduction, balancing, and analogy relate to one another.

  17. Probe specificity

    International Nuclear Information System (INIS)

    Laget, J.M.

    1986-11-01

    Specificity and complementarity of hadron and electron probes must be systematically developed to answer three questions currently asked in intermediate energy nuclear physics: what is nucleus structure at short distances, what is nature of short range correlations, what is three body force nature [fr

  18. HRT Specification

    CERN Document Server

    Möller, M

    1996-01-01

    In the context of the AIS Project (Advanced Informatics Systems for administration and management) a study has been conducted that resulted in the definition of a high level information systems model. Thirteen proposed systems were defined for detailed analysis. The Finance, Foundation, Human Resources, Logistics and Purchasing areas have been studied in detail. These studies have lead to the purchase and implementation of the ORIAC and SIRIAC packages, the Foundation database, the Oracle HR package, the Triton package and EDH and BHT. This specification describes the Human Resources Toolkit (HRT) intended to be used for accessing data in the HR and Foundation systems. This toolkit should help the divisions carry out their Human Resource management, planning and follow-up. It will have extensive report generation capabilities and offer a variety of standard graphs. It should have an easy-to-use graphical user interface and run on the CERN standard desktop platforms.

  19. Tyrosine phosphorylation of the human guanylyl cyclase C receptor

    Indian Academy of Sciences (India)

    Unknown

    **Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institute of Health, .... This construct expresses the N-terminal 330 amino acids ... C-terminal 112 amino acids of GCC as fusion with GST.

  20. Co-expression of the transcription factors CEH-14 and TTX-1 regulates AFD neuron-specific genes gcy-8 and gcy-18 in C. elegans.

    Science.gov (United States)

    Kagoshima, Hiroshi; Kohara, Yuji

    2015-03-15

    A wide variety of cells are generated by the expression of characteristic sets of genes, primarily those regulated by cell-specific transcription. To elucidate the mechanism regulating cell-specific gene expression in a highly specialized cell, AFD thermosensory neuron in Caenorhabditis elegans, we analyzed the promoter sequences of guanylyl cyclase genes, gcy-8 and gcy-18, exclusively expressed in AFD. In this study, we showed that AFD-specific expression of gcy-8 and gcy-18 requires the co-expression of homeodomain proteins, CEH-14/LHX3 and TTX-1/OTX1. We observed that mutation of ttx-1 or ceh-14 caused a reduction in the expression of gcy-8 and gcy-18 and that the expression was completely lost in double mutants. This synergy effect was also observed with other AFD marker genes, such as ntc-1, nlp-21and cng-3. Electrophoretic mobility shift assays revealed direct interaction of CEH-14 and TTX-1 proteins with gcy-8 and gcy-18 promoters in vitro. The binding sites of CEH-14 and TTX-1 proteins were confirmed to be essential for AFD-specific expression of gcy-8 and gcy-18 in vivo. We also demonstrated that forced expression of CEH-14 and TTX-1 in AWB chemosensory neurons induced ectopic expression of gcy-8 and gcy-18 reporters in this neuron. Finally, we showed that the regulation of gcy-8 and gcy-18 expression by ceh-14 and ttx-1 is evolutionally conserved in five Caenorhabditis species. Taken together, ceh-14 and ttx-1 expression determines the fate of AFD as terminal selector genes at the final step of cell specification. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. The roles of complement receptors type 1 (CR1, CD35) and type 3 (CR3, CD11b/CD18) in the regulation of the immune complex-elicited respiratory burst of polymorphonuclear leukocytes in whole blood

    DEFF Research Database (Denmark)

    Nielsen, C H; Antonsen, S; Matthiesen, S H

    1997-01-01

    cells using the monoclonal antibody (mAb) 3D9 resulted in a 1.9-fold increase in the IC-elicited PMN RB after 5 min of incubation, rising to 3.1-fold after 40 min. This enhancement was not due to increased IC deposition on PMN. Blockade of CR3 abrogated the mAb 3D9-induced rise in RB activity...... and inhibited the IC binding to PMN in a whole blood cell preparation, with or without mAb 3D9, by approximately 40% from 15-40 min while reducing their RB over 40 min to approximately one third. Blockade of CR1 on either erythrocytes (E) or leukocytes, before mixing the populations, revealed...... that the potentiation of the RB by mAb 3D9 was associated with abrogation of E-CR1 function, whereas blockade of leukocyte-CR1 had a diminishing effect. Exposure to IC at high concentrations induced release of both specific and azurophilic granule contents from PMN. The latter was CR3 dependent in that blockade...

  2. Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration.

    Science.gov (United States)

    McBrayer, Zofeyah L; Dimova, Jiva; Pisansky, Marc T; Sun, Mu; Beppu, Hideyuki; Gewirtz, Jonathan C; O'Connor, Michael B

    2015-01-01

    To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII) in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not reveal any differences in immobility between mutants and controls. In the Elevated Plus Maze, BMPRII mutants and Smad4 mutants showed reduced anxiety, while in exploratory tests, BMPRII mutants showed more interest in object exploration. These results suggest that loss of BMPRII in the mouse hippocampus and forebrain does not disrupt spatial learning and memory encoding, but instead impacts exploratory and anxiety-related behaviors.

  3. Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration.

    Directory of Open Access Journals (Sweden)

    Zofeyah L McBrayer

    Full Text Available To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not reveal any differences in immobility between mutants and controls. In the Elevated Plus Maze, BMPRII mutants and Smad4 mutants showed reduced anxiety, while in exploratory tests, BMPRII mutants showed more interest in object exploration. These results suggest that loss of BMPRII in the mouse hippocampus and forebrain does not disrupt spatial learning and memory encoding, but instead impacts exploratory and anxiety-related behaviors.

  4. Myositis specific autoantibodies; specificity and clinical applications.

    NARCIS (Netherlands)

    Hengstman, G.J.D.

    2005-01-01

    The sera of about half of the patients with myositis contain autoantibodies that are specific for this group of diseases compared to other inflammatory connective tissue disorders. In a recent study we showed that these myositis specific autoantibodies (MSAs) are also specific for myositis as

  5. Nitric Oxide Binds to and Modulates the Activity of a Pollen Specific Arabidopsis Diacylglycerol Kinase

    KAUST Repository

    Wong, Aloysius Tze

    2014-06-01

    Nitric oxide (NO) is an important signaling molecule in plants. In the pollen of Arabidopsis thaliana, NO causes re-orientation of the growing tube and this response is mediated by 3′,5′-cyclic guanosine monophosphate (cGMP). However, in plants, NO-sensors have remained somewhat elusive. Here, the findings of an NO-binding candidate, Arabidopsis thaliana DIACYLGLYCEROL KINASE 4 (ATDGK4; AT5G57690) is presented. In addition to the annotated diacylglycerol kinase domain, this molecule also harbors a predicted heme-NO/oxygen (H-NOX) binding site and a guanylyl cyclase (GC) catalytic domain which have been identified based on the alignment of functionally conserved amino acid residues across species. A 3D model of the molecule was constructed, and from which the locations of the kinase catalytic center, the ATP-binding site, the GC and H-NOX domains were estimated. Docking of ATP to the kinase catalytic center was also modeled. The recombinant ATDGK4 demonstrated kinase activity in vitro, catalyzing the ATP-dependent conversion of sn-1,2-diacylglycerol (DAG) to phosphatidic acid (PA). This activity was inhibited by the mammalian DAG kinase inhibitor R59949 and importantly also by the NO donors diethylamine NONOate (DEA NONOate) and sodium nitroprusside (SNP). Recombinant ATDGK4 also has GC activity in vitro, catalyzing the conversion of guanosine-5\\'-triphosphate (GTP) to cGMP. The catalytic domains of ATDGK4 kinase and GC may be independently regulated since the kinase but not the GC, was inhibited by NO while Ca2+ only stimulates the GC. It is likely that the DAG kinase product, PA, causes the release of Ca2+ from the intracellular stores and Ca2+ in turn activates the GC domain of ATDGK4 through a feedback mechanism. Analysis of publicly available microarray data has revealed that ATDGK4 is highly expressed in the pollen. Here, the pollen tubes of mis-expressing atdgk4 recorded slower growth rates than the wild-type (Col-0) and importantly, they showed altered

  6. How specific is specific self-efficacy?

    DEFF Research Database (Denmark)

    Nielsen, Tine; Makransky, Guido; Vang, Maria Louison

    2017-01-01

    academic learning self-efficacy (SAL-SE) and specific academic exam self-efficacy (SAE-SE), each scale being measurement invariant relative to age, Gender, admission method and specific course targeted. Furthermore, significant and relevant differences between the SAL-SE and SAE-SE scores dependent......Self-efficacy is an important and much used construct in psychology and social science studies. The validity of the measurements used is not always sufficiently evaluated. The aim was to evaluate the psychometric properties of the Danish translation of the self-efficacy subscale of The Motivated...... Strategies for Learning Questionnaire (MSLQ-SE) within a higher education context. Rasch measurement models were employed focusing on measurement invariance and dimensionality. Results with one students sample showed the MSLQ-SE to be not one, but two separate unidimensional subscales, measuring specific...

  7. Urine specific gravity test

    Science.gov (United States)

    ... medlineplus.gov/ency/article/003587.htm Urine specific gravity test To use the sharing features on this page, please enable JavaScript. Urine specific gravity is a laboratory test that shows the concentration ...

  8. Substrate specificity determinants of class III nucleotidyl cyclases.

    Science.gov (United States)

    Bharambe, Nikhil G; Barathy, Deivanayaga V; Syed, Wajeed; Visweswariah, Sandhya S; Colaςo, Melwin; Misquith, Sandra; Suguna, Kaza

    2016-10-01

    The two second messengers in signalling, cyclic AMP and cyclic GMP, are produced by adenylyl and guanylyl cyclases respectively. Recognition and discrimination of the substrates ATP and GTP by the nucleotidyl cyclases are vital in these reactions. Various apo-, substrate- or inhibitor-bound forms of adenylyl cyclase (AC) structures from transmembrane and soluble ACs have revealed the catalytic mechanism of ATP cyclization reaction. Previously reported structures of guanylyl cyclases represent ligand-free forms and inactive open states of the enzymes and thus do not provide information regarding the exact mode of substrate binding. The structures we present here of the cyclase homology domain of a class III AC from Mycobacterium avium (Ma1120) and its mutant in complex with ATP and GTP in the presence of calcium ion, provide the structural basis for substrate selection by the nucleotidyl cyclases at the atomic level. Precise nature of the enzyme-substrate interactions, novel modes of substrate binding and the ability of the binding pocket to accommodate diverse conformations of the substrates have been revealed by the present crystallographic analysis. This is the first report to provide structures of both the nucleotide substrates bound to a nucleotidyl cyclase. Coordinates and structure factors have been deposited in the Protein Data Bank with accession numbers: 5D15 (Ma1120 CHD +ATP.Ca 2+ ), 5D0E (Ma1120 CHD +GTP.Ca 2+ ), 5D0H (Ma1120 CHD (KDA→EGY)+ATP.Ca 2+ ), 5D0G (Ma1120 CHD (KDA→EGY)+GTP.Ca 2+ ). Adenylyl cyclase (EC number: 4.6.1.1). © 2016 Federation of European Biochemical Societies.

  9. Real-time specifications

    DEFF Research Database (Denmark)

    David, A.; Larsen, K.G.; Legay, A.

    2015-01-01

    A specification theory combines notions of specifications and implementations with a satisfaction relation, a refinement relation, and a set of operators supporting stepwise design. We develop a specification framework for real-time systems using Timed I/O Automata as the specification formalism......, with the semantics expressed in terms of Timed I/O Transition Systems. We provide constructs for refinement, consistency checking, logical and structural composition, and quotient of specifications-all indispensable ingredients of a compositional design methodology. The theory is implemented in the new tool Ecdar...

  10. Layer- and Cell Type-Specific Modulation of Excitatory Neuronal Activity in the Neocortex

    Directory of Open Access Journals (Sweden)

    Gabriele Radnikow

    2018-01-01

    Full Text Available From an anatomical point of view the neocortex is subdivided into up to six layers depending on the cortical area. This subdivision has been described already by Meynert and Brodmann in the late 19/early 20. century and is mainly based on cytoarchitectonic features such as the size and location of the pyramidal cell bodies. Hence, cortical lamination is originally an anatomical concept based on the distribution of excitatory neuron. However, it has become apparent in recent years that apart from the layer-specific differences in morphological features, many functional properties of neurons are also dependent on cortical layer or cell type. Such functional differences include changes in neuronal excitability and synaptic activity by neuromodulatory transmitters. Many of these neuromodulators are released from axonal afferents from subcortical brain regions while others are released intrinsically. In this review we aim to describe layer- and cell-type specific differences in the effects of neuromodulator receptors in excitatory neurons in layers 2–6 of different cortical areas. We will focus on the neuromodulator systems using adenosine, acetylcholine, dopamine, and orexin/hypocretin as examples because these neuromodulator systems show important differences in receptor type and distribution, mode of release and functional mechanisms and effects. We try to summarize how layer- and cell type-specific neuromodulation may affect synaptic signaling in cortical microcircuits.

  11. Experiences with effects specifications

    DEFF Research Database (Denmark)

    Simonsen, Jesper; Hertzum, Morten; Barlach, Anders

    2011-01-01

    We describe the effects-specification process from a project that was conducted during the fall 2010 and spring of 2011 in this chapter. The project configured and implemented an electronic patient record system at a maternity ward at a hospital located in a European region. The process comprised...... workshops with effects specification with management and end-users and an agile development process including prototypes configured from the effects specifications. We describe the project and the effects-specification process through which effects were related to the system design and instruments...... for measuring effects were designed. The project is analyzed and lessons learned are discussed....

  12. No beneficial effect of general and specific anti-inflammatory therapies on aortic dilatation in Marfan mice.

    Directory of Open Access Journals (Sweden)

    Romy Franken

    Full Text Available AIMS: Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. In the FBN1(C1039G/+ Marfan mouse model, losartan decreases aortic root dilatation. We recently confirmed this beneficial effect of losartan in adult patients with Marfan syndrome. The straightforward translation of this mouse model to man is reassuring to test novel treatment strategies. A number of studies have shown signs of inflammation in aortic tissue of Marfan patients. This study examined the efficacy of anti-inflammatory therapies in attenuating aortic root dilation in Marfan syndrome and compared effects to the main preventative agent, losartan. METHODS AND RESULTS: To inhibit inflammation in FBN1(C1039G/+ Marfan mice, we treated the mice with losartan (angiotensin II receptor type 1 inhibitor, methylprednisolone (corticosteroid or abatacept (T-cell-specific inhibitor. Treatment was initiated in adult Marfan mice with already existing aortic root dilatation, and applied for eight weeks. Methylprednisolone- or abatacept-treated mice did not reveal a reduction in aortic root dilatation. In this short time frame, losartan was the only treatment that significantly reduced aorta inflammation, transforming growth factor-beta (TGF-β signaling and aortic root dilatation rate in these adult Marfan mice. Moreover, the methylprednisolone-treated mice had significantly more aortic alcian blue staining as a marker for aortic damage. CONCLUSION: Anti-inflammatory agents do not reduce the aortic dilatation rate in Marfan mice, but possibly increase aortic damage. Currently, the most promising therapeutic drug in Marfan syndrome is losartan, by blocking the angiotensin II receptor type 1 and thereby inhibiting pSmad2 signaling.

  13. Review of technical specifications

    International Nuclear Information System (INIS)

    Bedrich, M.; Scholz, D.

    1980-01-01

    The present paper deals with position and function of technical specifications before and during the manufacturing of reactor components, their structure and reasons for specific regulations due to safety philosophy and explains the cooperation of supplier, manufacturer, utilities and supervisory organizations. (RW)

  14. Point specificity in acupuncture

    Directory of Open Access Journals (Sweden)

    Choi Emma M

    2012-02-01

    Full Text Available Abstract The existence of point specificity in acupuncture is controversial, because many acupuncture studies using this principle to select control points have found that sham acupoints have similar effects to those of verum acupoints. Furthermore, the results of pain-related studies based on visual analogue scales have not supported the concept of point specificity. In contrast, hemodynamic, functional magnetic resonance imaging and neurophysiological studies evaluating the responses to stimulation of multiple points on the body surface have shown that point-specific actions are present. This review article focuses on clinical and laboratory studies supporting the existence of point specificity in acupuncture and also addresses studies that do not support this concept. Further research is needed to elucidate the point-specific actions of acupuncture.

  15. FOXP3-specific immunity

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2013-01-01

    Forkhead box P3 (FOXP3)-specific cytotoxic CD8(+) T cells are present among human peripheral blood mononuclear cells (PBMCs), especially in cancer patients. Such T lymphocytes are able not only to specifically recognize dendritic cells (DCs) that have been exposed to recombinant FOXP3 and regulat...... and regulatory T cells, but also to kill FOXP3(+) malignant T cells. The natural occurrence of FOXP3-specific cytotoxic T lymphocytes among human PBMCs suggests a general role for these cells in the complex network of immune regulation....

  16. Place-Specific Computing

    DEFF Research Database (Denmark)

    Messeter, Jörn; Johansson, Michael

    project place- specific computing is explored through design oriented research. This article reports six pilot studies where design students have designed concepts for place-specific computing in Berlin (Germany), Cape Town (South Africa), Rome (Italy) and Malmö (Sweden). Background and arguments...... for place-specific computing as a genre of interaction design are described. A total number of 36 design concepts designed for 16 designated zones in the four cities are presented. An analysis of the design concepts is presented indicating potentials, possibilities and problems as directions for future......An increased interest in the notion of place has evolved in interaction design. Proliferation of wireless infrastructure, developments in digital media, and a ‘spatial turn’ in computing provides the base for place-specific computing as a suggested new genre of interaction design. In the REcult...

  17. TWRSview system requirements specification

    International Nuclear Information System (INIS)

    Caldwell, J.A.; Lee, A.K.

    1995-12-01

    This document provides the system requirements specification for the TWRSview software system. The TWRSview software system is being developed to integrate electronic data supporting the development of the TWRS technical baseline

  18. specific low back pain

    African Journals Online (AJOL)

    2015-09-01

    Sep 1, 2015 ... SPECIFIC LOW BACK PAIN: IMPLICATION FOR DIRECT HEALTH. CARE COST ... abundant evidence suggesting the benefits of therapeu- tic exercise on pain and ... Exercise and behavioural therapies in chronic pain. 174.

  19. Site Specific Vendor's License

    Data.gov (United States)

    Montgomery County of Maryland — This dataset contains information of a site-specific vendor's license which is required if an individual sells or offers to sell goods or services from a stationary...

  20. Construction and material specification

    Science.gov (United States)

    2002-01-01

    These Construction and Material Specifications are written to the Bidder before award of the : Contract and to the Contractor after award of the Contract. The sentences that direct the Contractor to perform Work are written as commands. For example, ...

  1. Specific radiography technique

    International Nuclear Information System (INIS)

    Abdul Nassir Ibrahim; Azali Muhammad; Ab. Razak Hamzah; Abd. Aziz Mohamed; Mohamad Pauzi Ismail

    2008-01-01

    Beside radiography testing using x-ray machine and gamma source, there are several technique that developed specifically to complete the testing that cannot be done with the two earlier. This technique was specific based on several factor, for the example, the advantages of neutron and electron using to show the image was unique compare to x-ray and gamma. Besides that, these special radiography techniques maybe differ in how to detect the radiation get through the object. These technique can used to inspect thin or specimen that contained radioactive material. There are several technique will discussed in this chapter such as neutron radiography, electron radiography, fluoroscopy and also autoradiography.

  2. Comparative Test Case Specification

    DEFF Research Database (Denmark)

    Kalyanova, Olena; Heiselberg, Per

     This document includes a definition of the comparative test cases DSF200_3 and DSF200_4, which previously described in the comparative test case specification for the test cases DSF100_3 and DSF200_3 [Ref.1]....... This document includes a definition of the comparative test cases DSF200_3 and DSF200_4, which previously described in the comparative test case specification for the test cases DSF100_3 and DSF200_3 [Ref.1]....

  3. IDC System Specification Document.

    Energy Technology Data Exchange (ETDEWEB)

    Clifford, David J.

    2014-12-01

    This document contains the system specifications derived to satisfy the system requirements found in the IDC System Requirements Document for the IDC Reengineering Phase 2 project. Revisions Version Date Author/Team Revision Description Authorized by V1.0 12/2014 IDC Reengineering Project Team Initial delivery M. Harris

  4. Specification of Concurrent Objects

    DEFF Research Database (Denmark)

    Sørensen, Morten U.

    relation over two objects and an event. In the model, objects can be composed by parallel composition, encapsulation, and hiding of operations. Refinement between objects is defined as fair trace inclusion.A specification language is presented where objects can be specified operationally by abstract...

  5. Place-Specific Computing

    DEFF Research Database (Denmark)

    Messeter, Jörn

    2009-01-01

    An increased interest in the notion of place has evolved in interaction design based on the proliferation of wireless infrastructures, developments in digital media, and a ‘spatial turn’ in computing. In this article, place-specific computing is suggested as a genre of interaction design that add......An increased interest in the notion of place has evolved in interaction design based on the proliferation of wireless infrastructures, developments in digital media, and a ‘spatial turn’ in computing. In this article, place-specific computing is suggested as a genre of interaction design...... that addresses the shaping of interactions among people, place-specific resources and global socio-technical networks, mediated by digital technology, and influenced by the structuring conditions of place. The theoretical grounding for place-specific computing is located in the meeting between conceptions...... of place in human geography and recent research in interaction design focusing on embodied interaction. Central themes in this grounding revolve around place and its relation to embodiment and practice, as well as the social, cultural and material aspects conditioning the enactment of place. Selected...

  6. Sports-specific injuries.

    Science.gov (United States)

    Plancher, K D; Minnich, J M

    1996-04-01

    Injuries to the upper extremities can happen in any sport. Injury patterns are common to specific sports. Understanding which injuries occur with these sports allows the examiner to diagnose and treat the athlete easily. This article reviews some of the injuries common in sports such as bicycling, golf, gymnastics, martial arts, racquet sports, and weightlifting.

  7. Site-Specific Innovation

    DEFF Research Database (Denmark)

    Reeh, Henrik; Hemmersam, Peter

    2015-01-01

    Currently, cities across the Northern European region are actively redeveloping their former industrial harbours. Indeed, harbours areas are essential in the long-term transition from industrial to information and experience societies; harbours are becoming sites for new businesses and residences...... question is how innovation may contribute to urban life and site-specific qualities....

  8. Specification of Nonmonotonic Reasoning.

    NARCIS (Netherlands)

    Engelfriet, J.; Treur, J.

    2000-01-01

    Two levels of description of nonmonotonic reasoning are distinguished. For these levels semantical formalizations are given. The first Level is defined semantically by the notion of belief state frame, the second Level by the notion of reasoning frame. We introduce two specification languages to

  9. Specification of Nonmonotonic Reasoning

    NARCIS (Netherlands)

    Engelfriet, J.; Treur, J.

    1996-01-01

    Two levels of description of nonmonotonic reasoning are distinguished. For these levels semantical formalizations are given. The first level is defined semantically by the notion of belief state frame, the second level by the notion of reasoning frame. We introduce two specification languages to

  10. Domain-Specific Multimodeling

    DEFF Research Database (Denmark)

    Hessellund, Anders

    the overall level of abstraction. It does, however, also introduce a new problem of coordinating multiple different languages in a single system. We call this problem the coordination problem. In this thesis, we present the coordination method for domain-specific multimodeling that explicitly targets...

  11. Specific Language Impairment

    Science.gov (United States)

    ... Some of the tests use interactions between the child and puppets and other toys to focus on specific rules of grammar, especially ... is not treated early, it can affect a child’s performance in school. ... language development. This kind of classroom program might enlist normally ...

  12. Specifications in software prototyping

    OpenAIRE

    Luqi; Chang, Carl K.; Zhu, Hong

    1998-01-01

    We explore the use of software speci®cations for software prototyping. This paper describes a process model for software prototyping, and shows how specifications can be used to support such a process via a cellular mobile phone switch example.

  13. New usable technical specifications

    International Nuclear Information System (INIS)

    Webster, S.A.; Tomasi, L.T.; Bernier, R.A.

    1989-01-01

    After 2 yr of preparation, 1988 finally saw the nuclear industry writing operator-oriented technical specifications. This effort is a continuation of previous efforts to develop improved and usable standard technical specifications (STSs), and is being conducted by the four nuclear steam supply system vendor owners' groups under the auspices of the Nuclear Management Resources Council. Each participant is currently preparing a set of improved STSs based on a writer's guide that was developed through a combined industry effort. In May of 1987, a Human Factors Improvements to Technical Specifications (HFITS) task group was formed to prepare a writer's guide for improved, industrywide STSs. This task group was composed of two representatives from each owners' group, one with a human factors background and one with some operations background. Two documents were prepared in 6 months, a human factors report laying the groundwork for the considerations to go into technical specifications and a writer's guide for their preparation. This paper reports on the application of this writer's guide to the writing of improved STS

  14. Sport-specific balance.

    Science.gov (United States)

    Zemková, Erika

    2014-05-01

    This review includes the latest findings based on experimental studies addressing sport-specific balance, an area of research that has grown dramatically in recent years. The main objectives of this work were to investigate the postural sway response to different forms of exercise under laboratory and sport-specific conditions, to examine how this effect can vary with expertise, and to provide examples of the association of impaired balance with sport performance and/or increasing risk of injury. In doing so, sports where body balance is one of the limiting factors of performance were analyzed. While there are no significant differences in postural stability between athletes of different specializations and physically active individuals during standing in a standard upright position (e.g., bipedal stance), they have a better ability to maintain balance in specific conditions (e.g., while standing on a narrow area of support). Differences in magnitude of balance impairment after specific exercises (rebound jumps, repeated rotations, etc.) and mainly in speed of its readjustment to baseline are also observed. Besides some evidence on an association of greater postural sway with the increasing risk of injuries, there are many myths related to the negative influence of impaired balance on sport performance. Though this may be true for shooting or archery, findings have shown that in many other sports, highly skilled athletes are able to perform successfully in spite of increased postural sway. These findings may contribute to better understanding of the postural control system under various performance requirements. It may provide useful knowledge for designing training programs for specific sports.

  15. ENVIRONMENTAL SPECIFICATION REQUIREMENTS

    International Nuclear Information System (INIS)

    TIFFT, S.R.

    2003-01-01

    Through regulations, permitting or binding negotiations, Regulators establish requirements, limits, permit conditions and Notice of Construction (NOC) conditions with which the Office of River Protection (ORP) and the Tank Farm Contractor (TFC) must comply. Operating Specifications are technical limits which are set on a process to prevent injury to personnel, or damage to the facility or environment. The main purpose of this document is to provide specification limits and recovery actions for the TFC Environmental Surveillance Program at the Hanford Site. Specification limits are given for monitoring frequencies and permissible variation of readings from an established baseline or previous reading. The requirements in this document are driven by environmental considerations and data analysis issues, rather than facility design or personnel safety issues. This document is applicable to all single-shell tank (SST) and double-shell tank (DST) waste tanks, and the associated catch tanks and receiver tanks, and transfer systems. This Tank Farm Environmental Specifications Document (ESD) implements environmental-regulatory limits on the configuration and operation of the Hanford Tank Farms facility that have been established by Regulators. This ESD contains specific field operational limits and recovery actions for compliance with airborne effluent regulations and agreements, liquid effluents regulations and agreements, and environmental tank system requirements. The scope of this ESD is limited to conditions that have direct impact on Operations Projects or that Operations/Projects have direct impact upon. This document does not supercede or replace any DOE Orders, regulatory permits, notices of construction, or Regulatory agency agreements binding on the ORP or the TFC. Refer to the appropriate regulation, permit, or NOC for an inclusive listing of requirements

  16. Comparative Test Case Specification

    DEFF Research Database (Denmark)

    Kalyanova, Olena; Heiselberg, Per

    This document includes the specification on the IEA task of evaluation building energy simulation computer programs for the Double Skin Facades (DSF) constructions. There are two approaches involved into this procedure, one is the comparative approach and another is the empirical one. In the comp....... In the comparative approach the outcomes of different software tools are compared, while in the empirical approach the modelling results are compared with the results of experimental test cases. The comparative test cases include: ventilation, shading and geometry....

  17. Empirical Test Case Specification

    DEFF Research Database (Denmark)

    Kalyanova, Olena; Heiselberg, Per

    This document includes the empirical specification on the IEA task of evaluation building energy simulation computer programs for the Double Skin Facades (DSF) constructions. There are two approaches involved into this procedure, one is the comparative approach and another is the empirical one. I....... In the comparative approach the outcomes of different software tools are compared, while in the empirical approach the modelling results are compared with the results of experimental test cases....

  18. ENVIRONMENTAL SPECIFICATION REQUIREMENTS

    International Nuclear Information System (INIS)

    TIFFT, S.R.

    2003-01-01

    Through regulations, permitting or binding negotiations, Regulators establish requirements, limits, permit conditions and Notice of Construction (NOC) conditions with which the Office of River Protection (ORP) and the Tank Farm Contractor (TFC) must comply. Operating Specifications are technical limits which are set on a process to prevent injury to personnel, or damage to the facility or environment. The main purpose of this document is to provide specification limits and recovery actions for the TFC Environmental Surveillance Program at the Hanford Site. Specification limits are given for monitoring frequencies and permissible variation of readings from an established baseline or previous reading. The requirements in this document are driven by environmental considerations and data analysis issues, rather than facility design or personnel safety issues. This document is applicable to all SST and DST waste tanks, and the associated catch tanks and receiver tanks, and transfer systems. This Tank Farm ESD implements environmental-regulatory limits on the configuration and operation of the Hanford Tank Farms facility that have been established by Regulators. This ESD contains specific field operational limits and recovery actions for compliance with airborne effluent regulations and agreements, liquid effluents regulations and agreements, and environmental tank system requirements. The scope of this ESD is limited to conditions that have direct impact on Operations/Projects or that Operations/Projects have direct impact upon. This document does not supercede or replace any DOE Orders, regulatory permits, notices of construction, or Regulatory agency agreements binding on the ORP or the TFC. Refer to the appropriate regulation, permit, or NOC for an inclusive listing of requirements

  19. Allergen-specific immunotherapy

    Directory of Open Access Journals (Sweden)

    Moote William

    2011-11-01

    Full Text Available Abstract Allergen-specific immunotherapy is a potentially disease-modifying therapy that is effective for the treatment of allergic rhinitis/conjunctivitis, allergic asthma and stinging insect hypersensitivity. However, despite its proven efficacy in these conditions, it is frequently underutilized in Canada. The decision to proceed with allergen-specific immunotherapy should be made on a case-by-case basis, taking into account individual patient factors such as the degree to which symptoms can be reduced by avoidance measures and pharmacological therapy, the amount and type of medication required to control symptoms, the adverse effects of pharmacological treatment, and patient preferences. Since this form of therapy carries the risk of anaphylactic reactions, it should only be prescribed by physicians who are adequately trained in the treatment of allergy. Furthermore, injections must be given under medical supervision in clinics that are equipped to manage anaphylaxis. In this article, the authors review the indications and contraindications, patient selection criteria, and the administration, safety and efficacy of allergen-specific immunotherapy.

  20. Data specifications for INSPIRE

    Science.gov (United States)

    Portele, Clemens; Woolf, Andrew; Cox, Simon

    2010-05-01

    In Europe a major recent development has been the entering in force of the INSPIRE Directive in May 2007, establishing an infrastructure for spatial information in Europe to support Community environmental policies, and policies or activities which may have an impact on the environment. INSPIRE is based on the infrastructures for spatial information established and operated by the 27 Member States of the European Union. The Directive addresses 34 spatial data themes needed for environmental applications, with key components specified through technical implementing rules. This makes INSPIRE a unique example of a legislative "regional" approach. One of the requirements of the INSPIRE Directive is to make existing spatial data sets with relevance for one of the spatial data themes available in an interoperable way, i.e. where the spatial data from different sources in Europe can be combined to a coherent result. Since INSPIRE covers a wide range of spatial data themes, the first step has been the development of a modelling framework that provides a common foundation for all themes. This framework is largely based on the ISO 19100 series of standards. The use of common generic spatial modelling concepts across all themes is an important enabler for interoperability. As a second step, data specifications for the first set of themes has been developed based on the modelling framework. The themes include addresses, transport networks, protected sites, hydrography, administrative areas and others. The data specifications were developed by selected experts nominated by stakeholders from all over Europe. For each theme a working group was established in early 2008 working on their specific theme and collaborating with the other working groups on cross-theme issues. After a public review of the draft specifications starting in December 2008, an open testing process and thorough comment resolution process, the draft technical implementing rules for these themes have been

  1. Substructural Logical Specifications

    Science.gov (United States)

    2012-11-14

    and independently in the context of CLF by Schack-Nielsen [SN07] and by Cruz and Hou [CH12]; Schack-Nielsen proves the equivalence of the two specifi...cations, whereas Cruz and Hou used the connection informally. The contribution of this section is to describe a general transformation (of which...Functional Programming (LFP’86), pages 13–27. ACM, 1986. 5.1 [CDE+11] Manuel Clavel, Francisco Durán, Steven Eker, Patrick Lincoln, Narciso Martı́- 290 Oliet

  2. Tendering specification and contracting

    International Nuclear Information System (INIS)

    Koch, E. von

    1975-01-01

    The lecture tendering, specification and contracting is prepared in two parts: This first part deals with technical aspects while part two features the commercial and legal situation in the partnership of two: the supplier of the fuel bundles and the utility. In this lecture a look is given on the way how a supplier can offer its fuel and some certain points are mentioned which are important to compare the bid of one competitor to the other. The major points are summarized which are or at least should be in an offer so as to find out which offer is the best. (orig./FW) [de

  3. Disease specific protein corona

    Science.gov (United States)

    Rahman, M.; Mahmoudi, M.

    2015-03-01

    It is now well accepted that upon their entrance into the biological environments, the surface of nanomaterials would be covered by various biomacromolecules (e.g., proteins and lipids). The absorption of these biomolecules, so called `protein corona', onto the surface of (nano)biomaterials confers them a new `biological identity'. Although the formation of protein coronas on the surface of nanoparticles has been widely investigated, there are few reports on the effect of various diseases on the biological identity of nanoparticles. As the type of diseases may tremendously changes the composition of the protein source (e.g., human plasma/serum), one can expect that amount and composition of associated proteins in the corona composition may be varied, in disease type manner. Here, we show that corona coated silica and polystyrene nanoparticles (after interaction with in the plasma of the healthy individuals) could induce unfolding of fibrinogen, which promotes release of the inflammatory cytokines. However, no considerable releases of inflammatory cytokines were observed for corona coated graphene sheets. In contrast, the obtained corona coated silica and polystyrene nanoparticles from the hypofibrinogenemia patients could not induce inflammatory cytokine release where graphene sheets do. Therefore, one can expect that disease-specific protein coronas can provide a novel approach for applying nanomedicine to personalized medicine, improving diagnosis and treatment of different diseases tailored to the specific conditions and circumstances.

  4. Code, standard and specifications

    International Nuclear Information System (INIS)

    Abdul Nassir Ibrahim; Azali Muhammad; Ab. Razak Hamzah; Abd. Aziz Mohamed; Mohamad Pauzi Ismail

    2008-01-01

    Radiography also same as the other technique, it need standard. This standard was used widely and method of used it also regular. With that, radiography testing only practical based on regulations as mentioned and documented. These regulation or guideline documented in code, standard and specifications. In Malaysia, level one and basic radiographer can do radiography work based on instruction give by level two or three radiographer. This instruction was produced based on guideline that mention in document. Level two must follow the specifications mentioned in standard when write the instruction. From this scenario, it makes clearly that this radiography work is a type of work that everything must follow the rule. For the code, the radiography follow the code of American Society for Mechanical Engineer (ASME) and the only code that have in Malaysia for this time is rule that published by Atomic Energy Licensing Board (AELB) known as Practical code for radiation Protection in Industrial radiography. With the existence of this code, all the radiography must follow the rule or standard regulated automatically.

