Sample records for delta f508 cftr

  1. Diminished self-chaperoning activity of the DeltaF508 mutant of CFTR results in protein misfolding.

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    Adrian W R Serohijos


    Full Text Available The absence of a functional ATP Binding Cassette (ABC protein called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR from apical membranes of epithelial cells is responsible for cystic fibrosis (CF. Over 90% of CF patients carry at least one mutant allele with deletion of phenylalanine at position 508 located in the N-terminal nucleotide binding domain (NBD1. Biochemical and cell biological studies show that the DeltaF508 mutant exhibits inefficient biosynthetic maturation and susceptibility to degradation probably due to misfolding of NBD1 and the resultant misassembly of other domains. However, little is known about the direct effect of the Phe508 deletion on the NBD1 folding, which is essential for rational design strategies of cystic fibrosis treatment. Here we show that the deletion of Phe508 alters the folding dynamics and kinetics of NBD1, thus possibly affecting the assembly of the complete CFTR. Using molecular dynamics simulations, we find that meta-stable intermediate states appearing on wild type and mutant folding pathways are populated differently and that their kinetic accessibilities are distinct. The structural basis of the increased misfolding propensity of the DeltaF508 NBD1 mutant is the perturbation of interactions in residue pairs Q493/P574 and F575/F578 found in loop S7-H6. As a proof-of-principle that the S7-H6 loop conformation can modulate the folding kinetics of NBD1, we virtually design rescue mutations in the identified critical interactions to force the S7-H6 loop into the wild type conformation. Two redesigned NBD1-DeltaF508 variants exhibited significantly higher folding probabilities than the original NBD1-DeltaF508, thereby partially rescuing folding ability of the NBD1-DeltaF508 mutant. We propose that these observed defects in folding kinetics of mutant NBD1 may also be modulated by structures separate from the 508 site. The identified structural determinants of increased misfolding propensity of

  2. Characterization of nasal potential difference in cftr knockout and F508del-CFTR mice.

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    Emilie Lyne Saussereau

    Full Text Available BACKGROUND: Treatments designed to correct cystic fibrosis transmembrane conductance regulator (CFTR defects must first be evaluated in preclinical experiments in the mouse model of cystic fibrosis (CF. Mice nasal mucosa mimics the bioelectric defect seen in humans. The use of nasal potential difference (V(TE to assess ionic transport is a powerful test evaluating the restoration of CFTR function. Nasal V(TE in CF mice must be well characterized for correct interpretation. METHODS: We performed V(TE measurements in large-scale studies of two mouse models of CF--B6;129 cftr knockout and FVB F508del-CFTR--and their respective wild-type (WT littermates. We assessed the repeatability of the test for cftr knockout mice and defined cutoff points distinguishing between WT and F508del-CFTR mice. RESULTS: We determined the typical V(TE values for CF and WT mice and demonstrated the existence of residual CFTR activity in F508del-CFTR mice. We characterized intra-animal variability in B6;129 mice and defined the cutoff points for F508del-CFTR chloride secretion rescue. Hyperpolarization of more than -2.15 mV after perfusion with a low-concentration Cl(- solution was considered to indicate a normal response. CONCLUSIONS: These data will make it possible to interpret changes in nasal V(TE in mouse models of CF, in future preclinical studies.

  3. Manipulating proteostasis to repair the F508del-CFTR defect in cystic fibrosis. (United States)

    Esposito, Speranza; Tosco, Antonella; Villella, Valeria R; Raia, Valeria; Kroemer, Guido; Maiuri, Luigi


    Cystic fibrosis (CF) is a lethal monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that entails the (diagnostic) increase in sweat electrolyte concentrations, progressive lung disease with chronic inflammation and recurrent bacterial infections, pancreatic insufficiency, and male infertility. Therapies aimed at restoring the CFTR defect have emerged. Thus, a small molecule which facilitates chloride channel opening, the potentiator Ivacaftor, has been approved for the treatment of CF patients bearing a particular class of rare CFTR mutations. However, small molecules that directly target the most common misfolded CFTR mutant, F508del, and improve its intracellular trafficking in vitro, have been less effective than expected when tested in CF patients, even in combination with Ivacaftor. Thus, new strategies are required to circumvent the F508del-CFTR defect. Airway and intestinal epithelial cells from CF patients bearing the F508del-CFTR mutation exhibit an impressive derangement of cellular proteostasis, with oxidative stress, overactivation of the tissue transglutaminase (TG2), and disabled autophagy. Proteostasis regulators such as cysteamine can rescue and stabilize a functional F508del-CFTR protein through suppressing TG2 activation and restoring autophagy in vivo in F508del-CFTR homozygous mice, in vitro in CF patient-derived cell lines, ex vivo in freshly collected primary patient's nasal cells, as well as in a pilot clinical trial involving homozygous F508del-CFTR patients. Here, we discuss how the therapeutic normalization of defective proteostasis can be harnessed for the treatment of CF patients with the F508del-CFTR mutation.

  4. Ribosomal Stalk Protein Silencing Partially Corrects the ΔF508-CFTR Functional Expression Defect.

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    Guido Veit


    Full Text Available The most common cystic fibrosis (CF causing mutation, deletion of phenylalanine 508 (ΔF508 or Phe508del, results in functional expression defect of the CF transmembrane conductance regulator (CFTR at the apical plasma membrane (PM of secretory epithelia, which is attributed to the degradation of the misfolded channel at the endoplasmic reticulum (ER. Deletion of phenylalanine 670 (ΔF670 in the yeast oligomycin resistance 1 gene (YOR1, an ABC transporter of Saccharomyces cerevisiae phenocopies the ΔF508-CFTR folding and trafficking defects. Genome-wide phenotypic (phenomic analysis of the Yor1-ΔF670 biogenesis identified several modifier genes of mRNA processing and translation, which conferred oligomycin resistance to yeast. Silencing of orthologues of these candidate genes enhanced the ΔF508-CFTR functional expression at the apical PM in human CF bronchial epithelia. Although knockdown of RPL12, a component of the ribosomal stalk, attenuated the translational elongation rate, it increased the folding efficiency as well as the conformational stability of the ΔF508-CFTR, manifesting in 3-fold augmented PM density and function of the mutant. Combination of RPL12 knockdown with the corrector drug, VX-809 (lumacaftor restored the mutant function to ~50% of the wild-type channel in primary CFTRΔF508F508 human bronchial epithelia. These results and the observation that silencing of other ribosomal stalk proteins partially rescue the loss-of-function phenotype of ΔF508-CFTR suggest that the ribosomal stalk modulates the folding efficiency of the mutant and is a potential therapeutic target for correction of the ΔF508-CFTR folding defect.

  5. Cystic fibrosis Delta F508 heterozygotes, smoking, and reproduction

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    Dahl, Morten; Tybjaerg-Hansen, A; Wittrup, H H


    Cystic fibrosis is the most common fatal autosomal recessive disease affecting Caucasian populations. It remains a puzzle how this disease is maintained at such a remarkably high incidence, however, it could be due to a reproductive advantage in cystic fibrosis heterozygotes. We tested this hypot......Cystic fibrosis is the most common fatal autosomal recessive disease affecting Caucasian populations. It remains a puzzle how this disease is maintained at such a remarkably high incidence, however, it could be due to a reproductive advantage in cystic fibrosis heterozygotes. We tested.......001). In conclusion, overall these results do not support a reproductive advantage for cystic fibrosis DeltaF508 heterozygotes. However, the data cannot totally exclude the possibility that nonsmoking DeltaF508 heterozygotes experience a reproductive advantage while smoking DeltaF508 heterozygotes experience...... the opposite, a reproductive disadvantage. Accordingly, the data suggest a previously undocumented role of smoking on fecundity among cystic fibrosis heterozygotes....

  6. Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation. (United States)

    De Stefano, Daniela; Villella, Valeria R; Esposito, Speranza; Tosco, Antonella; Sepe, Angela; De Gregorio, Fabiola; Salvadori, Laura; Grassia, Rosa; Leone, Carlo A; De Rosa, Giuseppe; Maiuri, Maria C; Pettoello-Mantovani, Massimo; Guido, Stefano; Bossi, Anna; Zolin, Anna; Venerando, Andrea; Pinna, Lorenzo A; Mehta, Anil; Bona, Gianni; Kroemer, Guido; Maiuri, Luigi; Raia, Valeria


    Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr(F508del) homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

  7. The CFTR-Associated Ligand Arrests the Trafficking of the Mutant ΔF508 CFTR Channel in the ER Contributing to Cystic Fibrosis

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    Emily Bergbower


    Full Text Available Background/Aims: The CFTR-Associated Ligand (CAL, a PDZ domain containing protein with two coiled-coil domains, reduces cell surface WT CFTR through degradation in the lysosome by a well-characterized mechanism. However, CAL’s regulatory effect on ΔF508 CFTR has remained almost entirely uninvestigated. Methods: In this study, we describe a previously unknown pathway for CAL by which it regulates the membrane expression of ΔF508 CFTR through arrest of ΔF508 CFTR trafficking in the endoplasmic reticulum (ER using a combination of cell biology, biochemistry and electrophysiology. Results: We demonstrate that CAL is an ER localized protein that binds to ΔF508 CFTR and is degraded in the 26S proteasome. When CAL is inhibited, ΔF508 CFTR retention in the ER decreases and cell surface expression of mature functional ΔF508 CFTR is observed alongside of enhanced expression of plasma membrane scaffolding protein NHERF1. Chaperone proteins regulate this novel process, and ΔF508 CFTR binding to HSP40, HSP90, HSP70, VCP, and Aha1 changes to improve ΔF508 CFTR cell surface trafficking. Conclusion: Our results reveal a pathway in which CAL regulates the cell surface availability and intracellular retention of ΔF508 CFTR.

  8. Biophysical characterisation of calumenin as a charged F508del-CFTR folding modulator.

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    Rashmi Tripathi

    Full Text Available The cystic fibrosis transmembrane regulator (CFTR is a cyclic-AMP dependent chloride channel expressed at the apical surface of epithelial cells lining various organs such as the respiratory tract. Defective processing and functioning of this protein caused by mutations in the CFTR gene results in loss of ionic balance, defective mucus clearance, increased proliferation of biofilms and inflammation of human airways observed in cystic fibrosis (CF patients. The process by which CFTR folds and matures under the influence of various chaperones in the secretory pathway remains incompletely understood. Recently, calumenin, a secretory protein, belonging to the CREC family of low affinity calcium binding proteins has been identified as a putative CFTR chaperone whose biophysical properties and functions remain uncharacterized. We compared hydropathy, instability, charge, unfoldability, disorder and aggregation propensity of calumenin and other CREC family members with CFTR associated chaperones and calcium binding proteins, wild-type and mutant CFTR proteins and intrinsically disordered proteins (IDPs. We observed that calumenin, along with other CREC proteins, was significantly more charged and less folded compared to CFTR associated chaperones. Moreover like IDPs, calumenin and other CREC proteins were found to be less hydrophobic and aggregation prone. Phylogenetic analysis revealed a close link between calumenin and other CREC proteins indicating how evolution might have shaped their similar biophysical properties. Experimentally, calumenin was observed to significantly reduce F508del-CFTR aggregation in a manner similar to AavLEA1, a well-characterized IDP. Fluorescence microscopy based imaging analysis also revealed altered trafficking of calumenin in bronchial cells expressing F508del-CFTR, indicating its direct role in the pathophysiology of CF. In conclusion, calumenin is characterized as a charged protein exhibiting close similarity with

  9. Association between F508 deletion in CFTR and chronic pancreatitis risk. (United States)

    Zhao, Dong; Xu, Yanzhen; Li, Jiatong; Fu, Shien; Xiao, Feifan; Song, Xiaowei; Xie, Zhibin; Jiang, Min; He, Yan; Liu, Chengwu; Wen, Qiongxian; Yang, Xiaoli


    The cystic fibrosis transmembrane conductance regulator (CFTR) has been reported to influence individual susceptibility to chronic pancreatitis (CP), but the results of previous studies are controversial. We performed a study to demonstrate the relationship between CFTR and CP. We searched PubMed, Scopus, and Embase for studies of patients with CP. Seven studies from 1995 to 2016 were identified, and included 64,832 patients. Pooled prevalence and 95% confidence intervals (CIs) were calculated. F508 deletion in CFTR was significantly positively associated with CP risk in the overall analysis (odds ratio [OR]=3.20, 95% CI: 2.30-4.44, I 2 =31.7%). In subgroup analysis stratified by ethnicity, F508 deletion was significantly associated with CP risk in Indian populations, using a fixed effects model (ORs=5.45, 95% CI: 2.52-11.79, I 2 =0.0%), and in non-Indian populations, using a random effects model (ORs=3.59, 95% CI: 1.73-7.48, I 2 =60.9%). At the same time, we found that Indians with F508 deletion had much higher CP prevalence than non-Indians. Interestingly, F508 deletion was also associated with CP and idiopathic CP risk in subgroup analysis stratified by aeitiology, using the fixed effects model. Based on current evidence, F508 deletion is a risk factor for CP, and Indians with F508 deletion have much higher CP morbidity. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  10. F508del-CFTR rescue: a matter of cell stress response. (United States)

    Nieddu, Erika; Pollarolo, Benedetta; Merello, Luisa; Schenone, Silvia; Mazzei, Mauro


    Cystic fibrosis (CF) is a common inherited fatal disease affecting 70,000 people worldwide, with a median predicted age of survival of approximately 38 years. The deletion of Phenylalanine in position 508 of the Cystic Fibrosis Transmembrane conductance Regulator (F508del-CFTR) is the most common mutation in CF patients: the deleted protein, not properly folded, is degraded. To date no commercial drugs are available. Low temperature, some osmolytes and conditions able to induce heat shock protein 70 (Hsp70) expression and heat shock cognate 70 (Hsc70) inhibition result in F508del-CFTR rescue, hence restoring its physiological function: this review sheds light on the correlation between these several evidences. Interestingly, all these approaches have a role in the cell stress response (CSR), a set of cell reactions to stress. In addition, unpredictably, F508del-CFTR rescue has to be considered in the frame of CSR: entities that induce - or are induced during - the CSR are, in general, also able to correct trafficking defect of CFTR. Specifically, the low temperature induces, by definition, a CSR; osmolytes, such as glycerol and trimethylamine N-oxide (TMAO), are products of the CSR; pharmacological correctors, such as Matrine and 4-phenylbutirric acid (4PBA), down-regulate the constitutive Hsc70 in favor of an up-regulation of the inducible chaperone Hsp70, another component of the CSR. The identification of a common mechanism of action for different types of correctors could drive the discovery of new active molecules in CF, overcoming methods clinically inapplicable, such as the low temperature.