  5. Specification of brachytherapy sources

    Energy Technology Data Exchange (ETDEWEB)

    1984-10-01

    BCRU recommends that the following specification of gamma-ray brachytherapy sources be adopted. Unless otherwise stated, the output of a cylindrical source should be specified in air kerma rate at a point in free space at a distance of 1 m from the source on the radial plane of symmetry, i.e. the plane bisecting the active length and perpendicular to the cylindrical axis of the source. For a wire source the output should be specified for a 1 cm length. For any other construction of source, the point at which the output is specified should be stated. It is also recommended that the units in which the air kerma rate is expressed should be micrograys per hour (..mu..Gy/h).

  6. Site specific plan

    International Nuclear Information System (INIS)

    Hutchison, J.; Jernigan, G.

    1989-12-01

    The Environmental Restoration and Waste Management Five-Year Plan (FYP) covers the period for FY 1989 through FY 1995. The plan establishes a Department of Energy -- Headquarters (DOE-HQ) agenda for cleanup and compliance against which overall progress can be measured. The FYP covers three areas: Corrective Activities, Environmental Restoration, and Waste Management Operations. Corrective Activities are those activities necessary to bring active or standby facilities into compliance with local, state, and federal environmental regulations. Environmental restoration activities include the assessment and cleanup of surplus facilities and inactive waste sites. Waste management operations includes the treatment, storage, and disposal of wastes which are generated as a result of ongoing operations. This Site Specific Plan (SSP) has been prepared by the Savannah River Site (SRS) in order to show how environmental restoration and waste management activities that were identified during the preparation of the FYP will be implemented, tracked, and reported. The SSP describes DOE Savannah River (DOE-SR) and operating contractor, Westinghouse Savannah River Company (WSRC), organizations that are responsible, for undertaking the activities identified in this plan. The SSP has been prepared in accordance with guidance received from DOE-HQ. DOE-SR is accountable to DOE-HQ for the implementation of this plan. 8 refs., 46 figs., 23 tabs

  7. ADANS database specification

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-01-16

    The purpose of the Air Mobility Command (AMC) Deployment Analysis System (ADANS) Database Specification (DS) is to describe the database organization and storage allocation and to provide the detailed data model of the physical design and information necessary for the construction of the parts of the database (e.g., tables, indexes, rules, defaults). The DS includes entity relationship diagrams, table and field definitions, reports on other database objects, and a description of the ADANS data dictionary. ADANS is the automated system used by Headquarters AMC and the Tanker Airlift Control Center (TACC) for airlift planning and scheduling of peacetime and contingency operations as well as for deliberate planning. ADANS also supports planning and scheduling of Air Refueling Events by the TACC and the unit-level tanker schedulers. ADANS receives input in the form of movement requirements and air refueling requests. It provides a suite of tools for planners to manipulate these requirements/requests against mobility assets and to develop, analyze, and distribute schedules. Analysis tools are provided for assessing the products of the scheduling subsystems, and editing capabilities support the refinement of schedules. A reporting capability provides formatted screen, print, and/or file outputs of various standard reports. An interface subsystem handles message traffic to and from external systems. The database is an integral part of the functionality summarized above.

  8. Dual specificity of activin type II receptor ActRIIb in dorso-ventral patterning during zebrafish embryogenesis.

    Science.gov (United States)

    Nagaso, H; Suzuki, A; Tada, M; Ueno, N

    1999-04-01

    Members of the transforming growth factor-beta (TGF-beta) superfamily are thought to regulate specification of a variety of tissue types in early embryogenesis. These effects are mediated through a cell surface receptor complex, consisting of two classes of ser/thr kinase receptor, type I and type II. In the present study, cDNA encoding zebrafish activin type II receptors, ActRIIa and ActRIIb was cloned and characterized. Overexpression of ActRIIb in zebrafish embryos caused dorsalization of embryos, as observed in activin-overexpressing embryos. However, in blastula stage embryos, ActRIIb induced formation of both dorsal and ventro-lateral mesoderm. It has been suggested that these inducing signals from ActRIIb are mediated through each specific type I receptor, TARAM-A and BMPRIA, depending on activin and bone morphogenetic protein (BMP), respectively. In addition, it was shown that a kinase-deleted form of ActRIIb (dnActRIIb) suppressed both activin- and BMP-like signaling pathways. These results suggest that ActRIIb at least has dual roles in both activin and BMP signaling pathways during zebrafish embryogenesis.

  9. The plant natriuretic peptide receptor is a guanylyl cyclase and enables cGMP-dependent signaling

    KAUST Repository

    Turek, Ilona; Gehring, Christoph A

    2016-01-01

    and water balance and responses to biotrophic plant pathogens. Although there is increasing understanding of the complex roles of PNPs in plant responses at the systems level, little is known about the underlying signaling mechanisms. Here we report

  10. In Vitro Assessment of Guanylyl Cyclase Activity of Plant Receptor Kinases

    KAUST Repository

    Raji, Misjudeen; Gehring, Christoph A

    2017-01-01

    Cyclic nucleotides such as 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) are increasingly recognized as key signaling molecules in plants, and a growing number of plant mononucleotide cyclases, both adenylate cyclases (ACs) and guanylate cyclases (GCs), have been reported. Catalytically active cytosolic GC domains have been shown to be part of many plant receptor kinases and hence directly linked to plant signaling and downstream cellular responses. Here we detail, firstly, methods to identify and express essential functional GC domains of receptor kinases, and secondly, we describe mass spectrometric methods to quantify cGMP generated by recombinant GCs from receptor kinases in vitro.

  11. Consistent expression of guanylyl cyclase-C in primary and metastatic gastrointestinal cancers.

    Directory of Open Access Journals (Sweden)

    Hadi Danaee

    Full Text Available The transmembrane receptor guanylate cyclase-C (GCC has been found to be expressed in colorectal cancers. However, limited data are available on GCC protein expression in non-colorectal gastrointestinal tumors and few studies have reported whether GCC protein expression was consistently preserved in synchronous primary and metastatic cancer tissues.GCC protein status was assessed by immunohistochemistry in tumor specimens from individuals (n = 627 with gastrointestinal tumors, including esophageal (n = 130, gastric (n = 276, pancreatic (n = 136, and colorectal (n = 85 primary and metastatic tumors. Tissue specimens consisted of tissue microarrays containing esophageal, gastric, pancreatic tumors, and whole-slide tissue sections from colorectal cancer patients with matching primary and metastatic tumors.Among the evaluated esophageal, gastric, and pancreatic tumors, the frequency of GCC positivity at the protein level ranged from 59% to 68%. GCC was consistently expressed in primary and matched/synchronous metastatic lesions of colorectal cancer tissues derived from the same patients.This observational study demonstrated the protein expression of GCC across various gastrointestinal malignancies. In all cancer histotypes, GCC protein localization was observed predominantly in the cytoplasm compared to the membrane region of tumor cells. Consistent immunohistochemistry detection of GCC protein expression in primary colorectal cancers and in their matched liver metastases suggests that the expression of GCC is maintained throughout the process of tumor progression and formation of metastatic disease.

  12. In Vitro Assessment of Guanylyl Cyclase Activity of Plant Receptor Kinases

    KAUST Repository

    Raji, Misjudeen

    2017-05-31

    Cyclic nucleotides such as 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) are increasingly recognized as key signaling molecules in plants, and a growing number of plant mononucleotide cyclases, both adenylate cyclases (ACs) and guanylate cyclases (GCs), have been reported. Catalytically active cytosolic GC domains have been shown to be part of many plant receptor kinases and hence directly linked to plant signaling and downstream cellular responses. Here we detail, firstly, methods to identify and express essential functional GC domains of receptor kinases, and secondly, we describe mass spectrometric methods to quantify cGMP generated by recombinant GCs from receptor kinases in vitro.

  13. Adequate procedures for specific exams

    International Nuclear Information System (INIS)

    Staevie, G.L.G.; Gattringer, D.K.; Dal Mas, C.R.; Tessman, M.

    1996-01-01

    Some ideal procedures for specific radiographic exams are briefly presented. The aim is to improve the quality standard, establishing a specific method for each exam in order to decrease films waste and reduce the patient dose exposure

  14. Teaching English for Specific Purposes

    Directory of Open Access Journals (Sweden)

    Nijolė Netikšienė

    2011-04-01

    Full Text Available Teaching English for Specific Purposes and General English is analysed in the article. The scientific approach of a scientist M. Rosenberg is presented. The experience of teaching English for Specific Purposesat VGTU is alsopresented. The ideas and teaching methods from the classes of general English can be transferred to the classes of English for Specific Purposes.

  15. Microvillus-Specific Protein Tyrosine Phosphatase SAP-1 Plays a Role in Regulating the Intestinal Paracellular Transport of Macromolecules.

    Science.gov (United States)

    Mori, Shingo; Kamei, Noriyasu; Murata, Yoji; Takayama, Kozo; Matozaki, Takashi; Takeda-Morishita, Mariko

    2017-09-01

    The stomach cancer-associated protein tyrosine phosphatase 1 (SAP-1) is a receptor-type protein tyrosine phosphatase that is specifically expressed on the apical membrane of the intestinal epithelium. SAP-1 is known to maintain the balance of phosphorylation of proteins together with protein kinases; however, its biological function and impact on pharmacokinetics in the intestine remain unclear. The present study, therefore, aimed at clarifying the relationship between SAP-1 and the intestinal absorption behaviors of typical transporter substrates and macromolecules. The endogenous levels of glucose and total cholesterol in the blood were similar between wild-type and SAP-1-deficient mice (Sap1 -/- ), suggesting no contribution of SAP-1 to biogenic influx. Moreover, in vitro transport study with everted ileal sacs demonstrated that there was no difference in the absorption of breast cancer resistance protein, P-glycoprotein, and peptide transporter substrates between both mice. However, absorptive clearance of macromolecular model dextrans (FD-4 and FD-10) in Sap1 -/- mice was significantly higher than that in wild-type mice, and this was confirmed by the trend of increased FD-4 absorption from colonic loops of Sap1 -/- mice. Therefore, the results of this study suggest the partial contribution of SAP-1 to the regulated transport of hydrophilic macromolecules through paracellular tight junctions. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  16. A family of octopamine [corrected] receptors that specifically induce cyclic AMP production or Ca2+ release in Drosophila melanogaster.

    Science.gov (United States)

    Balfanz, Sabine; Strünker, Timo; Frings, Stephan; Baumann, Arnd

    2005-04-01

    In invertebrates, the biogenic-amine octopamine is an important physiological regulator. It controls and modulates neuronal development, circadian rhythm, locomotion, 'fight or flight' responses, as well as learning and memory. Octopamine mediates its effects by activation of different GTP-binding protein (G protein)-coupled receptor types, which induce either cAMP production or Ca(2+) release. Here we describe the functional characterization of two genes from Drosophila melanogaster that encode three octopamine receptors. The first gene (Dmoa1) codes for two polypeptides that are generated by alternative splicing. When heterologously expressed, both receptors cause oscillatory increases of the intracellular Ca(2+) concentration in response to applying nanomolar concentrations of octopamine. The second gene (Dmoa2) codes for a receptor that specifically activates adenylate cyclase and causes a rise of intracellular cAMP with an EC(50) of approximately 3 x 10(-8) m octopamine. Tyramine, the precursor of octopamine biosynthesis, activates all three receptors at > or = 100-fold higher concentrations, whereas dopamine and serotonin are non-effective. Developmental expression of Dmoa genes was assessed by RT-PCR. Overlapping but not identical expression patterns were observed for the individual transcripts. The genes characterized in this report encode unique receptors that display signature properties of native octopamine receptors.

  17. Technical specification use and application

    International Nuclear Information System (INIS)

    Williamson, D.; Hoffman, D.R.

    1991-01-01

    Since early 1988 intensive efforts have been under way to produce a new and improved Standard Technical Specification. The program involves a coordinated effort between utility personnel representing each of the four nuclear steam supply system (NSSS) product lines, the NSSS vendors, and the US Nuclear Regulatory Commission (NRC). This intensive work period is actually the culmination of a decade of rhetoric about shortcomings of the existing technical specifications. Work on the improved technical specifications provided a unique forum for intense philosophical discussions between the users and enforcers of technical specifications, the outcome of which could have an impact on all licensees. Some of the more intriguing difficulties in the use and application of existing technical specifications, as well as discussions of the resolutions being applied in the improved technical specifications and the dilemmas remaining to be resolved are discussed in the paper

  18. [Multilingualism and specific language impairment].

    Science.gov (United States)

    Arkkila, Eva; Smolander, Sini; Laasonen, Marja

    2013-01-01

    Specific language impairment is one of the most common developmental disturbances in childhood. With the increase of the foreign language population group an increasing number of children assimilating several languages and causing concern in language development attend clinical examinations. Knowledge of factors underlying the specific language impairment and the specific impairment in general, special features of language development of those learning several languages, as well as the assessment and support of the linguistic skills of a multilingual child is essential. The risk of long-term problems and marginalization is high for children having specific language impairment.

  19. Trojan technical specification verification project

    International Nuclear Information System (INIS)

    Bates, L.; Rickenback, M.

    1991-01-01

    The Trojan Technical Specification Verification (TTSV) project at the Trojan plant of Portland General Electric Company was motivated by the recognition that many numbers in the Trojan technical specifications (TTS) potentially lacked the consideration of instrument- and/or process-related errors. The plant setpoints were known to consider such errors, but many of the values associated with the limiting conditions for operation (LCO) did not. In addition, the existing plant instrument error analyses were based on industry values that do not reflect the Trojan plant-specific experience. The purpose of this project is to ensure that the Trojan plant setpoint and LCO values include plant-specific instrument error

  20. Hanford Site environmental management specification

    International Nuclear Information System (INIS)

    Grygiel, M.L.

    1998-01-01

    The US Department of Energy, Richland Operations Office (RL) uses this Hanford Site Environmental Management Specification (Specification) to document top-level mission requirements and planning assumptions for the prime contractors involved in Hanford Site cleanup and infrastructure activities under the responsibility of the US Department of Energy, Office of Environmental Management. This Specification describes at a top level the activities, facilities, and infrastructure necessary to accomplish the cleanup of the Hanford Site and assigns this scope to Site contractors and their respective projects. This Specification also references the key National Environmental Policy Act of 1969 (NEPA), Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA), and safety documentation necessary to accurately describe the cleanup at a summary level. The information contained in this document reflects RL's application of values, priorities, and critical success factors expressed by those involved with and affected by the Hanford Site project. The prime contractors and their projects develop complete baselines and work plans to implement this Specification. These lower-level documents and the data that support them, together with this Specification, represent the full set of requirements applicable to the contractors and their projects. Figure 1-1 shows the relationship of this Specification to the other basic Site documents. Similarly, the documents, orders, and laws referenced in this specification represent only the most salient sources of requirements. Current and contractual reference data contain a complete set of source documents

  1. Hanford Site environmental management specification

    Energy Technology Data Exchange (ETDEWEB)

    Grygiel, M.L.

    1998-06-10

    The US Department of Energy, Richland Operations Office (RL) uses this Hanford Site Environmental Management Specification (Specification) to document top-level mission requirements and planning assumptions for the prime contractors involved in Hanford Site cleanup and infrastructure activities under the responsibility of the US Department of Energy, Office of Environmental Management. This Specification describes at a top level the activities, facilities, and infrastructure necessary to accomplish the cleanup of the Hanford Site and assigns this scope to Site contractors and their respective projects. This Specification also references the key National Environmental Policy Act of 1969 (NEPA), Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA), and safety documentation necessary to accurately describe the cleanup at a summary level. The information contained in this document reflects RL`s application of values, priorities, and critical success factors expressed by those involved with and affected by the Hanford Site project. The prime contractors and their projects develop complete baselines and work plans to implement this Specification. These lower-level documents and the data that support them, together with this Specification, represent the full set of requirements applicable to the contractors and their projects. Figure 1-1 shows the relationship of this Specification to the other basic Site documents. Similarly, the documents, orders, and laws referenced in this specification represent only the most salient sources of requirements. Current and contractual reference data contain a complete set of source documents.

  2. Measuring wood specific gravity, correctly

    Science.gov (United States)

    G. Bruce Williamson; Michael C. Wiemann

    2010-01-01

    The specific gravity (SG) of wood is a measure of the amount of structural material a tree species allocates to support and strength. In recent years, wood specific gravity, traditionally a forester’s variable, has become the domain of ecologists exploring the universality of plant functional traits and conservationists estimating global carbon stocks. While these...

  3. SPECIFIC RESISTANCE AND SPECIFIC INTENSITY OF BELT SANDING OF WOOD

    Directory of Open Access Journals (Sweden)

    Boleslaw Porankiewicz

    2010-06-01

    Full Text Available This paper examines and discusses the specific belt sanding resistance K (N·cm-2 and specific belt sanding intensity SI (g·cm-2·min-1, for wood of Pinus sylvestris L., Picea abies L., Quercus robra L., Acer pseudoplatanus L., Alnus glutinosa Gaertn., and Populus Nigra L., by different sanding pressure pS, different sanding grit NG number, and different wood grain angles Phi(v.

  4. Specificity of immunoassays. Pt. 2

    International Nuclear Information System (INIS)

    Pratt, J.J.; Woldring, M.G.; Boonman, R.; Kittikool, J.

    1979-01-01

    Practical aspects of the measurement of the specificity of immunoassay are reviewed. Antibody heterogeneity in an antiserum makes a pragmatic rather than a theoretical approach necessary. A new method for the measurement of immunoassay specificity is described. This method is based on the errors caused by the cross-reacting antigens and is directly relevant to the validity of results obtained by immunoassay methods. The effect of selectively blocking the least specific antibodies in antisera raised against steroid haptens is tested. The practical consequences of these considerations are tested using steroid radioimmunoassay and enzyme-immunoassay. (orig.) [de

  5. Patient-Specific Computational Modeling

    CERN Document Server

    Peña, Estefanía

    2012-01-01

    This book addresses patient-specific modeling. It integrates computational modeling, experimental procedures, imagine clinical segmentation and mesh generation with the finite element method (FEM) to solve problems in computational biomedicine and bioengineering. Specific areas of interest include cardiovascular problems, ocular and muscular systems and soft tissue modeling. Patient-specific modeling has been the subject of serious research over the last seven years and interest in the area is continually growing and this area is expected to further develop in the near future.

  6. Bid specifications and bid evaluations

    International Nuclear Information System (INIS)

    Zijl, N.A. van

    1977-01-01

    Bid specifications are in view of the size of these projects important and comprehensive documents. The basic content and set up of the specifications are discussed such as: 1) Bid invitation letter, 2) instruction to bidders, 3) draft contract (terms and conditions), 4) technical specifications, 5) side data and information. - The evaluations of bids for nuclear power stations is due to the complexity of such bids a difficult undertaking. Evaluation methods and approaches which can be applied for such bid evaluations are discussed as well as the preparations which are required for carrying out such evaluations. (orig.) [de

  7. Synergy of Technical Specification, functional specifications and scenarios in requirements specifications

    NARCIS (Netherlands)

    Miedema, J.; van der Voort, Mascha C.; Lutters, Diederick; van Houten, Frederikus J.A.M.; Krause, Frank-Lothar

    2007-01-01

    In the (mechanical) design process, the requirements specification is a formal registration of the conditions that are imposed on a new or altered product design, both preceding as well as during the corresponding product development cycle. For a long time, the use of technical specifications has

  8. Youth job market specific features

    Directory of Open Access Journals (Sweden)

    Evgeniya Yu. Zhuravleva

    2011-05-01

    Full Text Available The article considers youth job market peculiarities, its specific features and regulation means, determines theoretical and application tasks of qualitative and quantitative comparison of vocations, which are highly in demand at the job market.

  9. GPS Civil Monitoring Performance Specification

    Science.gov (United States)

    2009-02-10

    This Civil Monitoring Performance Specification (CMPS) is published and maintained at : the direction of the Program Manager for Civil Applications, Global Positioning Systems : Wing (GPSW). The purpose of this document is to provide a comprehensive ...

  10. The role of formal specifications

    International Nuclear Information System (INIS)

    McHugh, J.

    1994-01-01

    The role of formal requirements specification is discussed under the premise that the primary purpose of such specifications is to facilitate clear and unambiguous communications among the communities of interest for a given project. An example is presented in which the failure to reach such an understanding resulted in an accident at a chemical plant. Following the example, specification languages based on logical formalisms and notations are considered. These are rejected as failing to serve the communications needs of diverse communities. The notion of a specification as a surrogate for a program is also considered and rejected. The paper ends with a discussion of the type of formal notation that will serve the communications role and several encouraging developments are noted

  11. CCL22-specific T Cells

    DEFF Research Database (Denmark)

    Martinenaite, Evelina; Munir Ahmad, Shamaila; Hansen, Morten

    2016-01-01

    Tumor cells and tumor-infiltrating macrophages produce the chemokine CCL22, which attracts regulatory T cells (Tregs) into the tumor microenvironment, decreasing anticancer immunity. Here, we investigated the possibility of targeting CCL22-expressing cells by activating specific T cells. We...... analyzed the CCL22 protein signal sequence, identifying a human leukocyte antigen A2- (HLA-A2-) restricted peptide epitope, which we then used to stimulate peripheral blood mononuclear cells (PMBCs) to expand populations of CCL22-specific T cells in vitro. T cells recognizing an epitope derived from...... the signal-peptide of CCL22 will recognize CCL22-expressing cells even though CCL22 is secreted out of the cell. CCL22-specific T cells recognized and killed CCL22-expressing cancer cells. Furthermore, CCL22-specific T cells lysed acute monocytic leukemia cells in a CCL22 expression-dependent manner. Using...

  12. Eternity Variables to Simulate Specifications

    NARCIS (Netherlands)

    Hesselink, WH; Boiten, EA; Moller, B

    2002-01-01

    Simulation of specifications is introduced as a unification and generalization of refinement mappings, history variables, forward simulations, prophecy variables, and backward simulations. Eternity variables are introduced as a more powerful alternative for prophecy variables and backward

  13. Autonomic Fuselet Specification and Composition

    National Research Council Canada - National Science Library

    Mills, Peter H

    2006-01-01

    ... model for its business logic, and to perform workflow composition from a goal and specifications to executable model in a manner that enables feedback mechanisms that can assess and adapt the process...

  14. ATR Technical Specification Upgrade Program

    International Nuclear Information System (INIS)

    McCracken, R.T.; Durney, J.L.; Freund, G.A.

    1990-01-01

    The Advanced Test Reactor (ATR) is a 250 MW, uranium-aluminum fueled test reactor which began full power operation in 1969. The initial operation was controlled by an Operating Limits document based on the original Safety Analysis Report. Additional safety bases were later developed to support Technical Specifications which were approved and implemented in 1977. The Technical Specifications which were initially developed with content and format specified in ANSI/ANS--15.1, ''The Development of Technical Specifications for Research Reactors.'' The safety basis documentation and the Technical Specifications have been updated as required to maintain them current with the ATR facility configuration. All revisions have been made with a content, format and style consistent with the original. A major, two-phase program to upgrade the content, format and style is in progress. This paper describes the first phase of this program

  15. Specific immunotherapy ameliorates ulcerative colitis.

    Science.gov (United States)

    Cai, Min; Zeng, Lu; Li, Lin-Jing; Mo, Li-Hua; Xie, Rui-Di; Feng, Bai-Sui; Zheng, Peng-Yuan; Liu, Zhi-Gang; Liu, Zhan-Ju; Yang, Ping-Chang

    2016-01-01

    Hypersensitivity reaction to certain allergens plays a role in the pathogenesis of inflammatory bowel disease (IBD). This study aims to observe the effect of specific immunotherapy in a group of IBD patients. Patients with both ulcerative colitis (UC) and food allergy were recruited into this study. Food allergy was diagnosed by skin prick test and serum specific IgE. The patients were treated with specific immunotherapy (SIT) and Clostridium butyricum (CB) capsules. After treating with SIT and CB, the clinical symptoms of UC were markedly suppressed as shown by reduced truncated Mayo scores and medication scores. The serum levels of specific IgE, interleukin (IL)-4 and tumor necrosis factor (TNF)-α were also suppressed. Treating with SIT alone or CB alone did not show appreciable improvement of the clinical symptoms of UC. UC with food allergy can be ameliorated by administration with SIT and butyrate-production probiotics.

  16. SPECIFIC EMISSIONS FROM BIOMASS COMBUSTION

    Directory of Open Access Journals (Sweden)

    Pavel Skopec

    2014-02-01

    Full Text Available This paper deals with determining the specific emissions from the combustion of two kinds of biomass fuels in a small-scale boiler. The tested fuels were pellets made of wood and pellets made of rape plant straw. In order to evaluate the specific emissions, several combustion experiments were carried out using a commercial 25 kW pellet-fired boiler. The specific emissions of CO, SO2 and NOx were evaluated in relation to a unit of burned fuel, a unit of calorific value and a unit of produced heat. The specific emissions were compared with some data acquired from the reference literature, with relatively different results. The differences depend mainly on the procedure used for determining the values, and references provide no information about this. Although some of our experimental results may fit with one of the reference sources, they do not fit with the other. The reliability of the references is therefore disputable.

  17. Grade 6 Science Curriculum Specifications.

    Science.gov (United States)

    Alberta Dept. of Education, Edmonton. Curriculum Branch.

    This material describes curriculum specifications for grade 6 science in Alberta. Emphases recommended are: (1) process skills (50%); (2) psychomotor skills (10%); (3) attitudes (10%); and (4) subject matter (30%). Priorities within each category are identified. (YP)

  18. Patient-specific surgical simulation.

    Science.gov (United States)

    Soler, Luc; Marescaux, Jacques

    2008-02-01

    Technological innovations of the twentieth century have provided medicine and surgery with new tools for education and therapy definition. Thus, by combining Medical Imaging and Virtual Reality, patient-specific applications providing preoperative surgical simulation have become possible.

  19. Base compaction specification feasibility analysis.

    Science.gov (United States)

    2012-12-01

    The objective of this research is to establish the technical engineering and cost : analysis concepts that will enable WisDOT management to objectively evaluate the : feasibility of switching construction specification philosophies for aggregate base...

  20. [Tissue-specific nucleoprotein complexes].

    Science.gov (United States)

    Riadnova, I Iu; Shataeva, L K; Khavinson, V Kh

    2000-01-01

    A method of isolation of native nucleorprotein complexes from cattle cerebral cortex, thymus, and liver was developed. Compositions of these complexes were studied by means of gel-chromatography and ion-exchange chromatography. These preparations were shown to consist of several fractions of proteins and their complexes differ by molecular mass and electro-chemical properties. Native nucleoprotein complexes revealed high tissue specific activity, which was not species-specific.

  1. XML specifications DanRIS

    DEFF Research Database (Denmark)

    2009-01-01

    XML specifications for DanRIS (Danish Registration- og InformationsSystem), where the the aim is: Improved exchange of data Improved data processing Ensuring future access to all gathered data from the year 1999 until now......XML specifications for DanRIS (Danish Registration- og InformationsSystem), where the the aim is: Improved exchange of data Improved data processing Ensuring future access to all gathered data from the year 1999 until now...

  2. Niche-specific cognitive strategies

    DEFF Research Database (Denmark)

    Hulgard, K.; Ratcliffe, J. M.

    2014-01-01

    Related species with different diets are predicted to rely on different cognitive strategies: those best suited for locating available and appropriate foods. Here we tested two predictions of the niche-specific cognitive strategies hypothesis in bats, which suggests that predatory species should...... the niche-specific cognitive strategies hypothesis and suggest that for gleaning and clutter-resistant aerial hawking bats, learning to associate shape with food interferes with subsequent spatial memory learning....

  3. NIF optical specifications - the importance of the RMS gradient specification

    International Nuclear Information System (INIS)

    Auerbach, J. M.; Cotton, C. T.; English, R. E.; Henesian, M. A.; Hunt, J. T.; Kelly, J. H.; Lawson, J. K.; Sacks, J. B.; Shoup, M. J.; Trenholme, W. H.

    1998-01-01

    The performance of the National Ignition Facility (NIF), especially in terms of laser focusability, will be determined by several key factors. One of these key factors is the optical specification for the thousands of large aperture optics that will comprise the 192 beamlines. We have previously reported on the importance of the specification of the power spectral density (PSD) on NIF performance. Recently, we have been studying the importance of long spatial wavelength (>33 mm) phase errors on focusability. We have concluded that the preferred metric for determining the impact of these long spatial wavelength phase errors is the rms phase gradient. In this paper, we outline the overall approach to NIF optical specifications, detail the impact of the rms phase gradient on NIF focusability, discuss its trade-off with the PSD in determining the spot size and review measurements of optics similar to those to be manufactured for NIF

  4. CASL, the Common Algebraic Specification Language

    DEFF Research Database (Denmark)

    Mossakowski, Till; Haxthausen, Anne Elisabeth; Sannella, Donald

    2008-01-01

    CASL is an expressive specification language that has been designed to supersede many existing algebraic specification languages and provide a standard. CASL consists of several layers, including basic (unstructured) specifications, structured specifications and architectural specifications...

  5. Standard Technical Specifications, Westinghouse plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Westinghouse Plants and documents the positions of the Nuclear Regulatory Commission based on the Westinghouse Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. Volume 1 contains the Specifications for all chapters and sections of the improved STS. Volume 2 contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the improved STS. This document, Volume 3, contains the Bases for Sections 3.4--3.9 of the improved STS

  6. Standard Technical Specifications, Westinghouse Plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Westinghouse Plants and documents the positions of the Nuclear Regulatory Commission based on the Westinghouse Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. Volume 1 contains the Specifications for all chapters and sections of the improved STS. Volume 2 contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the unproved STS. Volume 3 contains the Bases for Sections 3.4--3.9 of the improved STS which contain information on safety limits, reactivity control systems, power distribution limits, and instrumentation

  7. Industry specific financial distress modeling

    Directory of Open Access Journals (Sweden)

    Naz Sayari

    2017-01-01

    Full Text Available This study investigates uncertainty levels of various industries and tries to determine financial ratios having the greatest information content in determining the set of industry characteristics. It then uses these ratios to develop industry specific financial distress models. First, we employ factor analysis to determine the set of ratios that are most informative in specified industries. Second, we use a method based on the concept of entropy to measure the level of uncertainty in industries and also to single out the ratios that best reflect the uncertainty levels in specific industries. Finally, we conduct a logistic regression analysis and derive industry specific financial distress models which can be used to judge the predictive ability of selected financial ratios for each industry. The results show that financial ratios do indeed echo industry characteristics and that information content of specific ratios varies among different industries. Our findings show diverging impact of industry characteristics on companies; and thus the necessity of constructing industry specific financial distress models.

  8. Technical specification for vacuum systems

    International Nuclear Information System (INIS)

    Khaw, J.

    1987-01-01

    The vacuum systems at the Stanford Linear Accelerator Center (SLAC) are primarily of all-metal construction and operate at pressures from 10 -5 to 10 -11 Torr. The primary gas loads during operation result from thermal desorption and beam-induced desorption from the vacuum chamber walls. These desorption rates can be extremely high in the case of hydrocarbons and other contaminants. These specifications place a major emphasis on eliminating contamination sources. The specifications and procedures have been written to insure the cleanliness and vacuum integrity of all SLAC vacuum systems, and to assist personnel involved with SLAC vacuum systems in choosing and designing components that are compatible with existing systems and meet the quality and reliability of SLAC vacuum standards. The specification includes requirements on design, procurement, fabrication, chemical cleaning, clean room practices, welding and brazing, helium leak testing, residual gas analyzer testing, bakeout, venting, and pumpdown. Also appended are specifications regarding acceptable vendors, isopropyl alcohol, bakeable valve cleaning procedure, mechanical engineering safety inspection, notes on synchrotron radiation, and specifications of numerous individual components

  9. Standard Technical Specifications, Westinghouse plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Westinghouse Plants and documents the positions of the Nuclear Regulatory Commission based on the Westinghouse Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. This document, Volume 1, contains the Specifications for all chapters and sections of the improved STS. Volume 2 contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the improved STS. Volume 3 contains the Bases for Sections 3.4--3.9 of the improved STS

  10. Age‑specific Serum Prostate Specific Antigen Ranges Among ...

    African Journals Online (AJOL)

    ethnic differences.[16] Although similar studies have been presented for a number of different groups of men and few studies have looked at the pattern of serum PSA among Nigerians[17‑20] but no such studies on normal serum PSA ranges and the age‑specific pattern have been carried out among healthy Nigerian men.

  11. ROS signalling - specificity is required

    DEFF Research Database (Denmark)

    Møller, Ian M; Sweetlove, Lee J

    2010-01-01

    Reactive oxygen species (ROS) production increases in plants under stress. ROS can damage cellular components, but they can also act in signal transduction to help the cell counteract the oxidative damage in the stressed compartment. H2O2 might induce a general stress response, but it does not have...... the required specificity to selectively regulate nuclear genes required for dealing with localized stress, e.g. in chloroplasts or mitochondria. Here we argue that peptides deriving from proteolytic breakdown of oxidatively damaged proteins have the requisite specificity to act as secondary ROS messengers...... and regulate source-specific genes and in this way contribute to retrograde ROS signalling during oxidative stress. Likewise, unmodified peptides deriving from the breakdown of redundant proteins could help coordinate organellar and nuclear gene expression...

  12. Methylation-Specific PCR Unraveled

    Directory of Open Access Journals (Sweden)

    Sarah Derks

    2004-01-01

    Full Text Available Methylation‐specific PCR (MSP is a simple, quick and cost‐effective method to analyze the DNA methylation status of virtually any group of CpG sites within a CpG island. The technique comprises two parts: (1 sodium bisulfite conversion of unmethylated cytosine's to uracil under conditions whereby methylated cytosines remains unchanged and (2 detection of the bisulfite induced sequence differences by PCR using specific primer sets for both unmethylated and methylated DNA. This review discusses the critical parameters of MSP and presents an overview of the available MSP variants and the (clinical applications.

  13. Determination of taste receptor type 1 member 1 (TAS1R1) gene ...

    African Journals Online (AJOL)

    In this article, the objective was to investigate variations in goat TAS1R1 gene and their associations with growth traits in 317 goats by PCR-SSCP and DNA sequencing methods. The results showed two novel single nucleotide polymorphisms (SNPs): HM449123:g. [T3974C, C4037T]. In detail, two different alleles, A and B, ...

  14. Increased melanin concentrating hormone receptor type I in the human hypothalamic infundibular nucleus in cachexia

    NARCIS (Netherlands)

    Unmehopa, Unga A.; van Heerikhuize, Joop J.; Spijkstra, Wenda; Woods, John W.; Howard, Andrew D.; Zycband, Emanuel; Feighner, Scott D.; Hreniuk, Donna L.; Palyha, Oksana C.; Guan, Xiao-Ming; Macneil, Douglas J.; van der Ploeg, Lex H. T.; Swaab, Dick F.

    2005-01-01

    Melanin-concentrating hormone (MCH) exerts a positive regulation on appetite and binds to the G protein-coupled receptors, MCH1R and MCH2R. In rodents, MCH is produced by neurons in the lateral hypothalamus with projections to various hypothalamic and other brain sites. In the present study, MCH1R

  15. Increased melanin concentrating hormone receptor type I in the human hypothalamic infundibular nucleus in cachexia.

    NARCIS (Netherlands)

    Unmehopa, U.A.; Heerikhuize, J.J. van; Spijkstra, W.; Woods, J.W.; Howard, A.D.; Zycband, E.; Feighner, S.D.; Hreniuk, D.L.; Palyha, O.C.; Guan, X.-M.; MacNeil, D.J.; Ploeg, L.H.T.; Swaab, D.F.

    2005-01-01

    Melanin-concentrating hormone (MCH) exerts a positive regulation on appetite and binds to the G protein-coupled receptors, MCH1R and MCH2R. In rodents, MCH is produced by neurons in the lateral hypothalamus with projections to various hypothalamic and other brain sites. In the present study, MCH1R

  16. Determination of taste receptor type 1 member 1 (TAS1R1) gene ...

    African Journals Online (AJOL)

    Jane

    2011-10-10

    Oct 10, 2011 ... 1Institute of Cellular and Molecular Biology, College of Life Science, Xuzhou Normal University, ... TAS1R1 and TAS1R3 form an L-amino acid sensor, ... 0.5 × TBE buffer (89 mM tris–borate, 2 mM EDTA, pH 8.3) for 2 h at.

  17. Human Complement Receptor Type 1/CD35 Is an Epstein-Barr Virus Receptor

    Directory of Open Access Journals (Sweden)

    Javier G. Ogembo

    2013-02-01

    Full Text Available Epstein-Barr virus (EBV attachment to primary B cells initiates virus entry. Although CD21 is the only known receptor for EBVgp350/220, a recent report documents EBV-infected B cells from a patient genetically deficient in CD21. On normal resting B cells, CD21 forms two membrane complexes: one with CD19 and another with CD35. Whereas the CD21/CD19 complex is widely retained on immortalized and B cell tumor lines, the related complement-regulatory protein CD35 is lost. To determine the role(s of CD35 in initial infection, we transduced a CD21-negative pre-B cell and myeloid leukemia line with CD35, CD21, or both. Cells expressing CD35 alone bound gp350/220 and became latently infected when the fusion receptor HLA II was coexpressed. Temporal, biophysical, and structural characteristics of CD35-mediated infection were distinct from CD21. Identification of CD35 as an EBV receptor uncovers a salient role in primary infection, addresses unsettled questions of virus tropism, and underscores the importance of EBVgp350/220 for vaccine development.

  18. The cannabinoid receptor type 2 as mediator of mesenchymal stromal cell immunosuppressive properties.

    Directory of Open Access Journals (Sweden)

    Francesca Rossi

    Full Text Available Mesenchymal stromal cells are non-hematopoietic, multipotent progenitor cells producing cytokines, chemokines, and extracellular matrix proteins that support hematopoietic stem cell survival and engraftment, influence immune effector cell development, maturation, and function, and inhibit alloreactive T-cell responses. The immunosuppressive properties of human mesenchymal stromal cells have attracted much attention from immunologists, stem cell biologists and clinicians. Recently, the presence of the endocannabinoid system in hematopoietic and neural stem cells has been demonstrated. Endocannabinoids, mainly acting through the cannabinoid receptor subtype 2, are able to modulate cytokine release and to act as immunosuppressant when added to activated T lymphocytes. In the present study, we have investigated, through a multidisciplinary approach, the involvement of the endocannabinoids in migration, viability and cytokine release of human mesenchymal stromal cells. We show, for the first time, that cultures of human mesenchymal stromal cells express all of the components of the endocannabinoid system, suggesting a potential role for the cannabinoid CB2 receptor as a mediator of anti-inflammatory properties of human mesenchymal stromal cells, as well as of their survival pathways and their capability to home and migrate towards endocannabinoid sources.

  19. Nonpeptide corticotropin-releasing hormone receptor type 1 antagonists and their applications in psychosomatic disorders.

    Science.gov (United States)

    Contoreggi, Carlo; Rice, Kenner C; Chrousos, George

    2004-01-01

    Overproduction of corticotropin-releasing hormone (CRH) and stress system abnormalities are seen in psychiatric diseases such as depression, anxiety, eating disorders, and addiction. Investigations of CRH type 1 receptor (CRHR1) nonpeptide antagonists suggest therapeutic potential for treatment of these and other neuropsychiatric diseases. However, overproduction of CRH in the brain and on its periphery and disruption of the hypothalamic-pituitary-adrenal axis are also found in 'somatic' disorders. Some rare forms of Cushing's disease and related pituitary/adrenal disorders are obvious applications for CRHR1 antagonists. In addition, however, these antagonists may also be effective in treating more common somatic diseases. Patients with obesity and metabolic syndrome who often have subtle, but chronic hypothalamic-pituitary-adrenal hyperactivity, which may reflect central dysregulation of CRH and consequently glucocorticoid hypersecretion, could possibly be treated by administration of CRHR1 antagonists. Hormonal, autonomic, and immune aberrations are also present in chronic inflammatory, autoimmune, and allergic diseases, with considerable evidence linking CRH with the observed abnormalities. Furthermore, autonomic dysregulation is a prominent feature of common gastrointestinal disorders, such as irritable bowel syndrome and peptic ulcer disease. Patients with irritable bowel syndrome and other gastrointestinal disorders frequently develop altered pain perception and affective symptoms. CRH acts peripherally to modulate bowel activity both directly through the autonomic system and centrally by processing viscerosensory and visceromotor neural signals. This review presents clinical and preclinical evidence for the role of CRH in the pathophysiology of these disorders and for potential diagnostic and therapeutic applications of CRHR1 antagonists. Recognition of a dysfunctional stress system in these and other diseases will alter the understanding and treatment of 'psychosomatic' disorders.

  20. Localization and functional roles of corticotropin-releasing factor receptor type 2 in the cerebellum

    NARCIS (Netherlands)

    Gounko, Natalia V.; Gramsbergen, Albert; van der Want, Johannes J. L.

    The corticotropin-releasing factor (CRF) type 2 receptor has three splice variants alpha, beta, and gamma. In the rodent brain only CRF-R2 alpha is present. In the cerebellum, CRF-R2 alpha has two different isoforms: a full-length form (fl) and truncated (tr). Both forms CRF-R2 have a unique

  1. Generation and Characterization of Mice Expressing a Conditional Allele of the Interleukin-1 Receptor Type 1.

    Directory of Open Access Journals (Sweden)

    Matthew J Robson

    Full Text Available The cytokines IL-1α and IL-1β exert powerful pro-inflammatory actions throughout the body, mediated primarily by the intracellular signaling capacity of the interleukin-1 receptor (IL-1R1. Although Il1r1 knockout mice have been informative with respect to a requirement for IL-1R1 signaling in inflammatory events, the constitutive nature of gene elimination has limited their utility in the assessment of temporal and spatial patterns of cytokine action. To pursue such questions, we have generated C57Bl/6J mice containing a floxed Il1r1 gene (Il1r1loxP/loxP, with loxP sites positioned to flank exons 3 and 4 and thereby the ability to spatially and temporally eliminate Il1r1 expression and signaling. We found that Il1r1loxP/loxP mice breed normally and exhibit no gross physical or behavioral phenotypes. Moreover, Il1r1loxP/loxP mice exhibit normal IL-1R1 receptor expression in brain and spleen, as well as normal IL-1R1-dependent increases in serum IL-6 following IL-1α injections. Breeding of Il1r1loxP/loxP mice to animals expressing a cytomegalovirus (CMV-driven Cre recombinase afforded efficient excision at the Il1r1 locus. The Il1r1loxP/loxP line should be a valuable tool for the assessment of contributions made by IL-1R1 signaling in diverse cell types across development.

  2. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome

    Czech Academy of Sciences Publication Activity Database

    Schormair, B.; Kemlink, D.; Roeske, D.; Eckstein, G.; Xiong, L.; Lichtner, P.; Ripke, S.; Trenkwalder, C.; Zimprich, A.; Stiasny-Kolster, K.; Oertel, W.; Bachmann, C. G.; Paulus, W.; Högl, B.; Frauscher, B.; Gschliesser, V.; Poewe, W.; Peglau, I.; Vodička, Pavel; Vávrová, J.; Šonka, K.; Nevšímalová, S.; Montplaisir, J.; Turecki, G.; Rouleau, G.; Gieger, Ch.; Illig, T.; Wichmann, H.E.; Holsboer, F.; Müller-Myhsok, B.; Meitinger, T.; Winkelmann, J.

    2008-01-01

    Roč. 40, č. 8 (2008), s. 946-948 ISSN 1061-4036 R&D Projects: GA MZd NR8563 Institutional research plan: CEZ:AV0Z50390703 Keywords : PTPRD * syndrom restless legs Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 30.259, year: 2008

  3. The role of protease-activated receptor type 2 in nociceptive signaling and pain

    Czech Academy of Sciences Publication Activity Database

    Mrózková, Petra; Paleček, Jiří; Špicarová, Diana

    2016-01-01

    Roč. 65, č. 3 (2016), s. 357-367 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LH12058; GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GA15-11138S; GA MŠk(CZ) LH15279; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : protease-activated receptor (PAR2) * signaling pathways * nociception * pain * spinal cord Subject RIV: FH - Neurology Impact factor: 1.461, year: 2016

  4. Portable File Format (PFF) specifications

    Energy Technology Data Exchange (ETDEWEB)

    Dolan, Daniel H. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-02-01

    Created at Sandia National Laboratories, the Portable File Format (PFF) allows binary data transfer across computer platforms. Although this capability is supported by many other formats, PFF files are still in use at Sandia, particularly in pulsed power research. This report provides detailed PFF specifications for accessing data without relying on legacy code.

  5. Human-Specific Endogenous Retroviruses

    Directory of Open Access Journals (Sweden)

    Anton Buzdin

    2007-01-01

    Full Text Available This review focuses on a small family of human-specific genomic repetitive elements, presented by 134 members that shaped ~330 kb of the human DNA. Although modest in terms of its copy number, this group appeared to modify the human genome activity by endogenizing ~50 functional copies of viral genes that may have important implications in the immune response, cancer progression, and antiretroviral host defense. A total of 134 potential promoters and enhancers have been added to the human DNA, about 50% of them in the close gene vicinity and 22% in gene introns. For 60 such human-specific promoters, their activity was confirmed by in vivo assays, with the transcriptional level varying ~1000-fold from hardly detectable to as high as ~3% of β-actin transcript level. New polyadenylation signals have been provided to four human RNAs, and a number of potential antisense regulators of known human genes appeared due to human-specific retroviral insertional activity. This information is given here in the context of other major genomic changes underlining differences between human and chimpanzee DNAs. Finally, a comprehensive database, is available for download, of human-specific and polymorphic endogenous retroviruses is presented, which encompasses the data on their genomic localization, primary structure, encoded viral genes, human gene neighborhood, transcriptional activity, and methylation status.

  6. Manufacturer Usage Description Specification Implementation

    OpenAIRE

    Srinivasan, Kaushik

    2017-01-01

    Manufacturer Usage Description Specification (MUDS) is aframework under RFC development that aims to automate Internet access control rules for IoT devices . These access controls prevent malicious IoT devices from attacking other devices and also protect the IoT devices from being attacked by other devices.We are implementing this framework and trying to improve its security.

  7. Competitive Procurement and Asset Specificity

    NARCIS (Netherlands)

    Sorana, V.

    2003-01-01

    This paper studies the effects of asset specificity on the performance of procurement auctions with subcontracting and asset sales.The analysis highlights the role of several asset features like transfer costs, type of alternative uses and maintenance requirements.It is argued that, if bargaining

  8. Final Empirical Test Case Specification

    DEFF Research Database (Denmark)

    Kalyanova, Olena; Heiselberg, Per

    This document includes the empirical specification on the IEA task of evaluation building energy simulation computer programs for the Double Skin Facades (DSF) constructions. There are two approaches involved into this procedure, one is the comparative approach and another is the empirical one....

  9. LOTOS specification style for OSI

    NARCIS (Netherlands)

    Turner, K.J.; van Sinderen, Marten J.; Bolognesi, T.; van de Lagemaat, J.; Vissers, C.A.

    1995-01-01

    The architecture of OSI is used to derive guidelines for writing LOTOS specifications of distributed systems. In particular, the architectural concepts that underlie service and protocol designs are examined in detail. For each of these concepts a representation in LOTOS is given. Examples are

  10. LOTOS specification style for OSI

    NARCIS (Netherlands)

    Brinksma, Hendrik; Turner, K.J.; Bolognesi, T.; van Sinderen, Marten J.; Vissers, C.A.

    1992-01-01

    The architecture of OSI is used to derive guidelines for writing LOTOS specifications of distributed systems. In particular, the architectural concepts that underlie service and protocol designs are examined in detail. For each of these concepts a representation in LOTOS is given. Examples are

  11. THE SPECIFICITY OF INTRACOMMUNITY TRANSACTIONS

    Directory of Open Access Journals (Sweden)

    PALIU-POPA LUCIA

    2011-09-01

    Full Text Available Considered from the perspective of Romania's accession to the European Union, we can say that starting with 1 January 2007, foreign trade transactions were delimited in relation to the customs borders in intra-Community transactions and international transactions. In this context, the way of conducting these operations is influenced by both the economic and financial features specific to both categories of transactions, that relate to the economic character of the activity, the diversity and specificity of the foreign trade activity, transport of goods, the complexity and regulation of intra-Community and international commercial transactions, and by the specific features of each category of transaction. Starting from the consideration that the economic and financial characteristics of foreign trade activity, specific to intra-Community commercial transactions, have a significant influence in the organization and management of accounting of the entities involved in such transactions, determining in a greater or lesser extent, the way of capitalization of the financial and accounting information in the processes of analysis, decision and control, in this paper we proposed to address the features of intra-Community trade.

  12. Microbeams, microdosimetry and specific dose

    International Nuclear Information System (INIS)

    Randers-Pehrson, H.

    2002-01-01

    Dose and its usefulness as a single parameter to describe the amount of radiation absorbed are well established for most situations. The conditions where the concept of dose starts to break down are well known, mostly from the study of microdosimetry. For low doses of high LET radiation it is noted that the process of taking the limiting value of the energy absorbed within a test volume divided by the mass within that volume yields either zero or a relatively large value. The problem is further exacerbated with microbeam irradiations where the uniformity of the energy deposition is experimentally manipulated on the spatial scale of cells being irradiated. Booz introduced a quantity to deal with these problems: the unfortunately named 'mean specific energy in affected volumes'. This quantity multiplied by the probability that a test volume has received an energy deposit is equal to dose (in situations where dose can be defined). I propose that Booz's quantity be renamed 'specific dose', that is the mean energy deposited divided by the mass within a specified volume. If we believe for instance that the nucleus of a cell is the critical volume for biological effects, we can refer to the nuclear specific dose. A microbeam experiment wherein 10 per cent of the cell nuclei were targeted with 10 alpha particles would be described as delivering a nuclear specific dose of 1.6 Gy to 10 per cent of the population. (author)

  13. [Specificities in children wound healing].

    Science.gov (United States)

    Sanchez, J; Antonicelli, F; Tuton, D; Mazouz Dorval, S; François, C

    2016-10-01

    Children have specific characteristics of wound healing. The aim of this study was to describe the specific clinical characteristics of wounds healing in children and to present the current knowledge on the specific mechanisms with regard to infant age. The tissue insult or injury in fetus can heal without scar, mainly due to reduced granulation tissue associated to diminished or even no inflammatory phase, modified extracellular matrix such as the concentration of hyaluronic acid in amniotic liquid, expression and arrangement of collagen and tenascin. Thickness of children skin is a serious negative factor in case of trauma, whereas poor co-morbidities and efficient growth tissue mechanisms are beneficial to good evolution, even in cases of extensive damage and loss of tissue. The subsequent tissue mechanical forces, wound healing during childhood, spanning from the age of 2 until the end of puberty, is associated with more hypertrophic scars, both in duration and in intensity. Consequently, unnecessary surgery has to be avoided during this period when possible, and children with abnormal or pathologic wound healing should benefit from complementary treatments (hydration, massage, brace, silicone, hydrotherapy…), which represent efficient factors to minimize tissue scarring. After wound healing, the growth body rate can be responsible for specific complications, such as contractures, alopecia, and scar intussusceptions. Its evolutionary character implies the need of an attentive follow-up until adult age. Psychologic repercussions, as a consequence of pathologic scars, must be prevented and investigated by the surgeon. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  14. Specific and non-specific match effects in negative priming.

    Science.gov (United States)

    Labossière, Danielle I; Leboe-McGowan, Jason P

    2018-01-01

    The negative priming effect occurs when withholding a response to a stimulus impairs generation of subsequent responding to a same or a related stimulus. Our goal was to use the negative priming procedure to obtain insights about the memory representations generated by ignoring vs. attending/responding to a prime stimulus. Across three experiments we observed that ignoring a prime stimulus tends to generate higher identity-independent, non-specific repetition effects, owing to an overlap in the coarse perceptual form of a prime distractor and a probe target. By contrast, attended repetition effects generate predominantly identity-specific sources of facilitation. We use these findings to advocate for using laboratory phenomena to illustrate general principles that can be of practical use to non-specialists. In the case of the negative priming procedure, we propose that the procedure provides a useful means for investigating attention/memory interactions, even if the specific cause (or causes) of negative priming effects remain unresolved. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. [Specific immunotherapy with depigmented allergoids].

    Science.gov (United States)

    Klimek, L; Thorn, C; Pfaar, O

    2010-01-01

    Specific immunotherapy is the only available causative treatment for IgE-mediated allergic conditions. The state of the art is treatment via the subcutaneous route with crude extracts in a water solution, with physically linked (semidepot) extracts or chemically modified semidepot extracts (allergoids). A relatively new purification method combines depigmentation followed by polymerization with glutaraldehyde. This modification results in increased tolerance with a reduction in both local and systemic adverse effects. As controlled clinical trials have shown, the effectiveness is comparable to that of specific immunotherapy with crude allergen extracts. Recent data suggest that the modified polymerized allergoids allow a safe rush titration in a few days or even in 1 day (ultra-rush titration).

  16. UNBIASED ESTIMATORS OF SPECIFIC CONNECTIVITY

    Directory of Open Access Journals (Sweden)

    Jean-Paul Jernot

    2011-05-01

    Full Text Available This paper deals with the estimation of the specific connectivity of a stationary random set in IRd. It turns out that the "natural" estimator is only asymptotically unbiased. The example of a boolean model of hypercubes illustrates the amplitude of the bias produced when the measurement field is relatively small with respect to the range of the random set. For that reason unbiased estimators are desired. Such an estimator can be found in the literature in the case where the measurement field is a right parallelotope. In this paper, this estimator is extended to apply to measurement fields of various shapes, and to possess a smaller variance. Finally an example from quantitative metallography (specific connectivity of a population of sintered bronze particles is given.

  17. Vibrio chromosome-specific families

    DEFF Research Database (Denmark)

    Lukjancenko, Oksana; Ussery, David

    2014-01-01

    We have compared chromosome-specific genes in a set of 18 finished Vibrio genomes, and, in addition, also calculated the pan- and core-genomes from a data set of more than 250 draft Vibrio genome sequences. These genomes come from 9 known species and 2 unknown species. Within the finished...... chromosomes, we find a core set of 1269 encoded protein families for chromosome 1, and a core of 252 encoded protein families for chromosome 2. Many of these core proteins are also found in the draft genomes (although which chromosome they are located on is unknown.) Of the chromosome specific core protein...... families, 1169 and 153 are uniquely found in chromosomes 1 and 2, respectively. Gene ontology (GO) terms for each of the protein families were determined, and the different sets for each chromosome were compared. A total of 363 different "Molecular Function" GO categories were found for chromosome 1...

  18. Specific bibliography on Anastrepha fraterculus

    International Nuclear Information System (INIS)

    Salles, L.A.; Jaldo, H.

    1999-01-01

    Most publications on Anastrepha fraterculus are in the literature sources from South America, and papers were published in Spanish or Portuguese. Many literature sources mentioned in this list are not indexed in entomological abstracts and, consequently, are not easily available outside their home state or country. Due to this fact, the inclusion of a list of specific bibliography on A. fraterculus could be a help for researchers and students interested in fruit flies. In this list are included only references directly dealing with Anastrepha fraterculus. Obviously, many more references exist that consider this species, but general or non-specific work or data concerning A. fraterculus were not included in the present list. (author)

  19. Multilingualism and Specific Language Impairment

    OpenAIRE

    Engel de Abreu, Pascale

    2014-01-01

    Is a multilingual education beneficial for children? What are the optimal conditions under which a child can become perfectly multilingual? When should we be concerned about a multilingual child's language skills? What are the signs of Specific Language Impairment in a child who speaks more than one language? Developmental psychologist and Associate Professor in multilingual cognitive development at the University of Luxembourg Pascale Engel de Abreu will address these questions based on what...

  20. Nanobody Based Dual Specific CARs

    Directory of Open Access Journals (Sweden)

    Stijn De Munter

    2018-01-01

    Full Text Available Recent clinical trials have shown that adoptive chimeric antigen receptor (CAR T cell therapy is a very potent and possibly curative option in the treatment of B cell leukemias and lymphomas. However, targeting a single antigen may not be sufficient, and relapse due to the emergence of antigen negative leukemic cells may occur. A potential strategy to counter the outgrowth of antigen escape variants is to broaden the specificity of the CAR by incorporation of multiple antigen recognition domains in tandem. As a proof of concept, we here describe a bispecific CAR in which the single chain variable fragment (scFv is replaced by a tandem of two single-antibody domains or nanobodies (nanoCAR. High membrane nanoCAR expression levels are observed in retrovirally transduced T cells. NanoCARs specific for CD20 and HER2 induce T cell activation, cytokine production and tumor lysis upon incubation with transgenic Jurkat cells expressing either antigen or both antigens simultaneously. The use of nanobody technology allows for the production of compact CARs with dual specificity and predefined affinity.

  1. Nanobody Based Dual Specific CARs.

    Science.gov (United States)

    De Munter, Stijn; Ingels, Joline; Goetgeluk, Glenn; Bonte, Sarah; Pille, Melissa; Weening, Karin; Kerre, Tessa; Abken, Hinrich; Vandekerckhove, Bart

    2018-01-30

    Recent clinical trials have shown that adoptive chimeric antigen receptor (CAR) T cell therapy is a very potent and possibly curative option in the treatment of B cell leukemias and lymphomas. However, targeting a single antigen may not be sufficient, and relapse due to the emergence of antigen negative leukemic cells may occur. A potential strategy to counter the outgrowth of antigen escape variants is to broaden the specificity of the CAR by incorporation of multiple antigen recognition domains in tandem. As a proof of concept, we here describe a bispecific CAR in which the single chain variable fragment (scFv) is replaced by a tandem of two single-antibody domains or nanobodies (nanoCAR). High membrane nanoCAR expression levels are observed in retrovirally transduced T cells. NanoCARs specific for CD20 and HER2 induce T cell activation, cytokine production and tumor lysis upon incubation with transgenic Jurkat cells expressing either antigen or both antigens simultaneously. The use of nanobody technology allows for the production of compact CARs with dual specificity and predefined affinity.

  2. Mutational specificity of SOS mutagenesis

    International Nuclear Information System (INIS)

    Kato, Takeshi

    1986-01-01

    In an approach to the isolation of mutants of E. coli unable to produce mutations by ultraviolet light, the author has found new umuC-mutants. Their properties could be explained by ''SOS hypothesis of Radman and Witkin'', which has now been justified by many investigators. Analysis of the umuC region of E. coli chromosome cloned in pSK 100 has led to the conclusion that two genes, umuD and umuC, having the capacity of mutation induction express in the same mechanism as that of SOS genes, which is known to be inhibited by LexA protein bonding to ''SOS box'' found at promotor region. Suppressor analysis for mutational specificity has revealed: (i) umuDC-independent mutagens, such as EMS and (oh) 4 Cy, induce selected base substitution alone; and (ii) umuDC-dependent mutagens, such as X-rays and gamma-rays, induce various types of base substitution simultaneously, although they have mutational specificity. In the umuDC-dependent processes of basechange mutagenesis, the spectra of base substitution were a mixture of base substitution reflecting the specific base damages induced by individual mutagens and nonspecific base substitution. In conclusion, base substitution plays the most important role in umuDC-dependent mutagenesis, although mutagenesis of umuDC proteins remains uncertain. (Namekawa, K.)

  3. Lactobacillus reuteri-specific immunoregulatory gene rsiR modulates histamine production and immunomodulation by Lactobacillus reuteri.

    Science.gov (United States)

    Hemarajata, P; Gao, C; Pflughoeft, K J; Thomas, C M; Saulnier, D M; Spinler, J K; Versalovic, J

    2013-12-01

    Human microbiome-derived strains of Lactobacillus reuteri potently suppress proinflammatory cytokines like human tumor necrosis factor (TNF) by converting the amino acid l-histidine to the biogenic amine histamine. Histamine suppresses mitogen-activated protein (MAP) kinase activation and cytokine production by signaling via histamine receptor type 2 (H2) on myeloid cells. Investigations of the gene expression profiles of immunomodulatory L. reuteri ATCC PTA 6475 highlighted numerous genes that were highly expressed during the stationary phase of growth, when TNF suppression is most potent. One such gene was found to be a regulator of genes involved in histidine-histamine metabolism by this probiotic species. During the course of these studies, this gene was renamed the Lactobacillus reuteri-specific immunoregulatory (rsiR) gene. The rsiR gene is essential for human TNF suppression by L. reuteri and expression of the histidine decarboxylase (hdc) gene cluster on the L. reuteri chromosome. Inactivation of rsiR resulted in diminished TNF suppression in vitro and reduced anti-inflammatory effects in vivo in a trinitrobenzene sulfonic acid (TNBS)-induced mouse model of acute colitis. A L. reuteri strain lacking an intact rsiR gene was unable to suppress colitis and resulted in greater concentrations of serum amyloid A (SAA) in the bloodstream of affected animals. The PhdcAB promoter region targeted by rsiR was defined by reporter gene experiments. These studies support the presence of a regulatory gene, rsiR, which modulates the expression of a gene cluster known to mediate immunoregulation by probiotics at the transcriptional level. These findings may point the way toward new strategies for controlling gene expression in probiotics by dietary interventions or microbiome manipulation.

  4. Conversion of NEK standard technical specifications into improved technical specifications

    International Nuclear Information System (INIS)

    Glaser, B.

    2003-01-01

    Neck is currently using a standard format of operation's Technical Specifications - STS (based on NUREG-0452), which are planned to be converted into Improved Technical Specifications - ITS (based on NUREG-1431). To facilitate the development of individual ITS, each reactor vendor owners group (OG) and the NRC staff developed improved standard TS (ISTS). For Westinghouse plants, the ISTS are published as NUREG-1431, and this document is going to be the basis for the new NEK ITS. It has been recognized that nuclear safety in all plants would benefit from improvement and standardization of ITS, so this was also addressed and recognized by the NRC. There are several plants around Europe and US, which have replaced the format into ITS which brings a lot of improvements and practical value in operations. The main objective of conversion is to completely rewrite, reformat, and streamline the existing STS. Emphasis is placed on human factors principles to improve clarity and understanding. The Bases section will be significantly expanded to clarify and better explain the purpose and foundation of each specification. There might be some proposed changes to the existing STS that deviated from the ITS in NUREG-1431 and constitute a relaxation of the existing STS. Each of these additional proposed changes will be described and evaluated in amendment application and justified on a case-by-case basis. Since the NEK is going to operate for more than 20 year without considering life extension, such conversion will be beneficial for operation personnel as well as regulation, surveillance and focus on operation's safety. At the present, only preliminary plan of STS conversion exists, showing the time frame of approximately 2 years of conversion process and numerous tasks that need to be performed. The plan is to begin with process in year 2004 and finish project in 2006, which means use of new ITS in main control room in year 2007. Beside the main process of conversion, there are

  5. JBK-75 microstructure specification recommendation

    International Nuclear Information System (INIS)

    Brewer, A.W.

    1977-01-01

    Since the ASTM-E-45 standard for microcleanliness is not applicable to superalloys like JBK-75 stainless steel (Modified A-286), Rocky Flats should adopt the Ladish microcleanliness standard (APML Cleanliness Classification of High Temperature Alloys Chart, 1971), as a guide for setting material acceptance specifications for JBK-75. Inclusion ratings of S-2, N-2, C-2, and M-2 should be acceptable. The microstructure should have a grain size of 5 or finer, but not smaller than 9, and microsegregation (banding) should be kept to a minimum

  6. Gender specific determinants of goitre

    International Nuclear Information System (INIS)

    Jamshid, F.; Kerstin, C.; Elena, G.; Wilhelm, O.; Karl, W.; Hwe, M.

    2004-01-01

    Despite the strong implications of differences between females and males in the risk of goitre, gender-specific issues have not been extensively addressed in investigations of goitre prevalence. The Objective of our analysis was to investigate the gender-specific determinants of goitre. Methods: A total of 853 healthy employees from 4 institutions in western part of Germany aged between 18 and 68 years were examined by ultrasound of the neck to determine the thyroid volume between April 2001 and April 2002. Information on sex, age, daily use of iodised salt, the history of goitre in the first degree relatives, type and amount of' smoking, oral contraceptives and number of pregnancies were assessed by standardised questionnaires. Gender-specific predictors of goitre prevalence were assessed by multivariate logistic regression. Results: The overall prevalence of goitre among study subjects was (204/853) 23.9%. Goitre was present in 80 out of 370 females (21.6%) vs. 124/483 (25.7%) in males.In general smoking (<0.0001), increasing age (p<0.0001) and lack of daily intake of iodised salt (p=0.004) associated with goitre prevalence, but not sex (0.4) and family history of goitre (p=0.2). In 370 females, parity (p=0.004) and lack of daily intake of iodised salt (p=0.01) were the major determinants for goitre, whereas, age (p=0.2), oral contraceptives (p=0.8), family history of goitre (p=0.3), and smoking (p=0.1) did not affect the goitre prevalence. In 483 males, smoking (p<0.0001) and age (p<0.001) affected the goitre prevalence, but not family history of goitre (p=0.4) and the iodine status failed just to reach the significant level (p=0.08) in this analysis. Conclusions: Gender specific determinants of goitre are parity and iodine status in females and smoking and increasing age in males. (authors)

  7. Specification for personal photographic dosemeters

    International Nuclear Information System (INIS)

    1981-01-01

    The 1981 British/International Standard Specification, prepared under the direction of the Nuclear Engineering Standards Committee and TC85 of the International Organization for Standardization, is described for personal photographic dosemeters. The Standard specifies classification, characteristics and test procedures to determine absorbed doses due to X or gamma radiations (energy less than 3 MeV) and absorbed doses due to beta radiation (max. energy 0.6 to 3 MeV), whether or not accompanied by X, gamma or bremsstrahlung photon radiation. The Standard is particularly applicable to dosemeters intended to be carried on the chest or wrist. (U.K.)

  8. Domain specific MT in use

    DEFF Research Database (Denmark)

    Offersgaard, Lene; Povlsen, Claus; Almsten, Lisbeth Kjeldgaard

    2008-01-01

    point scale evaluate the sentence from the point of view of the post-editor. The post-editor profile defined by the LSP is based on the experiences of introducing MT in the LSP workflow. The relation between the Translation Edit Rate (TER) scores and “Usability” scores is tested. We find TER a candidate......The paper focuses on domain specific use of MT with a special focus on SMT in the workflow of a Language Service Provider (LSP). We report on the feedback of post-editors using fluency/adequacy evaluation and the evaluation metric ’Usability’, understood in this context as where users on a three...

  9. Central Solenoid Insert Technical Specification

    Energy Technology Data Exchange (ETDEWEB)

    Martovetsky, Nicolai N [ORNL; Smirnov, Alexandre [ORNL

    2011-09-01

    The US ITER Project Office (USIPO) is responsible for the ITER central solenoid (CS) contribution to the ITER project. The Central Solenoid Insert (CSI) project will allow ITER validation the appropriate lengths of the conductors to be used in the full-scale CS coils under relevant conditions. The ITER Program plans to build and test a CSI to verify the performance of the CS conductor. The CSI is a one-layer solenoid with an inner diameter of 1.48 m and a height of 4.45 m between electric terminal ends. The coil weight with the terminals is approximately 820 kg without insulation. The major goal of the CSI is to measure the temperature margin of the CS under the ITER direct current (DC) operating conditions, including determining sensitivity to load cycles. Performance of the joints, ramp rate sensitivity, and stability against thermal or electromagnetic disturbances, electrical insulation, losses, and instrumentation are addressed separately and therefore are not major goals in this project. However, losses and joint performance will be tested during the CSI testing campaign. The USIPO will build the CSI that will be tested at the Central Solenoid Model Coil (CSMC) Test Facility at the Japan Atomic Energy Agency (JAEA), Naka, Japan. The industrial vendors (the Suppliers) will report to the USIPO (the Company). All approvals to proceed will be issued by the Company, which in some cases, as specified in this document, will also require the approval of the ITER Organization. Responsibilities and obligations will be covered by respective contracts between the USIPO, called Company interchangeably, and the industrial Prime Contractors, called Suppliers. Different stages of work may be performed by more than one Prime Contractor, as described in this specification. Technical requirements of the contract between the Company and the Prime Contractor will be covered by the Fabrication Specifications developed by the Prime Contractor based on this document and approved by

  10. The Specificity of Human Aesthetics

    DEFF Research Database (Denmark)

    Bouchet, Dominique

    2015-01-01

    Today, humankind is being reintroduced within nature. Humankind is no longer presented as supernatural to nature. There is no longer a clear divide between animal and human. What makes us human is neither culture, nor language nor labor, nor art, but the degree of complexity those products and ca...... creativity. Art is fundamentally about shaping visions and very closely related to this specific human ability to make projects. Especially in times of crisis, when the old sources of meaning hardly can make sense in a new context, imagination must be used in order to survive....

  11. Advances in bacterial specific imaging

    International Nuclear Information System (INIS)

    Wareham, David; Das, Satya; London Univ.

    2005-01-01

    Nuclear medicine is a powerful diagnostic technique able to detect inflammatory foci in human disease. A wide range of agents have been evaluated for their ability to distinguish lesions due to microbial infection from those due to sterile inflammation. Advances continue to be made on the use of radiolabelled antibiotics which as well as being highly specific in the diagnosis of infection may be useful in monitoring the treatment and course of disease. Here we provide an update on in-vitro and clinical studies with a number of established and novel radiopharmaceuticals. (author)

  12. Logic programming and metadata specifications

    Science.gov (United States)

    Lopez, Antonio M., Jr.; Saacks, Marguerite E.

    1992-01-01

    Artificial intelligence (AI) ideas and techniques are critical to the development of intelligent information systems that will be used to collect, manipulate, and retrieve the vast amounts of space data produced by 'Missions to Planet Earth.' Natural language processing, inference, and expert systems are at the core of this space application of AI. This paper presents logic programming as an AI tool that can support inference (the ability to draw conclusions from a set of complicated and interrelated facts). It reports on the use of logic programming in the study of metadata specifications for a small problem domain of airborne sensors, and the dataset characteristics and pointers that are needed for data access.