  11. Resveratrol increases F508del-CFTR dependent salivary secretion in cystic fibrosis mice

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    Barbara Dhooghe


    Full Text Available Cystic fibrosis (CF is a fatal genetic disease associated with widespread exocrine gland dysfunction. Studies have suggested activating effects of resveratrol, a naturally-occurring polyphenol compound with antioxidant and anti-inflammatory properties, on CF transmembrane conductance regulator (CFTR protein function. We assayed, in F508del-CFTR homozygous (CF and in wild-type mice, the effect of resveratrol on salivary secretion in basal conditions, in response to inhibition by atropine (basal β-adrenergic-dependent component and to stimulation by isoprenaline (CFTR-dependent component. Both components of the salivary secretion were smaller in CF mice than in controls. Two hours after intraperitoneal administration of resveratrol (50 mg/kg dissolved in DMSO, the compound was detected in salivary glands. As in both CF and in wild-type mice, DMSO alone increased the response to isoprenaline in males but not in females, the effect of resveratrol was only measured in females. In wild-type mice, isoprenaline increased secretion by more than half. In CF mice, resveratrol rescued the response to isoprenaline, eliciting a 2.5-fold increase of β-adrenergic-stimulated secretion. We conclude that the salivary secretion assay is suitable to test DMSO-soluble CFTR modulators in female mice. We show that resveratrol applied in vivo to mice reaches salivary glands and increases β-adrenergic secretion. Immunolabelling of CFTR in human bronchial epithelial cells suggests that the effect is associated with increased CFTR protein expression. Our data support the view that resveratrol is beneficial for treating CF. The salivary secretion assay has a potential application to test efficacy of novel CF therapies.

  12. Impact of the [delta]F508 Mutation in First Nucleotide-binding Domain of Human Cystic Fibrosis Transmembrane Conductance Regulator on Domain Folding and Structure

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    Lewis, Hal A.; Zhao, Xun; Wang, Chi; Sauder, J. Michael; Rooney, Isabelle; Noland, Brian W.; Lorimer, Don; Kearins, Margaret C.; Conners, Kris; Condon, Brad; Maloney, Peter C.; Guggino, William B.; Hunt, John F.; Emtage, Spencer (SG); (Columbia); (JHU)


    Cystic fibrosis is caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR), commonly the deletion of residue Phe-508 (DeltaF508) in the first nucleotide-binding domain (NBD1), which results in a severe reduction in the population of functional channels at the epithelial cell surface. Previous studies employing incomplete NBD1 domains have attributed this to aberrant folding of DeltaF508 NBD1. We report structural and biophysical studies on complete human NBD1 domains, which fail to demonstrate significant changes of in vitro stability or folding kinetics in the presence or absence of the DeltaF508 mutation. Crystal structures show minimal changes in protein conformation but substantial changes in local surface topography at the site of the mutation, which is located in the region of NBD1 believed to interact with the first membrane spanning domain of CFTR. These results raise the possibility that the primary effect of DeltaF508 is a disruption of proper interdomain interactions at this site in CFTR rather than interference with the folding of NBD1. Interestingly, increases in the stability of NBD1 constructs are observed upon introduction of second-site mutations that suppress the trafficking defect caused by the DeltaF508 mutation, suggesting that these suppressors might function indirectly by improving the folding efficiency of NBD1 in the context of the full-length protein. The human NBD1 structures also solidify the understanding of CFTR regulation by showing that its two protein segments that can be phosphorylated both adopt multiple conformations that modulate access to the ATPase active site and functional interdomain interfaces.

  13. DeltaF508 heterozygosity in cystic fibrosis and susceptibility to asthma

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    Dahl, Morten; Tybjaerg-Hansen, A; Lange, P


    Cystic fibrosis is a recessive disorder mainly characterised by lung disease. We tested the hypothesis that individuals heterozygous for the common cystic fibrosis deltaF508 mutation are at risk of obstructive pulmonary disease.......Cystic fibrosis is a recessive disorder mainly characterised by lung disease. We tested the hypothesis that individuals heterozygous for the common cystic fibrosis deltaF508 mutation are at risk of obstructive pulmonary disease....

  14. Lack of effect of delta F508 mutation on aerobic capacity in patients with cystic fibrosis. (United States)

    Kaplan, T A; Moccia-Loos, G; Rabin, M; McKey, R M


    As aerobic exercise capacity, as defined by VO2max, is associated with patient functioning and possibly prognosis in cystic fibrosis (CF), correlations between VO2max phenotype and genotype may be of value. Retrospective clinical series. Cystic fibrosis referral clinic. Convenience sample of 35 patients with CF consecutively referred for exercise testing. Blood samples were examined for mutations of cystic fibrosis transmembrane regulator (CFTR), Height, wight, pulmonary function, resting-energy expenditure, VO2max, and other exercise variables were assessed in each referred patient. Statistical comparison of 10 patients who were homozygous for the dF508 mutation of CFTR with 20 patients heterozygous for dF508 revealed no significant differences for height, weight, pulmonary function, resting-energy expenditure, VO2max, or any other exercise variables. These results imply a limited effect of the mutation status on overall patient functioning and prognosis. Future identification of more rare CFTR mutations and other genes and subsequent classification of patients in a manner reflective of the cellular physiology may lead to different results.

  15. Dendrimer-based selective autophagy-induction rescues ΔF508-CFTR and inhibits Pseudomonas aeruginosa infection in cystic fibrosis.

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    Scott Mackenzie Brockman

    Full Text Available Cystic Fibrosis (CF is a genetic disorder caused by mutation(s in the CF-transmembrane conductance regulator (Cftr gene. The most common mutation, ΔF508, leads to accumulation of defective-CFTR protein in aggresome-bodies. Additionally, Pseudomonas aeruginosa (Pa, a common CF pathogen, exacerbates obstructive CF lung pathology. In the present study, we aimed to develop and test a novel strategy to improve the bioavailability and potentially achieve targeted drug delivery of cysteamine, a potent autophagy-inducing drug with anti-bacterial properties, by developing a dendrimer (PAMAM-DEN-based cysteamine analogue.We first evaluated the effect of dendrimer-based cysteamine analogue (PAMAM-DENCYS on the intrinsic autophagy response in IB3-1 cells and observed a significant reduction in Ub-RFP and LC3-GFP co-localization (aggresome-bodies by PAMAM-DENCYS treatment as compared to plain dendrimer (PAMAM-DEN control. Next, we observed that PAMAM-DENCYS treatment shows a modest rescue of ΔF508-CFTR as the C-form. Moreover, immunofluorescence microscopy of HEK-293 cells transfected with ΔF508-CFTR-GFP showed that PAMAM-DENCYS is able to rescue the misfolded-ΔF508-CFTR from aggresome-bodies by inducing its trafficking to the plasma membrane. We further verified these results by flow cytometry and observed significant (p<0.05; PAMAM-DEN vs. PAMAM-DENCYS rescue of membrane-ΔF508-CFTR with PAMAM-DENCYS treatment using non-permeabilized IB3-1 cells immunostained for CFTR. Finally, we assessed the autophagy-mediated bacterial clearance potential of PAMAM-DENCYS by treating IB3-1 cells infected with PA01-GFP, and observed a significant (p<0.01; PAMAM-DEN vs. PAMAM-DENCYS decrease in intracellular bacterial counts by immunofluorescence microscopy and flow cytometry. Also, PAMAM-DENCYS treatment significantly inhibits the growth of PA01-GFP bacteria and demonstrates potent mucolytic properties.We demonstrate here the efficacy of dendrimer-based autophagy

  16. Stimulation of wild-type, F508del- and G551D-CFTR chloride channels by non toxic modified pyrrolo[2,3-b]pyrazine derivatives

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    Luc eDannhoffer


    Full Text Available Cystic Fibrosis is a major inherited disorder involving abnormalities of fluid and electrolyte transport in a number of different organs due to abnormal function of Cystic Fibrosis Transmembrane conductance Regulator (CFTR protein. We recently identified a family of CFTR activators, which contains the hit: RP107 [7-n-butyl-6-(4-hydroxyphenyl[5H]-pyrrolo[2,3-b]pyrazine]. Here, we further evaluated the effect of the chemical modifications of the RP107-OH radical on CFTR activation. The replacement of the OH radical by a fluorine atom at position 2 (RP193 or 4 (RP185 significantly decreased the toxicity of the compounds without altering the ability to activate CFTR, especially for RP193. The non-toxic compound RP193 has no effect on cAMP production but stimulates the channel activity of wild-type CFTR in stably transfected CHO cells, in human bronchial epithelial NuLi-1 cells and in primary culture of human bronchial epithelial cells. Whole cell and single patch clamp recordings showed that RP193 induced a linear, time and voltage-independent current, which was fully inhibited by two different and selective CFTR inhibitors (CFTRinh-172 and GPinh-5a. Moreover, RP193 stimulates CFTR in temperature-rescued CuFi-1 (F508del/F508del human bronchial epithelial cells and in CHO cells stably expressing G551D-CFTR. This study shows that it is feasible to reduce cytotoxicity of chemical compounds without affecting their potency to activate CFTR and to rescue the class 2 F508del-CFTR and class 3 G551D-CFTR CF mutant activities.

  17. Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases: an in vitro study using cell lines

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    Sampson Heidi M


    Full Text Available Abstract Background Many genetic diseases are due to defects in protein trafficking where the mutant protein is recognized by the quality control systems, retained in the endoplasmic reticulum (ER, and degraded by the proteasome. In many cases, the mutant protein retains function if it can be trafficked to its proper cellular location. We have identified structurally diverse correctors that restore the trafficking and function of the most common mutation causing cystic fibrosis, F508del-CFTR. Most of these correctors do not act directly as ligands of CFTR, but indirectly on other pathways to promote folding and correction. We hypothesize that these proteostasis regulators may also correct other protein trafficking diseases. Methods To test our hypothesis, we used stable cell lines or transient transfection to express 2 well-studied trafficking disease mutations in each of 3 different proteins: the arginine-vasopressin receptor 2 (AVPR2, also known as V2R, the human ether-a-go-go-related gene (KCNH2, also known as hERG, and finally the sulfonylurea receptor 1 (ABCC8, also known as SUR1. We treated cells expressing these mutant proteins with 9 structurally diverse F508del-CFTR correctors that function through different cellular mechanisms and assessed whether correction occurred via immunoblotting and functional assays. Results were deemed significantly different from controls by a one-way ANOVA (p  Results Here we show that F508del-CFTR correctors RDR1, KM60 and KM57 also correct some mutant alleles of other protein trafficking diseases. We also show that one corrector, the cardiac glycoside ouabain, was found to alter the glycosylation of all mutant alleles tested. Conclusions Correctors of F508del-CFTR trafficking might have broader applications to other protein trafficking diseases.

  18. Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases: an in vitro study using cell lines


    Sampson Heidi M; Lam Hung; Chen Pei-Chun; Zhang Donglei; Mottillo Cristina; Mirza Myriam; Qasim Karim; Shrier Alvin; Shyng Show-Ling; Hanrahan John W; Thomas David Y


    Abstract Background Many genetic diseases are due to defects in protein trafficking where the mutant protein is recognized by the quality control systems, retained in the endoplasmic reticulum (ER), and degraded by the proteasome. In many cases, the mutant protein retains function if it can be trafficked to its proper cellular location. We have identified structurally diverse correctors that restore the trafficking and function of the most common mutation causing cystic fibrosis, F508del-CFTR...

  19. Proinflammatory effect of sodium 4-phenylbutyrate in deltaF508-cystic fibrosis transmembrane conductance regulator lung epithelial cells: involvement of extracellular signal-regulated protein kinase 1/2 and c-Jun-NH2-terminal kinase signaling. (United States)

    Roque, Telma; Boncoeur, Emilie; Saint-Criq, Vinciane; Bonvin, Elise; Clement, Annick; Tabary, Olivier; Jacquot, Jacky


    Sodium 4-phenylbutyrate (4-PBA) has attracted a great deal of attention in cystic fibrosis (CF) pathology due to its capacity to traffic DeltaF508-cystic fibrosis transmembrane conductance regulator (CFTR) to the cell membrane and restore CFTR chloride function at the plasma membrane of CF lung cells in vitro and in vivo. Using two different DeltaF508-CFTR lung epithelial cell lines (CFBE41o- and IB3-1 cells, characterized with DeltaF508-homozygous and heterozygous genotype, respectively) in vitro, 4-PBA induced an increase of proinflammatory cytokine interleukin (IL)-8 production in a concentration-dependent manner. This 4-PBA-induced IL-8 production was associated with a strong reduction of proteasome and nuclear factor-kappaB transcriptional activities in the two DeltaF508-CFTR lung cells either in a resting state or after tumor necrosis factor-alpha stimulation. In contrast, a strong increase of activator protein-1 transcriptional activity was observed. The inhibition of extracellular signal-regulated protein kinase 1/2 (ERK1/2) by 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (U0126) and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) and c-Jun-NH(2)-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) by anthra[1,9-cd] pyrazol-6 (2H)-one (SP600125), respectively, was associated with a reduction (2-3.5-fold) of IL-8 production in both DeltaF508-CFTR lung cell lines treated with 4-PBA. No significant change of IL-8 production was observed after an inhibition of p38 MAPK with 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl] phenol (SB202190). Therefore, we suggest that inhibition of both ERK1/2 and JNK signaling may be a means to strongly reduce 4-PBA-induced IL-8 production in combination with 4-PBA treatment to restore CFTR Cl(-) channel function in lung epithelial cells of patients with CF.

  20. Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation. (United States)

    Ferrari, Eleonora; Monzani, Romina; Villella, Valeria R; Esposito, Speranza; Saluzzo, Francesca; Rossin, Federica; D'Eletto, Manuela; Tosco, Antonella; De Gregorio, Fabiola; Izzo, Valentina; Maiuri, Maria C; Kroemer, Guido; Raia, Valeria; Maiuri, Luigi


    Cystic fibrosis (CF), the most common lethal monogenic disease in Caucasians, is characterized by recurrent bacterial infections and colonization, mainly by Pseudomonas aeruginosa, resulting in unresolved airway inflammation. CF is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a chloride channel in epithelial cells, macrophages, and other cell types. Impaired bacterial handling by macrophages is a feature of CF airways, although it is still debated how defective CFTR impairs bacterial killing. Recent evidence indicates that a defective autophagy in CF macrophages leads to alterations of bacterial clearance upon infection. Here we use bone marrow-derived macrophages from transgenic mice to provide the genetic proof that defective CFTR compromises both uptake and clearance of internalized Pseudomonas aeruginosa. We demonstrate that the proteostasis regulator cysteamine, which rescues the function of the most common F508del-CFTR mutant and hence reduces lung inflammation in CF patients, can also repair the defects of CF macrophages, thus restoring both bacterial internalization and clearance through a process that involves upregulation of the pro-autophagic protein Beclin 1 and re-establishment of the autophagic pathway. Altogether these results indicate that cysteamine restores the function of several distinct cell types, including that of macrophages, which might contribute to its beneficial effects on CF.

  1. Curcumin/poly(2-methyl-2-oxazoline-b-tetrahydrofuran-b-2-methyl-2-oxazoline) formulation: An improved penetration and biological effect of curcumin in F508del-CFTR cell lines. (United States)

    Gonçalves, Cristine; Gomez, Jean-Pierre; Même, William; Rasolonjatovo, Bazoly; Gosset, David; Nedellec, Steven; Hulin, Philippe; Huin, Cécile; Le Gall, Tony; Montier, Tristan; Lehn, Pierre; Pichon, Chantal; Guégan, Philippe; Cheradame, Hervé; Midoux, Patrick


    Neutral amphiphilic triblock ABA copolymers are of great interest to solubilize hydrophobic drugs. We reported that a triblock ABA copolymer consisting of methyl-2-oxazoline (MeOx) and tetrahydrofuran (THF) (MeOx 6 -THF 19 -MeOx 6 ) (TBCP2) can solubilize curcumin (Cur) a very hydrophobic molecule exhibiting multiple therapeutic effects but whose insolubility and low stability in water is a major drawback for clinical applications. Here, we provide evidences by flow cytometry and confocal microscopy that Cur penetration in normal and ΔF508-CFTR human airway epithelial cell lines is facilitated by TBCP2. When used on ΔF508-CFTR cell lines, the Cur/TBCP2 formulation promotes the restoration of the expression of the CFTR protein in the plasma membrane. Furthermore, patch-clamp and MQAE fluorescence experiments show that this effect is associated with a correction of a Cl - selective current at the membrane surface of F508del-CFTR cells. The results show the great potential of the neutral amphiphilic triblock copolymer MeOx 6 -THF 19 -MeOx 6 as carrier for curcumin in a Cystic Fibrosis context. We anticipate that other MeOx n -THF m -MeOx n copolymers could have similar behaviours for other highly insoluble therapeutic drugs or cosmetic active ingredients. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. N- and C-alkylation of seven-membered iminosugars generates potent glucocerebrosidase inhibitors and F508del-CFTR correctors. (United States)

    Désiré, J; Mondon, M; Fontelle, N; Nakagawa, S; Hirokami, Y; Adachi, I; Iwaki, R; Fleet, G W J; Alonzi, D S; Twigg, G; Butters, T D; Bertrand, J; Cendret, V; Becq, F; Norez, C; Marrot, J; Kato, A; Blériot, Y


    The glycosidase inhibitory properties of synthetic C-alkyl and N-alkyl six-membered iminosugars have been extensively studied leading to therapeutic candidates. The related seven-membered iminocyclitols have been less examined despite the report of promising structures. Using an in house ring enlargement/C-alkylation as well as cross-metathesis methodologies as the key steps, we have undertaken the synthesis and biological evaluation of a library of fourteen 2C- and eight N-alkyl tetrahydroxylated azepanes starting from an easily available glucopyranose-derived azidolactol. Four, six, nine and twelve carbon atom alkyl chains have been introduced. The study of two distinct D-gluco and L-ido stereochemistries for the tetrol pattern as well as R and S configurations for the C-2 carbon bearing the C-alkyl chain is reported. We observed that C-alkylation of the L-ido tetrahydroxylated azepane converts it from an α-L-fucosidase to a β-glucosidase and β-galactosidase inhibitor while N-alkylation of the D-gluco iminosugar significantly improves its inhibition profile leading to potent β-glucosidase, β-galactosidase, α-L-rhamnosidase and β-glucuronidase inhibitors whatever the stereochemistry of the alkyl chain. Interestingly, the N-alkyl chain length usually parallels the azepane inhibitor potency as exemplified by the identification of a potent glucocerebrosidase inhibitor (Ki 1 μM) bearing a twelve carbon atom chain. Additionally, several C-alkyl azepanes demonstrated promising F508del-CFTR correction unlike the parent tetrahydroxyazepanes. None of the C-alkyl and N-alkyl azepanes did inhibit ER α-glucosidases I or II.

  3. Epithelial cell specific properties and genetic complementation in a delta F508 cystic fibrosis nasal polyp cell line. (United States)

    Kunzelmann, K; Lei, D C; Eng, K; Escobar, L C; Koslowsky, T; Gruenert, D C


    Analysis of vectorial ion transport and protein trafficking in transformed cystic fibrosis (CF) epithelial cells has been limited because the cells tend to lose their tight junctions with multiple subcultures. To elucidate ion transport and protein trafficking in CF epithelial cells, a polar cell line with apical and basolateral compartments will facilitate analysis of the efficacy of different gene therapy strategies in a "tight epithelium" in vitro. This study investigates the genotypic and phenotypic properties of a CF nasal polyp epithelial, delta F508 homozygote, cell line that has tight junctions pre-crisis. The cells (sigma CFNPE14o-) were transformed with an origin-of-replication defective SV40 plasmid. They develop transepithelial resistance in Ussing chambers and are defective in cAMP-dependent Cl- transport as measured by efflux of radioactive Cl-, short circuit current (Isc), or whole-cell patch clamp. Stimulation of the cells by bradykinin, histamine, or ATP seems to activate both K(+)- and Ca(+2)-dependent Cl- transport. Measurement of 36Cl- efflux following stimulation with A23187 and ionomycin indicate a Ca(+2)-dependent Cl- transport. Volume regulatory capacity of the cells is indicated by cell swelling conductance. Expression of the CF transmembrane conductance regulator mRNA was indicated by RT-PCR amplification. When cells are grown at 26 degrees C for 48 h there is no indication of cAMP-dependent Cl- as has been previously indicated in heterologous expression systems. Antibodies specific for secretory cell antigens indicate the presence of antigens found in goblet, serous, and mucous cells; in goblet and serous cells; or in goblet and mucous cells; but not antigens found exclusively in mucous or serous cells.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. EG-VEGF, BV8, and their receptor expression in human bronchi and their modification in cystic fibrosis: Impact of CFTR mutation (delF508). (United States)

    Chauvet, Sylvain; Traboulsi, Wael; Thevenon, Laura; Kouadri, Amal; Feige, Jean-Jacques; Camara, Boubou; Alfaidy, Nadia; Benharouga, Mohamed


    Enhanced lung angiogenesis has been reported in cystic fibrosis (CF). Recently, two highly homologous ligands, endocrine gland vascular endothelial growth factor (EG-VEGF) and mammalian Bv8, have been described as new angiogenic factors. Both ligands bind and activate two closely related G protein-coupled receptors, the prokineticin receptor (PROKR) 1 and 2. Yet, the expression, regulation, and potential role of EG-VEGF, BV8, and their receptors in normal and CF lung are still unknown. The expression of the receptors and their ligands was examined using molecular, biochemical, and immunocytochemistry analyses in lungs obtained from CF patients vs. control and in normal and CF bronchial epithelial cells. Cystic fibrosis transmembrane conductance regulator (CFTR) activity was evaluated in relation to both ligands, and concentrations of EG-VEGF were measured by ELISA. At the mRNA level, EG-VEGF, BV8, and PROKR2 gene expression was, respectively, approximately five, four, and two times higher in CF lungs compared with the controls. At the cellular level, both the ligands and their receptors showed elevated expressions in the CF condition. Similar results were observed at the protein level. The EG-VEGF secretion was apical and was approximately two times higher in CF compared with the normal epithelial cells. This secretion was increased following the inhibition of CFTR chloride channel activity. More importantly, EG-VEGF and BV8 increased the intracellular concentration of Ca(2+) and cAMP and stimulated CFTR-chloride channel activity. Altogether, these data suggest local roles for epithelial BV8 and EG-VEGF in the CF airway peribronchial vascular remodeling and highlighted the role of CFTR activity in both ligand biosynthesis and secretion. Copyright © 2015 the American Physiological Society.

  5. TALENs Facilitate Single-step Seamless SDF Correction of F508del CFTR in Airway Epithelial Submucosal Gland Cell-derived CF-iPSCs

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    Shingo Suzuki


    Full Text Available Cystic fibrosis (CF is a recessive inherited disease associated with multiorgan damage that compromises epithelial and inflammatory cell function. Induced pluripotent stem cells (iPSCs have significantly advanced the potential of developing a personalized cell-based therapy for diseases like CF by generating patient-specific stem cells that can be differentiated into cells that repair tissues damaged by disease pathology. The F508del mutation in airway epithelial cell-derived CF-iPSCs was corrected with small/short DNA fragments (SDFs and sequence-specific TALENs. An allele-specific PCR, cyclic enrichment strategy gave ≃100-fold enrichment of the corrected CF-iPSCs after six enrichment cycles that facilitated isolation of corrected clones. The seamless SDF-based gene modification strategy used to correct the CF-iPSCs resulted in pluripotent cells that, when differentiated into endoderm/airway-like epithelial cells showed wild-type (wt airway epithelial cell cAMP-dependent Cl ion transport or showed the appropriate cell-type characteristics when differentiated along mesoderm/hematopoietic inflammatory cell lineage pathways.

  6. Structure and Dynamics of NBD1 from CFTR Characterized Using Crystallography and Hydrogen/Deuterium Exchange Mass Spectrometry

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    Lewis, H.A.; Wang, C.; Zhao, X.; Hamuro, Y.; Conners, K.; Kearins, M.C.; Lu, F.; Sauder, J.M.; Molnar, K.S.; Coales, S.J.; Maloney, P.C.; Guggino, W.B.; Wetmore, D.R.; Weber, P.C.; Hunt, J.F. (SGX); (ExSAR); (Cystic); (JHU-MED); (Columbia)


    The {Delta}F508 mutation in nucleotide-binding domain 1 (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) is the predominant cause of cystic fibrosis. Previous biophysical studies on human F508 and {Delta}F508 domains showed only local structural changes restricted to residues 509-511 and only minor differences in folding rate and stability. These results were remarkable because {Delta}F508 was widely assumed to perturb domain folding based on the fact that it prevents trafficking of CFTR out of the endoplasmic reticulum. However, the previously reported crystal structures did not come from matched F508 and {Delta}F508 constructs, and the {Delta}F508 structure contained additional mutations that were required to obtain sufficient protein solubility. In this article, we present additional biophysical studies of NBD1 designed to address these ambiguities. Mass spectral measurements of backbone amide {sup 1}H/{sup 2}H exchange rates in matched F508 and {Delta}F508 constructs reveal that {Delta}F508 increases backbone dynamics at residues 509-511 and the adjacent protein segments but not elsewhere in NBD1. These measurements also confirm a high level of flexibility in the protein segments exhibiting variable conformations in the crystal structures. We additionally present crystal structures of a broader set of human NBD1 constructs, including one harboring the native F508 residue and others harboring the {Delta}F508 mutation in the presence of fewer and different solubilizing mutations. The only consistent conformational difference is observed at residues 509-511. The side chain of residue V510 in this loop is mostly buried in all non-{Delta}F508 structures but completely solvent exposed in all {Delta}F508 structures. These results reinforce the importance of the perturbation {Delta}F508 causes in the surface topography of NBD1 in a region likely to mediate contact with the transmembrane domains of CFTR. However, they also suggest that increased

  7. General anesthetic octanol and related compounds activate wild-type and delF508 cystic fibrosis chloride channels. (United States)

    Marcet, Brice; Becq, Frédéric; Norez, Caroline; Delmas, Patrick; Verrier, Bernard


    1. Cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is defective during cystic fibrosis (CF). Activators of the CFTR Cl(-) channel may be useful for therapy of CF. Here, we demonstrate that a range of general anesthetics like normal-alkanols (n-alkanols) and related compounds can stimulate the Cl(-) channel activity of wild-type CFTR and delF508-CFTR mutant. 2. The effects of n-alkanols like octanol on CFTR activity were measured by iodide ((125)I) efflux and patch-clamp techniques on three distinct cellular models: (1). CFTR-expressing Chinese hamster ovary cells, (2). human airway Calu-3 epithelial cells and (3). human airway JME/CF15 epithelial cells which express the delF508-CFTR mutant. 3. Our data show for the first time that n-alkanols activate both wild-type CFTR and delF508-CFTR mutant. Octanol stimulated (125)I efflux in a dose-dependent manner in CFTR-expressing cells (wild-type and delF508) but not in cell lines lacking CFTR. (125)I efflux and Cl(-) currents induced by octanol were blocked by glibenclamide but insensitive to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, as expected for a CFTR Cl(-) current. 4. CFTR activation by octanol was neither due to cell-to-cell uncoupling properties of octanol nor to an intracellular cAMP increase. CFTR activation by octanol requires phosphorylation by protein kinase-A (PKA) since it was prevented by H-89, a PKA inhibitor. 5. n-Alkanols chain length was an important determinant for channel activation, with rank order of potencies: 1-heptanoloctanoloctanol<1-decanol. Our findings may be of valuable interest for developing novel therapeutic strategies for CF.

  8. General anesthetic octanol and related compounds activate wild-type and delF508 cystic fibrosis chloride channels


    Marcet, Brice; Becq, Frédéric; Norez, Caroline; Delmas, Patrick; Verrier, Bernard


    Cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel is defective during cystic fibrosis (CF). Activators of the CFTR Cl− channel may be useful for therapy of CF. Here, we demonstrate that a range of general anesthetics like normal-alkanols (n-alkanols) and related compounds can stimulate the Cl− channel activity of wild-type CFTR and delF508-CFTR mutant.The effects of n-alkanols like octanol on CFTR activity were measured by iodide (125I) efflux and patch-clamp techniques o...

  9. Highly preferential association of NonF508del CF mutations with the M470 allele. (United States)

    Ciminelli, B M; Bonizzato, A; Bombieri, C; Pompei, F; Gabaldo, M; Ciccacci, C; Begnini, A; Holubova, A; Zorzi, P; Piskackova, T; Macek, M; Castellani, C; Modiano, G; Pignatti, P F


    On the basis of previous findings on random individuals, we hypothesized a preferential association of CF causing mutations with the M allele of the M470V polymorphic site of the CFTR gene. We have determined the M/V-CF mutation haplotype in a series of 201 North East Italian and 73 Czech CF patients who were not F508del homozygotes, as F508del was already known to be fully associated with the M allele. Out of 358 not F508del CF genes, 84 carried the V allele and 274 the less common M allele. In the N-E Italian population, MM subjects have a risk of carrying a CF causing mutation 6.9x greater than VV subjects when F508del is excluded and 15.4x when F508del is included. In the Czech population a similar, although less pronounced, association is observed. Besides the possible biological significance of this association, the possibility of exploiting it for a pilot screening program has been explored in a local North East Italian population for which CF patients were characterized for their CF mutation. General M470V genotyping followed by common CF mutation screening limited to couples in which each partner carries at least one M allele would need testing only 39% of the couples, which contribute 89% of the total risk, with a cost benefit.