  13. Phenylephrine Decreases Vascular Tension in Goat Arteries in Specific Circumstances.

    Directory of Open Access Journals (Sweden)

    Renu R Raj

    Full Text Available Phenylephrine (PE causes vasoconstriction through alpha adrenergic receptors. PE-induced vasodilatation has also been reported earlier in pre-constricted vessels. Here we demonstrate in spiral strips of goat arteries that addition of PE can decrease tone even from base-line levels (i.e. not pre-constricted and show that this process requires nitric oxide (NO and alpha adrenergic stimulation, but is cGMP-independent. Under control conditions, PE caused vasoconstriction, but under conditions where NO levels are higher, as with L-Arginine or sodium nitroprusside, PE decreased vessel tension. L-Arginine/PE combination was not able to decrease tension when alpha adrenoceptors were blocked with Phentolamine or endothelial nitric oxide synthase (eNOS was blocked with Nω-Nitro-L-arginine (L-NNA. Propranolol, a beta blocker, was unable to prevent the reduction in tension by the L-Arginine/PE combination. Adrenaline and noradrenaline (and not isoproterenol also reduced vessel tension in the presence of L-Arginine. Even when NO levels were not enhanced, relieving NO from having to stimulate the enzyme soluble guanylyl cyclase (sGC (either by using sGC blockers, namely ODQ or methylene blue, or by enhancing cGMP levels (with sildenafil which by negative feedback probably inhibits sGC led to PE-induced reduction of vascular tension. PMA-phorbol myristate acetate-an agonist which stimulates Protein Kinase C was able to prevent the ability of PE to reduce vascular tension in a high NO environment. Our conclusion is that PE reduces vascular tension through alpha adrenoceptors if there is excess NO availability to activate a putative pathway. Though the reduction of vessel tone by PE is dependent on NO, it is independent of cGMP. Prior treatment with PMA or PE itself can prevent further PE-induced reduction of tension in a high NO environment. The results here suggest, counter-intuitively, that alpha blockers may be of help in the treatment of septic shock

  14. Food Odours Direct Specific Appetite

    Directory of Open Access Journals (Sweden)

    Harriët F. A. Zoon

    2016-02-01

    Full Text Available Olfactory food cues were found to increase appetite for products similar in taste. We aimed to replicate this phenomenon for taste (sweet/savoury, determine whether it extends to energy density (high/low as well, and uncover whether this effect is modulated by hunger state. Twenty-nine healthy-weight females smelled four odours differing in the energy density and taste they signalled, one non-food odour, and one odourless solution (control, in random order, for three minutes each. Appetite for 15 food products was rated in the following two minutes. Mixed model analyses revealed that exposure to an odour signalling a specific taste (respectively sweet, savoury led to a greater appetite for congruent food products (sweet/savoury compared to incongruent food products (savoury p < 0.001; sweet p < 0.001 or neutral food products (p = 0.02; p = 0.003. A similar pattern was present for the energy-density category (respectively high-energy dense, low-energy dense signalled by the odours (low-energy products p < 0.001; high-energy products p = 0.008. Hunger state did not have a significant impact on sensory-specific appetite. These results suggest that exposure to food odours increases appetite for congruent products, in terms of both taste and energy density, irrespective of hunger state. We speculate that food odours steer towards intake of products with a congruent macronutrient composition.

  15. Hanford Site Environmental Management Specification

    International Nuclear Information System (INIS)

    DAILY, J.L.

    2001-01-01

    The US Department of Energy, Richland Operations Office (RL) has established a document hierarchy as part of its integrated management system. The Strategic Plan defines the vision, values, missions, strategic goals, high-level outcomes, and the basic strategies in achieving those outcomes. As shown in Figure 1-1, the Site Specification derives requirements from the Strategic Plan and documents the top-level mission technical requirements for the work involved in the RL Hanford Site cleanup and infrastructure activities under the responsibility of the U.S. Department of Energy, Office of Environmental Management (EM). It also provides the basis for all contract technical requirements. Since this is limited to the EM work, neither the Fast Flux Test Facility (FFTF) nor the Pacific Northwest National Laboratory (PNNL) non-EM science activities are included. Figure 1-1 also shows the relationship between this Site Specification and the other Site management and planning documents. Similarly, the documents, orders, and laws referenced in this document represent only the most salient sources of requirements. Current and contractual reference data contain a complete set of source documents

  16. [Specific immunotherapy. Hyposensitization with allergens].

    Science.gov (United States)

    Wedi, B; Kapp, A

    2004-04-01

    Successful allergen-specific immunotherapy (SIT) induces complex immunologic chan-ges resulting in reduced allergic inflammatory reactions. SIT has long-term effects in mild forms of inhalant allergies and is effective even when standard pharmacotherapy fails. Moreover, the risk to develop additional allergic sensitizations and the development of asthma is significantly reduced in children with allergic rhinitis. SIT is the treatment of choice in patients with systemic reactions to hymenoptera venoms. Although the exact effector mechanisms of SIT still have to be clarified, the most probable effect is a modulation of regulatory T cells associated with a switch of allergen-specific B-cells towards IgG4 production. The critical point to insure efficacy and safety is the selection of patients and allergens, task best performed by a specialist trained in allergology. Further details are available in the position papers of the German allergy societies - DGAI(Deutsche Gesellschaft fiir Allergologie und Klinische Immunologie) and ADA (Arzte-verband Deutscher Allergologen) - which can be found at www.dgaki.de.

  17. Is sexual victimization gender specific?

    DEFF Research Database (Denmark)

    Sundaram, Vanita; Laursen, Bjarne; Helweg-Larsen, Karin

    2008-01-01

    The present study investigates the prevalence of sexual victimization and correlations between sexual victimization and indicators of poor health in two representative samples of men and women in Denmark. Specifically, the authors explore the prevalence of self-reported victimization among...... adolescents (N = 5,829) and adults (N = 3,932) and analyze differences in self-reported health outcomes between male and female victims and corresponding controls. Gender differences are found in the reported prevalence of sexual victimization. Significantly more females than males reported forced sexual...... experiences in both samples. Associations between sexual victimization and poor health outcomes are found for both genders. Comparable patterns of association for men and women are found on a number of variables, particularly those pertaining to risk behavior....

  18. Compositional specification of commercial contracts

    DEFF Research Database (Denmark)

    Andersen, Jesper; Elsborg, Ebbe; Henglein, Fritz

    2006-01-01

    -definable analysis of their state before, during and after execution. We provide several realistic examples of commercial contracts and their analyses. A variety of (real) contracts can be expressed in such a fashion as to support their integration, management and analysis in an operational environment......We present a declarative language for compositional specification of contracts governing the exchange of resources. It extends Eber and Peyton Jones’s declarative language for specifying financial contracts (Jones et al. in The Fun of Programming. 2003) to the exchange of money, goods and services...... amongst multiple parties and complements McCarthy’s Resources, Events and Agents (REA) accounting model (McCarthy in Account Rev. LVII(3), 554–578, 1982) with a view- independent formal contract model that supports definition of user-defined contracts, automatic monitoring under execution and user...

  19. Specificity of discoveries in radiochemistry

    International Nuclear Information System (INIS)

    Krivomazov, A.N.

    1977-01-01

    The development of radiochemistry as a science is elucidated. On the basis of original papers and archives materials which have become available only recently, specific features of opening the law of radioactive displacements and isotopy of radioactive elements are presented in detail. A contribution of Hevesy, Russel, Fajans, and Soddy into the solution of this problem is considered; an important role of Rutherford in putting down the priority conflict is shown. Two stages of scientific generalization are singled out in the history of opening the law of radioactive displacements: the stage of the rules and the stage of the laws. On this basis the solutions of the priority problems have been reconsidered. It is shown that the history of radiochemistry is rich in discoveries which have undergone a relatively long evolution

  20. Genetic specificity of face recognition.

    Science.gov (United States)

    Shakeshaft, Nicholas G; Plomin, Robert

    2015-10-13

    Specific cognitive abilities in diverse domains are typically found to be highly heritable and substantially correlated with general cognitive ability (g), both phenotypically and genetically. Recent twin studies have found the ability to memorize and recognize faces to be an exception, being similarly heritable but phenotypically substantially uncorrelated both with g and with general object recognition. However, the genetic relationships between face recognition and other abilities (the extent to which they share a common genetic etiology) cannot be determined from phenotypic associations. In this, to our knowledge, first study of the genetic associations between face recognition and other domains, 2,000 18- and 19-year-old United Kingdom twins completed tests assessing their face recognition, object recognition, and general cognitive abilities. Results confirmed the substantial heritability of face recognition (61%), and multivariate genetic analyses found that most of this genetic influence is unique and not shared with other cognitive abilities.

  1. Testing of badminton specific endurance

    DEFF Research Database (Denmark)

    Madsen, Christian Møller; Højlyng, Mads; Nybo, Lars

    2016-01-01

    In the present study, a novel intermittent badminton endurance test (B-ENDURANCE) was developed and tested in elite (n=17) and skilled (n=9) badminton players as well as in age-matched physically active men (non-badminton players; n=8). In addition, B-ENDURANCE test-retest reproducibility...... was evaluated in nine badminton players.B-ENDURANCE is an incremental test where each level consists of repeated sequences of badminton specific actions towards the four corners on the court. The subject starts in the center of the court in front of a computer screen and within each sequence he must...... decreases until the subjects cannot follow the dictated tempo.B-ENDURANCE performance for elite players was better (Pbadminton players. In addition, B-ENDURANCE performance correlated (r=0.8; P

  2. FY97 ICCS prototype specification

    International Nuclear Information System (INIS)

    Woodruff, J.

    1997-01-01

    The ICCS software team will implement and test two iterations of their software product during FY97. This document specifies the products to be delivered in that first prototype and projects the direction that the second prototype will take. Detailed specification of the later iteration will be written when the results of the first iteration are complete. The selection of frameworks to be implemented early is made on a basis of risk analysis from the point of view of future development in the ICCS project. The prototype will address risks in integration of object- oriented components, in refining our development process, and in emulation testing for FEP devices. This document is a specification that identifies products and processes to undertake for resolving these risks. The goals of this activity are to exercise our development process at a modest scale and to probe our architecture plan for fundamental limits and failure modes. The product of the iterations will be the framework software which will be useful in future ICCS code. Thus the FY97 products are intended for internal usage by the ICCS team and for demonstration to the FEP software developers of the strategy for integrating supervisory software with FEP computers. This will be the first of several expected iterations of the software development process and the performance measurements that ICCS will demonstrate, intended to support confidence in our ability to meet project RAM goals. The design of the application software is being carried out in a separate WBS 1.5.2 activity. The design activity has as its FY97 product a series of Software Design Documents that will specify the functionality of the controls software of ICCS. During the testing of this year''s prototypes, the application functionality needed for test will be provided by sample maintenance controls. These are early precursors of controls that can be used for low level device control. Since the devices under test will be represented by

  3. Eternity Variables to Prove Simulation of Specifications

    NARCIS (Netherlands)

    Hesselink, Wim H.

    2005-01-01

    Simulations of specifications are introduced as a unification and generalization of refinement mappings, history variables, forward simulations, prophecy variables, and backward simulations. A specification implements another specification if and only if there is a simulation from the first one to

  4. Are specific emotions narrated differently?

    Science.gov (United States)

    Habermas, Tilmann; Meier, Michaela; Mukhtar, Barbara

    2009-12-01

    Two studies test the assertion that anger, sadness, fear, pride, and happiness are typically narrated in different ways. Everyday events eliciting these 5 emotions were narrated by young women (Study 1) and 5- and 8-year-old girls (Study 2). Negative narratives were expected to engender more effort to process the event, be longer, more grammatically complex, more often have a complication section, and use more specific emotion labels than global evaluations. Narratives of Hogan's (2003) juncture emotions anger and fear were expected to focus more on action and to contain more core narrative sections of orientation, complication, and resolution than narratives of the outcome emotions sadness and happiness. Hypotheses were confirmed for adults except for syntactic complexity, whereas children showed only some of these differences. Hogan's theory that juncture emotions are restricted to the complication section was not confirmed. Finally, in adults, indirect speech was more frequent in anger narratives and internal monologue in fear narratives. It is concluded that different emotions should be studied in how they are narrated, and that narratives should be analyzed according to qualitatively different emotions.

  5. [Amusia and its topic specification].

    Science.gov (United States)

    Buklina, S B; Skvortsova, V B

    2007-01-01

    A historical development of views on amusia and its clinical phenomenology is reviewed. The authors present a case of atypical amusia in a patient aged 32 years with glioma of the right temporal lobe including the upper temporal gyrus. Amusia was combined with euphoria and disturbances of evaluation of speech intonation. It has been assumed that different mechanisms implicated with different regions of both brain hemispheres may underlie amusia. Sometimes these mechanisms appear to be universal, e.g. disorders of symbolic gnosis in posterior hemisphere lesions, being comorbid with amusia as disturbances in reading music and letter agnosia. In our case, the right temporal lobe lesion, especially with involvement of the upper temporal gyrus, caused specific music agnosia with disturbances of perception of some notes and duration of their phonation or a musical contour of the whole melody. Motor amusia is developed due to additional disturbances of motor and premotor brain functions, with significant contribution of the Broca's speech area. Music may be a model for investigation into processes of multimodal integration and hemisphere interaction.

  6. Advances in bacterial specific imaging

    Directory of Open Access Journals (Sweden)

    David Wareham

    2005-10-01

    Full Text Available Nuclear medicine is a powerful diagnostic technique able to detect inflammatory foci in human disease. A wide range of agents have been evaluated for their ability to distinguish lesions due to microbial infection from those due to sterile inflammation. Advances continue to be made on the use of radiolabelled antibiotics which as well as being highly specific in the diagnosis of infection may be useful in monitoring the treatment and course of disease. Here we provide an update on in-vitro and clinical studies with a number of established and novel radiopharmaceuticalsA medicina nuclear é uma técnica poderosa de diagnóstico capaz de detectar focos inflamatórios em doenças humanas. Uma ampla gama de agentes tem sido avaliada em sua capacidade de distinguir lesões, devidas a infecções microbianas daquelas causadas por inflamações estéreis. Avanços continuam sendo realizados no uso de antibióticos radiomarcados que, da mesma forma que têm sido usados no diagnóstico altamente específico de infecções, podem ser úteis na monitoração do tratamento e do curso da doença. Neste estudo, nós apresentamos uma atualização sobre estudos in vitro e clínicos, com alguns novos radiofármacos e outros já consagrados.

  7. Specificities of sustainable tourism planning

    Directory of Open Access Journals (Sweden)

    Jegdić Vaso

    2013-01-01

    Full Text Available In the past two decades, companies have been mentioning achievement of sustainability in their activities as a target of companies, governments and non-profit organizations, although measuring the degree to which an organization conducts its activities in a sustainable manner, can be very difficult. Sustainable tourism development requires a process of planning and management that will unite the interests of various stakeholders in a sustainable and strategic way. It requires an understanding of the meaning of sustainable development and guiding values for promoting sustainable tourism. The paper points to the importance of cross-sector partnerships and the roles of different stakeholders in the planning of sustainable tourism projects. Special importance is given to the community of which a willingness to understand the impacts of tourism industry is expected, as well as various procedures of engagement in participatory planning, consensus building and conflict resolution among all stakeholders. The aim of this research is to find an optimal model of planning of sustainable tourism projects that would take into consideration the interests of all stakeholders and reflect the specificities imposed by the acceptance of the concept of sustainable development by all participants in the project.

  8. 31 CFR 596.309 - Specific license.

    Science.gov (United States)

    2010-07-01

    ... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY TERRORISM LIST GOVERNMENTS SANCTIONS REGULATIONS General Definitions § 596.309 Specific license. The term specific license means any license or...

  9. The Specificity Principle in Acculturation Science

    Science.gov (United States)

    Bornstein, Marc H.

    2016-01-01

    The Specificity Principle in Acculturation Science asserts that specific setting conditions of specific people at specific times moderate specific domains in acculturation by specific processes. Our understanding of acculturation depends critically on what is studied where, in whom, how, and when. This article defines, explains, and illustrates the Specificity Principle in Acculturation Science. Research hypotheses about acculturation can be more adequately tested, inconsistencies and discrepancies in the acculturation literature can be satisfactorily resolved, acculturation interventions can be tailored to be more successful, and acculturation policies can be brought to new levels of effectiveness if the specificity principle that governs acculturation science is more widely recognized. PMID:28073331

  10. Specific CT findings of eclampsia

    International Nuclear Information System (INIS)

    Takahashi, Hiroshi; Nakazawa, Shozo; Imaya, Hisatoshi

    1985-01-01

    Two cases of specific computed tomographic (CT) findings of eclampsia were reported. Case 1 was a 25-year-old primipara in the 10th month of pregnancy, and Case 2 was a 36-year-old primipara in the 9th month of pregnancy. Both were brought to our hospital because of attacks of preeclampsia and eclampsia. On admission, they were in a comatose state. Computed tomography (CT) on admission showed low- and high-density areas in the basal ganglia regions in Case 1 and low-density areas in the same regions in Case 2. In Case 1, cerebral angiograms obtained two days after the attack showed diffuse cerebral vasospasms in the anterior and middle cerebral arteries of both sides and the basilar artery. In Case 2, however, cerebral angiograms obtained three days after the attack showed no abnormal findings. The patients were saved by crisis-overcoming emergency treatment and care. The neurological condition gradually improved. Repeated CT three weeks after the onset showed only a slight low-density area and a small high-density area in the left basal ganglia region in Case 1, while the low-density areas in the bilateral basal ganglia regions disappeared in Case 2. Seven weeks after the attack, cerebral angiography was again performed, but the diffuse vasospasms had disappeared. The clinical courses were good, and the patients were discharged about eight weeks after the onset, by which time their consciousness had become clear and the neurological deficits had been well overcome. Cerebrovascular disorders caused by toxemia of pregnancy is rare; when they do occur, the main lesions of the brain are edema, focal ischemia, thrombosis, and hemorrhage. They may be related to cerebral vasospasm, and subsequent ischemic changes are observed at times with eclampsia. (author)

  11. Chronic intratracheal application of the soluble guanylyl cyclase stimulator BAY 41-8543 ameliorates experimental pulmonary hypertension.

    Science.gov (United States)

    Amirjanians, Matthieu; Egemnazarov, Bakytbek; Sydykov, Akylbek; Kojonazarov, Baktybek; Brandes, Ralf; Luitel, Himal; Pradhan, Kabita; Stasch, Johannes-Peter; Redlich, Gorden; Weissmann, Norbert; Grimminger, Friedrich; Seeger, Werner; Ghofrani, Hossein; Schermuly, Ralph

    2017-05-02

    Dysfunction of the NO/sGC/cGMP signaling pathway has been implicated in the pathogenesis of pulmonary hypertension (PH). Therefore, agents stimulating cGMP synthesis via sGC are important therapeutic options for treatment of PH patients. An unwanted effect of this novel class of drugs is their systemic hypotensive effect. We tested the hypothesis that aerosolized intra-tracheal delivery of the sGC stimulator BAY41-8543 could diminish its systemic vasodilating effect.Pharmacodynamics and -kinetics of BAY41-8543 after single intra-tracheal delivery was tested in healthy rats. Four weeks after a single injection of monocrotaline (MCT, 60 mg/kg s.c.), rats were randomized to a two-week treatment with either placebo, BAY 41-8543 (10 mg/kg per os (PO)) or intra-tracheal (IT) instillation (3 mg/kg or 1 mg/kg).Circulating concentrations of the drug 10 mg/kg PO and 3 mg/kg IT were comparable. BAY 41-8543 was detected in the lung tissue and broncho-alveolar fluid after IT delivery at higher concentrations than after PO administration. Systemic arterial pressure transiently decreased after oral BAY 41-8543 and was unaffected by intratracheal instillation of the drug. PO 10 mg/kg and IT 3 mg/kg regimens partially reversed pulmonary hypertension and improved heart function in MCT-injected rats. Minor efficacy was noted in rats treated IT with 1 mg/kg. The degree of pulmonary vascular remodeling was largely reversed in all treatment groups.Intratracheal administration of BAY 41-8543 reverses PAH and vascular structural remodeling in MCT-treated rats. Local lung delivery is not associated with systemic blood pressure lowering and represents thus a further development of PH treatment with sGC stimulators.

  12. Gender-Specific Health Challenges Facing Women

    Science.gov (United States)

    ... with facebook share with twitter share with linkedin Gender-Specific Health Challenges Facing Women Global Research Global ... adverse reactions to the drugs. Women also suffer gender-specific consequences of HIV, including recurrent vaginal yeast ...

  13. Model Commissioning Plan and Guide Specifications

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-03-01

    The objectives of Model Commissioning Plan and Guide Specifications are to ensure that the design team applies commissioning concepts to the design and prepares commissioning specifications and a commission plan for inclusion in the bid construction documents.

  14. Technical specification improvement through safety margin considerations

    International Nuclear Information System (INIS)

    Howard, R.C.; Jansen, R.L.

    1986-01-01

    Westinghouse has developed an approach for utilizing safety analysis margin considerations to improve plant operability through technical specification revision. This approach relies on the identification and use of parameter interrelations and sensitivities to identify acceptable operating envelopes. This paper summarizes technical specification activities to date and presents the use of safety margin considerations as another viable method to obtain technical specification improvement

  15. Genre-Specific Semantic Video Indexing

    NARCIS (Netherlands)

    Wu, J.; Worring, M.

    2010-01-01

    In many applications, we find large video collections from different genres where the user is often only interested in one or two specific video genres. So, when users are querying the system with a specific semantic concept, they are likely aiming a genre specific instantiation of this concept.

  16. 42 CFR 37.203 - Autopsy specifications.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Autopsy specifications. 37.203 Section 37.203... EXAMINATIONS SPECIFICATIONS FOR MEDICAL EXAMINATIONS OF UNDERGROUND COAL MINERS Autopsies § 37.203 Autopsy specifications. (a) Every autopsy for which a claim for payment is submitted pursuant to this part: (1) Shall be...

  17. Specific cooling capacity of liquid nitrogen

    Science.gov (United States)

    Kilgore, R. A.; Adcock, J. B.

    1977-01-01

    The assumed cooling process and the method used to calculate the specific cooling capacity of liquid nitrogen are described, and the simple equation fitted to the calculated specific cooling capacity data, together with the graphical form calculated values of the specific cooling capacity of nitrogen for stagnation temperatures from saturation to 350 K and stagnation pressures from 1 to 10 atmospheres, are given.

  18. Isothermal Gravitational Segregation: Algorithms and Specifications

    DEFF Research Database (Denmark)

    Halldórsson, Snorri; Stenby, Erling Halfdan

    2000-01-01

    New algorithms for calculating the isothermal equilibrium state of reservoir fluids under the influence of gravity are presented. Two types of specifications are considered: the specification of pressure and composition at a reference depth; and the specification of the total overall content of t...

  19. Information Concerning Preparation of Specifications for Carpeting.

    Science.gov (United States)

    Gilliland, John W.

    This paper argues for detailed, written carpeting specifications to assure that schools obtain quality products at competitive prices. The advantages of and specifications for school carpeting are given. A sample written specification contains items on: scope, general features, materials, acoustic characteristics, identification and acoustic…

  20. 14 CFR 91.1015 - Management specifications.

    Science.gov (United States)

    2010-01-01

    ... complete and separate set of its management specifications at its principal base of operations, or at a... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Management specifications. 91.1015 Section... Operations Program Management § 91.1015 Management specifications. (a) Each person conducting operations...

  1. Towards a theory of product design specifications

    DEFF Research Database (Denmark)

    Hansen, Claus Thorp; Andreasen, Mogens Myrup

    2004-01-01

    , which express the customers¿ need and perception of value. In this paper we will scrutinize this assumption. We outline the roles and tasks of the product design specification in order to identify the requirements on a theory of product design specifications and we identify existing theory elements....... In the design methodology literature we find guidelines and methods to compile a product design specification. The contributions are based on the common underlying assumption that it is meaningful and the only feasible approach to interpret the result of a need analysis into a set of technical specifications...... to build such a theory of product design specifications upon....

  2. Standard technical specifications combustion engineering plants

    International Nuclear Information System (INIS)

    1992-09-01

    This report documents the results of the combined effort of the NRC and the industry to produce improved Standard Technical Specifications (STS) for Combustion Engineering Plants. The improved STS wee developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. This document, Volume 1, contains the Specifications for all chapters and sections of the improved STS. Volume 2 contains the Bases for Sections 3.4--3.9 of the improved STS

  3. Crystal structure of the RNase T1 Gp c U complex

    International Nuclear Information System (INIS)

    Arni, R.K.

    1996-01-01

    Full text. Ribonuclease T 1 (RNase T 1 ; EC 3.1.27.3) a member of an extensive gene family of orthologous enzymes from fungi and bacteria that display sequence and structural homology. RNase T 1 is a guanine specific extracellular enzyme from Aspergillus oryzae that cleaves single stranded RNA by catalytic transesterification of 3,5 diester links to 2,3 cyclic diesters at guanylyl residues followed by their catalytic hydrolysis to corresponding 3 monoester. It has been suggested that subsites at both the 5 and 3 sides of a cleavable guanylyl residue in RNA substrates exist. The structure of the monomeric RNase T 1 2 guanosine mono phosphate was determined at 1.9 A resolution using syncrotron radiation (Arni et al. 1987) and revealed the specific interactions at the base recognition and catalytic sites (Arni et al., 1988). The structure of native RNase T 1 indicated the conformational changes of the amino acids forming the base recognition site (Arni et al., 1992). This protein has now been crystallized with Gpc U (Guanylyl (3,6) 6 deoxyhomouridine) which is an isosteric phosphonate analogue of the RNA fragment GpU (Guanylyl (3,5) Uridine), with the 5 oxygen of the uridine moiety replaced by a methylene. The structure has been determined and refined at 2.0 A resolution and indicates the existence of subsites and a novel ribose interaction. (author)

  4. Technical specifications and performance of CANDU fuel

    International Nuclear Information System (INIS)

    Sejnoha, R.

    1997-01-01

    The relations between Technical Specifications and fuel performance are discussed in terms of design limits and margins. The excellent performance record of CANDU reactor fuel demonstrates that the fuel design defined in the Technical Specifications (and with it other components of the procurement cycle, such as fuel manufacturing), satisfy the requirements. New requirements, changing conditions of fuel application and accumulating experience make periodic updates of the Technical Specifications necessary. Under the CANDU Owners Group (COG) Working Party 9, a Work Package has been conducted to support the review of the Specifications and the documentation of the rationales for their requirements. So far, the review has been completed for 4 Specifications: 1 for Zircaloy tubing, and 3 for uranium dioxide powder. It is planned to complete the review of all 11 currently used specifications by 1999. The paper summarizes the results achieved to mid 1997. (author)

  5. An Algebraic Specification of the Semantic Web

    OpenAIRE

    Ksystra, Katerina; Triantafyllou, Nikolaos; Stefaneas, Petros; Frangos, Panayiotis

    2011-01-01

    We present a formal specification of the Semantic Web, as an extension of the World Wide Web using the well known algebraic specification language CafeOBJ. Our approach allows the description of the key elements of the Semantic Web technologies, in order to give a better understanding of the system, without getting involved with their implementation details that might not yet be standardized. This specification is part of our work in progress concerning the modeling the Social Semantic Web.

  6. Map Specifications and Exchange of Geographical Information

    DEFF Research Database (Denmark)

    Frederiksen, Poul

    1999-01-01

    Specifications for Technical Maps 1993 – 99 are described giving an overview of the specification structure including the object description of the latest version: TK99.The technical map specifications are related to the standards for topographical maps - especially the TOP10DK standard. Common...... object definitions are essential for the standards. Technical as well as topographical map information is exchangeable through the Danish developed “Standard for Exchange of Digital Map Information”, known as the DSFL-format....

  7. Cervical cancer: intracavitary dose specification and prescription

    International Nuclear Information System (INIS)

    Potish, R.A.; Gerbi, B.J.

    1987-01-01

    Dose and volume specifications for reporting intracavitary therapy were analyzed according to criteria recommended by the International Commission on Radiation Units and Measurements (ICRU). Ninety Fletcher-Suit radium applications were studied to examine the validity of the assumptions of the ICRU and the merit of their routine reporting. It was demonstrated that the reporting recommendations were inconsistent with clinical prescription systems and added little to dose specification. The distinction between dose specification and dose prescription was stressed

  8. Product specifications for the end use

    International Nuclear Information System (INIS)

    Navaretta, G.

    1992-01-01

    This paper reports on the concept of total quality which provides a foundation upon which NGL specifications could be built. Total quality has been embraced by a large constituency within the Refining and Petrochemical business, so, the NGL industry can not afford to discount it. As a concept, total quality certainly includes a specific management approach, but the roots of the quality movement lie with traditional product quality values. Naturally, the subject of product quality leads directly to product specifications, thus proving the intimate relationship between the total quality concept and NGL specifications

  9. Steps in Modular Specifications for Concurrent Modules

    DEFF Research Database (Denmark)

    Da Rocha Pinto, Pedro; Dinsdale-Young, Thomas; Gardner, Philippa

    2015-01-01

    The specification of a concurrent program module is a difficult problem. The specifications must be strong enough to enable reasoning about the intended clients without reference to the underlying module implementation. We survey a range of verification techniques for specifying concurrent module......, in particular highlighting four key concepts: auxiliary state, interference abstraction, resource ownership and atomicity. We show how these concepts combine to provide powerful approaches to specifying concurrent modules.......The specification of a concurrent program module is a difficult problem. The specifications must be strong enough to enable reasoning about the intended clients without reference to the underlying module implementation. We survey a range of verification techniques for specifying concurrent modules...

  10. Technical specifications for the Bulk Shielding Reactor

    International Nuclear Information System (INIS)

    1982-04-01

    Technical specifications are presented concerning the safety limits and limiting safety system settings; limiting conditions for operation; surveillance requirements; design features; and administrative controls

  11. AOV Facility Tool/Facility Safety Specifications -

    Data.gov (United States)

    Department of Transportation — Develop and maintain authorizing documents that are standards that facilities must follow. These standards are references of FAA regulations and are specific to the...

  12. A technical assessment of the porcine ejaculated spermatozoa for a sperm-specific RNA-seq analysis.

    Science.gov (United States)

    Gòdia, Marta; Mayer, Fabiana Quoos; Nafissi, Julieta; Castelló, Anna; Rodríguez-Gil, Joan Enric; Sánchez, Armand; Clop, Alex

    2018-04-26

    RNA; Mt rRNA: mitochondrial ribosomal RNA; Mt tRNA: mitochondrial transference RNA; OAZ3: ornithine decarboxylase antizyme 3; ORT: osmotic resistance test; piRNA: Piwi-interacting RNA; PRM1: protamine 1; PTPRC: protein tyrosine phosphatase receptor type C; rRNA: ribosomal RNA; snoRNA: small nucleolar RNA; snRNA: small nuclear RNA; SRR: sperm recovery rate; tRNA: transfer RNA.

  13. User Interface Technology for Formal Specification Development

    Science.gov (United States)

    Lowry, Michael; Philpot, Andrew; Pressburger, Thomas; Underwood, Ian; Lum, Henry, Jr. (Technical Monitor)

    1994-01-01

    Formal specification development and modification are an essential component of the knowledge-based software life cycle. User interface technology is needed to empower end-users to create their own formal specifications. This paper describes the advanced user interface for AMPHION1 a knowledge-based software engineering system that targets scientific subroutine libraries. AMPHION is a generic, domain-independent architecture that is specialized to an application domain through a declarative domain theory. Formal specification development and reuse is made accessible to end-users through an intuitive graphical interface that provides semantic guidance in creating diagrams denoting formal specifications in an application domain. The diagrams also serve to document the specifications. Automatic deductive program synthesis ensures that end-user specifications are correctly implemented. The tables that drive AMPHION's user interface are automatically compiled from a domain theory; portions of the interface can be customized by the end-user. The user interface facilitates formal specification development by hiding syntactic details, such as logical notation. It also turns some of the barriers for end-user specification development associated with strongly typed formal languages into active sources of guidance, without restricting advanced users. The interface is especially suited for specification modification. AMPHION has been applied to the domain of solar system kinematics through the development of a declarative domain theory. Testing over six months with planetary scientists indicates that AMPHION's interactive specification acquisition paradigm enables users to develop, modify, and reuse specifications at least an order of magnitude more rapidly than manual program development.

  14. Motorcycle Education Curriculum Specifications. Final Report.

    Science.gov (United States)

    McKnight, A. James; And Others

    This report contains specifications for a motorcycle safety education curriculum designed to reduce the incidence and severity of motorcycle accidents. The specifications prescribe objectives, prerequisites, methods, materials, equipment, facilities, and proficiency measures for six units of instruction: (1) basic riding skills, (2) street riding…

  15. Domain-specific languages in perspective

    NARCIS (Netherlands)

    J. Heering (Jan); M. Mernik (Marjan)

    2007-01-01

    textabstractDomain-specific languages (DSLs) are languages tailored to a specific application domain. They offer substantial gains in expressiveness and ease of use compared with general-purpose languages in their domain of application. Although the use of DSLs is by no means new, it is receiving

  16. The Logic of the RAISE Specification Language

    DEFF Research Database (Denmark)

    George, Chris; Haxthausen, Anne Elisabeth

    2003-01-01

    This paper describes the logic of the RAISE Specification Language, RSL. It explains the particular logic chosen for RAISE, and motivates this choice as suitable for a wide spectrum language to be used for designs as well as initial specifications, and supporting imperative and concurrent...

  17. Specific and social phobias in ICD-11

    NARCIS (Netherlands)

    Emmelkamp, P.M.G.

    2012-01-01

    The purpose of this article is to discuss the current status of research with respect to specific phobias and social phobia as defined in the ICD-10 and DSM-IV, and to provide op- tions for their classification in the ICD-11. Both ICD-10 and DSM-IV identify three main classes of phobias: specific

  18. Technical specifications: Health Physics Research Reactor

    International Nuclear Information System (INIS)

    1979-02-01

    The technical specifications define the key limitations that must be observed for safe operation of the Health Physics Research Reactor (HPRR) and an envelope of operation within which there is assurance that these limits will not be exceeded. The specifications were written to satisfy the requirements of the Department of Energy (DOE) Manual Chapter 0540, September 1, 1972

  19. Guidelines for writing user friendly technical specifications

    International Nuclear Information System (INIS)

    Webster, S.A.; Braun, J.C.; Pearce, R.T.

    1986-01-01

    This study investigates some of the ergonomic considerations of writer's guides for the preparation of instructions. It is a precedent for the preparation of such a writer's guide for technical specifications for nuclear power plants. This writer's guide will be part of a revision to the industry's standard ANSI/ANS 58.4, Criteria for Technical Specifications for Nuclear Power Stations

  20. Specific skills and social competence in schizophrenia

    NARCIS (Netherlands)

    Appelo, M.T.; van Nieuwenhuizen, C.J.; Emmelkamp, P.M.G.; Slooff, C.J.; Louwerens, J.W.

    1992-01-01

    Generalization of skills is a major problem in social skills training for schizophrenic patients. Assessment of skills is mostly not based on objective indices of specific skill deficits. The results of this study show that global competence of schizophrenics can be differentiated from specific

  1. The Logic of the RAISE Specification Language

    DEFF Research Database (Denmark)

    George, Chris; Haxthausen, Anne Elisabeth

    2008-01-01

    This chapter describes the logic of the RAISE Specification Language, RSL. It explains the particular logic chosen for RAISE, and motivates this choice as suitable for a wide spectrum language to be used for designs as well as initial specifications, and supporting imperative and concurrent...

  2. Specific heats of degenerate ideal gases

    OpenAIRE

    Caruso, Francisco; Oguri, Vitor; Silveira, Felipe

    2017-01-01

    From arguments based on Heisenberg's uncertainty principle and Pauli's exclusion principle, the molar specific heats of degenerate ideal gases at low temperatures are estimated, giving rise to values consistent with the Nerst-Planck Principle (third law of Thermodynamics). The Bose-Einstein condensation phenomenon based on the behavior of specific heat of massive and non-relativistic boson gases is also presented.

  3. Shape configuration and category-specificity

    DEFF Research Database (Denmark)

    Gerlach, Christian; Law, Ian; Paulson, Olaf B.

    2006-01-01

    a recent account of category-specificity and lends support to the notion that category-specific impairments can occur for both natural objects and artefacts following damage to pre-semantic stages in visual object recognition. The implications of the present findings are discussed in relation to theories...

  4. Fundamental Characteristics of Industrial Variant Specification Systems

    DEFF Research Database (Denmark)

    Hansen, Benjamin Loer; Hvam, Lars

    2004-01-01

    fundamental concepts related to this task, which are relevant to understand for academia and practitioners working with the subject. This is done through a description of variant specification tasks and typical aspects of system solutions. To support the description of variant specification tasks and systems...

  5. SPECIFIC SKILLS AND SOCIAL COMPETENCE IN SCHIZOPHRENIA

    NARCIS (Netherlands)

    APPELO, MT; WOONINGS, FMJ; VANNIEUWENHUIZEN, CJ; EMMELKAMP, PMG; SLOOFF, CJ; LOUWERENS, JW

    Generalization of skills is a major problem in social skills training for schizophrenic patients. Assessment of skills is mostly not based on objective indices of specific skill deficits. The results of this study show that global competence of schizophrenics can be differentiated from specific

  6. Building finite automata from DI specifications

    NARCIS (Netherlands)

    Udding, J.T

    1998-01-01

    Numerous formalisms exist to specify delay-insensitive computations and their implementations. It is not always straightforward to compare specifications in the different formalisms. One way of comparing specifications is transforming them to automata in which nodes are annotated with progress

  7. The Specificity of Creativity: Figurative and Scientific

    Science.gov (United States)

    Bernal, Ana; Esparza, Javier; Ruiz, María-José; Ferrando, Mercedes; Sainz, Marta

    2017-01-01

    Introduction: This work tackles the question about the nature of creativity as a general vs. domain-specific ability. First we deal with the concept of creativity and then, the main approaches to the debate of generality vs. specificity are exposed. Method: A total of 133 students attending 3rd grade of secondary education in Murcia Region took…

  8. Efficient genre-specific semantic video indexing

    NARCIS (Netherlands)

    Wu, J.; Worring, M.

    2012-01-01

    Large video collections such as YouTube contain many different video genres, while in many applications the user might be interested in one or two specific video genres only. Thus, when users are querying the system with a specific semantic concept like AnchorPerson, and MovieStars, they are likely

  9. Autonomy Level Specification for Intelligent Autonomous Vehicles

    Science.gov (United States)

    2003-09-01

    Autonomy Level Specification for Intelligent Autonomous Vehicles : Interim Progress Report Hui-Min Huang, Elena Messina, James Albus...Level Specification for Intelligent Autonomous Vehicles : Interim Progress Report 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6

  10. 324 and 327 Facilities Environmental Effluent Specifications

    International Nuclear Information System (INIS)

    JOHNSON, D.L.

    1999-01-01

    These effluent specifications address requirements for the 324/321 Facilities, which are undergoing stabilization activities. Effluent specifications are imposed to protect personnel, the environment and the public, by ensuring adequate implementation and compliance with federal and state regulatory requirements and Hanford programs

  11. PCR specific for Actinobacillus pleuropneumoniae serotype 3

    DEFF Research Database (Denmark)

    Zhou, L.; Jones, S.C.P.; Angen, Øystein

    2008-01-01

    , but the method has liminations, for example, cross-reactions between serotypes 3, 6, and 8. This study describes the development of a serotype 3-specific PCR, based on the capsule locus, which can be used in a multiplex format with the organism's specific gene apxIV. The PCR test was evaluated on 266 strains...

  12. ITER ISS system alternative specification study

    International Nuclear Information System (INIS)

    Kveton, O.K.

    1990-08-01

    Recent comments suggested that the fuel systems, in particular the ISS, could be simplified if the ITER specifications were relaxed from the data specified for ITER. This interim report addresses the first part of the analysis, which considers the impact of design specifications on fuel systems design

  13. Plutonium Immobilization Can Loading Preliminary Specifications

    Energy Technology Data Exchange (ETDEWEB)

    Kriikku, E.

    1998-11-25

    This report discusses the Plutonium Immobilization can loading preliminary equipment specifications and includes a process block diagram, process description, equipment list, preliminary equipment specifications, plan and elevation sketches, and some commercial catalogs. This report identifies loading pucks into cans and backfilling cans with helium as the top priority can loading development areas.

  14. Technical specifications: Tower Shielding Reactor II

    International Nuclear Information System (INIS)

    1979-02-01

    The technical specifications define the key limitations that must be observed for safe operation of the Tower Shielding Reactor II (TSR-II) and an envelope of operation within which there is reasonable assurance that these limits cannot be exceeded. The specifications were written to satisfy the requirements of the Department of Energy (DOE) Manual Chapter 0540, September 1, 1972

  15. Development of technical specifications for research reactors

    International Nuclear Information System (INIS)

    Anon.

    1983-01-01

    This standard identifies and establishes the content of technical specifications for research reactors. Areas addressed are: definitions, safety limits, limiting safety system settings, limiting conditions for operation, surveillance requirements, design features and administrative controls. Sufficient detail is incorporated so that applicable specifications can be derived or extracted

  16. 11 CFR 1.14 - Specific exemptions.

    Science.gov (United States)

    2010-01-01

    ... to refer apparent violations of the Act to the Attorney General or other law enforcement authorities... 11 Federal Elections 1 2010-01-01 2010-01-01 false Specific exemptions. 1.14 Section 1.14 Federal Elections FEDERAL ELECTION COMMISSION PRIVACY ACT § 1.14 Specific exemptions. (a) No individual, under the...

  17. Determining the specific electric resistance of rock

    Energy Technology Data Exchange (ETDEWEB)

    Persad' ko, V.Ia.

    1982-01-01

    Data are presented on perfecting the method of laboratory determination of the specific electric resistance of a rock formation. The average error in determining the specific electric resistance of the core at various locations is no more than two percent with low resistance values (2-5 ohms).

  18. Specific phobia predicts psychopathology in young women

    NARCIS (Netherlands)

    Trumpf, J.; Margraf, J.; Vriends, N.; Meyer, A.H.; Becker, E.S.

    2010-01-01

    Although specific phobia is characterized by an early age at onset and by high rates of comorbidity, few studies have examined comorbid relationships prospectively. The present study investigated the association between specific phobia and the risk of a broad range of psychopathology among young

  19. Screening specifications for Gulf Coast salt domes

    International Nuclear Information System (INIS)

    Brunton, G.D.; Laughon, R.B.; McClain, W.C.

    1978-01-01

    A reconnaissance survey of the salt domes of Mississippi, Louisiana, and east Texas is being planned to identify study areas for potential sites for radioactive waste disposal. Preliminary screening specifications were derived for each of the geological evaluation criteria by application of the significant factors that will have an impact on the reconnaissance survey. The procedure for the derivation of each screening specification is discussed. The screening specifications are the official OWI values to be used for the first-cut acceptance for salt dome study areas along the Gulf Coast. The derivation of the screening specifications is illustrated by (1) a statement of the geological evaluation criterion, (2) a discussion of the pertinent factors affecting the criterion, and (3) the evaluation of the value of the specification

  20. Tissue Specific Promoters in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    A. R. Rama

    2015-01-01

    Full Text Available Colorectal carcinoma is the third most prevalent cancer in the world. In the most advanced stages, the use of chemotherapy induces a poor response and is usually accompanied by other tissue damage. Significant progress based on suicide gene therapy has demonstrated that it may potentiate the classical cytotoxic effects in colorectal cancer. The inconvenience still rests with the targeting and the specificity efficiency. The main target of gene therapy is to achieve an effective vehicle to hand over therapeutic genes safely into specific cells. One possibility is the use of tumor-specific promoters overexpressed in cancers. They could induce a specific expression of therapeutic genes in a given tumor, increasing their localized activity. Several promoters have been assayed into direct suicide genes to cancer cells. This review discusses the current status of specific tumor-promoters and their great potential in colorectal carcinoma treatment.

  1. Specifications in early conceptual design work

    DEFF Research Database (Denmark)

    Hansen, Claus Thorp; Andreasen, Mogens Myrup

    2007-01-01

    In early conceptual design the design team is working in an uncertain situation, where the understanding of a need is limited and not much is known about the solution space. In this situation the design team has to both analyse need and explore solution space. Thus, the team has to formulate design...... specifications, which express attractive product goals, and has to synthesise the product idea. The authors of this paper see a challenge to enhance and improve our understanding of the nature of design specifications as a means to support the synthesis of a product idea. In this empirical study we analyse...... the structure and content of design specifications during early ideation activities, where initial design specifications are formulated and a product idea is synthesised. We have analysed specification documents of 19 teams of novice designers. Our analysis indicates that a productive product design...

  2. Improvements to Technical Specifications surveillance requirements

    International Nuclear Information System (INIS)

    Lobel, R.; Tjader, T.R.

    1992-12-01

    In August 1983 an NRC task group was formed to investigate problems with surveillance testing required by Technical Specifications, and to recommend approaches to effect improvements. NUREG-1024 (''Technical Specifications-Enhancing Safety Impact'') resulted, and it contained recommendations to review the basis for test frequencies; to ensure that the tests promote safety and do not degrade equipment; and to review surveillance tests so that they do not unnecessarily burden personnel. The Technical Specifications Improvement Program (TSIP) was established in December 1984 to provide the framework for rewriting and improving the Technical Specifications. As an element of the TSIP, all Technical Specifications surveillance requirements were comprehensively examined as recommended in NUREG-1024. The results of that effort are presented in this report. The study found that while some testing at power is essential to verify equipment and system operability, safety can be improved, equipment degradation decreased, and unnecessary personnel burden relaxed by reducing the amount of testing at power

  3. Standard Technical Specifications, Babcock and Wilcox plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Babcock and Wilcox (B ampersand W) Plants and documents the positions of the Nuclear Regulatory Commission based on the B ampersand W Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The unproved STS were developed based on the, criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop proved plant-specific technical specifications. This report contains three volumes. This document, Volume 1 contains the Specifications for all chapters and sections of the improved STS

  4. Rf system specifications for a linear accelerator

    International Nuclear Information System (INIS)

    Young, A.; Eaton, L.E.

    1992-01-01

    A linear accelerator contains many systems; however, the most complex and costly is the RF system. The goal of an RF system is usually simply stated as maintaining the phase and amplitude of the RF signal within a given tolerance to accelerate the charged particle beam. An RF system that drives a linear accelerator needs a complete system specification, which should contain specifications for all the subsystems (i.e., high-power RF, low-level RF, RF generation/distribution, and automation control). This paper defines a format for the specifications of these subsystems and discusses each RF subsystem independently to provide a comprehensive understanding of the function of each subsystem. This paper concludes with an example of a specification spreadsheet allowing one to input the specifications of a subsystem. Thus, some fundamental parameters (i.e., the cost and size) of the RF system can be determined

  5. Specificity of transmembrane protein palmitoylation in yeast.

    Directory of Open Access Journals (Sweden)

    Ayelén González Montoro

    Full Text Available Many proteins are modified after their synthesis, by the addition of a lipid molecule to one or more cysteine residues, through a thioester bond. This modification is called S-acylation, and more commonly palmitoylation. This reaction is carried out by a family of enzymes, called palmitoyltransferases (PATs, characterized by the presence of a conserved 50- aminoacids domain called "Asp-His-His-Cys- Cysteine Rich Domain" (DHHC-CRD. There are 7 members of this family in the yeast Saccharomyces cerevisiae, and each of these proteins is thought to be responsible for the palmitoylation of a subset of substrates. Substrate specificity of PATs, however, is not yet fully understood. Several yeast PATs seem to have overlapping specificity, and it has been proposed that the machinery responsible for palmitoylating peripheral membrane proteins in mammalian cells, lacks specificity altogether.Here we investigate the specificity of transmembrane protein palmitoylation in S. cerevisiae, which is carried out predominantly by two PATs, Swf1 and Pfa4. We show that palmitoylation of transmembrane substrates requires dedicated PATs, since other yeast PATs are mostly unable to perform Swf1 or Pfa4 functions, even when overexpressed. Furthermore, we find that Swf1 is highly specific for its substrates, as it is unable to substitute for other PATs. To identify where Swf1 specificity lies, we carried out a bioinformatics survey to identify amino acids responsible for the determination of specificity or Specificity Determination Positions (SDPs and showed experimentally, that mutation of the two best SDP candidates, A145 and K148, results in complete and partial loss of function, respectively. These residues are located within the conserved catalytic DHHC domain suggesting that it could also be involved in the determination of specificity. Finally, we show that modifying the position of the cysteines in Tlg1, a Swf1 substrate, results in lack of palmitoylation, as

  6. Validating Avionics Conceptual Architectures with Executable Specifications

    Directory of Open Access Journals (Sweden)

    Nils Fischer

    2012-08-01

    Full Text Available Current avionics systems specifications, developed after conceptual design, have a high degree of uncertainty. Since specifications are not sufficiently validated in the early development process and no executable specification exists at aircraft level, system designers cannot evaluate the impact of their design decisions at aircraft or aircraft application level. At the end of the development process of complex systems, e. g. aircraft, an average of about 65 per cent of all specifications have to be changed because they are incorrect, incomplete or too vaguely described. In this paper, a model-based design methodology together with a virtual test environment is described that makes complex high level system specifications executable and testable during the very early levels of system design. An aircraft communication system and its system context is developed to demonstrate the proposed early validation methodology. Executable specifications for early conceptual system architectures enable system designers to couple functions, architecture elements, resources and performance parameters, often called non-functional parameters. An integrated executable specification at Early Conceptual Architecture Level is developed and used to determine the impact of different system architecture decisions on system behavior and overall performance.

  7. Position paper: the science of deep specification.

    Science.gov (United States)

    Appel, Andrew W; Beringer, Lennart; Chlipala, Adam; Pierce, Benjamin C; Shao, Zhong; Weirich, Stephanie; Zdancewic, Steve

    2017-10-13

    We introduce our efforts within the project 'The science of deep specification' to work out the key formal underpinnings of industrial-scale formal specifications of software and hardware components, anticipating a world where large verified systems are routinely built out of smaller verified components that are also used by many other projects. We identify an important class of specification that has already been used in a few experiments that connect strong component-correctness theorems across the work of different teams. To help popularize the unique advantages of that style, we dub it deep specification , and we say that it encompasses specifications that are rich , two-sided , formal and live (terms that we define in the article). Our core team is developing a proof-of-concept system (based on the Coq proof assistant) whose specification and verification work is divided across largely decoupled subteams at our four institutions, encompassing hardware microarchitecture, compilers, operating systems and applications, along with cross-cutting principles and tools for effective specification. We also aim to catalyse interest in the approach, not just by basic researchers but also by users in industry.This article is part of the themed issue 'Verified trustworthy software systems'. © 2017 The Author(s).

  8. Cell-cycle phase specificity of chloroethylnitrosoureas

    International Nuclear Information System (INIS)

    Linfoot, P.A.

    1986-01-01

    Although the cancer chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is considered a non-cell cycle phase specific drug, it has been shown to produce differential cell killing in G 1 , S, and G 2 /M phase cells, with S phase cells appearing relatively resistant. Studies of cell cycle phase specific cell killing produced by nitrosoureas with different chemical reactivities, clearly indicated that the ability of compounds to cross-link DNA was important in determining their phase specificity. Cells that lacked guanine O 6 -alkytransferase activity showed similar patterns of BCNU phase specificity regardless of their intrinsic sensitivity to BCNU. DNA inter-strand cross-linking, as measured by alkaline elution, was similar in cells exposed to BCNU in G 1 or S phase. 3 H [1-chloroethyl-1nitrosourea] binding to DNA was the same in G 1 , S and G 2 /M phase cells indicating that phase-specific differences in drug uptake and intracellular drug dose were not responsible for phase specific cell kill. These studies suggest that cross-link lesions, other than DNA inter-strand cross-links, and/or effects on DNA repair, other than guanine O 6 -alkyltransferase, are additional important determinants of BCNU phase specific cell killing

  9. Formal specifications for safety grade systems

    International Nuclear Information System (INIS)

    Chisholm, G.H.; Smith, B.T.; Wojcik, A.S.

    1992-01-01

    The authors describe the findings of a study into the application of formal methods to the specification of a safety system for an operating nuclear reactor. They developed a formal specification that is used to verify and validate that no unsafe condition will result from action or inaction of the system. For this reason, the specification must facilitate thinking about, talking about, and implementing the system. In fact, the specification must provide a bridge between people (designers, engineers, policy makers) and diverse implementations (hardware, software, sensors, power supplies) at all levels. For a specification to serve as an effective linkage, it must have the following properties: (1) completeness, (2) conciseness, (3) unambiguity, and (4) communicativeness. In this paper they describe the development of a specification that has three properties. This development is based on the use of formal methods, i.e., methods that add mathematical rigor to the development, analysis and operation of computer systems and to applications based thereon (Neumann). They demonstrate that a specification derived from a formal basis facilitates development of the design and its subsequent verification

  10. Non-specific immunization against babesiosis

    International Nuclear Information System (INIS)

    Cox, F.E.G.

    1980-01-01

    The rodent babesias, Babesia rodhaini and the less virulent B. microti, are useful models with which to study immunity to and immunization against babesiosis. In contrast with the difficulty in inducing specific immunity to these parasites it is comparatively easy to induce non-specific immunity by prior exposure to related and unrelated intra-erythrocytic protozoa, micro-organisms such as Mycobacterium bovis (BCG) and Corynebacterium parvum, microbial extracts and muramyl dipeptide. This non-specific immunity is long lasting and extremely effective. It is characterized by the facts that (a) it occurs early in the infection at the height of the first peak of parasitaemia, and (b) it involves the intra-erythrocytic death of the parasites. After the primary parasitaemia has resolved, some parasites continue to persist at a low level and when introduced into clean mice produce only low-level 'attenuated' infections in these. Non-specific immunity is not equally effective in all strains of mice. It is suggested that immunity to babesiosis, and infections caused by other intra-erythrocytic protozoa, involves two mechanisms, the first non-specific and the second specific. The actual balance between these two mechanisms varies from parasite to parasite and from host to host. An effective vaccine would have to be based on an understanding of the roles of non-specific immunity in the actual disease under consideration, and would ideally combine an adjuvant that would also stimulate non-specific immunity and an attenuated strain of parasite that would induce a specific response. (author)

  11. Assessment of the specificity of norethisterone radioimmunoassays

    Energy Technology Data Exchange (ETDEWEB)

    Bedolla-Tovar, N; Rahman, S A; Cekan, S Z; Diczfalusy, E [Swedish Medical Research Council, Karolinska Hospital, Stockholm

    1978-06-01

    It is concluded that (1) the significance of cross- reaction studies as well as that of the parallelism test for the assessment of the over-all specificity of the assay is limited, (2) a single chromatography prior to the radioimmunoassay proper improves the assay specificity, but may not be sufficient to remove all interfering compounds, (3) a comparison of the direct and chromatographic assay procedures using several antisera is useful for the selection of the relatively most specific radioimmunoassay procedure. In the present study, this is the technique employing either antiserum C or antiserum D, the latter, however, only after chromatography.

  12. PD-L1-specific T cells

    DEFF Research Database (Denmark)

    Ahmad, Shamaila Munir; Borch, Troels Holz; Hansen, Morten

    2016-01-01

    -specific T cells that recognize both PD-L1-expressing immune cells and malignant cells. Thus, PD-L1-specific T cells have the ability to modulate adaptive immune reactions by reacting to regulatory cells. Thus, utilization of PD-L1-derived T cell epitopes may represent an attractive vaccination strategy...... for targeting the tumor microenvironment and for boosting the clinical effects of additional anticancer immunotherapy. This review summarizes present information about PD-L1 as a T cell antigen, depicts the initial findings about the function of PD-L1-specific T cells in the adjustment of immune responses...

  13. Quality Assurance for Iraqi Bottled Water Specifications

    Directory of Open Access Journals (Sweden)

    May George Kassir

    2015-10-01

    Full Text Available In this research the specifications of Iraqi drinking bottled water brands are investigated throughout the comparison between local brands, Saudi Arabia and the World Health Organization (WHO for bottled water standard specifications. These specifications were also compared to that of Iraqi Tap Water standards. To reveal variations in the specifications for Iraqi bottled water, and above mentioned standards some quality control tools are conducted for more than 33% of different bottled water brands (of different origins such as spring, purified,..etc in Iraq by investigating the selected quality parameters registered on their marketing labels. Results employing Minitab software (ver. 16 to generate X bar, and Pareto chart. It was found from X bar charts that the quality parameters of some drinking bottled water brands are not within Iraqi standards set by the “Central Agency for Standardization and Quality Control” such as pH values, Fe, Na, and Mg concentrations. While the comparison of previously mentioned standard specifications through radar chart many important issues are detected such as the absence of lower limits the whole bottled water quality parameters such as for Na and Mg also the radar chart shows that Iraqi bottled and tap water specifications are almost equal in their quality values. Also the same chart pictured the limited range of Iraqi specifications compared to that of Saudi Arabia, and WHO and the need to introduce other water specifications such as K, Na, etc. This confirms the need to improve Iraqi bottled water specifications since it was introduced on 2000. These results also highlighted the weakness of quality assurance activities since only 33 % of the investigated companies registered the whole water quality specifications as shown in Pareto chart. Other companies do not register any quality characteristics. Also certain companies should be stopped due to non-conforming specifications, yet these companies are

  14. Technical specification optimization program - engineered safety features

    International Nuclear Information System (INIS)

    Andre, G.R.; Jansen, R.L.

    1986-01-01

    The Westinghouse Technical Specification Program (TOP) was designed to evaluate on a quantitative basis revisions to Nuclear Power Plant Technical Specifications. The revisions are directed at simplifying plant operation, and reducing unnecessary transients, shutdowns, and manpower requirements. In conjunction with the Westinghouse Owners Group, Westinghouse initiated a program to develop a methodology to justify Technical Specification revisions; particularly revisions related to testing and maintenance requirements on plant operation for instrumentation systems. The methodology was originally developed and applied to the reactor trip features of the reactor protection system (RPS). The current study further refined the methodology and applied it to the engineered safety features of the RPS

  15. Table of specific activities of selected isotopes

    International Nuclear Information System (INIS)

    Shipley, G.

    The bulk of this publication consists of a table of the half-lives, decay modes, and specific activities of isotopes selected for their particular interest to the Environmental Health and Safety Department, LBL. The specific activities were calculated with a PDP 9/15 computer. Also included in the report is a table of stable isotopes, the Th and U decay chains, a chart of the nuclides for elements 101 through 106, the heavy element region of the periodic table, and a specific activity monograph. 5 figures, 2 tables

  16. Mining software specifications methodologies and applications

    CERN Document Server

    Lo, David

    2011-01-01

    An emerging topic in software engineering and data mining, specification mining tackles software maintenance and reliability issues that cost economies billions of dollars each year. The first unified reference on the subject, Mining Software Specifications: Methodologies and Applications describes recent approaches for mining specifications of software systems. Experts in the field illustrate how to apply state-of-the-art data mining and machine learning techniques to address software engineering concerns. In the first set of chapters, the book introduces a number of studies on mining finite

  17. Breckinridge Project, initial effort. Report III, Volume 2. Specifications

    Energy Technology Data Exchange (ETDEWEB)

    None

    1982-01-01

    Report III, Volume 2 contains those specifications numbered K through Y, as follows: Specifications for Compressors (K); Specifications for Piping (L); Specifications for Structures (M); Specifications for Insulation (N); Specifications for Electrical (P); Specifications for Concrete (Q); Specifications for Civil (S); Specifications for Welding (W); Specifications for Painting (X); and Specifications for Special (Y). The standard specifications of Bechtel Petroleum Incorporated have been amended as necessary to reflect the specific requirements of the Breckinridge Project and the more stringent specifications of Ashland Synthetic Fuels, Inc. These standard specifications are available for the Initial Effort (Phase Zero) work performed by all contractors and subcontractors.

  18. Interior Design's Role in Educational Specifications.

    Science.gov (United States)

    Keller, Mary Ann

    1986-01-01

    An experienced interior designer, equipped with a well-written educational specification, will specify the best materials and coordinate colors, materials, and furnishings in line with the district's budget. (MLF)

  19. Cockpit management and Specific Behavioral Objectives (SBOs)

    Science.gov (United States)

    Mudge, R. W.

    1987-01-01

    One of the primary tools used to accomplish the task of effective training is the specific behavioral objective (SBO). An SBO is simply a statement which specifically identifies a small segment of the final behavior sought, and a little more. The key word is specific. The company pinpoints exactly what it is it wants the pilot to do after completing training, and what it should evaluate from the point of view of both the program and the pilot. It tells the junior crewmember exactly, specifically, what he should monitor and support insofar as the management function is concerned. It gives greater meaning to the term second in command. And finally, it tells the supervisory pilot exactly what he should observe, evaluate, and instruct, insofar as the management function is concerned.

  20. 14 CFR 211.10 - Filing specifications.

    Science.gov (United States)

    2010-01-01

    ...) ECONOMIC REGULATIONS APPLICATIONS FOR PERMITS TO FOREIGN AIR CARRIERS General Requirements § 211.10 Filing... in § 302.3 of this chapter as to execution, number of copies, and formal specifications of papers. (b...

  1. Non-specific immunization against parasites

    International Nuclear Information System (INIS)

    Cox, F.E.G.

    1981-01-01

    Non-specific resistance to tumours can be induced by pretreating animals with micro-organisms, microbial extracts or various synthetic substances. Mycobacterium bovis, Corynebacterium parvum and a number of other micro-organisms also protect mice against rodent piroplasms and there is evidence that they are also protective against other parasites including Schistosoma mansoni. The actual mechanisms of non-specific immunity are still unclear but it is influenced by both the genetic make-up of the host and the nature of the parasite. Non-specific immunization may be a possible alternative to specific immunization and may avoid many of the potential immunopathological changes induced during parasite infections. Irradiated vaccines (Dictyocaulus viviparus, schistomiasis) are mentioned marginally only

  2. Standard specification for silvered flat glass mirror

    CERN Document Server

    American Society for Testing and Materials. Philadelphia

    2008-01-01

    1.1 This specification covers the requirements for silvered flat glass mirrors of rectangular shape supplied as cut sizes, stock sheets or as lehr ends and to which no further processing (such as edgework or other fabrication) has been done. 1.2 This specification covers the quality requirements of silvered annealed monolithic clear and tinted flat glass mirrors up to 6 mm (¼ in.) thick. The mirrors are intended to be used indoors for mirror glazing, for components of decorative accessories or for similar uses. 1.3 This specification does not address safety glazing materials nor requirements for mirror applications. Consult model building codes and other applicable standards for safety glazing applications. 1.4 Mirrors covered in this specification are not intended for use in environments where high humidity or airborne corrosion promoters, or both, are consistently present (such as swimming pool areas, ocean-going vessels, chemical laboratories and other corrosive environments). 1.5 The dimensional val...

  3. Chemical cleaning specification: few tube test model

    International Nuclear Information System (INIS)

    Hampton, L.V.; Simpson, J.L.

    1979-09-01

    The specification is for the waterside chemical cleaning of the 2 1/4 Cr - 1 Mo steel steam generator tubes. It describes the reagents and conditions for post-chemical cleaning passivation of the evaporator tubes

  4. Performance evaluation and specification of trackless tack.

    Science.gov (United States)

    2016-09-01

    Several trackless tack products have come to market in Texas; however, there are currently no specifications to : ensure the products have trackless properties and adequate bond strength. The objectives of this project were to : (1) evaluate the trac...

  5. ROS signalling – Specificity is required

    DEFF Research Database (Denmark)

    Møller, Ian Max; Sweetlove, Lee J

    2011-01-01

    The production of reactive oxygen species (ROS) increases in plants under stress. ROS can damage cellular components, but they can also act in signal transduction to help the cell counteract the oxidative damage in the stressed compartment. H2O2 may induce a general stress response, but it does...... messengers and regulate source-specific genes and in this way contribute to retrograde ROS signalling during oxidative stress. (This is a new project funded by FNU) References: Møller, I.M. & Sweetlove, L.J. 2010. ROS signalling – Specificity is required. Trends Plant Sci. 15: 370-374...... not have the required specificity to selectively regulate nuclear genes required for dealing with localized stress, e.g., in chloroplasts or mitochondria. We here argue that peptides deriving from proteolytic breakdown of oxidatively damaged proteins have the requisite specificity to act as secondary ROS...

  6. Technical specifications: Health Physics Research Reactor

    International Nuclear Information System (INIS)

    1986-03-01

    These technical specifications define the key limitations that must be observed for safe operation of the Health Physics Research Reactor (HPRR) and an envelope of operation within which there is assurance that these limits will not be exceeded

  7. Iteration and Prototyping in Creating Technical Specifications.

    Science.gov (United States)

    Flynt, John P.

    1994-01-01

    Claims that the development process for computer software can be greatly aided by the writers of specifications if they employ basic iteration and prototyping techniques. Asserts that computer software configuration management practices provide ready models for iteration and prototyping. (HB)

  8. Computational network design from functional specifications

    KAUST Repository

    Peng, Chi Han; Yang, Yong Liang; Bao, Fan; Fink, Daniel; Yan, Dongming; Wonka, Peter; Mitra, Niloy J.

    2016-01-01

    of people in a workspace. Designing such networks from scratch is challenging as even local network changes can have large global effects. We investigate how to computationally create networks starting from only high-level functional specifications

  9. Double-Shell Tank (DST) Utilities Specification

    International Nuclear Information System (INIS)

    SUSIENE, W.T.

    2000-01-01

    This specification establishes the performance requirements and provides the references to the requisite codes and standards to he applied during the design of the Double-Shell Tank (DST) Utilities Subsystems that support the first phase of waste feed delivery (WFD). The DST Utilities Subsystems provide electrical power, raw/potable water, and service/instrument air to the equipment and structures used to transfer low-activity waste (LAW) and high-level waste (HLW) to designated DST staging tanks. The DST Utilities Subsystems also support the equipment and structures used to deliver blended LAW and HLW feed from these staging tanks to the River Protection Project (RPP) Privatization Contractor facility where the waste will be immobilized. This specification is intended to be the basis for new projects/installations. This specification is not intended to retroactively affect previously established project design criteria without specific direction by the program

  10. Specific energy released in power reactors

    International Nuclear Information System (INIS)

    Zaritskaya, T.S.; Kiselev, G.V.; Rudik, A.P.; Tsenter, Eh.M.

    1986-01-01

    Technique of determination are described and analysis of specific energy for different methods of critically maintance of RBMK and WWER-440 reactors are conducted. Characteristics of the optimal mode of critically maintanance are determined

  11. Finding Specification Pages from the Web

    Science.gov (United States)

    Yoshinaga, Naoki; Torisawa, Kentaro

    This paper presents a method of finding a specification page on the Web for a given object (e.g., ``Ch. d'Yquem'') and its class label (e.g., ``wine''). A specification page for an object is a Web page which gives concise attribute-value information about the object (e.g., ``county''-``Sauternes'') in well formatted structures. A simple unsupervised method using layout and symbolic decoration cues was applied to a large number of the Web pages to acquire candidate attributes for each class (e.g., ``county'' for a class ``wine''). We then filter out irrelevant words from the putative attributes through an author-aware scoring function that we called site frequency. We used the acquired attributes to select a representative specification page for a given object from the Web pages retrieved by a normal search engine. Experimental results revealed that our system greatly outperformed the normal search engine in terms of this specification retrieval.

  12. High Flux Isotope Reactor technical specifications

    International Nuclear Information System (INIS)

    1985-11-01

    This report gives technical specifications for the High Flux Isotope Reactor (HFIR) on the following: safety limits and limiting safety system settings; limiting conditions for operation; surveillance requirements; design features; and administrative controls

  13. Cdc42-mediated tubulogenesis controls cell specification

    DEFF Research Database (Denmark)

    Kesavan, Gokul; Sand, Fredrik Wolfhagen; Greiner, Thomas Uwe

    2009-01-01

    Understanding how cells polarize and coordinate tubulogenesis during organ formation is a central question in biology. Tubulogenesis often coincides with cell-lineage specification during organ development. Hence, an elementary question is whether these two processes are independently controlled......, or whether proper cell specification depends on formation of tubes. To address these fundamental questions, we have studied the functional role of Cdc42 in pancreatic tubulogenesis. We present evidence that Cdc42 is essential for tube formation, specifically for initiating microlumen formation and later...... for maintaining apical cell polarity. Finally, we show that Cdc42 controls cell specification non-cell-autonomously by providing the correct microenvironment for proper control of cell-fate choices of multipotent progenitors. For a video summary of this article, see the PaperFlick file with the Supplemental Data...

  14. Site-specific weed control technologies

    DEFF Research Database (Denmark)

    Christensen, Svend; Søgaard, Henning Tangen; Kudsk, Per

    2009-01-01

    Site-specific weed control technologies are defined as machinery or equipment embedded with technologies that detect weeds growing in a crop and, taking into account predefined factors such as economics, takes action to maximise the chances of successfully controlling them. In the article, we...... describe the basic parts of site specific weed control technologies, comprising of weed sensing systems, weed management models and precision weed control implements. A review of state-of-the-art technologies shows that several weed sensing systems and precision implements have been developed over the last...... of knowledge about the economic and environmental potential for increasing the resolution of weed control. The integration of site-specific information on weed distribution, weed species composition and density, and the effect on crop yield, is decisive for successful site-specific weed management.   Keywords...

  15. Cancer Chemotherapy Specific to Acidic Nests.

    Science.gov (United States)

    Kobayashi, Hiroshi

    2017-04-20

    The realization of cancer therapeutics specific to cancer cells with less of an effect on normal tissues is our goal. Many trials have been carried out for this purpose, but this goal is still far from being realized. It was found more than 80 years ago that solid cancer nests are acidified, but in vitro studies under acidic conditions have not been extensively studied. Recently, in vitro experiments under acidic conditions were started and anti-cancer drugs specific to acidic areas have been identified. Many genes have been reported to be expressed at a high level under acidic conditions, and such genes may be potent targets for anti-cancer drugs specific to acidic nests. In this review article, recent in vitro, in vivo, and clinical achievements in anti-cancer drugs with marked efficacy under acidic conditions are summarized, and the clinical use of anti-cancer drugs specific to acidic nests is discussed.

  16. Specification for symbol for ionizing radiation

    International Nuclear Information System (INIS)

    1974-01-01

    This Malaysia Standard specification specifies a symbol recommended for use only to signify the actual or potential presence of ionizing radiation (#betta#, α, #betta# only) and to identify objects, devices, materials or combinations of materials which emit such radiation. (author)

  17. Standard Technical Specifications, Babcock and Wilcox Plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Babcock and Wilcox (B ampersand W) plants and documents the positions of the Nuclear Regulatory Commission (NRC) based on the B ampersand W Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council. The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for developing improved plant-specific technical specifications by individual nuclear power plant licensees. This volume contains sections 3.4--3.9 which cover: Reactor coolant systems, emergency core cooling systems, containment systems, plant systems, electrical power systems, refueling operations

  18. Factors influencing women's decisions to purchase specific ...

    African Journals Online (AJOL)

    aimed at identifying the factors that influence women's decisions to purchase specific .... influence of all the factors influencing their decision to purchase a selected .... one free” promotions seemed to have had the greatest influence on this ...