  10. Structures of a minimal human CFTR first nucleotide-binding domain as a monomer, head-to-tail homodimer, and pathogenic mutant

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    Atwell, Shane; Brouillette, Christie G.; Conners, Kris; Emtage, Spencer; Gheyi, Tarun; Guggino, William B.; Hendle, Jorg; Hunt, John F.; Lewis, Hal A.; Lu, Frances; Protasevich, Irina I.; Rodgers, Logan A.; Romero, Rich; Wasserman, Stephen R.; Weber, Patricia C.; Wetmore, Diana; Zhang, Feiyu F.; Zhao, Xun (Cystic); (UAB); (JHU); (Columbia); (Lilly)


    Upon removal of the regulatory insert (RI), the first nucleotide binding domain (NBD1) of human cystic fibrosis transmembrane conductance regulator (CFTR) can be heterologously expressed and purified in a form that remains stable without solubilizing mutations, stabilizing agents or the regulatory extension (RE). This protein, NBD1 387-646({Delta}405-436), crystallizes as a homodimer with a head-to-tail association equivalent to the active conformation observed for NBDs from symmetric ATP transporters. The 1.7-{angstrom} resolution X-ray structure shows how ATP occupies the signature LSGGQ half-site in CFTR NBD1. The {Delta}F508 version of this protein also crystallizes as a homodimer and differs from the wild-type structure only in the vicinity of the disease-causing F508 deletion. A slightly longer construct crystallizes as a monomer. Comparisons of the homodimer structure with this and previously published monomeric structures show that the main effect of ATP binding at the signature site is to order the residues immediately preceding the signature sequence, residues 542-547, in a conformation compatible with nucleotide binding. These residues likely interact with a transmembrane domain intracellular loop in the full-length CFTR channel. The experiments described here show that removing the RI from NBD1 converts it into a well-behaved protein amenable to biophysical studies yielding deeper insights into CFTR function.

  11. Important role of platelets in modulating endotoxin-induced lung inflammation in CFTR-deficient mice.

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    Caiqi Zhao

    Full Text Available Mutation of CFTR (cystic fibrosis transmembrane conductance regulator leads to cystic fibrosis (CF. Patients with CF develop abnormalities of blood platelets and recurrent lung inflammation. However, whether CFTR-mutated platelets play a role in the development of lung inflammation is elusive. Therefore, we intratracheally challenged wildtype and F508del (a common type of CFTR mutation mice with LPS to observe changes of F508del platelets in the peripheral blood and indexes of lung inflammation (BAL neutrophils and protein levels. Furthermore, we investigated whether or not and how F508del platelets modulate the LPS-induced acute lung inflammation by targeting anti-platelet aggregation, depletion of neutrophils, reconstitution of bone marrow or neutrophils, blockade of P-selectin glycoprotein ligand-1 (PSGL-1, platelet activating factor (PAF, and correction of mutated CFTR trafficking. We found that LPS-challenged F508del mice developed severe thrombocytopenia and had higher levels of plasma TXB2 coincided with neutrophilic lung inflammation relative to wildtype control. Inhibition of F508del platelet aggregation or depletion of F508del neutrophils diminished the LPS-induced lung inflammation in the F508del mice. Moreover, wildtype mice reconstituted with either F508del bone marrow or neutrophils developed worse thrombocytopenia. Blocking PSGL-1, platelet activating factor (PAF, or rectifying trafficking of mutated CFTR in F508del mice diminished and alveolar neutrophil transmigration in the LPS-challenged F508del mice. These findings suggest that F508del platelets and their interaction with neutrophils are requisite for the development of LPS-induced lung inflammation and injury. As such, targeting platelets might be an emerging strategy for dampening recurrent lung inflammation in cystic fibrosis patients.

  12. The cystic-fibrosis-associated ΔF508 mutation confers post-transcriptional destabilization on the C. elegans ABC transporter PGP-3

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    Liping He


    Membrane proteins make up ∼30% of the proteome. During the early stages of maturation, this class of proteins can experience localized misfolding in distinct cellular compartments, such as the cytoplasm, endoplasmic reticulum (ER lumen and ER membrane. ER quality control (ERQC mechanisms monitor folding and determine whether a membrane protein is appropriately folded or is misfolded and warrants degradation. ERQC plays crucial roles in human diseases, such as cystic fibrosis, in which deletion of a single amino acid (F508 results in the misfolding and degradation of the cystic fibrosis transmembrane conductance regulator (CFTR Cl– channel. We introduced the ΔF508 mutation into Caenorhabditis elegans PGP-3, a 12-transmembrane ABC transporter with 15% identity to CFTR. When expressed in intestinal epithelial cells, PGP-3wt was stable and efficiently trafficked to the apical plasma membrane through a COPII-dependent mechanism. However, PGP-3ΔF508 was post-transcriptionally destabilized, resulting in reduced total and apical membrane protein levels. Genetic or physiological activation of the osmotic stress response pathway, which causes accumulation of the chemical chaperone glycerol, stabilized PGP-3ΔF508. Efficient degradation of PGP-3ΔF508 required the function of several C. elegans ER-associated degradation (ERAD homologs, suggesting that destabilization occurs through an ERAD-type mechanism. Our studies show that the ΔF508 mutation causes post-transcriptional destabilization and degradation of PGP-3 in C. elegans epithelial cells. This model, combined with the power of C. elegans genetics, provides a new opportunity to genetically dissect metazoan ERQC.

  13. Targeting the intracellular environment in cystic fibrosis: restoring autophagy as a novel strategy to circumvent the CFTR defect

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    Valeria Rachela Villella


    Full Text Available Cystic fibrosis (CF patients harboring the most common deletion mutation of the cystic fibrosis transmembrane conductance regulator (CFTR, F508del, are poor responders to potentiators of CFTR channel activity which can be used to treat a small subset of CF patients who genetically carry plasma membrane-resident CFTR mutants. The misfolded F508del-CFTR protein is unstable in the plasma membrane even if rescued by pharmacological agents that prevent its intracellular retention and degradation. CF is a conformational disease in which defective CFTR induces an impressive derangement of general proteostasis resulting from disabled autophagy. In this review, we discuss how rescuing Beclin 1 (BECN1, a major player of autophagosome formation, either by means of direct gene transfer or indirectly by administration of proteostasis regulators, could stabilize F508del-CFTR at the plasma membrane. We focus on the relationship between the improvement of peripheral proteostasis and CFTR plasma membrane stability in F508del-CFTR homozygous bronchial epithelia or mouse lungs. Moreover, this article reviews recent preclinical evidence indicating that targeting the intracellular environment surrounding the misfolded mutant CFTR instead of protein itself could constitute an attractive therapeutic option to sensitize patients carrying the F508del-CFTR mutation to the beneficial action of CFTR potentiators on lung inflammation.

  14. Targeting the Intracellular Environment in Cystic Fibrosis: Restoring Autophagy as a Novel Strategy to Circumvent the CFTR Defect (United States)

    Villella, Valeria Rachela; Esposito, Speranza; Bruscia, Emanuela M.; Maiuri, Maria Chiara; Raia, Valeria; Kroemer, Guido; Maiuri, Luigi


    Cystic fibrosis (CF) patients harboring the most common deletion mutation of the CF transmembrane conductance regulator (CFTR), F508del, are poor responders to potentiators of CFTR channel activity which can be used to treat a small subset of CF patients who genetically carry plasma membrane (PM)-resident CFTR mutants. The misfolded F508del-CFTR protein is unstable in the PM even if rescued by pharmacological agents that prevent its intracellular retention and degradation. CF is a conformational disease in which defective CFTR induces an impressive derangement of general proteostasis resulting from disabled autophagy. In this review, we discuss how rescuing Beclin 1 (BECN1), a major player of autophagosome formation, either by means of direct gene transfer or indirectly by administration of proteostasis regulators, could stabilize F508del-CFTR at the PM. We focus on the relationship between the improvement of peripheral proteostasis and CFTR PM stability in F508del-CFTR homozygous bronchial epithelia or mouse lungs. Moreover, this article reviews recent pre-clinical evidence indicating that targeting the intracellular environment surrounding the misfolded mutant CFTR instead of protein itself could constitute an attractive therapeutic option to sensitize patients carrying the F508del-CFTR mutation to the beneficial action of CFTR potentiators on lung inflammation. PMID:23346057

  15. Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients

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    Mercier, B.; Verlingue, C.; Audrezet, M.P.; Ferec, C. [Centre de Biogenetique C.D.T.S., Brest (France); Lissens, W.; Bonduelle, M. [University Hospital VUB, Brussels (United Kingdom); Silber, S.J. [St. Luke`s Hospital, St. Louis, MO (United States); Novelli, G. [Catholic Univ. of Rome (Italy)


    Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of sterility in men. Although the genetic basis of this condition is still unclear, it has been shown recently that some of these patients carry mutations in their cystic fibrosis transmembrane conductance regulator (CFTR) genes. To extend this observation, we have analyzed the entire coding sequence of the CFTR gene in a cohort of 67 men with CBAVD, who are otherwise healthy. We have identified four novel missense mutations (A800G, G149R, R258G, and E193K). We have shown that 42% of subjects were carriers of one CFTR allele and that 24% are compound heterozygous for CFTR alleles. Thus, we have been unable to identify 76% of these patients as carrying two CFTR mutations. Furthermore, we have described the segregation of CFTR haplotypes in the family of one CBAVD male; in this family are two male siblings, with identical CFTR loci but displaying different phenotypes, one of them being fertile and the other sterile. The data presented in this family, indicating a discordance between the CBAVD phenotype and a marked carrier ({delta}F508) chromosome, support the involvement of another gene(s), in the etiology of CBAVD. 35 refs., 2 figs., 1 tab.

  16. Assembly and misassembly of cystic fibrosis transmembrane conductance regulator: folding defects caused by deletion of F508 occur before and after the calnexin-dependent association of membrane spanning domain (MSD) 1 and MSD2. (United States)

    Rosser, Meredith F N; Grove, Diane E; Chen, Liling; Cyr, Douglas M


    Cystic fibrosis transmembrane conductance regulator (CFTR) is a polytopic membrane protein that functions as a Cl(-) channel and consists of two membrane spanning domains (MSDs), two cytosolic nucleotide binding domains (NBDs), and a cytosolic regulatory domain. Cytosolic 70-kDa heat shock protein (Hsp70), and endoplasmic reticulum-localized calnexin are chaperones that facilitate CFTR biogenesis. Hsp70 functions in both the cotranslational folding and posttranslational degradation of CFTR. Yet, the mechanism for calnexin action in folding and quality control of CFTR is not clear. Investigation of this question revealed that calnexin is not essential for CFTR or CFTRDeltaF508 degradation. We identified a dependence on calnexin for proper assembly of CFTR's membrane spanning domains. Interestingly, efficient folding of NBD2 was also found to be dependent upon calnexin binding to CFTR. Furthermore, we identified folding defects caused by deletion of F508 that occurred before and after the calnexin-dependent association of MSD1 and MSD2. Early folding defects are evident upon translation of the NBD1 and R-domain and are sensed by the RMA-1 ubiquitin ligase complex.

  17. Lipoxin A4 and platelet activating factor are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice.

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    Haiya Wu

    Full Text Available CFTR (cystic fibrosis transmembrane conductance regulator is expressed by both neutrophils and platelets. Lack of functional CFTR could lead to severe lung infection and inflammation. Here, we found that mutation of CFTR (F508del or inhibition of CFTR in mice led to more severe thrombocytopenia, alveolar neutrocytosis and bacteriosis, and lower lipoxin A4/MIP-2 (macrophage inhibitory protein-2 or lipoxin A4/neutrophil ratios in the BAL (bronchoalveolar lavage during acute E. coli pneumonia. In vitro, inhibition of CFTR promotes MIP-2 production in LPS-stimulated neutrophils; however, lipoxin A4 could dose-dependently suppress this effect. In LPS-induced acute lung inflammation, blockade of PSGL-1 (P-selectin glycoprotein ligand-1 or P-selectin, antagonism of PAF by WEB2086, or correction of mutated CFTR trafficking by KM11060 could significantly increase plasma lipoxin A4 levels in F508del relevant to wildtype mice. Concurrently, F508del mice had higher plasma platelet activating factor (PAF levels and PAF-AH activity compared to wildtype under LPS challenge. Inhibiting hydrolysis of PAF by a specific PAF-AH (PAF-acetylhydrolase inhibitor, MAFP, could worsen LPS-induced lung inflammation in F508del mice compared to vehicle treated F508del group. Particularly, depletion of platelets in F508del mice could significantly decrease plasma lipoxin A4 and PAF-AH activity and deteriorate LPS-induced lung inflammation compared to control F508del mice. Taken together, lipoxin A4 and PAF are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice, suggesting that lipoxin A4 and PAF might be therapeutic targets for ameliorating CFTR-deficiency deteriorated lung inflammation.

  18. Insulin-like growth factor 1 (IGF-1 enhances the protein expression of CFTR.

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    Ha Won Lee

    Full Text Available Low levels of insulin-like growth factor 1 (IGF-1 have been observed in the serum of cystic fibrosis (CF patients. However, the effects of low serum IGF-1 on the cystic fibrosis transmembrane conductance regulator (CFTR, whose defective function is the primary cause of cystic fibrosis, have not been studied. Here, we show in human cells that IGF-1 increases the steady-state levels of mature wildtype CFTR in a CFTR-associated ligand (CAL- and TC10-dependent manner; moreover, IGF-1 increases CFTR-mediated chloride transport. Using an acceptor photobleaching fluorescence resonance energy transfer (FRET assay, we have confirmed the binding of CAL and CFTR in the Golgi. We also show that CAL overexpression inhibits forskolin-induced increases in the cell-surface expression of CFTR. We found that IGF-1 activates TC10, and active TC10 alters the functional association between CAL and CFTR. Furthermore, IGF-1 and active TC10 can reverse the CAL-mediated reduction in the cell-surface expression of CFTR. IGF-1 does not increase the expression of ΔF508 CFTR, whose processing is arrested in the ER. This finding is consistent with our observation that IGF-1 alters the functional interaction of CAL and CFTR in the Golgi. However, when ΔF508 CFTR is rescued with low temperature or the corrector VRT-325 and proceeds to the Golgi, IGF-1 can increase the expression of the rescued ΔF508 CFTR. Our data support a model indicating that CAL-CFTR binding in the Golgi inhibits CFTR trafficking to the cell surface, leading CFTR to the degradation pathway instead. IGF-1-activated TC10 changes the interaction of CFTR and CAL, allowing CFTR to progress to the plasma membrane. These findings offer a potential strategy using a combinational treatment of IGF-1 and correctors to increase the post-Golgi expression of CFTR in cystic fibrosis patients bearing the ΔF508 mutation.

  19. Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants. (United States)

    Chin, Stephanie; Hung, Maurita; Bear, Christine E


    Cystic fibrosis transmembrane conductance regulator (CFTR) channel gating is predominantly regulated by protein kinase A (PKA)-dependent phosphorylation. In addition to regulating CFTR channel activity, PKA phosphorylation is also involved in enhancing CFTR trafficking and mediating conformational changes at the interdomain interfaces of the protein. The major cystic fibrosis (CF)-causing mutation is the deletion of phenylalanine at position 508 (F508del); it causes many defects that affect CFTR trafficking, stability, and gating at the cell surface. Due to the multiple roles of PKA phosphorylation, there is growing interest in targeting PKA-dependent signaling for rescuing the trafficking and functional defects of F508del-CFTR. This review will discuss the effects of PKA phosphorylation on wild-type CFTR, the consequences of CF mutations on PKA phosphorylation, and the development of therapies that target PKA-mediated signaling.