  19. Disease specific therapies in leukodystrophies and leukoencephalopathies

    NARCIS (Netherlands)

    Helman, Guy; van Haren, Keith; Bonkowsky, Joshua L.; Bernard, Genevieve; Pizzino, Amy; Braverman, Nancy; Suhr, Dean; Patterson, Marc C.; Ali Fatemi, S.; Leonard, Jeff; van der Knaap, Marjo S.; Back, Stephen A.; Damiani, Stephen; Goldman, Steven A.; Takanohashi, Asako; Petryniak, Magdalena; Rowitch, David; Messing, Albee; Wrabetz, Lawrence; Schiffmann, Raphael; Eichler, Florian; Escolar, Maria L.; Vanderver, Adeline

    2015-01-01

    Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms

  20. Peptide binding specificity of the chaperone calreticulin

    DEFF Research Database (Denmark)

    Sandhu, N.; Duus, K.; Jorgensen, C.S.

    2007-01-01

    Calreticulin is a molecular chaperone with specificity for polypeptides and N-linked monoglucosylated glycans. In order to determine the specificity of polypeptide binding, the interaction of calreticulin with polypeptides was investigated using synthetic peptides of different length and composit......Calreticulin is a molecular chaperone with specificity for polypeptides and N-linked monoglucosylated glycans. In order to determine the specificity of polypeptide binding, the interaction of calreticulin with polypeptides was investigated using synthetic peptides of different length...... than 5 amino acids showed binding and a clear correlation with hydrophobicity was demonstrated for oligomers of different hydrophobic amino acids. Insertion of hydrophilic amino acids in a hydrophobic sequence diminished or abolished binding. In conclusion our results show that calreticulin has...

  1. Prostate-Specific Antigen (PSA) Test

    Science.gov (United States)

    ... Cancer Prostate Cancer Screening Research Prostate-Specific Antigen (PSA) Test On This Page What is the PSA ... parts of the body before being detected. The PSA test may give false-positive or false-negative ...

  2. Bottomland Hardwood Planting: Example Contract Specifications

    National Research Council Canada - National Science Library

    Humprey, Monica

    2002-01-01

    This technical note provides an example of contract specifications that can be used as a template by USACE biologists, engineers, or contracting officers for contracting the planting of bottomland hardwood (BLH) seedlings...

  3. Specific detection of proteins using Nanomechanical resonators

    DEFF Research Database (Denmark)

    Fischer, Lee MacKenzie; Wright, V.A.; Guthy, C.

    2008-01-01

    of probes onto their surfaces in order to enable the specificity of the detection. Such nanoresonator-based specific detection of proteins is here reported using streptavidin as target system, and immobilized biotin as probe. Nanomechanical resonators resistant to stiction were first realized from silicon...... carbonitride using a novel fabrication method. Vapor-phase deposition of mercaptopropyl trimethoxysilane was performed, and an added mass of 2.22 +/- 0.07 fg/mu m(2) was measured. This linker molecule was used to attach biotin onto the devices, enabling the specific detection of streptavidin. A mass of 3.6 fg....../mu m(2) was attributed to the added streptavidin, corresponding to one molecule per 27 nm(2). The specificity of this recognition was confirmed by exposing the devices to a solution of streptavidin that was already saturated with biotin. An additional negative control was also performed by also...

  4. Analyzing Security-Enhanced Linux Policy Specifications

    National Research Council Canada - National Science Library

    Archer, Myla

    2003-01-01

    NSA's Security-Enhanced (SE) Linux enhances Linux by providing a specification language for security policies and a Flask-like architecture with a security server for enforcing policies defined in the language...

  5. Technical specifications for the bulk shielding reactor

    International Nuclear Information System (INIS)

    1986-05-01

    This report provides information concerning the technical specifications for the Bulk Shielding Reactor. Areas covered include: safety limits and limiting safety settings; limiting conditions for operation; surveillance requirements; design features; administrative controls; and monitoring of airborne effluents. 10 refs

  6. Technical specifications for the pool critical assembly

    International Nuclear Information System (INIS)

    1978-07-01

    Technical specifications for the ORNL-PCA Reactor are presented concerning safety limits and limiting safety system settings, limiting conditions for operation, surveillance requirements, design features, and administrative controls

  7. Index to Drug-Specific Information

    Science.gov (United States)

    ... Postmarket Drug Safety Information for Patients and Providers Index to Drug-Specific Information Share Tweet Linkedin Pin ... options Linkedin Pin it Email Print Note: This Index does not include all FDA approved drugs. It ...

  8. Project NEO Specific Impulse Testing Solutions

    Science.gov (United States)

    Baffa, Bill

    2018-01-01

    The Neo test stand is currently configured to fire a horizontally mounted rocket motor with up to 6500 lbf thrust. Currently, the Neo test stand can measure flow of liquid propellant and oxidizer, pressures residing in the closed system up to the combustion chamber. The current configuration does not have the ability to provide all data needed to compute specific impulse. This presents three methods to outfit the NEO test fixture with instrumentation allowing for calculation of specific impulse.

  9. Affect and person specificity in mood regulation

    OpenAIRE

    Corby, Emma Kate

    2007-01-01

    489 university students in three countries completed questionnaires in a study investigating affect and person specificity in the use of mood regulation strategies. The major aims of the study were to (1) describe the relationship between specific affective states and the strategies utilised, (2) explore the role that individual differences variables played in the tendency to use particular strategies, and (3) measure the impact that the use of different strategies had upon subjective well-b...

  10. Production of Monoclonal Antibodies specific for Progesterone

    OpenAIRE

    YÜCEL, Fatıma

    2014-01-01

    Progesterone levels in milk and serum are indicators of pregnancy in cattle. The progesterone level reaches a peak on the 21 st and 22 nd days of pregnancy. Monoclonal antibodies specific to progesterone could be used for the immunodetection of milk and serum progesterone levels. We report here the development of hybrid cells prdoducing monoclonal antibodies specific for progesterone using hybridoma technology. Hybridoma cells secreting monoclonal antibodies against progesterone (MAM 2H1...

  11. Chemical and radiochemical specifications - PWR power plants

    International Nuclear Information System (INIS)

    Stutzmann, A.

    1997-01-01

    Published by EDF this document gives the chemical specifications of the PWR (Pressurized Water Reactor) nuclear power plants. Among the chemical parameters, some have to be respected for the safety. These parameters are listed in the STE (Technical Specifications of Exploitation). The values to respect, the analysis frequencies and the time states of possible drops are noticed in this document with the motion STE under the concerned parameter. (A.L.B.)

  12. [Psychological specificities of living donor kidney transplantation].

    Science.gov (United States)

    Papeloux-Heitzmann, Élodie

    2016-12-01

    For people with end-stage kidney disease, a transplant is the promise of a future without dialysis. Living donor kidney transplantation comprises many specificities and is distinct from cadaveric donor transplantation. Some psychological aspects explain these specificities. They may be subconscious and difficult to access, but it is essential to decipher them in order to adapt the support provided to these people. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  13. Patient-Specific Modeling in Tomorrow's Medicine

    CERN Document Server

    2012-01-01

    This book reviews the frontier of research and clinical applications of Patient Specific Modeling, and provides a state-of-the-art update as well as perspectives on future directions in this exciting field. The book is useful for medical physicists, biomedical engineers and other engineers who are interested in the science and technology aspects of Patient Specific Modeling, as well as for radiologists and other medical specialists who wish to be updated about the state of implementation.

  14. Task-Specific Training and Job Design

    OpenAIRE

    Felipe Balmaceda

    2006-01-01

    This paper provides a simple theoretical framework based on a new type of human capital introduced by Gibbons and Waldman (2004), called task-specific training, to understand job design. Mainly, in the presence of task-specific training, promotions might result ex-post in the underutilization of human capital and thus firms at the time of designing jobs should attempt to diversify this risk.

  15. Specific phobia predicts psychopathology in young women

    OpenAIRE

    Trumpf, Julia; Margraf, Jürgen; Vriends, Noortje; Meyer, Andrea Hans; Becker, Eni S.

    2010-01-01

    Background Although specific phobia is characterized by an early age at onset and by high rates of comorbidity, few studies have examined comorbid relationships prospectively. Objectives The present study investigated the association between specific phobia and the risk of a broad range of psychopathology among young women in the community. Method Data came from the Dresden Predictor Study in which 1,538 German women (18?25?years) completed a diagnostic interview at two time points. Results W...

  16. Enzyme specific activity in functionalized nanoporous supports

    International Nuclear Information System (INIS)

    Lei Chenghong; Soares, Thereza A; Shin, Yongsoon; Liu Jun; Ackerman, Eric J

    2008-01-01

    Here we reveal that enzyme specific activity can be increased substantially by changing the protein loading density (P LD ) in functionalized nanoporous supports so that the enzyme immobilization efficiency (I e , defined as the ratio of the specific activity of the immobilized enzyme to the specific activity of the free enzyme in solution) can be much higher than 100%. A net negatively charged glucose oxidase (GOX) and a net positively charged organophosphorus hydrolase (OPH) were entrapped spontaneously in NH 2 - and HOOC-functionalized mesoporous silica (300 A, FMS) respectively. The specific activity of GOX entrapped in FMS increased with decreasing P LD . With decreasing P LD , I e of GOX in FMS increased from 150%. Unlike GOX, OPH in HOOC-FMS showed increased specific activity with increasing P LD . With increasing P LD , the corresponding I e of OPH in FMS increased from 100% to>200%. A protein structure-based analysis of the protein surface charges directing the electrostatic interaction-based orientation of the protein molecules in FMS demonstrates that substrate access to GOX molecules in FMS is limited at high P LD , consequently lowering the GOX specific activity. In contrast, substrate access to OPH molecules in FMS remains open at high P LD and may promote a more favorable confinement environment that enhances the OPH activity

  17. Autobiographical memory specificity in dissociative identity disorder.

    Science.gov (United States)

    Huntjens, Rafaële J C; Wessel, Ineke; Hermans, Dirk; van Minnen, Agnes

    2014-05-01

    A lack of adequate access to autobiographical knowledge has been related to psychopathology. More specifically, patients suffering from depression or a history of trauma have been found to be characterized by overgeneral memory, in other words, they show a relative difficulty in retrieving a specific event from memory located in time and place. Previous studies of overgeneral memory have not included patients with dissociative disorders. These patients are interesting to consider, as they are hypothesized to have the ability to selectively compartmentalize information linked to negative emotions. This study examined avoidance and overgeneral memory in patients with dissociative identity disorder (DID; n = 12). The patients completed the autobiographical memory test (AMT). Their performance was compared with control groups of posttraumatic stress disorder (PTSD) patients (n = 26), healthy controls (n = 29), and DID simulators (n = 26). Specifically, we compared the performance of separate identity states in DID hypothesized to diverge in the use of avoidance as a coping strategy to deal with negative affect. No significant differences in memory specificity were found between the separate identities in DID. Irrespective of identity state, DID patients were characterized by a lack of memory specificity, which was similar to the lack of memory specificity found in PTSD patients. The converging results for DID and PTSD patients add empirical evidence for the role of overgeneral memory involved in the maintenance of posttraumatic psychopathology.

  18. Standardized Technical Specifications for Westinghouse PWRs

    International Nuclear Information System (INIS)

    1978-01-01

    This Standard Technical Specification (STS) has been structured for the broadest possible use on Westinghouse plants currently being reviewed for an Operating License. Accordingly, the document contains specifications applicable to plants (1) with either 3 or 4 loops and (2) with and without loop stop valves. In addition, four separate and discrete containment specification sections are provided for each of the following containment types: Atmospheric, Ice Condenser, Sub-Atmospheric, and Dual. Optional specifications are provided for those features and systems which may be included in individual plant designs but are not generic in their scope of application. Alternate specifications are provided in a limited number of cases to cover situations where alternate specification requirements are necessary on a generic basis because of design differences. The format of the STS addresses the categories required by 10 CFR 50 and consists of six sections covering the areas of: Definitions, Safety Limits and Limiting Safety System Settings, Limiting Conditions for Operation, Surveillance Requirements, Design Features, and Administrative Controls

  19. Age-specific reference ranges of serum prostate-specific antigen in Iranian men

    Directory of Open Access Journals (Sweden)

    Gholamreza Pourmand

    2015-08-01

    Conclusion: Findings of the present study showed that PSA levels are correlated with age. It was also revealed that the PSA age-specific reference range obtained in this study is different from other races and is specific to Iranian men. Therefore, age-specific reference ranges of PSA obtained in the present study can increase PSA test sensitivity and specificity by reducing unnecessary diagnostic procedures and early detection of prostate cancer in Iranian men.

  20. Domain Specific Language Support for Exascale

    Energy Technology Data Exchange (ETDEWEB)

    Mellor-Crummey, John [Rice Univ., Houston, TX (United States)

    2017-10-20

    A multi-institutional project known as D-TEC (short for “Domain- specific Technology for Exascale Computing”) set out to explore technologies to support the construction of Domain Specific Languages (DSLs) to map application programs to exascale architectures. DSLs employ automated code transformation to shift the burden of delivering portable performance from application programmers to compilers. Two chief properties contribute: DSLs permit expression at a high level of abstraction so that a programmer’s intent is clear to a compiler and DSL implementations encapsulate human domain-specific optimization knowledge so that a compiler can be smart enough to achieve good results on specific hardware. Domain specificity is what makes these properties possible in a programming language. If leveraging domain specificity is the key to keep exascale software tractable, a corollary is that many different DSLs will be needed to encompass the full range of exascale computing applications; moreover, a single application may well need to use several different DSLs in conjunction. As a result, developing a general toolkit for building domain-specific languages was a key goal for the D-TEC project. Different aspects of the D-TEC research portfolio were the focus of work at each of the partner institutions in the multi-institutional project. D-TEC research and development work at Rice University focused on on three principal topics: understanding how to automate the tuning of code for complex architectures, research and development of the Rosebud DSL engine, and compiler technology to support complex execution platforms. This report provides a summary of the research and development work on the D-TEC project at Rice University.

  1. Formal specification level concepts, methods, and algorithms

    CERN Document Server

    Soeken, Mathias

    2015-01-01

    This book introduces a new level of abstraction that closes the gap between the textual specification of embedded systems and the executable model at the Electronic System Level (ESL). Readers will be enabled to operate at this new, Formal Specification Level (FSL), using models which not only allow significant verification tasks in this early stage of the design flow, but also can be extracted semi-automatically from the textual specification in an interactive manner.  The authors explain how to use these verification tasks to check conceptual properties, e.g. whether requirements are in conflict, as well as dynamic behavior, in terms of execution traces. • Serves as a single-source reference to a new level of abstraction for embedded systems, known as the Formal Specification Level (FSL); • Provides a variety of use cases which can be adapted to readers’ specific design flows; • Includes a comprehensive illustration of Natural Language Processing (NLP) techniques, along with examples of how to i...

  2. Standard Technical Specifications, Babcock and Wilcox plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Babcock and Wilcox (B ampersand W) Plants and documents the positions of the Nuclear Regulatory Commission based on the B ampersand W Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. Volume 1 contains the Specifications for all chapters and sections of the improved STS. This document Volume 2, contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the improved STS. Volume 3 contains the Bases for Sections 3.4--3.10 of the improved STS

  3. Standard Technical Specifications, Combustion Engineering plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (M) for Combustion Engineering (CE) Plants and documents the positions of the Nuclear Regulatory Commission based on the CE Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. Volume 1 contains the Specifications for all chapters and sections of the improved STS. This document Volume 2 contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the improved STS. Volume 3 contains the Bases for Sections 3.4--3.9 of the improved STS

  4. Chromosome-specific DNA Repeat Probes

    Energy Technology Data Exchange (ETDEWEB)

    Baumgartner, Adolf; Weier, Jingly Fung; Weier, Heinz-Ulrich G.

    2006-03-16

    In research as well as in clinical applications, fluorescence in situ hybridization (FISH) has gained increasing popularity as a highly sensitive technique to study cytogenetic changes. Today, hundreds of commercially available DNA probes serve the basic needs of the biomedical research community. Widespread applications, however, are often limited by the lack of appropriately labeled, specific nucleic acid probes. We describe two approaches for an expeditious preparation of chromosome-specific DNAs and the subsequent probe labeling with reporter molecules of choice. The described techniques allow the preparation of highly specific DNA repeat probes suitable for enumeration of chromosomes in interphase cell nuclei or tissue sections. In addition, there is no need for chromosome enrichment by flow cytometry and sorting or molecular cloning. Our PCR-based method uses either bacterial artificial chromosomes or human genomic DNA as templates with {alpha}-satellite-specific primers. Here we demonstrate the production of fluorochrome-labeled DNA repeat probes specific for human chromosomes 17 and 18 in just a few days without the need for highly specialized equipment and without the limitation to only a few fluorochrome labels.

  5. Standard Technical Specifications, Combustion Engineering plants

    International Nuclear Information System (INIS)

    1992-09-01

    This NUREG contains improved Standard Technical Specifications (STS) for Combustion Engineering (CE) Plants and documents the positions of the Nuclear Regulatory Commission based on the CE Owners Group's proposed STS. This document is the result of extensive technical meetings and discussions among the NRC staff, the Nuclear Steam Supply System (NSSS) Owners Groups, the NSSS vendors, and the Nuclear Management and Resources Council (NUMARC). The improved STS were developed based on the criteria in the interim Commission Policy Statement on Technical Specification Improvements for Nuclear Power Reactors, dated February 6, 1987. The improved STS will be used as the basis for individual nuclear power plant licensees to develop improved plant-specific technical specifications. This report contains three volumes. Volume 1 contains the Specifications for all chapters and sections of the improved SM. Volume 2 contains the Bases for Chapters 2.0 and 3.0, and Sections 3.1--3.3 of the improved STS. This document Volume 3 contains the Bases for Sections 3.4--3.9 of the improved M

  6. The specificity and organisation of autobiographical memories.

    Science.gov (United States)

    Schulkind, Matthew D; Rahhal, Tamara A; Klein, Megan R; Lacher, Samantha R

    2012-01-01

    Previous research suggests that autobiographical memories are over-general and are organised according to life periods. One experiment assessed the specificity and organisation of autobiographical memory by manipulating two variables. The retrieval cues were either a set of three words (a theme, a time period, and an emotional valence) or a short narrative that included a specific theme, time period, and emotional valence. The instructions either encouraged the participants to respond as though they were conversing with a friend (social instructions) or did not specify a target audience (standard instructions). Narrative cues and standard instructions elicited more specific responses than word cues and social instructions, respectively. Whereas word cues elicited memories that were most likely to match the cues in terms of time period, narrative cues elicited memories that were most likely to match the cues in terms of theme. These data suggest that previous research underestimated the specificity of the autobiographical knowledge base and overestimated the importance of temporally defined life periods for organising autobiographical memory. Previous conclusions regarding the specificity and organisation of autobiographical memory may reflect the structure of autobiographical narratives and the methodologies used to collect such narratives rather than the content of autobiographical memory itself.

  7. Pharmacogenetic Analysis of Captopril Effects on Blood Pressure: Possible Role of the Ednrb (Endothelin Receptor Type B) Candidate Gene

    Czech Academy of Sciences Publication Activity Database

    Zicha, Josef; Dobešová, Zdenka; Zídek, Václav; Šilhavý, Jan; Šimáková, Miroslava; Mlejnek, Petr; Vaněčková, Ivana; Kuneš, Jaroslav; Pravenec, Michal

    2014-01-01

    Roč. 63, č. 2 (2014), s. 263-265 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LH11049 Institutional support: RVO:67985823 Keywords : captopril * blood pressure * QTL * Ednrb gene * spontaneously hypertensive rat Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.293, year: 2014

  8. Antidepressant-like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 (AGTR2) and recruitment of FYN.

    Science.gov (United States)

    Diniz, Cassiano R A F; Casarotto, Plinio C; Fred, Senem M; Biojone, Caroline; Castrén, Eero; Joca, Sâmia R L

    2018-06-01

    The renin-angiotensin system (RAS) is associated with peripheral fluid homeostasis and cardiovascular function, but recent evidence also suggests a functional role in the brain. RAS regulates physiological and behavioral parameters related to the stress response, including depressive symptoms. Apparently, RAS can modulate levels of brain-derived neurotrophic factor (BDNF) and TRKB, which are important in the neurobiology of depression and antidepressant action. However, the interaction between the BDNF/TRKB system and RAS in depression has not been investigated before. Accordingly, in the forced swimming test, we observed an antidepressant-like effect of systemic losartan but not with captopril or enalapril treatment. Moreover, infusion of losartan into the ventral hippocampus (vHC) and prelimbic prefrontal cortex (PL) mimicked the consequences of systemically injected losartan, whereas K252a (a blocker of TRK) infused into these brain areas impaired such effect. PD123319, an antagonist of AT2 receptor (AGTR2), also prevented the systemic losartan effect when infused into PL but not into vHC. Cultured cortical cells of rat embryos revealed that angiotensin II (ANG2), possibly through AGTR2, increased the surface levels of TRKB and its coupling to FYN, a SRC family kinase. Higher Agtr2 levels in cortical cells were reduced after stimulation with glutamate, and only under this condition an interaction between losartan and ANG2 was achieved. TRKB/AGTR2 heterodimers were also observed, in MG87 cells GFP-tagged AGTR2 co-immunoprecipitated with TRKB. Therefore, the antidepressant-like effect of losartan is proposed to occur through a shift of ANG2 towards AGTR2, followed by coupling of TRK/FYN and putative TRKB transactivation. Thus, the blockade of AGTR1 has therapeutic potential as a novel antidepressant therapy. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  9. Cannabinoid Receptor Type 1 Expression in the Developing Avian Retina: Morphological and Functional Correlation With the Dopaminergic System

    Directory of Open Access Journals (Sweden)

    Luzia da Silva Sampaio

    2018-03-01

    Full Text Available The avian retina has been used as a model to study signaling by different neuro- and gliotransmitters. It is unclear how dopaminergic and cannabinoid systems are related in the retina. Here we studied the expression of type 1 and 2 cannabinoid receptors (CB1 and CB2, as well as monoacylglycerol lipase (MAGL, the enzyme that degrades 2-arachidonoylglycerol (2-AG, during retina development. Our data show that CB1 receptor is highly expressed from embryonic day 5 (E5 until post hatched day 7 (PE7, decreasing its levels throughout development. CB1 is densely found in the ganglion cell layer (GCL and inner plexiform layer (IPL. CB2 receptor was also found from E5 until PE7 with a decrease in its contents from E9 afterwards. CB2 was mainly present in the lamination of the IPL at PE7. MAGL is expressed in all retinal layers, mainly in the IPL and OPL from E9 to PE7 retina. CB1 and CB2 were found both in neurons and glia cells, but MAGL was only expressed in Müller glia. Older retinas (PE7 show CB1 positive cells mainly in the INL and co-expression of CB1 and tyrosine hydroxylase (TH are shown in a few cells when both systems are mature. CB1 co-localized with TH and was heavily associated to D1 receptor labeling in primary cell cultures. Finally, cyclic AMP (cAMP was activated by the selective D1 agonist SKF38393, and inhibited when cultures were treated with WIN55, 212–2 (WIN in a CB1 dependent manner. The results suggest a correlation between the endocannabinoid and dopaminergic systems (DSs during the avian retina development. Activation of CB1 limits cAMP accumulation via D1 receptor activation and may influence embryological parameters during avian retina differentiation.

  10. Lipid rafts are required for signal transduction by angiotensin II receptor type 1 in neonatal glomerular mesangial cells

    Energy Technology Data Exchange (ETDEWEB)

    Adebiyi, Adebowale, E-mail: aadebiyi@uthsc.edu; Soni, Hitesh; John, Theresa A.; Yang, Fen

    2014-05-15

    Angiotensin II (ANG-II) receptors (AGTRs) contribute to renal physiology and pathophysiology, but the underlying mechanisms that regulate AGTR function in glomerular mesangium are poorly understood. Here, we show that AGTR1 is the functional AGTR subtype expressed in neonatal pig glomerular mesangial cells (GMCs). Cyclodextrin (CDX)-mediated cholesterol depletion attenuated cell surface AGTR1 protein expression and ANG-II-induced intracellular Ca{sup 2+} ([Ca{sup 2+}]{sub i}) elevation in the cells. The COOH-terminus of porcine AGTR1 contains a caveolin (CAV)-binding motif. However, neonatal GMCs express CAV-1, but not CAV-2 and CAV-3. Colocalization and in situ proximity ligation assay detected an association between endogenous AGTR1 and CAV-1 in the cells. A synthetic peptide corresponding to the CAV-1 scaffolding domain (CSD) sequence also reduced ANG-II-induced [Ca{sup 2+}]{sub i} elevation in the cells. Real-time imaging of cell growth revealed that ANG-II stimulates neonatal GMC proliferation. ANG-II-induced GMC growth was attenuated by EMD 66684, an AGTR1 antagonist; BAPTA, a [Ca{sup 2+}]{sub i} chelator; KN-93, a Ca{sup 2+}/calmodulin-dependent protein kinase II inhibitor; CDX; and a CSD peptide, but not PD 123319, a selective AGTR2 antagonist. Collectively, our data demonstrate [Ca{sup 2+}]{sub i}-dependent proliferative effect of ANG-II and highlight a critical role for lipid raft microdomains in AGTR1-mediated signal transduction in neonatal GMCs. - Highlights: • AGTR1 is the functional AGTR subtype expressed in neonatal mesangial cells. • Endogenous AGTR1 associates with CAV-1 in neonatal mesangial cells. • Lipid raft disruption attenuates cell surface AGTR1 protein expression. • Lipid raft disruption reduces ANG-II-induced [Ca{sup 2+}]{sub i} elevation in neonatal mesangial cells. • Lipid raft disruption inhibits ANG-II-induced neonatal mesangial cell growth.

  11. Progestins oppose the effects of estradiol on the endothelin-1 receptor type B in coronary arteries from ovariectomized hyperlipidemic rabbits

    DEFF Research Database (Denmark)

    Pedersen, Susan H; Nielsen, Lars B; Mortensen, Alicja

    2008-01-01

    OBJECTIVE: Progestins may be associated with the adverse cardiovascular outcomes observed with estrogen plus progestogen therapy, but the mechanism is not resolved. In this study we examined the effect of 17beta-estradiol (E2) alone and in combination with two progestins on the endothelin-1 (ET-1...

  12. The Role of Non-specific and Specific Immune Systems in Poultry against Newcastle Disease

    Directory of Open Access Journals (Sweden)

    Dyah Ayu Hewajuli

    2015-09-01

    Full Text Available Newcastle disease (ND is caused by avian paramyxovirus-1 which belong to Avulavirus genus and Paramyxoviridae family. The birds have abnormalities in humoral (bursa fabricius and cellular (thymus and spleen lymphoid organs. Lesions decrease the immune system. Immune system consists of non-specific and specific immune systems. The main components of non-specific immunity are physical and chemical barrier (feather and skin or mucosa, phagocytic cells (macrophages and natural killer, protein complement and the mediator of inflammation and cytokines. Interferons (IFNs belong to a group of cytokines that play a major role in the nonspecific or innate (natural immunity. The virulent ND virus encodes protein of V gene can be suppressed IFN type I. This leads to non-specific immune system fail to respond to the virulent strains resulting in severe pathogenicity. The defense mechanism of the host is replaced by specific immunity (adaptive immunity when natural immunity fails to overcome the infection. The specific immune system consists of humoral mediated immunity (HMI and cell-mediated immunity (CMI. The cells of immune system that react specifically with the antigen are B lymphocytes producing the antibodies, T lymphocytes that regulate the synthesis of antibodies and T cells as effector or the direct cytotoxic cells. Both non-specific and specific immunities are complementary against the invasion of ND virus in the birds. The objective of this article is to discuss the role of non specific and specific immune system in ND.

  13. Forum on specification and Design Languages

    CERN Document Server

    Maehne, Torsten

    2015-01-01

    This book brings together a selection of the best papers from the sixteenth edition of the Forum on specification and Design Languages Conference (FDL), which was held in September 2013 in Paris, France. FDL is a well-established international forum devoted to dissemination of research results, practical experiences and new ideas in the application of specification, design and verification languages to the design, modeling and verification of integrated circuits, complex hardware/software embedded systems, and mixed-technology systems. • Covers applications of formal methods for specification, verification and debug; • Includes embedded analog and mixed-signal system design; • Enables model-driven engineering for embedded systems design and development.

  14. Safety of MR liver specific contrast media

    Energy Technology Data Exchange (ETDEWEB)

    Bellin, Marie-France [Hopital Paul Brousse, Universite Paris 11, Villejuif Cedex (France); Webb, Judith A.W. [St. Bartholomew' s Hospital, Department of Diagnostic Imaging, London (United Kingdom); Molen, Aart J. van der [Leiden University Medical Centre, Department of Radiology, Leiden (Netherlands); Thomsen, Henrik S. [Copenhagen University Hospital at Herlev, Department of Diagnostic Radiology 54E2, Herlev (Denmark); Morcos, Sameh K. [Northern General Hospital, Sheffield Teaching Hospitals NHS Trust, Department of Diagnostic Imaging, Sheffield (United Kingdom)

    2005-08-01

    Over the past few years a number of magnetic resonance (MR) liver specific contrast agents have been introduced. In this report the safety issues of these agents are addressed. A literature search was carried out. Based on the available information, simple guidelines on the safety issue of liver specific contrast agents have been produced by the Contrast Media Safety Committee of the European Society of Urogenital Radiology. The report and guidelines were discussed at the 11th European Symposium on Urogenital Radiology in Santiago de Compostela. Liver specific contrast agents appear in general to be safe and well tolerated. However, the incidence of adverse reactions with iron oxides and the intravenous manganese based agent seems to be slightly higher than with gadolinium based agents. However, no safety information from comparative clinical trials has been published. Guidelines on the safety aspects are presented. (orig.)

  15. Safety of MR liver specific contrast media

    International Nuclear Information System (INIS)

    Bellin, Marie-France; Webb, Judith A.W.; Molen, Aart J. van der; Thomsen, Henrik S.; Morcos, Sameh K.

    2005-01-01

    Over the past few years a number of magnetic resonance (MR) liver specific contrast agents have been introduced. In this report the safety issues of these agents are addressed. A literature search was carried out. Based on the available information, simple guidelines on the safety issue of liver specific contrast agents have been produced by the Contrast Media Safety Committee of the European Society of Urogenital Radiology. The report and guidelines were discussed at the 11th European Symposium on Urogenital Radiology in Santiago de Compostela. Liver specific contrast agents appear in general to be safe and well tolerated. However, the incidence of adverse reactions with iron oxides and the intravenous manganese based agent seems to be slightly higher than with gadolinium based agents. However, no safety information from comparative clinical trials has been published. Guidelines on the safety aspects are presented. (orig.)

  16. Procedures for evaluating technical specifications (PETS)

    International Nuclear Information System (INIS)

    Samanta, P.K.; Boccio, J.L.; Vesely, W.E.

    1987-01-01

    In this paper, aspects of technical specifications relating to Generic Issues B-56 and B-61 are discussed from a risk-standpoint. These primarily deal with the risk issues associated with (1) adaptive diesel test requirements/surveillance test intervals, and (2) the effectiveness of cumulative outage time requirements for controlling downtime risk. Risk and reliability approaches are presented which (1) allow risk-acceptable test intervals to be determined for any diesel and (2) show the potential risk-control capability of prescribed allowed cumulative outage times. This work was conducted through NRC's Procedures for Evaluating Technical Specifications (PETS) Program. The overall objective of this program is to develop and demonstrate methodologies that utilize risk insights and reliability techniques for evaluating the scope, detailed requirements, and safety impact of plant technical specifications

  17. Technical specifications requirements: Automated reasoning applications

    International Nuclear Information System (INIS)

    Lidsky, L.M.; Dobrzeniecki, A.B.

    1990-03-01

    Several software systems were developed and tested to determine what advantages could be gained from explicitly translating complicated regulatory requirements into computerized relationships. The Technical Specifications for US nuclear power plants were chosen as the test-bed application domain, and two analysis systems were developed to monitor plant compliance with operational limits, and track and schedule equipment test and maintenance activities mandated by Technical Specifications. Choosing PROLOG as the computer language to represent these regulatory requirements resulted in a natural match between the semantic structure of the written specifications and the corollary coded rules. Additional research results affirmed the utility of declarative programming styles, explicit management of problem complexity, and attention to the robustness and flexibility of the overall software systems. 5 refs., 2 figs

  18. Specifications for human factors guiding documents

    Energy Technology Data Exchange (ETDEWEB)

    Rhodes, W; Szlapetis, I; MacGregor, C [Rhodes and Associates Inc., Toronto, ON (Canada)

    1995-04-01

    This report specifies the content, function and appearance of three proposed human factors guiding documents to be used by the Atomic Energy Control board and its licensees. These three guiding documents, to be developed at a later date, are: (a) Human Factors Process Guide; (b) Human Factors Activities Guide; and (c) Human Factors Design Integration Guide. The specifications were developed by examining the best documents as identified in a previous contract with the AECB (Review of Human Factors Guidelines and Methods by W. Rhodes, I. Szlapetis et al. 1992), and a brief literature review. The best features and content were selected from existing documents and used to develop specifications for the guiding documents. The developer of the actual guides would use these specifications to produce comprehensive and consolidated documents at a later date. (author). 128 ref., 7 figs.

  19. Specifications for human factors guiding documents

    International Nuclear Information System (INIS)

    Rhodes, W.; Szlapetis, I.; MacGregor, C.

    1995-04-01

    This report specifies the content, function and appearance of three proposed human factors guiding documents to be used by the Atomic Energy Control board and its licensees. These three guiding documents, to be developed at a later date, are: (a) Human Factors Process Guide; (b) Human Factors Activities Guide; and (c) Human Factors Design Integration Guide. The specifications were developed by examining the best documents as identified in a previous contract with the AECB (Review of Human Factors Guidelines and Methods by W. Rhodes, I. Szlapetis et al. 1992), and a brief literature review. The best features and content were selected from existing documents and used to develop specifications for the guiding documents. The developer of the actual guides would use these specifications to produce comprehensive and consolidated documents at a later date. (author). 128 ref., 7 figs

  20. Property Specification Patterns for intelligence building software

    Science.gov (United States)

    Chun, Seungsu

    2018-03-01

    In this paper, through the property specification pattern research for Modal MU(μ) logical aspects present a single framework based on the pattern of intelligence building software. In this study, broken down by state property specification pattern classification of Dwyer (S) and action (A) and was subdivided into it again strong (A) and weaknesses (E). Through these means based on a hierarchical pattern classification of the property specification pattern analysis of logical aspects Mu(μ) was applied to the pattern classification of the examples used in the actual model checker. As a result, not only can a more accurate classification than the existing classification systems were easy to create and understand the attributes specified.

  1. Emergency Medicine Gender-specific Education.

    Science.gov (United States)

    Ashurst, John V; McGregor, Alyson J; Safdar, Basmah; Weaver, Kevin R; Quinn, Shawn M; Rosenau, Alex M; Goyke, Terrence E; Roth, Kevin R; Greenberg, Marna R

    2014-12-01

    The 2014 Academic Emergency Medicine consensus conference has taken the first step in identifying gender-specific care as an area of importance to both emergency medicine (EM) and research. To improve patient care, we need to address educational gaps in this area concurrent with research gaps. In this article, the authors highlight the need for sex- and gender-specific education in EM and propose guidelines for medical student, resident, and faculty education. Specific examples of incorporating this content into grand rounds, simulation, bedside teaching, and journal club sessions are reviewed. Future challenges and strategies to fill the gaps in the current education model are also described. © 2014 by the Society for Academic Emergency Medicine.