  20. Computational design of a PDZ domain peptide inhibitor that rescues CFTR activity.

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    Kyle E Roberts

    Full Text Available The cystic fibrosis transmembrane conductance regulator (CFTR is an epithelial chloride channel mutated in patients with cystic fibrosis (CF. The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators ("potentiators" and "correctors", but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL, which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called "stabilizers" that rescue ΔF508-CFTR activity. To design the "stabilizers", we extended our structural ensemble-based computational protein redesign algorithm K* to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01 binds six-fold more tightly than the previous best hexamer (iCAL35, and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods.

  1. Sphingosine-1-Phosphate Is a Novel Regulator of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR Activity.

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    Firhan A Malik

    Full Text Available The cystic fibrosis transmembrane conductance regulator (CFTR attenuates sphingosine-1-phosphate (S1P signaling in resistance arteries and has emerged as a prominent regulator of myogenic vasoconstriction. This investigation demonstrates that S1P inhibits CFTR activity via adenosine monophosphate-activated kinase (AMPK, establishing a potential feedback link. In Baby Hamster Kidney (BHK cells expressing wild-type human CFTR, S1P (1μmol/L attenuates forskolin-stimulated, CFTR-dependent iodide efflux. S1P's inhibitory effect is rapid (within 30 seconds, transient and correlates with CFTR serine residue 737 (S737 phosphorylation. Both S1P receptor antagonism (4μmol/L VPC 23019 and AMPK inhibition (80μmol/L Compound C or AMPK siRNA attenuate S1P-stimluated (i AMPK phosphorylation, (ii CFTR S737 phosphorylation and (iii CFTR activity inhibition. In BHK cells expressing the ΔF508 CFTR mutant (CFTRΔF508, the most common mutation causing cystic fibrosis, both S1P receptor antagonism and AMPK inhibition enhance CFTR activity, without instigating discernable correction. In summary, we demonstrate that S1P/AMPK signaling transiently attenuates CFTR activity. Since our previous work positions CFTR as a negative S1P signaling regulator, this signaling link may positively reinforce S1P signals. This discovery has clinical ramifications for the treatment of disease states associated with enhanced S1P signaling and/or deficient CFTR activity (e.g. cystic fibrosis, heart failure. S1P receptor/AMPK inhibition could synergistically enhance the efficacy of therapeutic strategies aiming to correct aberrant CFTR trafficking.

  2. The human CFTR protein expressed in CHO cells activates aquaporin-3 in a cAMP-dependent pathway: study by digital holographic microscopy

    KAUST Repository

    Jourdain, P.


    The transmembrane water movements during cellular processes and their relationship to ionic channel activity remain largely unknown. As an example, in epithelial cells it was proposed that the movement of water could be directly linked to cystic fibrosis transmembrane conductance regulator (CFTR) protein activity through a cAMP-stimulated aqueous pore, or be dependent on aquaporin. Here, we used digital holographic microscopy (DHM) an interferometric technique to quantify in situ the transmembrane water fluxes during the activity of the epithelial chloride channel, CFTR, measured by patch-clamp and iodide efflux techniques. We showed that the water transport measured by DHM is fully inhibited by the selective CFTR blocker CFTRinh172 and is absent in cells lacking CFTR. Of note, in cells expressing the mutated version of CFTR (F508del-CFTR), which mimics the most common genetic alteration encountered in cystic fibrosis, we also show that the water movement is profoundly altered but restored by pharmacological manipulation of F508del-CFTR-defective trafficking. Importantly, whereas activation of this endogenous water channel required a cAMP-dependent stimulation of CFTR, activation of CFTR or F508del-CFTR by two cAMP-independent CFTR activators, genistein and MPB91, failed to trigger water movements. Finally, using a specific small-interfering RNA against the endogenous aquaporin AQP3, the water transport accompanying CFTR activity decreased. We conclude that water fluxes accompanying CFTR activity are linked to AQP3 but not to a cAMP-stimulated aqueous pore in the CFTR protein.

  3. Rescuing mutant CFTR: a multi-task approach to a better outcome in treating cystic fibrosis. (United States)

    Amaral, Margarida D; Farinha, Carlos M


    Correcting multiple defects of mutant CFTR with small molecule compounds has been the goal of an increasing number of recent Cystic Fibrosis (CF) drug discovery programmes. However, the mechanism of action (MoA) by which these molecules restore mutant CFTR is still poorly understood, in particular of CFTR correctors, i.e., compounds rescuing to the cells surface the most prevalent mutant in CF patients--F508del-CFTR. However, there is increasing evidence that to fully restore the multiple defects associated with F508del-CFTR, different small molecules with distinct corrective properties may be required. Towards this goal, a better insight into MoA of correctors is needed and several constraints should be addressed. The methodological approaches to achieve this include: 1) testing the combined effect of compounds with that of other (non-pharmacological) rescuing strategies (e.g., revertants or low temperature); 2) assessing effects in multiple cellular models (non-epithelial vs epithelial, non-human vs human, immortalized vs primary cultures, polarized vs non polarized, cells vs tissues); 3) assessing compound effects on isolated CFTR domains (e.g., compound binding by surface plasmon resonance, assessing effects on domain folding and aggregation); and finally 4) assessing compounds specificity in rescuing different CFTR mutants and other mutant proteins. These topics are reviewed and discussed here so as to provide a state-of-the art review on how to combine multiple ways of rescuing mutant CFTR to the ultimate benefit of CF patients.

  4. Cystic fibrosis transmembrane conductance regulator (CFTR allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients.

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    Serena Schippa

    Full Text Available INTRODUCTION: In this study we investigated the effects of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR gene variants on the composition of faecal microbiota, in patients affected by Cystic Fibrosis (CF. CFTR mutations (F508del is the most common lead to a decreased secretion of chloride/water, and to mucus sticky secretions, in pancreas, respiratory and gastrointestinal tracts. Intestinal manifestations are underestimated in CF, leading to ileum meconium at birth, or small bowel bacterial overgrowth in adult age. METHODS: Thirty-six CF patients, fasting and under no-antibiotic treatment, were CFTR genotyped on both alleles. Faecal samples were subjected to molecular microbial profiling through Temporal Temperature Gradient Electrophoresis and species-specific PCR. Ecological parameters and multivariate algorithms were employed to find out if CFTR variants could be related to the microbiota structure. RESULTS: Patients were classified by two different criteria: 1 presence/absence of F508del mutation; 2 disease severity in heterozygous and homozygous F508del patients. We found that homozygous-F508del and severe CF patients exhibited an enhanced dysbiotic faecal microbiota composition, even within the CF cohort itself, with higher biodiversity and evenness. We also found, by species-specific PCR, that potentially harmful species (Escherichia coli and Eubacterium biforme were abundant in homozygous-F508del and severe CF patients, while beneficial species (Faecalibacterium prausnitzii, Bifidobacterium spp., and Eubacterium limosum were reduced. CONCLUSIONS: This is the first report that establishes a link among CFTR variants and shifts in faecal microbiota, opening the way to studies that perceive CF as a 'systemic disease', linking the lung and the gut in a joined axis.

  5. Cystic fibrosis transmembrane conductance regulator (CFTR) allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients. (United States)

    Schippa, Serena; Iebba, Valerio; Santangelo, Floriana; Gagliardi, Antonella; De Biase, Riccardo Valerio; Stamato, Antonella; Bertasi, Serenella; Lucarelli, Marco; Conte, Maria Pia; Quattrucci, Serena


    In this study we investigated the effects of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene variants on the composition of faecal microbiota, in patients affected by Cystic Fibrosis (CF). CFTR mutations (F508del is the most common) lead to a decreased secretion of chloride/water, and to mucus sticky secretions, in pancreas, respiratory and gastrointestinal tracts. Intestinal manifestations are underestimated in CF, leading to ileum meconium at birth, or small bowel bacterial overgrowth in adult age. Thirty-six CF patients, fasting and under no-antibiotic treatment, were CFTR genotyped on both alleles. Faecal samples were subjected to molecular microbial profiling through Temporal Temperature Gradient Electrophoresis and species-specific PCR. Ecological parameters and multivariate algorithms were employed to find out if CFTR variants could be related to the microbiota structure. Patients were classified by two different criteria: 1) presence/absence of F508del mutation; 2) disease severity in heterozygous and homozygous F508del patients. We found that homozygous-F508del and severe CF patients exhibited an enhanced dysbiotic faecal microbiota composition, even within the CF cohort itself, with higher biodiversity and evenness. We also found, by species-specific PCR, that potentially harmful species (Escherichia coli and Eubacterium biforme) were abundant in homozygous-F508del and severe CF patients, while beneficial species (Faecalibacterium prausnitzii, Bifidobacterium spp., and Eubacterium limosum) were reduced. This is the first report that establishes a link among CFTR variants and shifts in faecal microbiota, opening the way to studies that perceive CF as a 'systemic disease', linking the lung and the gut in a joined axis.

  6. Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene

    Energy Technology Data Exchange (ETDEWEB)

    Mercier, B.; Audrezet, M.P.; Guillermit, H.; Quere, I.; Verlingue, C.; Ferec, C. (CDTS, Brest (France)); Lissens, W.; Bonduelle, M.; Liebaers, I. (University Hospital VUB, Brussels (Belgium)); Novelli, G.; Sangiuolo, F.; Dallapiccola, B. (IRCCS, Rotondo (Italy)); Kalaydjieva, L. (Inst. of Obstetrics, Sofia (Bulgaria)); Arce, M. De; Cashman, S. (Trinity College, Dublin (Ireland)); Kapranov, N. (NRC of medical Genetics, Moscow (Russian Federation)); Canki Klain, N. (Tozd Univerzitetna Ginekoloska Klinika, Ljubljana (Yugoslavia)); Lenoir, G. (Hopital des Enfants Malades Necker, Paris (France)); Chauveau, P. (Centre Hospitalier General, Le Havre (France)); Lanaerts, C. (Centre Hospitalier Regional et Universitaire, Amiens (France)); Rault, G. (Centre Helio-Marin, Roscoff (France))


    Cystic fibrosis transmembrane conductance regulator (CFTR), the gene responsible, when mutated, for cystic fibrosis (CF), spans over 230 kb on the long arm of chromosome 7 and is composed of 27 exons. The most common mutation responsible for CF worldwide is the deletion of a phenylalanine amino acid at codon 508 in the first nucleotide-binding fold and accounts for approximately 70% of CF chromosomes studied. More than 250 other mutations have been reported through the CF Genetic Analysis Consortium. The majority of the mutations previously described lie in the two nucleotide-binding folds. To explore exhaustively other regions of the gene, particularly exons coding for transmembrane domains, the authors have initiated a collaborative study between different laboratories to screen 369 non-[Delta]F508 CF chromosomes of seven ethnic European populations (Belgian, French, Breton, Irish, Italian, Yugoslavian, Russian). Among these chromosomes carrying an unidentified mutation, 63 were from Brittany, 50 of various French origin, 45 of Irish origin, 56 of Italian origin, 41 of Belgian origin, 2 of Turkish origin, 38 of Yugoslavian origin, 22 of Russian origin, and 52 of Bulgarian origin. Diagnostic criteria for CF included at least one positive sweat test and pulmonary disease with or without pancreatic disease. Using a denaturing gradient gel electrophoresis (DGGE) assay, they have identified eight novel mutations in exon 17b coding for part of the second transmembrane domain of the CFTR and they describe them in this report. 8 refs., 1 fig., 1 tab.

  7. Determination of CFTR densities in erythrocyte plasma membranes using recognition imaging

    Energy Technology Data Exchange (ETDEWEB)

    Ebner, Andreas; Hinterdorfer, Peter [Institute for Biophysics, University of Linz, A-4040 Linz (Austria); Nikova, Dessy; Lange, Tobias; Bruns, Reimer; Oberleithner, Hans; Schillers, Hermann [Institute of Physiology II, University of Muenster, D-48149 Muenster (Germany); Haeberle, Johannes; Falk, Sabine; Duebbers, Angelika [Department of Pediatrics, University Hospitals of Muenster, D-48149 Muenster (Germany)], E-mail:


    CFTR (cystic fibrosis transmembrane conductance regulator) is a cAMP-regulated chloride (Cl{sup -}) channel that plays an important role in salt and fluid movement across epithelia. Cystic fibrosis (CF), the most common genetic disease among Caucasians, is caused by mutations in the gene encoding CFTR. The most predominant mutation, F508del, disturbs CFTR protein trafficking, resulting in a reduced number of CFTR in the plasma membrane. Recent studies indicate that CFTR is not only found in epithelia but also in human erythrocytes. Although considerable attempts have been made to quantify CFTR in cells, conclusions on numbers of CFTR molecules localized in the plasma membrane have been drawn indirectly. AFM has the power to provide the needed information, since both sub-molecular spatial resolution and direct protein recognition via antibody-antigen interaction can be observed. We performed a quantification study of the CFTR copies in erythrocyte membranes at the single molecule level, and compared the difference between healthy donors and CF patients. We detected that the number of CFTR molecules is reduced by 70% in erythrocytes of cystic fibrosis patients.

  8. Determination of CFTR densities in erythrocyte plasma membranes using recognition imaging

    International Nuclear Information System (INIS)

    Ebner, Andreas; Hinterdorfer, Peter; Nikova, Dessy; Lange, Tobias; Bruns, Reimer; Oberleithner, Hans; Schillers, Hermann; Haeberle, Johannes; Falk, Sabine; Duebbers, Angelika


    CFTR (cystic fibrosis transmembrane conductance regulator) is a cAMP-regulated chloride (Cl - ) channel that plays an important role in salt and fluid movement across epithelia. Cystic fibrosis (CF), the most common genetic disease among Caucasians, is caused by mutations in the gene encoding CFTR. The most predominant mutation, F508del, disturbs CFTR protein trafficking, resulting in a reduced number of CFTR in the plasma membrane. Recent studies indicate that CFTR is not only found in epithelia but also in human erythrocytes. Although considerable attempts have been made to quantify CFTR in cells, conclusions on numbers of CFTR molecules localized in the plasma membrane have been drawn indirectly. AFM has the power to provide the needed information, since both sub-molecular spatial resolution and direct protein recognition via antibody-antigen interaction can be observed. We performed a quantification study of the CFTR copies in erythrocyte membranes at the single molecule level, and compared the difference between healthy donors and CF patients. We detected that the number of CFTR molecules is reduced by 70% in erythrocytes of cystic fibrosis patients

  9. From the endoplasmic reticulum to the plasma membrane: mechanisms of CFTR folding and trafficking. (United States)

    Farinha, Carlos M; Canato, Sara


    CFTR biogenesis starts with its co-translational insertion into the membrane of endoplasmic reticulum and folding of the cytosolic domains, towards the acquisition of a fully folded compact native structure. Efficiency of this process is assessed by the ER quality control system that allows the exit of folded proteins but targets unfolded/misfolded CFTR to degradation. If allowed to leave the ER, CFTR is modified at the Golgi and reaches the post-Golgi compartments to be delivered to the plasma membrane where it functions as a cAMP- and phosphorylation-regulated chloride/bicarbonate channel. CFTR residence at the membrane is a balance of membrane delivery, endocytosis, and recycling. Several adaptors, motor, and scaffold proteins contribute to the regulation of CFTR stability and are involved in continuously assessing its structure through peripheral quality control systems. Regulation of CFTR biogenesis and traffic (and its dysregulation by mutations, such as the most common F508del) determine its overall activity and thus contribute to the fine modulation of chloride secretion and hydration of epithelial surfaces. This review covers old and recent knowledge on CFTR folding and trafficking from its synthesis to the regulation of its stability at the plasma membrane and highlights how several of these steps can be modulated to promote the rescue of mutant CFTR.

  10. CFTR Genotype and Maximal Exercise Capacity in Cystic Fibrosis: A Cross-sectional Study. (United States)

    Radtke, Thomas; Hebestreit, Helge; Gallati, Sabina; Schneiderman, Jane E; Braun, Julia; Stevens, Daniel; Hulzebos, Erik Hj; Takken, Tim; Boas, Steven R; Urquhart, Don S; Lands, Larry C; Tejero, Sergio; Sovtic, Aleksandar; Dwyer, Tiffany; Petrovic, Milos; Harris, Ryan A; Karila, Chantal; Savi, Daniela; Usemann, Jakob; Mei-Zahav, Meir; Hatziagorou, Elpis; Ratjen, Felix; Kriemler, Susi


    Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human skeletal muscle cells. Variations of CFTR dysfunction among patients with cystic fibrosis may be an important determinant of maximal exercise capacity in cystic fibrosis. Previous studies on the relationship between CFTR genotype and maximal exercise capacity are scarce and contradictory. This study was designed to explore factors influencing maximal exercise capacity, expressed as peak oxygen uptake (V.O2peak), with a specific focus on CFTR genotype in children and adults with cystic fibrosis. In an international, multicenter, cross-sectional study, we collected data on CFTR genotype and cardiopulmonary exercise tests in patients with cystic fibrosis who were ages 8 years and older. CFTR mutations were classified into functional classes I–V. The final analysis included 726 patients (45% females; age range, 8–61 yr; forced expiratory volume in 1 s, 16 to 123% predicted) from 17 cystic fibrosis centers in North America, Europe, Australia, and Asia, all of whom had both valid maximal cardiopulmonary exercise tests and complete CFTR genotype data. Overall, patients exhibited exercise intolerance (V.O2peak, 77.3 ± 19.1% predicted), but values were comparable among different CFTR classes. We did not detect an association between CFTR genotype functional classes I–III and either V.O2peak (percent predicted) (adjusted β = −0.95; 95% CI, −4.18 to 2.29; P = 0.57) or maximum work rate (Wattmax) (adjusted β = −1.38; 95% CI, −5.04 to 2.27; P = 0.46) compared with classes IV–V. Those with at least one copy of a F508del-CFTR mutation and one copy of a class V mutation had a significantly lower V.O2peak (β = −8.24%; 95% CI, −14.53 to −2.99; P = 0.003) and lower Wattmax (adjusted β = −7.59%; 95% CI, −14.21 to −0.95; P = 0.025) than those with two copies of a class II mutation. On the basis of linear regression analysis adjusted for

  11. Investigating CFTR and KCa3.1 Protein/Protein Interactions.

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    Hélène Klein

    Full Text Available In epithelia, Cl- channels play a prominent role in fluid and electrolyte transport. Of particular importance is the cAMP-dependent cystic fibrosis transmembrane conductance regulator Cl- channel (CFTR with mutations of the CFTR encoding gene causing cystic fibrosis. The bulk transepithelial transport of Cl- ions and electrolytes needs however to be coupled to an increase in K+ conductance in order to recycle K+ and maintain an electrical driving force for anion exit across the apical membrane. In several epithelia, this K+ efflux is ensured by K+ channels, including KCa3.1, which is expressed at both the apical and basolateral membranes. We show here for the first time that CFTR and KCa3.1 can physically interact. We first performed a two-hybrid screen to identify which KCa3.1 cytosolic domains might mediate an interaction with CFTR. Our results showed that both the N-terminal fragment M1-M40 of KCa3.1 and part of the KCa3.1 calmodulin binding domain (residues L345-A400 interact with the NBD2 segment (G1237-Y1420 and C- region of CFTR (residues T1387-L1480, respectively. An association of CFTR and F508del-CFTR with KCa3.1 was further confirmed in co-immunoprecipitation experiments demonstrating the formation of immunoprecipitable CFTR/KCa3.1 complexes in CFBE cells. Co-expression of KCa3.1 and CFTR in HEK cells did not impact CFTR expression at the cell surface, and KCa3.1 trafficking appeared independent of CFTR stimulation. Finally, evidence is presented through cross-correlation spectroscopy measurements that KCa3.1 and CFTR colocalize at the plasma membrane and that KCa3.1 channels tend to aggregate consequent to an enhanced interaction with CFTR channels at the plasma membrane following an increase in intracellular Ca2+ concentration. Altogether, these results suggest 1 that the physical interaction KCa3.1/CFTR can occur early during the biogenesis of both proteins and 2 that KCa3.1 and CFTR form a dynamic complex, the formation of which

  12. Prevalência da mutação ΔF508 no gene cystic fibrosis transmembrane conductance regulator em pacientes com fibrose cística em um centro de referência no Brasil Prevalence of ΔF508 mutation in the cystic fibrosis transmembrane conductance regulator gene among cystic fibrosis patients from a Brazilian referral center

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    Andréia Marisa Bieger


    Full Text Available OBJETIVO: Verificar a presença da mutação ΔF508 no gene cystic fibrosis transmembrane conductance regulator na população de pacientes com fibrose cística, diagnosticados pelo teste de sódio e cloro no suor, em acompanhamento no Ambulatório de Pneumologia Pediátrica da Universidade Estadual de Campinas, centro de referência no tratamento da fibrose cística. MÉTODOS: Foram analisadas 167 amostras de DNA de pacientes com fibrose cística. O genótipo dos pacientes foi determinado pela técnica de reação da polimerase e realizado cálculo para a frequência dos alelos e genótipos da mutação ΔF508. RESULTADOS: A frequência genotípica encontrada foi, respectivamente, para os genótipos -/-, ΔF508/- e ΔF508F508: 43,7% (73 pacientes, 32,9% (55 pacientes e 23,4% (39 pacientes. Do total de 334 alelos analisados, foi observada a frequência de 201 (60,18% alelos para a ausência da mutação ΔF508 e de 133 (39,82% para a presença da mutação ΔF508. O cálculo do equilíbrio de Hardy-Weinberg foi realizado, e obtivemos o valor de qui-quadrado = 16,34 (p OBJECTIVE: To verify the presence of ΔF508 mutation in the cystic fibrosis transmembrane conductance regulator gene among patients with cystic fibrosis diagnosed by the sweat test for sodium and chlorine and followed at the Pediatric Pneumology Outpatient Clinic of Universidade Estadual de Campinas, Brazil, a referral center for the treatment of cystic fibrosis. METHODS: The study analyzed 167 DNA samples from cystic fibrosis patients. Patients' genotype was determined by polymerase chain reaction, and allele and genotype frequencies of ΔF508 mutation were calculated. RESULTS: The genotype frequencies found for -/-, ΔF508/-, and ΔF508F508 genotypes were respectively: 43.7% (73 patients, 32.9% (55 patients, and 23.4% (39 patients. Of the 334 alleles analyzed, we observed a frequency of 201 (60.18% alleles for the absence of ΔF508 mutation and of 133 (39.82% for the

  13. Analysis of Y chromosome microdeletions and CFTR gene mutations as genetic markers of infertility in Serbian men

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    Dinić Jelena


    Full Text Available Background/Aim. Impaired fertility of a male partner is the main cause of infertility in up to one half of all infertile couples. At the genetic level, male infertility can be caused by chromosome aberrations or gene mutations. The presence and types of Y chromosome microdeletions and cystic fybrosis transmembrane conductance regulator (CFTR gene mutations as genetic cause of male infertility was tested in Serbian men. The aim of this study was to analyze CFTR gene mutations and Y chromosome microdelations as potential causes of male infertility in Serbian patients, as well as to test the hypothesis that CFTR mutations in infertile men are predominantly located in the several last exons of the gene. Methods. This study has encompassed 33 men with oligo- or azoospermia. The screening for Y chromosome microdeletions in the azoospermia factor (AZF region was performed by multiplex PCR analysis. The screening of the CFTR gene was performed by denaturing gradient gel electrophoresis (DGGE method. Results. Deletions on Y chromosome were detected in four patients, predominantly in AZFc region (four of total six deletions. Mutations in the CFTR gene were detected on eight out of 66 analyzed chromosomes of infertile men. The most common mutation was F508del (six of total eight mutations. Conclusion. This study confirmed that both Y chromosome microdeletions and CFTR gene mutations played important role in etiology of male infertility in Serbian infertile men. Genetic testing for Y chromosome microdeletions and CFTR gene mutations has been introduced in routine diagnostics and offered to couples undergoing assisted reproduction techniques. Considering that both the type of Y chromosome microdeletion and the type of CFTR mutation have a prognostic value, it is recommended that AZF and CFTR genotyping should not only be performed in patients with reduced sperm quality before undergoing assisted reproduction, but also for the purpose of preimplantation and

  14. Lumacaftor/ivacaftor, a novel agent for the treatment of cystic fibrosis patients who are homozygous for the F580del CFTR mutation. (United States)

    Bulloch, Marilyn N; Hanna, Cameron; Giovane, Richard


    Cystic Fibrosis (CF) is an autosomal recessive disease affecting up to 90,000 people worldwide. Approximately 73% of patients are homozygous for the F508del cystic fibrosis transmembrane conductance regulator [CFTR] mutation. Traditionally treatment has only included supportive care. Therefore, there is a need for safe and effective novel therapies targeting the underlying molecular defects seen with CF. Areas covered: In 2016, the Food and Drug Administration and the European Commission approved LUM/IVA (Orkambi), a CFTR modulator that includes both a CFTR corrector and potentiator, for CF patients homozygous for the F508del CFTR mutation. This article reviews the pharmacologic features, clinical efficacy, and safety of LUM/IVA and summarize the available pre-clinical and clinical data of LUM/IVA use. Expert commentary: LUM/IVA showed modest, but significant improvements from baseline in percent predicted FEV 1 (ppFEV 1 ) as well as a reduction in pulmonary exacerbations by 35% It was shown to be safe for short- and long-term use. Currently, LUM/IVA is the only oral agent in its class available and represents a milestone the development of therapies for the management of CF. Nonetheless, pharmacoeconomic data are necessary to justify its high cost before is use becomes standard of care.

  15. Distribution of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR Mutations in a Cohort of Patients Residing in Palestine.

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    Issa Siryani

    Full Text Available Cystic fibrosis (CF is an autosomal recessive inherited life-threatening disorder that causes severe damage to the lungs and the digestive system. In Palestine, mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR that contributes to the clinical presentation of CF are ill defined. A cohort of thirty three clinically diagnosed CF patients from twenty one different Palestinian families residing in the central and southern part of Palestine were incorporated in this study. Sweat chloride testing was performed using the Sweat Chek Conductivity Analyzer (ELITECH Group, France to confirm the clinical diagnosis of CF. In addition, nucleic acid from the patients' blood samples was extracted and the CFTR mutation profiles were assessed by direct sequencing of the CFTR 27 exons and the intron-exon boundaries. For patient's DNA samples where no homozygous or two heterozygous CFTR mutations were identified by exon sequencing, DNA samples were tested for deletions or duplications using SALSA MLPA probemix P091-D1 CFTR assay. Sweat chloride testing confirmed the clinical diagnosis of CF in those patients. All patients had NaCl conductivity >60 mmol/l. In addition, nine different CFTR mutations were identified in all 21 different families evaluated. These mutations were c.1393-1G>A, F508del, W1282X, G85E, c.313delA, N1303K, deletion exons 17a-17b-18, deletion exons 17a-17b and Q1100P. c.1393-1G>A was shown to be the most frequent occurring mutation among tested families. We have profiled the underling mutations in the CFTR gene of a cohort of 21 different families affected by CF. Unlike other studies from the Arab countries where F508del was reported to be the most common mutation, in southern/central Palestine, the c.1393-1G>A appeared to be the most common. Further studies are needed per sample size and geographic distribution to account for other possible CFTR genetic alterations and their frequencies. Genotype

  16. Spectrum of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the p.H609R mutation. (United States)

    Ortiz, Sofía C; Aguirre, Santiago J; Flores, Sofía; Maldonado, Claudio; Mejía, Juan; Salinas, Lilian


    High heterogeneity in the CFTR gene mutations disturbs the molecular diagnosis of cystic fibrosis (CF). In order to improve the diagnosis of CF in our country, the present study aims to define a panel of common CFTR gene mutations by sequencing 27 exons of the gene in Ecuadorian Cystic Fibrosis patients. Forty-eight Ecuadorian individuals with suspected/confirmed CF diagnosis were included. Twenty-seven exons of CFTR gene were sequenced to find sequence variations. Prevalence of pathogenic variations were determined and compared with other countries' data. We found 70 sequence variations. Eight of these are CF-causing mutations: p.F508del, p.G85E, p.G330E, p.A455E, p.G970S, W1098X, R1162X, and N1303K. Also this study is the second report of p.H609R in Ecuadorian population. Mutation prevalence differences between Ecuadorian population and other Latin America countries were found. The panel of mutations suggested as an initial screening for the Ecuadorian population with cystic fibrosis should contain the mutations: p.F508del, p.G85E, p.G330E, p.A455E, p.G970S, W1098X, R1162X, and N1303K. © 2017 NETLAB Laboratorios Especializados. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

  17. A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor.

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    Jessica E Char

    Full Text Available To determine if oral dosing with the CFTR-potentiator ivacaftor (VX-770, Kalydeco improves CFTR-dependent sweating in CF subjects carrying G551D or R117H-5T mutations, we optically measured sweat secretion from 32-143 individually identified glands in each of 8 CF subjects; 6 F508del/G551D, one G551D/R117H-5T, and one I507del/R117H-5T. Two subjects were tested only (- ivacaftor, 3 only (+ ivacaftor and 3 (+/- ivacaftor (1-5 tests per condition. The total number of gland measurements was 852 (- ivacaftor and 906 (+ ivacaftor. A healthy control was tested 4 times (51 glands. For each gland we measured both CFTR-independent (M-sweat and CFTR-dependent (C-sweat; C-sweat was stimulated with a β-adrenergic cocktail that elevated [cAMP]i while blocking muscarinic receptors. Absent ivacaftor, almost all CF glands produced M-sweat on all tests, but only 1/593 glands produced C-sweat (10 tests, 5 subjects. By contrast, 6/6 subjects (113/342 glands produced C-sweat in the (+ ivacaftor condition, but with large inter-subject differences; 3-74% of glands responded with C/M sweat ratios 0.04%-2.57% of the average WT ratio of 0.265. Sweat volume losses cause proportionally larger underestimates of CFTR function at lower sweat rates. The losses were reduced by measuring C/M ratios in 12 glands from each subject that had the highest M-sweat rates. Remaining losses were estimated from single channel data and used to correct the C/M ratios, giving estimates of CFTR function (+ ivacaftor  = 1.6%-7.7% of the WT average. These estimates are in accord with single channel data and transcript analysis, and suggest that significant clinical benefit can be produced by low levels of CFTR function.