  2. Computational network design from functional specifications

    KAUST Repository

    Peng, Chi Han

    2016-07-11

    Connectivity and layout of underlying networks largely determine agent behavior and usage in many environments. For example, transportation networks determine the flow of traffic in a neighborhood, whereas building floorplans determine the flow of people in a workspace. Designing such networks from scratch is challenging as even local network changes can have large global effects. We investigate how to computationally create networks starting from only high-level functional specifications. Such specifications can be in the form of network density, travel time versus network length, traffic type, destination location, etc. We propose an integer programming-based approach that guarantees that the resultant networks are valid by fulfilling all the specified hard constraints and that they score favorably in terms of the objective function. We evaluate our algorithm in two different design settings, street layout and floorplans to demonstrate that diverse networks can emerge purely from high-level functional specifications.

  3. Transactions in domain-specific information systems

    Science.gov (United States)

    Zacek, Jaroslav

    2017-07-01

    Substantial number of the current information system (IS) implementations is based on transaction approach. In addition, most of the implementations are domain-specific (e.g. accounting IS, resource planning IS). Therefore, we have to have a generic transaction model to build and verify domain-specific IS. The paper proposes a new transaction model for domain-specific ontologies. This model is based on value oriented business process modelling technique. The transaction model is formalized by the Petri Net theory. First part of the paper presents common business processes and analyses related to business process modeling. Second part defines the transactional model delimited by REA enterprise ontology paradigm and introduces states of the generic transaction model. The generic model proposal is defined and visualized by the Petri Net modelling tool. Third part shows application of the generic transaction model. Last part of the paper concludes results and discusses a practical usability of the generic transaction model.

  4. Spent nuclear fuel project product specification

    International Nuclear Information System (INIS)

    Pajunen, A.L.

    1998-01-01

    Product specifications are limits and controls established for each significant parameter that potentially affects safety and/or quality of the Spent Nuclear Fuel (SNF) packaged for transport to dry storage. The product specifications in this document cover the spent fuel packaged in MultiCanister Overpacks (MCOs) to be transported throughout the SNF Project. The SNF includes N Reactor fuel and single-pass reactor fuel. The FRS removes the SNF from the storage canisters, cleans it, and places it into baskets. The MCO loading system places the baskets into MCO/Cask assembly packages. These packages are then transferred to the Cold Vacuum Drying (CVD) Facility. After drying at the CVD Facility, the MCO cask packages are transferred to the Canister Storage Building (CSB), where the MCOs are removed from the casks, staged, inspected, sealed (by welding), and stored until a suitable permanent disposal option is implemented. The key criteria necessary to achieve these goals are documented in this specification

  5. Naturally occurring, tumor-specific, therapeutic proteins.

    Science.gov (United States)

    Argiris, Konstantinos; Panethymitaki, Chrysoula; Tavassoli, Mahvash

    2011-05-01

    The emerging approach to cancer treatment known as targeted therapies offers hope in improving the treatment of therapy-resistant cancers. Recent understanding of the molecular pathogenesis of cancer has led to the development of targeted novel drugs such as monoclonal antibodies, small molecule inhibitors, mimetics, antisense and small interference RNA-based strategies, among others. These compounds act on specific targets that are believed to contribute to the development and progression of cancers and resistance of tumors to conventional therapies. Delivered individually or combined with chemo- and/or radiotherapy, such novel drugs have produced significant responses in certain types of cancer. Among the most successful novel compounds are those which target tyrosine kinases (imatinib, trastuzumab, sinutinib, cetuximab). However, these compounds can cause severe side-effects as they inhibit pathways such as epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor, which are also important for normal functions in non-transformed cells. Recently, a number of proteins have been identified which show a remarkable tumor-specific cytotoxic activity. This toxicity is independent of tumor type or specific genetic changes such as p53, pRB or EGFR aberrations. These tumor-specific killer proteins are either derived from common human and animal viruses such as E1A, E4ORF4 and VP3 (apoptin) or of cellular origin, such as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and MDA-7 (melanoma differentiation associated-7). This review aims to present a current overview of a selection of these proteins with preferential toxicity among cancer cells and will provide an insight into the possible mechanism of action, tumor specificity and their potential as novel tumor-specific cancer therapeutics.

  6. Engineered waste-package-system design specification

    International Nuclear Information System (INIS)

    1983-05-01

    This report documents the waste package performance requirements and geologic and waste form data bases used in developing the conceptual designs for waste packages for salt, tuff, and basalt geologies. The data base reflects the latest geotechnical information on the geologic media of interest. The parameters or characteristics specified primarily cover spent fuel, defense high-level waste, and commercial high-level waste forms. The specification documents the direction taken during the conceptual design activity. A separate design specification will be developed prior to the start of the preliminary design activity

  7. Automated effect-specific mammographic pattern measures

    DEFF Research Database (Denmark)

    Raundahl, Jakob; Loog, Marco; Pettersen, Paola

    2008-01-01

    We investigate the possibility to develop methodologies for assessing effect specific structural changes of the breast tissue using a general statistical machine learning framework. We present an approach of obtaining objective mammographic pattern measures quantifying a specific biological effect......, such as hormone replacement therapy (HRT). We compare results using this approach to using standard density measures. We show that the proposed method can quantify both age related effects and effects caused by HRT. Age effects are significantly detected by our method where standard methodologies fail...

  8. System specifications for the NDS EXFOR System

    International Nuclear Information System (INIS)

    Attree, P.M.; Smith, P.M.

    1979-07-01

    EXFOR is the agreed exchange format for the magnetic-tape exchange of nuclear reaction data between national and international nuclear data centres for the benefit of nuclear data users in all countries. The NDS EXFOR System is a computerized system for the storage and retrieval of EXFOR information compiled or received by the IAEA. This document is an internal manual for the system specifications of the NDS EXFOR System. It includes flow charts, system and program summaries, input and output specifications and file and record descriptions. The manual is updated from time to time when system modifications are made

  9. Technical specifications for PWR secondary water chemistry

    International Nuclear Information System (INIS)

    Weeks, J.R.; van Rooyen, D.

    1977-08-01

    The bases for establishing Technical Specifications for PWR secondary water chemistry are reviewed. Whereas extremely stringent control of secondary water needs to be maintained to prevent denting in some units, sound bases for establishing limits that will prevent stress corrosion, wastage, and denting do not exist at the present time. This area is being examined very thoroughly by industry-sponsored research programs. Based on the evidence available to date, short term control limits are suggested; establishment of these or other limits as Technical Specifications is not recommended until the results of the research programs have been obtained and evaluated

  10. Asian product specifications to tighten by 2000

    International Nuclear Information System (INIS)

    Anon.

    1995-01-01

    The Asia/Pacific region is characterized by much diversity in environmental standards for petroleum products. Specifications in Japan, for example, are quite stringent, while, in India, kerosene--even that used for cooking or lighting--may contain as much as 0.2% sulfur. Widhyawan Prawiraatmadja and Fereidun Fesharaki of the East-West Center in Honolulu outlined regional product quality in a report titled, ''Trends in Petroleum Product Specifications in the Asia-Pacific Region: A Supply/Demand Analysis and Government Policy Responses.'' This paper summarizes the findings of this report with emphasis on gasoline, diesel fuels, and fuel oil demand, fuel consumption, and quality

  11. Site-Specific Infrared Probes of Proteins

    Science.gov (United States)

    Ma, Jianqiang; Pazos, Ileana M.; Zhang, Wenkai; Culik, Robert M.; Gai, Feng

    2015-01-01

    Infrared spectroscopy has played an instrumental role in studying a wide variety of biological questions. However, in many cases it is impossible or difficult to rely on the intrinsic vibrational modes of biological molecules of interest, such as proteins, to reveal structural and/or environmental information in a site-specific manner. To overcome this limitation, many recent efforts have been dedicated to the development and application of various extrinsic vibrational probes that can be incorporated into biological molecules and used to site-specifically interrogate their structural and/or environmental properties. In this Review, we highlight some recent advancements of this rapidly growing research area. PMID:25580624

  12. Clojure for domain-specific languages

    CERN Document Server

    Kelker, Ryan D

    2013-01-01

    An example-oriented approach to develop custom domain-specific languages.If you've already developed a few Clojure applications and wish to expand your knowledge on Clojure or domain-specific languages in general, then this book is for you. If you're an absolute Clojure beginner, then you may only find the detailed examples of the core Clojure components of value. If you've developed DSLs in other languages, this Lisp and Java-based book might surprise you with the power of Clojure.

  13. Photomask specifications for high energy physics detectors

    CERN Document Server

    Pindo, M

    2002-01-01

    Planar technologies used for radiation detector fabrication imply an extensive use of photomasks whose characteristics are critical in determining final detector performance. Compatibly with their manufacturing process, photomasks must satisfy the application-specific requirements dictated both by wafer manufacturers and detector final users. The design and realization of microstrip and pixel detectors, widely used in high energy physics experiments, ask for intensive scientific effort, advanced technology and important economical investments. Photomask specification definition is one of the fundamental steps to optimize detector fabrication processes and fulfill experimental requirements at the most appropriate cost.

  14. System specifications for the NDS EXFOR System

    Energy Technology Data Exchange (ETDEWEB)

    Attree, P M; Smith, P M

    1982-06-01

    EXFOR is the agreed exchange format for the magnetic-tape exchange of nuclear reaction data between national and international nuclear data centers for the benefit of nuclear data users in all countries. The NDS EXFOR System is a computerized system for the storage and retrieval of EXFOR information compiled or received of the IAEA. This document is an internal manual for the system specifications of the NDS EXFOR System. It includes flow charts, system and program summaries, input and output specifications and file and record descriptions. The manual is updated from time to time when system modifications are made; the first version was issued in July 1979. (author)

  15. Immunotherapy with GD2 specific monoclonal antibodies

    International Nuclear Information System (INIS)

    Cheung, N.K.V.; Medof, E.M.; Munn, D.

    1988-01-01

    Targeted immunotherapy focuses anti-tumor activity of antibodies and effector cells, which are actively developed by the host or adoptively transferred, onto tumor cells and into tumor sites. Such tumor selective therapy can be more specific and efficient. The value of such an approach is evident in the classical interaction of antibodies. This paper reports that the ganglioside G D2 is an ideal antigen for specific tumor targeting because of its relative lack of heterogeneity among human neuroblastoma, its high density on tumor cells, its lack of antigen modulation upon binding to antibody, and its restricted distribution in normal tissues

  16. A Class-Specific Optimizing Compiler

    Directory of Open Access Journals (Sweden)

    Michael D. Sharp

    1993-01-01

    Full Text Available Class-specific optimizations are compiler optimizations specified by the class implementor to the compiler. They allow the compiler to take advantage of the semantics of the particular class so as to produce better code. Optimizations of interest include the strength reduction of class:: array address calculations, elimination of large temporaries, and the placement of asynchronous send/recv calls so as to achieve computation/communication overlap. We will outline our progress towards the implementation of a C++ compiler capable of incorporating class-specific optimizations.

  17. DOE site-specific threat assessment

    International Nuclear Information System (INIS)

    West, D.J.; Al-Ayat, R.A.; Judd, B.R.

    1985-01-01

    A facility manager faced with the challenges of protecting a nuclear facility against potential threats must consider the likelihood and consequences of such threats, know the capabilities of the facility safeguards and security systems, and make informed decisions about the cost-effectivness of safeguards and security upgrades. To help meet these challenges, the San Francisco Operations Office of the Department of Energy, in conjunction with the Lawrence Livermore Laboratory, has developed a site-specific threat assessment approach and a quantitative model to improve the quality and consistency of site-specific threat assessment and resultant security upgrade decisions at sensitive Department of Energy facilities. 5 figs

  18. Software engineering with application-specific languages

    Science.gov (United States)

    Campbell, David J.; Barker, Linda; Mitchell, Deborah; Pollack, Robert H.

    1993-01-01

    Application-Specific Languages (ASL's) are small, special-purpose languages that are targeted to solve a specific class of problems. Using ASL's on software development projects can provide considerable cost savings, reduce risk, and enhance quality and reliability. ASL's provide a platform for reuse within a project or across many projects and enable less-experienced programmers to tap into the expertise of application-area experts. ASL's have been used on several software development projects for the Space Shuttle Program. On these projects, the use of ASL's resulted in considerable cost savings over conventional development techniques. Two of these projects are described.

  19. System specifications for the NDS Dictionary System

    International Nuclear Information System (INIS)

    Attree, P.M.; Smith, P.M.

    1979-09-01

    The NDS Dictionary System is a computerized system for maintaining and distributing the EXFOR dictionaries and for preparing internal versions of these dictionaries for use in the NDS EXFOR System and other NDS systems. This document is an internal manual for the system specifications of the NDS Dictionary System. It includes flow charts, system and program summaries, input and output specifications and file and record descriptions. This manual is updated from time to time when system modifications are made; this is the version of January 1979

  20. [Development of domain specific search engines].

    Science.gov (United States)

    Takai, T; Tokunaga, M; Maeda, K; Kaminuma, T

    2000-01-01

    As cyber space exploding in a pace that nobody has ever imagined, it becomes very important to search cyber space efficiently and effectively. One solution to this problem is search engines. Already a lot of commercial search engines have been put on the market. However these search engines respond with such cumbersome results that domain specific experts can not tolerate. Using a dedicate hardware and a commercial software called OpenText, we have tried to develop several domain specific search engines. These engines are for our institute's Web contents, drugs, chemical safety, endocrine disruptors, and emergent response for chemical hazard. These engines have been on our Web site for testing.

  1. Specifications from a biotechnology industry perspective.

    Science.gov (United States)

    Garnick, R L

    1997-01-01

    The emergence of new analytical technology and the production of pharmaceuticals for a global market in a cost-effective manner necessitate the establishment of worldwide specifications that are appropriate for the product and the manufacturing process. This requires a thorough knowledge of the protein and control of the systems that produce it as well as an understanding of the accuracy and precision of the assays used for testing. Harmonization of specifications among the worldwide regulatory authorities is critical for the future development of new pharmaceuticals. A continuing dialogue between industry and regulators to achieve this goal needs to be encouraged and supported.

  2. From UML Specification into FPGA Implementation

    Directory of Open Access Journals (Sweden)

    Grzegorz Bazydlo

    2014-01-01

    Full Text Available In the paper a method of using the Unified Modeling Language for specification of digital systems, especially logic controllers, is presented. The proposed method is based mainly on the UML state machine diagrams and uses Hierarchical Concurrent Finite State Machines (HCFSMs as a temporary model. The paper shows a way to transform the UML diagrams, expressed in XML language, to the form that is acceptable by reconfigurable FPGAs (Field Programmable Gate Arrays. The UML specification is used to generate an effective program in Hardware Description Languages (HDLs, especially Verilog.

  3. Domain Specific Language Support for Exascale

    Energy Technology Data Exchange (ETDEWEB)

    Sadayappan, Ponnuswamy [The Ohio State Univ., Columbus, OH (United States)

    2017-02-24

    Domain-Specific Languages (DSLs) offer an attractive path to Exascale software since they provide expressive power through appropriate abstractions and enable domain-specific optimizations. But the advantages of a DSL compete with the difficulties of implementing a DSL, even for a narrowly defined domain. The DTEC project addresses how a variety of DSLs can be easily implemented to leverage existing compiler analysis and transformation capabilities within the ROSE open source compiler as part of a research program focusing on Exascale challenges. The OSU contributions to the DTEC project are in the area of code generation from high-level DSL descriptions, as well as verification of the automatically-generated code.

  4. NEEDS ANALYSIS IN ENGLISH FOR SPECIFIC PURPOSES

    Directory of Open Access Journals (Sweden)

    SIMION MINODORA OTILIA

    2015-03-01

    Full Text Available Needs analysis is considered to be the cornerstone of English for Specific Purposes(ESP. The concept of Needs analysis has been different along the decades. At the initial stages of ESP( the 1960s and early 1970s, needs analysis consisted in assessing the communicative needs of the learners and the techniques of achieving specific teaching objectives. Nowadays, the tasks of needs analysis is much more complex: it aims at collecting information about the learners and at defining the target situation and environment of studying ESP.

  5. Spent Nuclear Fuel (SNF) Project Product Specification

    International Nuclear Information System (INIS)

    PAJUNEN, A.L.

    2000-01-01

    The process for removal of Spent Nuclear Fuel (SNF) from the K Basins has been divided into major sub-systems. The Fuel Retrieval System (FRS) removes fuel from the existing storage canisters, cleans it, and places it into baskets. The multi-canister overpack (MCO) loading system places the baskets into an MCO that has been pre-loaded in a cask. The cask, containing a loaded MCO, is then transferred to the Cold Vacuum Drying (CVD) Facility. After drying at the CVD Facility, the cask, and MCO, are transferred to the Canister Storage Building (CSB), where the MCO is removed from the cask, staged, inspected, sealed (by welding), and stored until a suitable permanent disposal option is implemented. The purpose of this document is to specify the process related characteristics of an MCO at the interface between major process systems. The characteristics are derived from the primary technical documents that form the basis for safety analysis and design calculations. This document translates the calculation assumptions into implementation requirements and describes the method of verifying that the requirement is achieved. These requirements are used to define validation test requirements and describe requirements that influence multiple sub-project safety analysis reports. This product specification establishes limits and controls for each significant process parameter at interfaces between major sub-systems that potentially affect the overall safety and/or quality of the SNF packaged for processing, transport, and interim dry storage. The product specifications in this document cover the SNF packaged in MCOs to be transported throughout the SNF Project. The description of the product specifications are organized in the document as follows: Section 2.0--Summary listing of product specifications at each major sub-system interface. Section 3.0--Summary description providing guidance as to how specifications are complied with by equipment design or processing within a major

  6. Spent Nuclear Fuel (SNF) Project Product Specification

    Energy Technology Data Exchange (ETDEWEB)

    PAJUNEN, A.L.

    2000-12-07

    The process for removal of Spent Nuclear Fuel (SNF) from the K Basins has been divided into major sub-systems. The Fuel Retrieval System (FRS) removes fuel from the existing storage canisters, cleans it, and places it into baskets. The multi-canister overpack (MCO) loading system places the baskets into an MCO that has been pre-loaded in a cask. The cask, containing a loaded MCO, is then transferred to the Cold Vacuum Drying (CVD) Facility. After drying at the CVD Facility, the cask, and MCO, are transferred to the Canister Storage Building (CSB), where the MCO is removed from the cask, staged, inspected, sealed (by welding), and stored until a suitable permanent disposal option is implemented. The purpose of this document is to specify the process related characteristics of an MCO at the interface between major process systems. The characteristics are derived from the primary technical documents that form the basis for safety analysis and design calculations. This document translates the calculation assumptions into implementation requirements and describes the method of verifying that the requirement is achieved. These requirements are used to define validation test requirements and describe requirements that influence multiple sub-project safety analysis reports. This product specification establishes limits and controls for each significant process parameter at interfaces between major sub-systems that potentially affect the overall safety and/or quality of the SNF packaged for processing, transport, and interim dry storage. The product specifications in this document cover the SNF packaged in MCOs to be transported throughout the SNF Project. The description of the product specifications are organized in the document as follows: Section 2.0--Summary listing of product specifications at each major sub-system interface. Section 3.0--Summary description providing guidance as to how specifications are complied with by equipment design or processing within a major

  7. Ultrahigh Specific Impulse Nuclear Thermal Propulsion

    Energy Technology Data Exchange (ETDEWEB)

    Anne Charmeau; Brandon Cunningham; Samim Anghaie

    2009-02-09

    Research on nuclear thermal propulsion systems (NTP) have been in forefront of the space nuclear power and propulsion due to their design simplicity and their promise for providing very high thrust at reasonably high specific impulse. During NERVA-ROVER program in late 1950's till early 1970's, the United States developed and ground tested about 18 NTP systems without ever deploying them into space. The NERVA-ROVER program included development and testing of NTP systems with very high thrust (~250,000 lbf) and relatively high specific impulse (~850 s). High thrust to weight ratio in NTP systems is an indicator of high acceleration that could be achieved with these systems. The specific impulse in the lowest mass propellant, hydrogen, is a function of square root of absolute temperature in the NTP thrust chamber. Therefor optimizing design performance of NTP systems would require achieving the highest possible hydrogen temperature at reasonably high thrust to weight ratio. High hydrogen exit temperature produces high specific impulse that is a diret measure of propellant usage efficiency.

  8. Language specific bootstraps for UG categories

    NARCIS (Netherlands)

    van Kampen, N.J.

    2005-01-01

    This paper argues that the universal categories N/V are not applied to content words before the grammatical markings for reference D(eterminers) and predication I(nflection) have been acquired (van Kampen, 1997, contra Pinker, 1984). Child grammar starts as proto-grammar with language-specific

  9. DETERMINATION OF THE SPECIFIC GROWTH RATE ON ...

    African Journals Online (AJOL)

    Sewage generation is one of the dense problems Nigerians encounter on daily bases, mostly at the urbanized area where factories and industries are located. This paper is aimed at determining the specific growth rate “K” of biological activities on cassava wastewater during degradation using Michaelis-Menten Equation.

  10. Side-Specific Reward Memories in Honeybees

    Science.gov (United States)

    Gil, Mariana; Menzel, Randolf; De Marco, Rodrigo J.

    2009-01-01

    We report a hitherto unknown form of side-specific learning in honeybees. We trained bees individually by coupling gustatory and mechanical stimulation of each antenna with either increasing or decreasing volumes of sucrose solution offered to the animal's proboscis along successive learning trials. Next, we examined their proboscis extension…

  11. Autobiographical Memory Specificity in Dissociative Identity Disorder

    NARCIS (Netherlands)

    Huntjens, R.J.C.; Wessel, I.; Hermans, D.; Minnen, A. van

    2014-01-01

    A lack of adequate access to autobiographical knowledge has been related to psychopathology. More specifically, patients suffering from depression or a history of trauma have been found to be characterized by overgeneral memory, in other words, they show a relative difficulty in retrieving a

  12. Autobiographical memory specificity in dissociative identity disorder

    NARCIS (Netherlands)

    Huntjens, Rafaële J. C.; Wessel, Ineke; Hermans, Dirk; van Minnen, Agnes

    A lack of adequate access to autobiographical knowledge has been related to psychopathology. More specifically, patients suffering from depression or a history of trauma have been found to be characterized by overgeneral memory, in other words, they show a relative difficulty in retrieving a

  13. Patient-specific models of cardiac biomechanics

    Science.gov (United States)

    Krishnamurthy, Adarsh; Villongco, Christopher T.; Chuang, Joyce; Frank, Lawrence R.; Nigam, Vishal; Belezzuoli, Ernest; Stark, Paul; Krummen, David E.; Narayan, Sanjiv; Omens, Jeffrey H.; McCulloch, Andrew D.; Kerckhoffs, Roy C. P.

    2013-07-01

    Patient-specific models of cardiac function have the potential to improve diagnosis and management of heart disease by integrating medical images with heterogeneous clinical measurements subject to constraints imposed by physical first principles and prior experimental knowledge. We describe new methods for creating three-dimensional patient-specific models of ventricular biomechanics in the failing heart. Three-dimensional bi-ventricular geometry is segmented from cardiac CT images at end-diastole from patients with heart failure. Human myofiber and sheet architecture is modeled using eigenvectors computed from diffusion tensor MR images from an isolated, fixed human organ-donor heart and transformed to the patient-specific geometric model using large deformation diffeomorphic mapping. Semi-automated methods were developed for optimizing the passive material properties while simultaneously computing the unloaded reference geometry of the ventricles for stress analysis. Material properties of active cardiac muscle contraction were optimized to match ventricular pressures measured by cardiac catheterization, and parameters of a lumped-parameter closed-loop model of the circulation were estimated with a circulatory adaptation algorithm making use of information derived from echocardiography. These components were then integrated to create a multi-scale model of the patient-specific heart. These methods were tested in five heart failure patients from the San Diego Veteran's Affairs Medical Center who gave informed consent. The simulation results showed good agreement with measured echocardiographic and global functional parameters such as ejection fraction and peak cavity pressures.

  14. Community-Specific Strategies of Intergenerational Language ...

    African Journals Online (AJOL)

    This study concerns minority language maintenance, specifically it explores local practices that make it possible for a community to sustain its traditional language. Two variables were the focus of the research; speakers' attitudes and language use patterns. These were examined to determine their influence in facilitating ...

  15. SPECIFICITY IN DEVELOPMENT OF CONSTRUCTION INDUSTRY

    Directory of Open Access Journals (Sweden)

    O. S. Golubova

    2012-01-01

    Full Text Available Specificity in development of construction industry of the Republic of Belarus determines  character of competition on the construction market, forms a pricing, marketing and product policy of building companies. Construction represents itself as a highly developed complex where interaction of business entities is of rather complicated multilateral character.

  16. Essential Specification Elements for Heat Exchanger Replacement

    Energy Technology Data Exchange (ETDEWEB)

    Bower, L.

    2015-07-01

    Performance upgrade and equipment degradation are the primary impetuses for a nuclear power plant to engage in the large capital cost project of heat exchanger replacement. Along with attention to these issues, consideration of heat exchanger Codes and Standards, material improvements, thermal redesign, and configuration are essential for developing User’s Design Specifications for successful replacement projects. The User’s Design Specification is the central document in procuring ASME heat exchangers. Properly stated objectives for the heat exchanger replacement are essential for obtaining the materials, configurations and thermal designs best suited for the nuclear power plant. Additionally, the code of construction required and the applied manufacturing standard (TEMA or HEI) affects how the heat exchanger may be designed or configured to meet the replacement goals. Knowledge of how Codes and Standards affect design and configuration details will aid in writing the User’s Design Specification. Joseph Oat Corporation has designed and fabricated many replacement heat exchangers for the nuclear power industry. These heat exchangers have been constructed per ASME Section III to various Code-Years or ASME Section VIII-1 to the current Code-Year also in accordance with TEMA and HEI. These heat exchangers have been a range of like-for-like replacement to complete thermal, material and configuration redesigns. Several examples of these heat exchangers with their Code, Standard and specification implications are presented. (Author.

  17. Research overview : design specifications for hybrid vehicles

    NARCIS (Netherlands)

    Hofman, T.; Druten, van R.M.

    2004-01-01

    In this paper a method is proposed for determination of the design specifications regarding the energy exchange systems for different chargesustaining hybrid vehicles of different vehicle classes. Hybrid drivetrains for vehicles combine multiple power sources in order to increase the driving

  18. Isotope specific arbitrary material flow meter

    Science.gov (United States)

    Barty, Christopher P. J.; Post, John C.; Jones, Edwin

    2016-10-25

    A laser-based mono-energetic gamma-ray source is used to provide non-destructive and non-intrusive, quantitative determination of the absolute amount of a specific isotope contained within pipe as part of a moving fluid or quasi-fluid material stream.

  19. Composing a Tumor Specific Bacterial Promoter.

    Directory of Open Access Journals (Sweden)

    Igor V Deyneko

    Full Text Available Systemically applied Salmonella enterica spp. have been shown to invade and colonize neoplastic tissues where it retards the growth of many tumors. This offers the possibility to use the bacteria as a vehicle for the tumor specific delivery of therapeutic molecules. Specificity of such delivery is solely depending on promoter sequences that control the production of a target molecule. We have established the functional structure of bacterial promoters that are transcriptionally active exclusively in tumor tissues after systemic application. We observed that the specific transcriptional activation is accomplished by a combination of a weak basal promoter and a strong FNR binding site. This represents a minimal set of control elements required for such activation. In natural promoters, additional DNA remodeling elements are found that alter the level of transcription quantitatively. Inefficiency of the basal promoter ensures the absence of transcription outside tumors. As a proof of concept, we compiled an artificial promoter sequence from individual motifs representing FNR and basal promoter and showed specific activation in a tumor microenvironment. Our results open possibilities for the generation of promoters with an adjusted level of expression of target proteins in particular for applications in bacterial tumor therapy.

  20. Specific Ion Effects in Cholesterol Monolayers

    Directory of Open Access Journals (Sweden)

    Teresa Del Castillo-Santaella

    2016-05-01

    Full Text Available The interaction of ions with interfaces and, in particular, the high specificity of these interactions to the particular ions considered, are central questions in the field of surface forces. Here we study the effect of different salts (NaI, NaCl, CaCl2 and MgCl2 on monolayers made of cholesterol molecules, both experimentally (surface area vs. lateral pressure isotherms measured by a Langmuir Film Balance and theoretically (molecular dynamics (MD all-atomic simulations. We found that surface isotherms depend, both quantitatively and qualitatively, on the nature of the ions by altering the shape and features of the isotherm. In line with the experiments, MD simulations show clear evidences of specific ionic effects and also provide molecular level details on ion specific interactions with cholesterol. More importantly, MD simulations show that the interaction of a particular ion with the surface depends strongly on its counterion, a feature ignored so far in most theories of specific ionic effects in surface forces.

  1. Measurement of low-temperature specific heat

    International Nuclear Information System (INIS)

    Stewart, G.R.

    1983-01-01

    The measurement of low-temperature specific heat (LTSH) (0.1 K< T<60 K) has seen a number of breakthroughs both in design concepts and instrumentation in the last 15 years: particularly in small sample calorimetry. This review attempts to provide an overview of both large and small sample calorimetry techniques at temperatures below 60 K, with sufficient references to enable more detailed study. A comprehensive review is made of the most reliable measurements of the LTSH of 84 of the elements to illustrate briefly some of the problems of measurements and analysis, as well as to provide additional references. More detail is devoted to three special areas of low-temperature calorimetry that have seen rapid development recently: (1) measurement of the specific heat of highly radioactive samples, (2) measurement of the specific heat of materials in high magnetic fields (18 T), and (3) measurement of the specific heat of very small (100 μg) samples. The review ends with a brief discussion of the frontier research currently underway on microcalorimetry for nanogram sample weights

  2. Specificity, Transfer, and the Development of Expertise

    Science.gov (United States)

    Brookes, David T.; Ross, Brian H.; Mestre, Jose P.

    2011-01-01

    In this paper we present the results of two experiments designed to understand how physics students' learning of the concept of refraction is influenced by the cognitive phenomenon of "specificity." In both experiments participants learned why light bends as it travels from one optical medium to another with an analogy made to a car…

  3. 21 CFR 107.100 - Nutrient specifications.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Nutrient specifications. 107.100 Section 107.100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD... Maximum level Protein Grams 1.8 4.5 Fat do 3.3 6.0 Percent calories 30 54 Linoleic acid Milligrams 300...

  4. Population specific analysis of Yakut exomes

    NARCIS (Netherlands)

    Zlobin, A. S.; Sharapov, S. Sh.; Guryev, V. P.; Bevova, M. R.; Tsepilov, Y. A.; Sivtseva, T. M.; Boyarskih, U. A.; Sokolova, E. A.; Aulchenko, Y. S.; Filipenko, M. L.; Osakovsky, V. L.

    We studied the genetic diversity of the Yakut population using exome sequencing. We performed comparative analysis of the Yakut population and the populations that are included in the "1000 Genomes" project and we identified the alleles specific to the Yakut population. We showed, that the Yakuts

  5. Brayton Isotope Power System (BIPS) facility specification

    International Nuclear Information System (INIS)

    1976-01-01

    General requirements for the Brayton Isotope Power System (BIPS)/Ground Demonstration System (GDS) assembly and test facility are defined. The facility will include provisions for a complete test laboratory for GDS checkout, performance, and endurance testing, and a contamination-controlled area for assembly, fabrication, storage, and storage preparation of GDS components. Specifications, schedules, and drawings are included

  6. Prospects for site specific weed management

    DEFF Research Database (Denmark)

    Christensen, Svend; Rasmussen, Jesper; Pedersen, Søren Marcus

    2014-01-01

    Research on Site Specific Weed Management (SSWM) started in the late 80's. Since that moment, considerable research has been conducted on different aspects of SSWM, from fundamental studies on the spatial ecology of weeds to the applied development and testing of new technologies for weed detection...

  7. Social-psychological specific of individual adaptation

    OpenAIRE

    Ovsyanik, Olga

    2012-01-01

    There is analyzing of specific of social-psychological adaptation person by model of adaptation. Structure model of adaptation of women of our age group, which was named “adaptation complex” was made by theoretic analyzes of problem of adaptation adult.

  8. Structural similarity and category-specificity

    DEFF Research Database (Denmark)

    Gerlach, Christian; Law, Ian; Paulson, Olaf B

    2004-01-01

    It has been suggested that category-specific recognition disorders for natural objects may reflect that natural objects are more structurally (visually) similar than artefacts and therefore more difficult to recognize following brain damage. On this account one might expect a positive relationshi...

  9. Methodes for identification of specific language impairment

    Directory of Open Access Journals (Sweden)

    Toktam Maleki Shahmahmood

    2014-06-01

    Full Text Available Background and Aim: Specific language impiarment (SLI is one of the most prevalent developmental language disorders its diagnosis is a problematic issue among researchers and clinicians because of the heterogeneity of language profiles in the affected population and overlapping with other developmental language disorders. The aim of this study was to review the suggested diagnostic criteria for this disorder, controversies about these criteria and identify the most accurate diagnostic methods.Methods: Published article from 1980 to 2012 in bibliographic and publisher databases including Pubmed, Google scholar, Cochran library, Web of Science, ProQuest, Springer, Oxford, Science direct, Ovid, Iran Medex and Magiran about the diagnostic methods for discriminating preschoool children with specific language impiarment from normal developing children were reviewd in this article. These keywords were used for research: “specific language impairment”, “SLI”, “diagnosis or identification”, “standardized tests”, and “tests for language development”.Conclusion: The results of this study show inspite of agreement of researchers and clinicians about exclusionary criteria as one basic part of the diagnosis of specific language impiarment , there is no consensus about the other part, inclusionary criteria. Different studies used different inclusionary criteria which can be divided to categories of clincal judgment, discrepancy-based criteria, standardized testing, clinical markers and markers from spontaneous speech samples. Advantages, disadvantages, and clinical applicability of each diagnostic method are discussed in this article.

  10. IPv6-specific misconfigurations in the DNS

    NARCIS (Netherlands)

    Hendriks, Luuk; de Boer, Pieter-Tjerk; Pras, Aiko

    2017-01-01

    With the Internet transitioning from IPv4 to IPv6, the number of IPv6-specific DNS records (AAAA) increases. Misconfigurations in these records often go unnoticed, as most systems are provided with connectivity over both IPv4 and IPv6, and automatically fall back to IPv4 in case of connection

  11. 31 CFR 595.312 - Specific license.

    Science.gov (United States)

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Specific license. 595.312 Section 595.312 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY TERRORISM SANCTIONS REGULATIONS General Definitions...

  12. Ultrasonic hydrometer. [Specific gravity of electrolyte

    Science.gov (United States)

    Swoboda, C.A.

    1982-03-09

    The disclosed ultrasonic hydrometer determines the specific gravity (density) of the electrolyte of a wet battery, such as a lead-acid battery. The hydrometer utilizes a transducer that when excited emits an ultrasonic impulse that traverses through the electrolyte back and forth between spaced sonic surfaces. The transducer detects the returning impulse, and means measures the time t between the initial and returning impulses. Considering the distance d between the spaced sonic surfaces and the measured time t, the sonic velocity V is calculated with the equation V = 2d/t. The hydrometer also utilizes a thermocouple to measure the electrolyte temperature. A hydrometer database correlates three variable parameters including sonic velocity in and temperature and specific gravity of the electrolyte, for temperature values between 0 and 40/sup 0/C and for specific gravity values between 1.05 and 1.30. Upon knowing two parameters (the calculated sonic velocity and the measured temperature), the third parameter (specific gravity) can be uniquely found in the database. The hydrometer utilizes a microprocessor for data storage and manipulation.