  18. Targeting autophagy as a novel strategy for facilitating the therapeutic action of potentiators on ΔF508 cystic fibrosis transmembrane conductance regulator

    NARCIS (Netherlands)

    A. Luciani (Alessandro); V.R. Villella (Valeria Rachela); S. Esposito (Susanna); M. Gavina (Manuela); I. Russo (Ilaria); M. Silano (Marco); S. Guido (Stefano); M. Pettoello-Mantovani (Massimo); R. Carnuccio (Rosa); B.J. Scholte (Bob); A. de Matteis (Antonella); M.C. Maiuri (Maria Chiara); V. Raia (Valeria); A. Luini (Alberto); H.K. Kroemer (Heyo); L. Maiuri (Luigi)


    textabstractChannel activators (potentiators) of cystic fibrosis (CF) transmembrane conductance regulator (CFTR), can be used for the treatment of the small subset of CF patients that carry plasma membrane-resident CFTR mutants. However, approximately 90% of CF patients carry the misfolded

  19. CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients.

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    Ewa Ziętkiewicz

    Full Text Available Cystic fibrosis (CF is caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR. In light of the strong allelic heterogeneity and regional specificity of the mutation spectrum, the strategy of molecular diagnostics and counseling in CF requires genetic tests to reflect the frequency profile characteristic for a given population. The goal of the study was to provide an updated comprehensive estimation of the distribution of CFTR mutations in Polish CF patients and to assess the effectiveness of INNOLiPA_CFTR tests in Polish population. The analyzed cohort consisted of 738 patients with the clinically confirmed CF diagnosis, prescreened for molecular defects using INNOLiPA_CFTR panels from Innogenetics. A combined efficiency of INNOLiPA CFTR_19 and CFTR_17_TnUpdate tests was 75.5%; both mutations were detected in 68.2%, and one mutation in 14.8% of the affected individuals. The group composed of all the patients with only one or with no mutation detected (109 and 126 individuals, respectively was analyzed further using a mutation screening approach, i.e. SSCP/HD (single strand conformational polymorphism/heteroduplex analysis of PCR products followed by sequencing of the coding sequence. As a result, 53 more mutations were found in 97 patients. The overall efficiency of the CF allele detection was 82.5% (7.0% increase compared to INNOLiPA tests alone. The distribution of the most frequent mutations in Poland was assessed. Most of the mutations repetitively found in Polish patients had been previously described in other European populations. The most frequent mutated allele, F508del, represented 54.5% of Polish CF chromosomes. Another eight mutations had frequencies over 1%, 24 had frequencies between 1 and 0.1%; c.2052-2053insA and c.3468+2_3468+3insT were the most frequent non-INNOLiPA mutations. Mutation distribution described herein is also relevant to the Polish diaspora. Our study also demonstrates that the reported

  20. Optimizing nasal potential difference analysis for CFTR modulator development: assessment of ivacaftor in CF subjects with the G551D-CFTR mutation.

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    Steven M Rowe

    Full Text Available Nasal potential difference (NPD is used as a biomarker of the cystic fibrosis transmembrane conductance regulator (CFTR and epithelial sodium channel (ENaC activity. We evaluated methods to detect changes in chloride and sodium transport by NPD based on a secondary analysis of a Phase II CFTR-modulator study. Thirty-nine subjects with CF who also had the G551D-CFTR mutation were randomized to receive ivacaftor (Kalydeco™; also known as VX-770 in four doses or placebo twice daily for at least 14 days. All data were analyzed by a single investigator who was blinded to treatment assignment. We compared three analysis methods to determine the best approach to quantify changes in chloride and sodium transport: (1 the average of both nostrils; (2 the most-polarized nostril at each visit; and (3 the most-polarized nostril at screening carried forward. Parameters of ion transport included the PD change with zero chloride plus isoproterenol (CFTR activity, the basal PD, Ringer's PD, and change in PD with amiloride (measurements of ENaC activity, and the delta NPD (measuring CFTR and ENaC activity. The average and most-polarized nostril at each visit were most sensitive to changes in chloride and sodium transport, whereas the most-polarized nostril at screening carried forward was less discriminatory. Based on our findings, NPD studies should assess both nostrils rather than a single nostril. We also found that changes in CFTR activity were more readily detected than changes in ENaC activity, and that rigorous standardization was associated with relatively good within-subject reproducibility in placebo-treated subjects (± 2.8 mV. Therefore, we have confirmed an assay of reasonable reproducibility for detecting chloride-transport improvements in response to CFTR modulation.

  1. Robust method for TALEN-edited correction of pF508del in patient-specific induced pluripotent stem cells. (United States)

    Camarasa, María Vicenta; Gálvez, Víctor Miguel


    Cystic fibrosis is one of the most frequent inherited rare diseases, caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. Apart from symptomatic treatments, therapeutic protocols for curing the disease have not yet been established. The regeneration of genetically corrected, disease-free epithelia in cystic fibrosis patients is envisioned by designing a stem cell/genetic therapy in which patient-derived pluripotent stem cells are genetically corrected, from which target tissues are derived. In this framework, we present an efficient method for seamless correction of pF508del mutation in patient-specific induced pluripotent stem cells by gene edited homologous recombination. Gene edition has been performed by transcription activator-like effector nucleases and a homologous recombination donor vector which contains a PiggyBac transposon-based double selectable marker cassette.This new method has been designed to partially avoid xenobiotics from the culture system, improve cell culture efficiency and genome stability by using a robust culture system method, and optimize timings. Overall, once the pluripotent cells have been amplified for the first nucleofection, the procedure can be completed in 69 days, and can be easily adapted to edit and change any gene of interest.

  2. The effect of NO-donors on chloride efflux, intracellular Ca(2+) concentration and mRNA expression of CFTR and ENaC in cystic fibrosis airway epithelial cells. (United States)

    Oliynyk, Igor; Hussain, Rashida; Amin, Ahmad; Johannesson, Marie; Roomans, Godfried M


    Since previous studies showed that the endogenous bronchodilator, S-nitrosglutathione (GSNO), caused a marked increase in CFTR-mediated chloride (Cl(-)) efflux and improved the trafficking of CFTR to the plasma membrane, and that also the nitric oxide (NO)-donor GEA3162 had a similar, but smaller, effect on Cl(-) efflux, it was investigated whether the NO-donor properties of GSNO were relevant for its effect on Cl(-) efflux from airway epithelial cells. Hence, the effect of a number of other NO-donors, sodium nitroprusside (SNP), S-nitroso-N-acetyl-DL-penicillamine (SNAP), diethylenetriamine/nitric oxide adduct (DETA-NO), and diethylenetriamine/nitric oxide adduct (DEA-NONOate) on Cl(-) efflux from CFBE (∆F508/∆F508-CFTR) airway epithelial cells was tested. Cl(-) efflux was determined using the fluorescent N-(ethoxycarbonylmethyl)-6-methoxyquinoliniu bromide (MQAE)-technique. Possible changes in the intracellular Ca(2+) concentration were tested by the fluorescent fluo-4 method in a confocal microscope system. Like previously with GSNO, after 4 h incubation with the NO-donor, an increased Cl(-) efflux was found (in the order SNAP>DETA-NO>SNP). The effect of DEA-NONOate on Cl(-) efflux was not significant, and the compound may have (unspecific) deleterious effects on the cells. Again, as with GSNO, after a short (5 min) incubation, SNP had no significant effect on Cl(-) efflux. None of the NO-donors that had a significant effect on Cl(-) efflux caused significant changes in the intracellular Ca(2+) concentration. After 4 h preincubation, SNP caused a significant increase in the mRNA expression of CFTR. SNAP and DEA-NONOate decreased the mRNA expression of all ENaC subunits significantly. DETA-NO caused a significant decrease only in α-ENaC expression. After a short preincubation, none of the NO-donors had a significant effect, neither on the expression of CFTR, nor on that of the ENaC subunits in the presence and absence of L-cysteine. It can be concluded that

  3. Clinical expression of patients with the D1152H CFTR mutation. (United States)

    Terlizzi, Vito; Carnovale, Vincenzo; Castaldo, Giuseppe; Castellani, Carlo; Cirilli, Natalia; Colombo, Carla; Corti, Fabiola; Cresta, Federico; D'Adda, Alice; Lucarelli, Marco; Lucidi, Vincenzina; Macchiaroli, Annamaria; Madarena, Elisa; Padoan, Rita; Quattrucci, Serena; Salvatore, Donatello; Zarrilli, Federica; Raia, Valeria


    Discordant results were reported on the clinical expression of subjects bearing the D1152H CFTR mutation, and also for the small number of cases reported so far. A retrospective review of clinical, genetic and biochemical data was performed from individuals homozygous or compound heterozygous for the D1152H mutation followed in 12 Italian cystic fibrosis (CF) centers. 89 subjects carrying at least D1152H on one allele were identified. 7 homozygous patients had very mild clinical expression. Over half of the 74 subjects compound heterozygous for D1152H and a I-II-III class mutation had borderline or pathological sweat test and respiratory or gastrointestinal symptoms; one third had pulmonary bacteria colonization and 10/74 cases had complications (i.e. diabetes, allergic bronchopulmonary aspergillosis, and hemoptysis). However, their clinical expression was less severe as compared to a group of CF patients homozygous for the F508del mutation. Finally, 8 subjects compound heterozygous for D1152H and a IV-V class mutation showed very mild disease. The natural history of subjects bearing the D1152H mutation is widely heterogeneous and is influenced by the mutation in trans. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  4. The hypertonic environment differentially regulates wild-type CFTR and TNR-CFTR chloride channels. (United States)

    Lassance-Soares, Roberta M; Cheng, Jie; Krasnov, Kristina; Cebotaru, Liudmila; Cutting, Garry R; Souza-Menezes, Jackson; Morales, Marcelo M; Guggino, William B


    This study tested the hypotheses that the hypertonic environment of the renal medulla regulates the expression of cystic fibrosis transmembrane conductance regulator protein (CFTR) and its natural splice variant, TNR-CFTR. To accomplish this, Madin-Darby canine kidney (MDCK) stable cell lines expressing TNR-CFTR or CFTR were used. The cells were treated with hypertonic medium made with either NaCl or urea or sucrose (480 mOsm/kg or 560 mOsm/kg) to mimic the tonicity of the renal medulla environment. Western blot data showed that CFTR and TNR-CFTR total cell protein is increased by hypertonic medium, but using the surface biotinylation technique, only CFTR was found to be increased in cell plasma membrane. Confocal microscopy showed TNR-CFTR localization primarily at the endoplasmic reticulum and plasma membrane. In conclusion, CFTR and TNR-CFTR have different patterns of distribution in MDCK cells and they are modulated by a hypertonic environment, suggesting their physiological importance in renal medulla. Copyright © 2010 S. Karger AG, Basel.

  5. CFTR depletion results in changes in fatty acid composition and promotes lipogenesis in intestinal Caco 2/15 cells.

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    Geneviève Mailhot


    Full Text Available Abnormal fatty acid composition (FA in plasma and tissue lipids frequently occurs in homozygous and even in heterozygous carriers of cystic fibrosis transmembrane conductance regulator (CFTR mutations. The mechanism(s underlying these abnormalities remained, however, poorly understood despite the potentially CFTR contributing role.The aim of the present study was to investigate the impact of CFTR depletion on FA uptake, composition and metabolism using the intestinal Caco-2/15 cell line. shRNA-mediated cftr gene silencing induced qualitative and quantitative modifications in FA composition in differentiated enterocytes as determined by gas-liquid chromatography. With the cftr gene disruption, there was a 1,5 fold increase in the total FA amount, largely attributable to monounsaturated and saturated FA compared to controls. The activity of delta-7 desaturase, estimated by the 16:1(n-7/16:0, was significantly higher in knockdown cells and consistent with the striking elevation of the n-7 FA family. When incubated with [14C]-oleic acid, CFTR-depleted cells were capable of quick incorporation and export to the medium concomitantly with the high protein expression of L-FABP known to promote intracellular FA trafficking. Accordingly, lipoprotein vehicles (CM, VLDL, LDL and HDL, isolated from CFTR knockdown cells, exhibited higher levels of radiolabeled FA. Moreover, in the presence of [14C]-acetate, knockdown cells exhibited enhanced secretion of newly synthesized phospholipids, triglycerides, cholesteryl esters and free FA, thereby suggesting a stimulation of the lipogenic pathway. Conformably, gene expression of SREBP-1c, a key lipogenic transcription factor, was increased while protein expression of the phosphorylated and inactive form of acetylCoA carboxylase was reduced, confirming lipogenesis induction. Finally, CFTR-depleted cells exhibited lower gene expression of transcription factors (PPARalpha, LXRalpha, LXRbeta and RXRalpha

  6. The molecular analysis of mutations in exons 4, 11 and 21 of the cystic fibrosis transmembrane conductance regulator (CFTR gene in cystic fibrosis patients in Kermanshah, Iran

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    Nasibe Karimi


    Full Text Available Introduction: Cystic fibrosis (CF is a common genetic disorder in white populations with an autosomal recessive pattern, caused by mutations in the CFTR gene. The frequency of more than 1950 various mutations reported in the CFTR gene significantly varies in different populations. ∆F508 is a common mutation in exon 10, which is first addressed in the molecular analysis of the disease. Other exons are required to be investigated owing to failing to identify mutations in the patients. The present study was conducted to investigate mutations in exons 4, 11 and 21 of the CFTR gene using the sequencing method in CF patients in Kermanshah province, Iran. Methods: The present descriptive study was conducted on all patients with CF presenting to the medical genetics center in Kermanshah in 2010-2011. After taking blood samples and extracting DNA using saturated NaCl solution, sequences of exons were amplified using PCR and sequenced for identifying mutations. Results: The frequency of mutations was found to be respectively 0, 0 and 5.5% in exon 11, 21 and 4. The D110H mutation was found to be homozygous in one subject and heterozygous in another. Moreover, the 4029A>G polymorphism (12.9% was found to be homozygous in two subjects and heterozygous in three others. Conclusion: The D110H mutation is recommended to be included in the screening programs of the study population. The results obtained support the effects of ethnic and geographical factors on the distribution of CF mutations.