  13. COMPARATIVE STUDY ON SPECIFIC AND EARLY DETECTION ...

    African Journals Online (AJOL)

    The objective of this study was to compare the sensitivity and specificity of smear and culture methods with rapid serological EIA myco kits manufactured by Omega diagnostics, for the early detection of Mycobacterium tuberculosis (MTB) complex. Sera from various categories of smear and culture results were compared ...

  14. 32 CFR 292.4 - Specific policy.

    Science.gov (United States)

    2010-07-01

    ... INFORMATION ACT PROGRAM DEFENSE INTELLIGENCE AGENCY (DIA) FREEDOM OF INFORMATION ACT § 292.4 Specific policy... of source and object codes, regardless of medium are not agency records. (This does not include the... existing computer program or printout for retrieval of the requested information. (c) The prior application...

  15. Radioimmunoassay for a human prostate specific antigen

    International Nuclear Information System (INIS)

    Machida, T.; Miki, M.; Ohishi, Y.; Kido, A.; Morikawa, J.; Ogawa, Y.

    1983-01-01

    As a marker for prostatic cancer, a prostate-specific antigen was purified from human prostatic tissues. Double antibody radioimmunoassay utilizing immune reaction was developed on the basis of the purified prostatic antigen (PA). Measurement results have revealed that PA radioimmunoassay is much better than prostatic acid phosphatase (PAP) radioimmunoassay in the diagnosis of prostatic cancer

  16. Justifying group-specific common morality.

    Science.gov (United States)

    Strong, Carson

    2008-01-01

    Some defenders of the view that there is a common morality have conceived such morality as being universal, in the sense of extending across all cultures and times. Those who deny the existence of such a common morality often argue that the universality claim is implausible. Defense of common morality must take account of the distinction between descriptive and normative claims that there is a common morality. This essay considers these claims separately and identifies the nature of the arguments for each claim. It argues that the claim that there is a universal common morality in the descriptive sense has not been successfully defended to date. It maintains that the claim that there is a common morality in the normative sense need not be understood as universalist. This paper advocates the concept of group specific common morality, including country-specific versions. It suggests that both the descriptive and the normative claims that there are country-specific common moralities are plausible, and that a country-specific normative common morality could provide the basis for a country's bioethics.

  17. Modular specification of real-time systems

    DEFF Research Database (Denmark)

    Inal, Recep

    1994-01-01

    Duration Calculus, a real-time interval logic, has been embedded in the Z specification language to provide a notation for real-time systems that combines the modularisation and abstraction facilities of Z with a logic suitable for reasoning about real-time properties. In this article the notation...

  18. Canine specific ELISA for coagulation factor VII

    DEFF Research Database (Denmark)

    Knudsen, Tom; Kjelgaard-Hansen, Mads; Tranholm, Mikael

    2011-01-01

    available to date. In this study, a canine specific ELISA for measurement of FVII:Ag in plasma was developed and validated. The FVII:Ag ELISA correctly diagnosed homozygous and heterozygous hereditary FVII deficiency. Together with activity based assays, such as FVII:C, the FVII:Ag ELISA should be valuable...

  19. Specificity of Structural Assessment of Knowledge

    Science.gov (United States)

    Trumpower, David L.; Sharara, Harold; Goldsmith, Timothy E.

    2010-01-01

    This study examines the specificity of information provided by structural assessment of knowledge (SAK). SAK is a technique which uses the Pathfinder scaling algorithm to transform ratings of concept relatedness into network representations (PFnets) of individuals' knowledge. Inferences about individuals' overall domain knowledge based on the…

  20. Parallel object-oriented specification language

    NARCIS (Netherlands)

    Florescu, O.; Voeten, J.P.M.; Theelen, B.D.; Geilen, M.C.W.; Corporaal, H.; Burns, Alan

    2008-01-01

    The Parallel Object-Oriented Specification Language (POOSL) is an expressive modelling language for hardware/software systems [10]. It was originally defined in [7] as an object-oriented extension of process algebra CCS [6], supporting (conditional) synchronous message passing between

  1. Primary Auditory Cortex Regulates Threat Memory Specificity

    Science.gov (United States)

    Wigestrand, Mattis B.; Schiff, Hillary C.; Fyhn, Marianne; LeDoux, Joseph E.; Sears, Robert M.

    2017-01-01

    Distinguishing threatening from nonthreatening stimuli is essential for survival and stimulus generalization is a hallmark of anxiety disorders. While auditory threat learning produces long-lasting plasticity in primary auditory cortex (Au1), it is not clear whether such Au1 plasticity regulates memory specificity or generalization. We used…

  2. 48 CFR 836.202 - Specifications.

    Science.gov (United States)

    2010-10-01

    ... specifications. (b) During the design stage, contract architect-engineers must not use “brand name or equal” or... phase, prior to award of a contract for design. (c) If VA has determined that only one product will meet.... This clause places bidders on notice that the “brand name or equal” provisions of the clause found at...

  3. Specificity in liquid metal induced embrittlement

    CSIR Research Space (South Africa)

    Fernandes, PJL

    1996-12-01

    Full Text Available One of the most intriguing features of liquid metal induced embrittlement (LMIE) is the observation that some liquid metal-solid metal couples are susceptible to embrittlement, while others appear to be immune. This is referred to as the specificity...

  4. Age-Specific Correlates of Child Growth

    NARCIS (Netherlands)

    M. Rieger (Matthias); S.K. Trommlerová (Sofia Karina)

    2016-01-01

    textabstractGrowth faltering describes a widespread phenomenon that height- and weight-for-age of children in developing countries collapse rapidly in the first two years of life. We study age-specific correlates of child nutrition using Demographic and Health Surveys from 56 developing countries to

  5. Brayton Isotope Power System (BIPS) facility specification

    Energy Technology Data Exchange (ETDEWEB)

    1976-05-31

    General requirements for the Brayton Isotope Power System (BIPS)/Ground Demonstration System (GDS) assembly and test facility are defined. The facility will include provisions for a complete test laboratory for GDS checkout, performance, and endurance testing, and a contamination-controlled area for assembly, fabrication, storage, and storage preparation of GDS components. Specifications, schedules, and drawings are included.

  6. 12 CFR 347.119 - Specific consent.

    Science.gov (United States)

    2010-01-01

    ... processing procedure. (d) Specific consent. Direct or indirect investments in or activities of foreign... control such organization as a result of a foreign investment; or (ii) A bank would be establishing a... foreign country. (1) Applicable law or practice in the foreign country where the foreign organization or...

  7. TAL effectors specificity stems from negative discrimination.

    Directory of Open Access Journals (Sweden)

    Basile I M Wicky

    Full Text Available Transcription Activator-Like (TAL effectors are DNA-binding proteins secreted by phytopathogenic bacteria that interfere with native cellular functions by binding to plant DNA promoters. The key element of their architecture is a domain of tandem-repeats with almost identical sequences. Most of the polymorphism is located at two consecutive amino acids termed Repeat Variable Diresidue (RVD. The discovery of a direct link between the RVD composition and the targeted nucleotide allowed the design of TAL-derived DNA-binding tools with programmable specificities that revolutionized the field of genome engineering. Despite structural data, the molecular origins of this specificity as well as the recognition mechanism have remained unclear. Molecular simulations of the recent crystal structures suggest that most of the protein-DNA binding energy originates from non-specific interactions between the DNA backbone and non-variable residues, while RVDs contributions are negligible. Based on dynamical and energetic considerations we postulate that, while the first RVD residue promotes helix breaks--allowing folding of TAL as a DNA-wrapping super-helix--the second provides specificity through a negative discrimination of matches. Furthermore, we propose a simple pharmacophore-like model for the rationalization of RVD-DNA interactions and the interpretation of experimental findings concerning shared affinities and binding efficiencies. The explanatory paradigm presented herein provides a better comprehension of this elegant architecture and we hope will allow for improved designs of TAL-derived biotechnological tools.

  8. Accounting valuation development of specific assets

    Directory of Open Access Journals (Sweden)

    I.V. Zhigley

    2017-12-01

    Full Text Available The current issues of accounting estimate development are considered. The necessity of the development of accounting estimate in the context of the non-institutional theory principles based on the selection of a number of reasons is grounded. The reasons for deterioration of accounting reputation as a separate socio-economic institute in the context of developing the methodology for specific assets accounting are discovered. The system of normative regulation of accounting estimate of enterprise non-current assets in the case of diminishing their usefulness is analyzed. The procedure for determining and accounting for the depreciation of assets in accordance with IFRS 36 «Depreciation of Assets» is developed. The features of the joint use of the concept of «value in use» and «fair value» in the accounting system are disclosed. The procedure for determining the value of compensation depending on the degree of specificity of assets is developed. The necessity to clarify the features that indicate the possibility of diminishing the usefulness of specific assets (termination or pre-term termination of the contract for the use of a specific asset is grounded.

  9. Iron addition to soil specifically stabilized lignin

    Science.gov (United States)

    Steven J. Hall; Whendee L. Silver; Vitaliy I. Timokhin; Kenneth E. Hammel

    2016-01-01

    The importance of lignin as a recalcitrant constituent of soil organic matter (SOM) remains contested. Associations with iron (Fe) oxides have been proposed to specifically protect lignin from decomposition, but impacts of Fe-lignin interactions on mineralization rates remain unclear. Oxygen (O2) fluctuations characteristic of humid tropical...

  10. Chapter 9: Questions from CNEN specific exams

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2018-04-01

    The following are real questions from CNEN specific exams for obtaining the certification of RSO for gamma irradiators. These are questions that require essay answers, that are interpretative ones and therefore that may accept more than one interpretation, therefore more than one answer. For this reason, suggestions of answers will be presented in the second part of this chapter.

  11. 14 CFR 29.1397 - Color specifications.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Color specifications. 29.1397 Section 29.1397 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT...) Aviation green— x is not greater than 0.440−0.320y; x is not greater than y−0.170; and y is not less than 0...

  12. 14 CFR 23.1397 - Color specifications.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Color specifications. 23.1397 Section 23.1397 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT... greater than 0.002. (b) Aviation green— x is not greater than 0.440−0.320y; x is not greater than y−0.170...

  13. 14 CFR 25.1397 - Color specifications.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Color specifications. 25.1397 Section 25.1397 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT...) Aviation green— x is not greater than 0.440−0.320y ; x is not greater than y−0.170; and y is not less than...

  14. 14 CFR 27.1397 - Color specifications.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Color specifications. 27.1397 Section 27.1397 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT...) Aviation green— x is not greater than 0.440−0.320y; x is not greater than y−0.170; and y is not less than 0...

  15. MODEL OF TEACHING PROFESSION SPECIFIC BILATERAL TRANSLATION

    Directory of Open Access Journals (Sweden)

    Yana Fabrychna

    2017-03-01

    Full Text Available The article deals with the author’s interpretation of the process of teaching profession specific bilateral translation to student teacher of English in the Master’s program. The goal of the model of teaching profession specific bilateral translation development is to determine the logical sequence of educational activities of the teacher as the organizer of the educational process and students as its members. English and Ukrainian texts on methods of foreign languages and cultures teaching are defined as the object of study. Learning activities aimed at the development of student teachers of English profession specific competence in bilateral translation and Translation Proficiency Language Portfolio for Student Teachers of English are suggested as teaching tools. The realization of the model of teaching profession specific bilateral translation to student teachers of English in the Master’s program is suggested within the module topics of the academic discipline «Practice of English as the first foreign language»: Globalization; Localization; Education; Work; The role of new communication technologies in personal and professional development. We believe that the amount of time needed for efficient functioning of the model is 48 academic hours, which was determined by calculating the total number of academic hours allotted for the academic discipline «Practice of English as the first foreign language» in Ukrainian universities. Peculiarities of the model realization as well as learning goals and content of class activities and home self-study work of students are outlined.

  16. Slicing AADL specifications for model checking

    NARCIS (Netherlands)

    Odenbrett, M.R.; Nguyen, V.Y.; Noll, T.

    2010-01-01

    To combat the state-space explosion problem in model checking larger systems, abstraction techniques can be employed. Here, methods that operate on the system specification before constructing its state space are preferable to those that try to minimize the resulting transition system as they

  17. [The "specific" liability regime for blood products].

    Science.gov (United States)

    Byk, Christian

    2017-10-13

    Based on the system of liability for defective products as organized by the European Directive of 25 July 1985, responsibility for blood products does not therefore constitute a genuine specific regime. However, European law leaves States a margin of discretion in the implementation of the Directive with regard to health products. This is the case in particular with the exemption for development risk.

  18. Digital PET compliance to EARL accreditation specifications

    NARCIS (Netherlands)

    Koopman, Daniëlle; Groot Koerkamp, Maureen; Jager, Pieter L.; Arkies, Hester; Knollema, Siert; Slump, Cornelis H.; Sanches, Pedro G.; van Dalen, Jorn A.

    2017-01-01

    Background: Our aim was to evaluate if a recently introduced TOF PET system with digital photon counting technology (Philips Healthcare), potentially providing an improved image quality over analogue systems, can fulfil EANM research Ltd (EARL) accreditation specifications for tumour imaging with

  19. Chapter 9: Questions from CNEN specific exams

    International Nuclear Information System (INIS)

    2018-01-01

    The following are real questions from CNEN specific exams for obtaining the certification of RSO for gamma irradiators. These are questions that require essay answers, that are interpretative ones and therefore that may accept more than one interpretation, therefore more than one answer. For this reason, suggestions of answers will be presented in the second part of this chapter

  20. Standard specification for agencies performing nondestructive testing

    CERN Document Server

    American Society for Testing and Materials. Philadelphia

    2009-01-01

    1.1 This specification covers minimum requirements for agencies performing nondestructive testing (NDT). 1.2 When using this specification to assess the capability of, or to accredit NDT agencies, Guide E 1359 shall be used as a basis for the survey. It can be supplemented as necessary with more detail in order to meet the auditor's specific needs. 1.3 This specification can be used as a basis to evaluate testing or inspection agencies, or both, and is intended for use for the qualifying or accrediting, or both, of testing or inspection agencies, public or private. 1.4 The use of SI or inch-pound units, or combination thereof, will be the responsibility of the technical committee whose standards are referred to in this standard. 1.5 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to...

  1. NIF small optics laser damage test specifications

    International Nuclear Information System (INIS)

    Sheehan, L

    1999-01-01

    The Laser Damage Group is currently conducting tests on small optics samples supplied for initial evaluation of potential NIF suppliers. This document is meant to define the specification of laser-induced damage for small optics and the test methods used to collect the data. A rating system which will be applied for vendor selection is presented

  2. Spent nuclear fuel project product specification

    International Nuclear Information System (INIS)

    PAJUNEN, A.L.

    1999-01-01

    This document establishes the limits and controls for the significant parameters that could potentially affect the safety and/or quality of the Spent Nuclear Fuel (SNF) packaged for processing, transport, and storage. The product specifications in this document cover the SNF packaged in Multi-Canister Overpacks to be transported throughout the SNF Project

  3. A camera specification for tendering purposes

    International Nuclear Information System (INIS)

    Lunt, M.J.; Davies, M.D.; Kenyon, N.G.

    1985-01-01

    A standardized document is described which is suitable for sending to companies which are being invited to tender for the supply of a gamma camera. The document refers to various features of the camera, the performance specification of the camera, maintenance details, price quotations for various options and delivery, installation and warranty details. (U.K.)

  4. Teaching Case: Enterprise Architecture Specification Case Study

    Science.gov (United States)

    Steenkamp, Annette Lerine; Alawdah, Amal; Almasri, Osama; Gai, Keke; Khattab, Nidal; Swaby, Carval; Abaas, Ramy

    2013-01-01

    A graduate course in enterprise architecture had a team project component in which a real-world business case, provided by an industry sponsor, formed the basis of the project charter and the architecture statement of work. The paper aims to share the team project experience on developing the architecture specifications based on the business case…

  5. Ontology Assisted Formal Specification Extraction from Text

    Directory of Open Access Journals (Sweden)

    Andreea Mihis

    2010-12-01

    Full Text Available In the field of knowledge processing, the ontologies are the most important mean. They make possible for the computer to understand better the natural language and to make judgments. In this paper, a method which use ontologies in the semi-automatic extraction of formal specifications from a natural language text is proposed.

  6. Cell-specific targeting by heterobivalent ligands.

    Science.gov (United States)

    Josan, Jatinder S; Handl, Heather L; Sankaranarayanan, Rajesh; Xu, Liping; Lynch, Ronald M; Vagner, Josef; Mash, Eugene A; Hruby, Victor J; Gillies, Robert J

    2011-07-20

    Current cancer therapies exploit either differential metabolism or targeting to specific individual gene products that are overexpressed in aberrant cells. The work described herein proposes an alternative approach--to specifically target combinations of cell-surface receptors using heteromultivalent ligands ("receptor combination approach"). As a proof-of-concept that functionally unrelated receptors can be noncovalently cross-linked with high avidity and specificity, a series of heterobivalent ligands (htBVLs) were constructed from analogues of the melanocortin peptide ligand ([Nle(4), dPhe(7)]-α-MSH) and the cholecystokinin peptide ligand (CCK-8). Binding of these ligands to cells expressing the human Melanocortin-4 receptor and the Cholecystokinin-2 receptor was analyzed. The MSH(7) and CCK(6) were tethered with linkers of varying rigidity and length, constructed from natural and/or synthetic building blocks. Modeling data suggest that a linker length of 20-50 Å is needed to simultaneously bind these two different G-protein coupled receptors (GPCRs). These ligands exhibited up to 24-fold enhancement in binding affinity to cells that expressed both (bivalent binding), compared to cells with only one (monovalent binding) of the cognate receptors. The htBVLs had up to 50-fold higher affinity than that of a monomeric CCK ligand, i.e., Ac-CCK(6)-NH(2). Cell-surface targeting of these two cell types with labeled heteromultivalent ligand demonstrated high avidity and specificity, thereby validating the receptor combination approach. This ability to noncovalently cross-link heterologous receptors and target individual cells using a receptor combination approach opens up new possibilities for specific cell targeting in vivo for therapy or imaging.

  7. microRNA expression during trophectoderm specification.

    Directory of Open Access Journals (Sweden)

    Srinivas R Viswanathan

    2009-07-01

    Full Text Available Segregation of the trophectoderm from the inner cell mass of the embryo represents the first cell-fate decision of mammalian development. Transcription factors essential for specifying trophectoderm have been identified, but the role of microRNAs (miRNAs in modulating this fate-choice has been largely unexplored. We have compared miRNA expression in embryonic stem cell (ESC-derived trophectoderm and in staged murine embryos to identify a set of candidate miRNAs likely to be involved in trophectoderm specification.We profiled embryonic stem cells (ESCs as they were induced to differentiate into trophectodermal cells by ectopic expression of HRas/Q61L. We also profiled murine embryos at progressive stages of preimplantation development (zygote, 2-cell, 4-cell, 8-cell, morula, and blastocyst, which includes the time window in which the trophectoderm is specified in vivo Q61L/H.We describe miRNA expression changes that occur during trophectoderm specification and validate that our in vitro system faithfully recapitulates trophectoderm specification in vivo. By comparing our in vitro and in vivo datasets, we have identified a minimal set of candidate miRNAs likely to play a role in trophectoderm specification. These miRNAs are predicted to regulate a host of development-associated target genes, and many of these miRNAs have previously reported roles in development and differentiation. Additionally, we highlight a number of miRNAs whose tight developmental regulation may reflect a functional role in other stages of embryogenesis. Our embryo profiling data may be useful to investigators studying trophectoderm specification and other stages of preimplantation development.

  8. Hepatocyte specific expression of human cloned genes

    Energy Technology Data Exchange (ETDEWEB)

    Cortese, R

    1986-01-01

    A large number of proteins are specifically synthesized in the hepatocyte. Only the adult liver expresses the complete repertoire of functions which are required at various stages during development. There is therefore a complex series of regulatory mechanisms responsible for the maintenance of the differentiated state and for the developmental and physiological variations in the pattern of gene expression. Human hepatoma cell lines HepG2 and Hep3B display a pattern of gene expression similar to adult and fetal liver, respectively; in contrast, cultured fibroblasts or HeLa cells do not express most of the liver specific genes. They have used these cell lines for transfection experiments with cloned human liver specific genes. DNA segments coding for alpha1-antitrypsin and retinol binding protein (two proteins synthesized both in fetal and adult liver) are expressed in the hepatoma cell lines HepG2 and Hep3B, but not in HeLa cells or fibroblasts. A DNA segment coding for haptoglobin (a protein synthesized only after birth) is only expressed in the hepatoma cell line HepG2 but not in Hep3B nor in non hepatic cell lines. The information for tissue specific expression is located in the 5' flanking region of all three genes. In vivo competition experiments show that these DNA segments bind to a common, apparently limiting, transacting factor. Conventional techniques (Bal deletions, site directed mutagenesis, etc.) have been used to precisely identify the DNA sequences responsible for these effects. The emerging picture is complex: they have identified multiple, separate transcriptional signals, essential for maximal promoter activation and tissue specific expression. Some of these signals show a negative effect on transcription in fibroblast cell lines.

  9. Hand Specific Representations in Language Comprehension

    Directory of Open Access Journals (Sweden)

    Claire eMoody-Triantis

    2014-06-01

    Full Text Available Theories of embodied cognition argue that language comprehension involves sensory-motor re-enactments of the actions described. However, the degree of specificity of these re-enactments as well as the relationship between action and language remains a matter of debate. Here we investigate these issues by examining how hand-specific information (left or right hand is recruited in language comprehension and action execution. An fMRI study tested right-handed participants in two separate tasks that were designed to be as similar as possible to increase sensitivity of the comparison across task: an action execution go/no-go task where participants performed right or left hand actions, and a language task where participants read sentences describing the same left or right handed actions as in the execution task. We found that language-induced activity did not match the hand-specific patterns of activity found for action execution in primary somatosensory and motor cortex, but it overlapped with pre-motor and parietal regions associated with action planning. Within these pre-motor regions, both right hand actions and sentences elicited stronger activity than left hand actions and sentences - a dominant hand effect -. Importantly, both dorsal and ventral sections of the left pre-central gyrus were recruited by both tasks, suggesting different action features being recruited. These results suggest that (a language comprehension elicits motor representations that are hand-specific and akin to multimodal action plans, rather than full action re-enactments; and (b language comprehension and action execution share schematic hand-specific representations that are richer for the dominant hand, and thus linked to previous motor experience.

  10. Are videogame training gains specific or general?

    Science.gov (United States)

    Oei, Adam C; Patterson, Michael D

    2014-01-01

    Many recent studies using healthy adults document enhancements in perception and cognition from playing commercial action videogames (AVGs). Playing action games (e.g., Call of Duty, Medal of Honor) is associated with improved bottom-up lower-level information processing skills like visual-perceptual and attentional processes. One proposal states a general improvement in the ability to interpret and gather statistical information to predict future actions which then leads to better performance across different perceptual/attentional tasks. Another proposal claims all the tasks are separately trained in the AVGs because the AVGs and laboratory tasks contain similar demands. We review studies of action and non-AVGs to show support for the latter proposal. To explain transfer in AVGs, we argue that the perceptual and attention tasks share common demands with the trained videogames (e.g., multiple object tracking (MOT), rapid attentional switches, and peripheral vision). In non-AVGs, several studies also demonstrate specific, limited transfer. One instance of specific transfer is the specific enhancement to mental rotation after training in games with a spatial emphasis (e.g., Tetris). In contrast, the evidence for transfer is equivocal where the game and task do not share common demands (e.g., executive functioning). Thus, the "common demands" hypothesis of transfer not only characterizes transfer effects in AVGs, but also non-action games. Furthermore, such a theory provides specific predictions, which can help in the selection of games to train human cognition as well as in the design of videogames purposed for human cognitive and perceptual enhancement. Finally this hypothesis is consistent with the cognitive training literature where most post-training gains are for tasks similar to the training rather than general, non-specific improvements.

  11. Are videogame training gains specific or general?

    Directory of Open Access Journals (Sweden)

    Adam C. Oei

    2014-04-01

    Full Text Available Many recent studies using healthy adults document enhancements in perception and cognition from playing commercial action videogames. Playing action games (e.g., Call of Duty, Medal of Honor is associated with improved bottom-up lower-level information processing skills like visual-perceptual and attentional processes. One proposal states a general improvement in the ability to interpret and gather statistical information to predict future actions which then leads to better performance across different perceptual/attentional tasks. Another proposal claims all the tasks are separately trained in the action videogames because the action videogames and laboratory tasks contain similar demands. We review studies of action and non-action videogames to show support for the latter proposal. To explain transfer in action videogames, we argue that the perceptual and attention tasks share common demands with the trained videogames (e.g., multiple object tracking, rapid attentional switches, and peripheral vision. In non-action videogames, several studies also demonstrate specific, limited transfer. One instance of specific transfer is the specific enhancement to mental rotation after training in games with a spatial emphasis (e.g, Tetris. In contrast, the evidence for transfer is equivocal where the game and task do not share common demands (e.g., executive functioning. Thus, the common demands hypothesis of transfer not only characterizes transfer effects in action videogames, but also non-action games. Furthermore, such a theory provides specific predictions, which can help in the selection of games to train human cognition as well as in the design of videogames purposed for human cognitive and perceptual enhancement. Finally this hypothesis is consistent with the cognitive training literature where most post-training gains are for tasks similar to the training rather than general, non-specific improvements.

  12. Are videogame training gains specific or general?

    Science.gov (United States)

    Patterson, Michael D.

    2014-01-01

    Many recent studies using healthy adults document enhancements in perception and cognition from playing commercial action videogames (AVGs). Playing action games (e.g., Call of Duty, Medal of Honor) is associated with improved bottom-up lower-level information processing skills like visual-perceptual and attentional processes. One proposal states a general improvement in the ability to interpret and gather statistical information to predict future actions which then leads to better performance across different perceptual/attentional tasks. Another proposal claims all the tasks are separately trained in the AVGs because the AVGs and laboratory tasks contain similar demands. We review studies of action and non-AVGs to show support for the latter proposal. To explain transfer in AVGs, we argue that the perceptual and attention tasks share common demands with the trained videogames (e.g., multiple object tracking (MOT), rapid attentional switches, and peripheral vision). In non-AVGs, several studies also demonstrate specific, limited transfer. One instance of specific transfer is the specific enhancement to mental rotation after training in games with a spatial emphasis (e.g., Tetris). In contrast, the evidence for transfer is equivocal where the game and task do not share common demands (e.g., executive functioning). Thus, the “common demands” hypothesis of transfer not only characterizes transfer effects in AVGs, but also non-action games. Furthermore, such a theory provides specific predictions, which can help in the selection of games to train human cognition as well as in the design of videogames purposed for human cognitive and perceptual enhancement. Finally this hypothesis is consistent with the cognitive training literature where most post-training gains are for tasks similar to the training rather than general, non-specific improvements. PMID:24782722

  13. Hand specific representations in language comprehension.

    Science.gov (United States)

    Moody-Triantis, Claire; Humphreys, Gina F; Gennari, Silvia P

    2014-01-01

    Theories of embodied cognition argue that language comprehension involves sensory-motor re-enactments of the actions described. However, the degree of specificity of these re-enactments as well as the relationship between action and language remains a matter of debate. Here we investigate these issues by examining how hand-specific information (left or right hand) is recruited in language comprehension and action execution. An fMRI study tested self-reported right-handed participants in two separate tasks that were designed to be as similar as possible to increase sensitivity of the comparison across task: an action execution go/no-go task where participants performed right or left hand actions, and a language task where participants read sentences describing the same left or right handed actions as in the execution task. We found that language-induced activity did not match the hand-specific patterns of activity found for action execution in primary somatosensory and motor cortex, but it overlapped with pre-motor and parietal regions associated with action planning. Within these pre-motor regions, both right hand actions and sentences elicited stronger activity than left hand actions and sentences-a dominant hand effect. Importantly, both dorsal and ventral sections of the left pre-central gyrus were recruited by both tasks, suggesting different action features being recruited. These results suggest that (a) language comprehension elicits motor representations that are hand-specific and akin to multimodal action plans, rather than full action re-enactments; and (b) language comprehension and action execution share schematic hand-specific representations that are richer for the dominant hand, and thus linked to previous motor experience.

  14. Adolescents with specific learning disabilities - perceptions of specific learning disabilities in the environment of secondary schools

    OpenAIRE

    Pospíšilová, Zuzana

    2012-01-01

    The thesis focuses on adolescents with specific learning disabilities in the milieu of secondary schools. It is divided into a theoretical part and an empirical part. The first part introduces a topic of specific learning disabilities in the developmental stage of adolescence. It first describes the most relevant aspects of adolescent development. The attention is then paid to typical manifestations of specific learning disabilities in adolescence, and also to secondary symptoms usually conne...

  15. Specific developmental pathways underlie host specificity in the parasitic plant Orobanche

    Science.gov (United States)

    Hiscock, Simon

    2010-01-01

    Parasitic angiosperms are an ecologically and economically important group of plants. However our understanding of the basis for host specificity in these plants is embryonic. Recently we investigated host specificity in the parasitic angiosperm Orobanche minor, and demonstrated that this host generalist parasite comprises genetically defined races that are physiologically adapted to specific hosts. Populations occurring naturally on red clover (Trifolium pratense) and sea carrot (Daucus carota subsp. gummifer) respectively, showed distinct patterns of host specificity at various developmental stages, and a higher fitness on their natural hosts, suggesting these races are locally adapted. Here we discuss the implications of our findings from a broader perspective. We suggest that differences in signal responsiveness and perception by the parasite, as well as qualitative differences in signal production by the host, may elicit host specificity in this parasitic plant. Together with our earlier demonstration that these O. minor races are genetically distinct based on molecular markers, our recent data provide a snapshot of speciation in action, driven by host specificity. Indeed, host specificity may be an underestimated catalyst for speciation in parasitic plants generally. We propose that identifying host specific races using physiological techniques will complement conventional molecular marker-based approaches to provide a framework for delineating evolutionary relationships among cryptic host-specific parasitic plants. PMID:20081361

  16. Risk management through dynamic technical specifications

    International Nuclear Information System (INIS)

    Klopp, George T.; Petersen, Thomas A.

    2004-01-01

    The wide deployment of plant specific probabilistic risk assessments for nuclear power plants has provided the means to effect a fresh risk management perspective and a fresh, risk based, regulatory outlook on nuclear power. There has been a great deal of conversation on risk based regulation within the U. S. nuclear power industry but, curiously, very little on effective risk management. This paper proposes a means to link the two subjects through the plant Technical Specifications. A revised concept for Technical Specifications is suggested which is based on deterministic analyses and probabilistic risk assessments for each plant. The revised Technical Specifications would consider, on a real-time basis, the exact state of the plant in terms of the status of key components and systems. It would depict current plant risk levels and compare those levels to the desired and limiting (alert/action) levels. It would advise the plant operator on the risk impact of proposed actions through a simple query system and illustrate the impact of such actions on plant status relative to designated risk values. The basis for the proposed approach lies in realistic deterministic plant analyses and probabilistic risk assessment (PRA) deployment tools being developed, in parallel, by a number of parties in the U.S. today. These PRAs are based primarily on the existing plant responses to Generic Letter 88-20, 'Individual Plant Examinations' (IPEs). Each of these tools allows the plant operator to input, on a real-time basis, the status of key equipment and systems. The tools then provide explicit illustrations of dependency effects; updated, 'real-time' risk status indications such as core damage frequency; and, in some cases, allow the operator to assess the risk impact of removing from service selected components for maintenance or testing. These systems generally operate on personal computers and provide nearly instantaneous responses to plant queries. Moving from these tools to

  17. Nanoparticles for Site Specific Genome Editing

    Science.gov (United States)

    McNeer, Nicole Ali

    Triplex-forming peptide nucleic acids (PNAs) can be used to coordinate the recombination of short 50-60 by "donor DNA" fragments into genomic DNA, resulting in site-specific correction of genetic mutations or the introduction of advantageous genetic modifications. Site-specific gene editing in hematopoietic stem and progenitor cells (HSPCs) could result in treatment or cure of inherited disorders of the blood such as beta-thalassemia. Gene editing in HSPCs and differentiated T cells could help combat HIV/AIDs by modifying receptors, such as CCR5, necessary for R5-tropic HIV entry. However, translation of genome modification technologies to clinical practice is limited by challenges in intracellular delivery, especially in difficult-to-transfect hematolymphoid cells. In vivo gene editing could also provide novel treatment for systemic monogenic disorders such as cystic fibrosis, an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane receptor. Here, we have engineered biodegradable nanoparticles to deliver oligonucleotides for site-specific genome editing of disease-relevant genes in human cells, with high efficiency, low toxicity, and editing of clinically relevant cell types. We designed nanoparticles to edit the human beta-globin and CCR5 genes in hematopoietic cells. We show that poly(lactic-co-glycolic acid) (PLGA) nanoparticles can delivery PNA and donor DNA for site-specific gene modification in human hematopoietic cells in vitro and in vivo in NOD-scid IL2rgammanull mice. Nanoparticles delivered by tail vein localized to hematopoietic compartments in the spleen and bone marrow of humanized mice, resulting in modification of the beta-globin and CCR5 genes. Modification frequencies ranged from 0.005 to 20% of cells depending on the organ and cell type, without detectable toxicity. This project developed highly versatile methods for delivery of therapeutics to hematolymphoid cells and hematopoietic stem cells, and will help to

  18. Development of industrial variant specification systems

    DEFF Research Database (Denmark)

    Hansen, Benjamin Loer

    be developed from a holistic and strategically anchored point of view. Another assumption is that this is a challenge for many industrial companies. Even though the literature presents many considerations on general issues covering new information technology, little work is found on the business perspectives...... are discussed. A list of structural variables and solution components has been created. These are related to four design aspects in the holistic system design covering the aspects of process design, selection of resources (such as hardware, software and humans), the design of information structures...... solution elements and structural variables to be used in the design of variant specification systems. The thesis presents a “top-down” procedure to be used to develop variant specification systems from a strategically anchored and holistic point of view. A methodology and related task variables...

  19. Risk based technique for improving technical specifications

    International Nuclear Information System (INIS)

    Kim, I. S.; Jae, M. S.; Kim, B. S.; Hwang, S. W.; Kang, K. M.; Park, S. S.; Yu, Y. S.

    2001-03-01

    The objective of this study is to develop the systematic guidance for reviewing the documents associated with the changes of technical specifications. The work done in this fiscal year is the following : surveys in TS requirements, TS improvements and TS regulations in foreign countries as well as Korea, surveys on the state-of-the-art of RITSs and their use in Korea, development of a decision-making framework for both the licensee and the regulation agency, description of risk measures, assessment methodology on STI/AOT, and adverse effects caused by periodic maintenance, which are explained in appendix. The results of this study might contribute to enhancing the quality of the current technical specifications and contribute to preparing the risk informed regulation program using the decision-making framework developed in this study

  20. Duration and specificity of olfactory nonassociative memory.

    Science.gov (United States)

    Freedman, Kaitlin G; Radhakrishna, Sreya; Escanilla, Olga; Linster, Christiane

    2013-05-01

    Olfactory habituation is a simple form of nonassociative memory in which responsiveness to stable but behaviorally nonsignificant stimuli is decreased. Olfactory habituation has recently become a paradigm widely used to probe the neural substrate underlying olfactory perception and memory. This simple behavioral paradigm has been used successfully used to probe many aspects of olfactory processing, and it has recently become clear that the neural processes underlying olfactory habituation can depend on the task parameters used. We here further investigate memory specificity and duration using 2 variations in task parameters: the number of habituation trials and the time delay between habituation and cross-habituation testing. We find that memory specificity increases with the number of habituation trials but decreases with time after the last habituation trial.