  7. CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. (United States)

    Claustres, Mireille; Thèze, Corinne; des Georges, Marie; Baux, David; Girodon, Emmanuelle; Bienvenu, Thierry; Audrezet, Marie-Pierre; Dugueperoux, Ingrid; Férec, Claude; Lalau, Guy; Pagin, Adrien; Kitzis, Alain; Thoreau, Vincent; Gaston, Véronique; Bieth, Eric; Malinge, Marie-Claire; Reboul, Marie-Pierre; Fergelot, Patricia; Lemonnier, Lydie; Mekki, Chadia; Fanen, Pascale; Bergougnoux, Anne; Sasorith, Souphatta; Raynal, Caroline; Bareil, Corinne


    Most of the 2,000 variants identified in the CFTR (cystic fibrosis transmembrane regulator) gene are rare or private. Their interpretation is hampered by the lack of available data and resources, making patient care and genetic counseling challenging. We developed a patient-based database dedicated to the annotations of rare CFTR variants in the context of their cis- and trans-allelic combinations. Based on almost 30 years of experience of CFTR testing, CFTR-France ( currently compiles 16,819 variant records from 4,615 individuals with cystic fibrosis (CF) or CFTR-RD (related disorders), fetuses with ultrasound bowel anomalies, newborns awaiting clinical diagnosis, and asymptomatic compound heterozygotes. For each of the 736 different variants reported in the database, patient characteristics and genetic information (other variations in cis or in trans) have been thoroughly checked by a dedicated curator. Combining updated clinical, epidemiological, in silico, or in vitro functional data helps to the interpretation of unclassified and the reassessment of misclassified variants. This comprehensive CFTR database is now an invaluable tool for diagnostic laboratories gathering information on rare variants, especially in the context of genetic counseling, prenatal and preimplantation genetic diagnosis. CFTR-France is thus highly complementary to the international database CFTR2 focused so far on the most common CF-causing alleles. © 2017 Wiley Periodicals, Inc.

  8. Predominant constitutive CFTR conductance in small airways

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    Lytle Christian


    Full Text Available Abstract Background The pathological hallmarks of chronic obstructive pulmonary disease (COPD are inflammation of the small airways (bronchiolitis and destruction of lung parenchyma (emphysema. These forms of disease arise from chronic prolonged infections, which are usually never present in the normal lung. Despite the fact that primary hygiene and defense of the airways presumably requires a well controlled fluid environment on the surface of the bronchiolar airway, very little is known of the fluid and electrolyte transport properties of airways of less than a few mm diameter. Methods We introduce a novel approach to examine some of these properties in a preparation of minimally traumatized porcine bronchioles of about 1 mm diameter by microperfusing the intact bronchiole. Results In bilateral isotonic NaCl Ringer solutions, the spontaneous transepithelial potential (TEP; lumen to bath of the bronchiole was small (mean ± sem: -3 ± 1 mV; n = 25, but when gluconate replaced luminal Cl-, the bionic Cl- diffusion potentials (-58 ± 3 mV; n = 25 were as large as -90 mV. TEP diffusion potentials from 2:1 NaCl dilution showed that epithelial Cl- permeability was at least 5 times greater than Na+ permeability. The anion selectivity sequence was similar to that of CFTR. The bionic TEP became more electronegative with stimulation by luminal forskolin (5 μM+IBMX (100 μM, ATP (100 μM, or adenosine (100 μM, but not by ionomycin. The TEP was partially inhibited by NPPB (100 μM, GlyH-101* (5–50 μM, and CFTRInh-172* (5 μM. RT-PCR gave identifying products for CFTR, α-, β-, and γ-ENaC and NKCC1. Antibodies to CFTR localized specifically to the epithelial cells lining the lumen of the small airways. Conclusion These results indicate that the small airway of the pig is characterized by a constitutively active Cl- conductance that is most likely due to CFTR.

  9. Regulatory crosstalk by protein kinases on CFTR trafficking and activity (United States)

    Farinha, Carlos Miguel; Swiatecka-Urban, Agnieszka; Brautigan, David; Jordan, Peter


    Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a member of the ATP binding cassette (ABC) transporter superfamily that functions as a cAMP-activated chloride ion channel in fluid-transporting epithelia. There is abundant evidence that CFTR activity (i.e. channel opening and closing) is regulated by protein kinases and phosphatases via phosphorylation and dephosphorylation. Here, we review recent evidence for the role of protein kinases in regulation of CFTR delivery to and retention in the plasma membrane. We review this information in a broader context of regulation of other transporters by protein kinases because the overall functional output of transporters involves the integrated control of both their number at the plasma membrane and their specific activity. While many details of the regulation of intracellular distribution of CFTR and other transporters remain to be elucidated, we hope that this review will motivate research providing new insights into how protein kinases control membrane transport to impact health and disease.

  10. Steviol reduces MDCK Cyst formation and growth by inhibiting CFTR channel activity and promoting proteasome-mediated CFTR degradation.

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    Chaowalit Yuajit

    Full Text Available Cyst enlargement in polycystic kidney disease (PKD involves cAMP-activated proliferation of cyst-lining epithelial cells and transepithelial fluid secretion into the cyst lumen via cystic fibrosis transmembrane conductance regulator (CFTR chloride channel. This study aimed to investigate an inhibitory effect and detailed mechanisms of steviol and its derivatives on cyst growth using a cyst model in Madin-Darby canine kidney (MDCK cells. Among 4 steviol-related compounds tested, steviol was found to be the most potent at inhibiting MDCK cyst growth. Steviol inhibition of cyst growth was dose-dependent; steviol (100 microM reversibly inhibited cyst formation and cyst growth by 72.53.6% and 38.2±8.5%, respectively. Steviol at doses up to 200 microM had no effect on MDCK cell viability, proliferation and apoptosis. However, steviol acutely inhibited forskolin-stimulated apical chloride current in MDCK epithelia, measured with the Ussing chamber technique, in a dose-dependent manner. Prolonged treatment (24 h with steviol (100 microM also strongly inhibited forskolin-stimulated apical chloride current, in part by reducing CFTR protein expression in MDCK cells. Interestingly, proteasome inhibitor, MG-132, abolished the effect of steviol on CFTR protein expression. Immunofluorescence studies demonstrated that prolonged treatment (24 h with steviol (100 microM markedly reduced CFTR expression at the plasma membrane. Taken together, the data suggest that steviol retards MDCK cyst progression in two ways: first by directly inhibiting CFTR chloride channel activity and second by reducing CFTR expression, in part, by promoting proteasomal degradation of CFTR. Steviol and related compounds therefore represent drug candidates for treatment of polycystic kidney disease.

  11. 21 CFR 866.5900 - Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system. (United States)


    ... regulator (CFTR) gene mutation detection system. 866.5900 Section 866.5900 Food and Drugs FOOD AND DRUG...) gene mutation detection system. (a) Identification. The CFTR gene mutation detection system is a device... Guidance Document: CFTR Gene Mutation Detection System.” See § 866.1(e) for the availability of this...

  12. CFTR is a tumor suppressor gene in murine and human intestinal cancer

    NARCIS (Netherlands)

    Than, B. L. N.; Linnekamp, J. F.; Starr, T. K.; Largaespada, D. A.; Rod, A.; Zhang, Y.; Bruner, V.; Abrahante, J.; Schumann, A.; Luczak, T.; Niemczyk, A.; O'Sullivan, M. G.; Medema, J. P.; Fijneman, R. J. A.; Meijer, G. A.; van den Broek, E.; Hodges, C. A.; Scott, P. M.; Vermeulen, L.; Cormier, R. T.


    CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base

  13. CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis (United States)

    Lopes-Pacheco, Miquéias


    Cystic fibrosis (CF) is the most common life-threatening monogenic disease afflicting Caucasian people. It affects the respiratory, gastrointestinal, glandular and reproductive systems. The major cause of morbidity and mortality in CF is the respiratory disorder caused by a vicious cycle of obstruction of the airways, inflammation and infection that leads to epithelial damage, tissue remodeling and end-stage lung disease. Over the past decades, life expectancy of CF patients has increased due to early diagnosis and improved treatments; however, these patients still present limited quality of life. Many attempts have been made to rescue CF transmembrane conductance regulator (CFTR) expression, function and stability, thereby overcoming the molecular basis of CF. Gene and protein variances caused by CFTR mutants lead to different CF phenotypes, which then require different treatments to quell the patients’ debilitating symptoms. In order to seek better approaches to treat CF patients and maximize therapeutic effects, CFTR mutants have been stratified into six groups (although several of these mutations present pleiotropic defects). The research with CFTR modulators (read-through agents, correctors, potentiators, stabilizers and amplifiers) has achieved remarkable progress, and these drugs are translating into pharmaceuticals and personalized treatments for CF patients. This review summarizes the main molecular and clinical features of CF, emphasizes the latest clinical trials using CFTR modulators, sheds light on the molecular mechanisms underlying these new and emerging treatments, and discusses the major breakthroughs and challenges to treating all CF patients. PMID:27656143

  14. CFTR, Mucins, and Mucus Obstruction in Cystic Fibrosis (United States)

    Kreda, Silvia M.; Davis, C. William; Rose, Mary Callaghan


    Mucus pathology in cystic fibrosis (CF) has been known for as long as the disease has been recognized and is sometimes called mucoviscidosis. The disease is marked by mucus hyperproduction and plugging in many organs, which are usually most fatal in the airways of CF patients, once the problem of meconium ileus at birth is resolved. After the CF gene, CFTR, was cloned and its protein product identified as a cAMP-regulated Cl− channel, causal mechanisms underlying the strong mucus phenotype of the disease became obscure. Here we focus on mucin genes and polymeric mucin glycoproteins, examining their regulation and potential relationships to a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR). Detailed examination of CFTR expression in organs and different cell types indicates that changes in CFTR expression do not always correlate with the severity of CF disease or mucus accumulation. Thus, the mucus hyperproduction that typifies CF does not appear to be a direct cause of a defective CFTR but, rather, to be a downstream consequence. In organs like the lung, up-regulation of mucin gene expression by inflammation results from chronic infection; however, in other instances and organs, the inflammation may have a non-infectious origin. The mucus plugging phenotype of the β-subunit of the epithelial Na+ channel (βENaC)-overexpressing mouse is proving to be an archetypal example of this kind of inflammation, with a dehydrated airway surface/concentrated mucus gel apparently providing the inflammatory stimulus. Data indicate that the luminal HCO3 − deficiency recently described for CF epithelia may also provide such a stimulus, perhaps by causing a mal-maturation of mucins as they are released onto luminal surfaces. In any event, the path between CFTR dysfunction and mucus hyperproduction has proven tortuous, and its unraveling continues to offer its own twists and turns, along with fascinating glimpses into biology. PMID:22951447

  15. Transmembrane helical interactions in the CFTR channel pore.

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    Jhuma Das


    Full Text Available Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR gene affect CFTR protein biogenesis or its function as a chloride channel, resulting in dysregulation of epithelial fluid transport in the lung, pancreas and other organs in cystic fibrosis (CF. Development of pharmaceutical strategies to treat CF requires understanding of the mechanisms underlying channel function. However, incomplete 3D structural information on the unique ABC ion channel, CFTR, hinders elucidation of its functional mechanism and correction of cystic fibrosis causing mutants. Several CFTR homology models have been developed using bacterial ABC transporters as templates but these have low sequence similarity to CFTR and are not ion channels. Here, we refine an earlier model in an outward (OWF and develop an inward (IWF facing model employing an integrated experimental-molecular dynamics simulation (200 ns approach. Our IWF structure agrees well with a recently solved cryo-EM structure of a CFTR IWF state. We utilize cysteine cross-linking to verify positions and orientations of residues within trans-membrane helices (TMHs of the OWF conformation and to reconstruct a physiologically relevant pore structure. Comparison of pore profiles of the two conformations reveal a radius sufficient to permit passage of hydrated Cl- ions in the OWF but not the IWF model. To identify structural determinants that distinguish the two conformations and possible rearrangements of TMHs within them responsible for channel gating, we perform cross-linking by bifunctional reagents of multiple predicted pairs of cysteines in TMH 6 and 12 and 6 and 9. To determine whether the effects of cross-linking on gating observed are the result of switching of the channel from open to close state, we also treat the same residue pairs with monofunctional reagents in separate experiments. Both types of reagents prevent ion currents indicating that pore blockage is primarily responsible.

  16. Activation of CFTR by ASBT-mediated bile salt absorption

    NARCIS (Netherlands)

    Bijvelds, MJC; Jorna, H; Verkade, HJ; Bot, AGM; Hofmann, F; Agellon, LB; Sinaasappel, M; de Jonge, HR


    In cholangiocytes, bile salt (BS) uptake via the apical sodium-dependent bile acid transporter (ASBT) may evoke ductular flow by enhancing cAMP-mediated signaling to the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. We considered that ASBT-mediated BS uptake in the distal

  17. Delta Dynamics

    DEFF Research Database (Denmark)

    Bendixen, Mette

    . The warming air temperature affects the soil temperature and permafrost thaws and destabilizes the material in the coastal zone. In Greenland, the warming temperature lowers the surface mass balance of the Greenland Ice Sheet and more material is transported to the coastal zone. The sea ice extent is thinning...... of a fjord and the second type is a wider fan-shaped open delta. Most deltas are directly coupled to the Greenland Ice Sheet or local icecaps and are highly influenced by the dynamics in the catchments. It is demonstrated how a modern changing climate directly affects delta dynamics, and that Greenlandic...... deltas are prograding, contrary to the global trend showing eroding Arctic coasts. Moreover, it is revealed that the increasing proglacial freshwater runoff, caused by a lowering of the surface mass balance of the Greenland Ice Sheet is the main determining agent in delta progradation. The final part...

  18. Sweat chloride as a biomarker of CFTR activity: proof of concept and ivacaftor clinical trial data. (United States)

    Accurso, Frank J; Van Goor, Fredrick; Zha, Jiuhong; Stone, Anne J; Dong, Qunming; Ordonez, Claudia L; Rowe, Steven M; Clancy, John Paul; Konstan, Michael W; Hoch, Heather E; Heltshe, Sonya L; Ramsey, Bonnie W; Campbell, Preston W; Ashlock, Melissa A


    We examined data from a Phase 2 trial {NCT00457821} of ivacaftor, a CFTR potentiator, in cystic fibrosis (CF) patients with aG551D mutation to evaluate standardized approaches to sweat chloride measurement and to explore the use of sweat chloride and nasal potential difference (NPD) to estimate CFTR activity. Sweat chloride and NPD were secondary endpoints in this placebo-controlled, multicenter trial. Standardization of sweat collection, processing,and analysis was employed for the first time. Sweat chloride and chloride ion transport (NPD) were integrated into a model of CFTR activity. Within-patient sweat chloride determinations showed sufficient precision to detect differences between dose-groups and assess ivacaftor treatment effects. Analysis of changes in sweat chloride and NPD demonstrated that patients treated with ivacaftor achieved CFTR activity equivalent to approximately 35%–40% of normal. Sweat chloride is useful in multicenter trials as a biomarker of CFTR activity and to test the effect of CFTR potentiators.

  19. Frequency of common CFTR gene mutations in Venezuelan patients with cystic fibrosis


    Sánchez, Karen; Arcia, Orlando; Matute, Xiorama; Mindiola, Luz; Chaustre, Ismenia; Takiff, Howard


    Mutations in the CFTR gene in Cystic Fibrosis (CF) patients have geographic differences and there is scant data on their prevalence in Venezuelan patients. This study determined the frequency of common CFTR gene mutations in these patients. We amplified and sequenced exons 7, 10, 11, 19, 20 and 21, which contain the most common CFTR mutations, from 105 Venezuelan patients in the National CF Program. Eleven different mutations were identified, four with frequencies greater than 1%: p.Phe508del...

  20. Crystallization and Preliminary Diffraction Analysis of the CAL PDZ Domain in Complex with a Selective Peptide Inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    J Amacher; P Cushing; J Weiner; D Madden


    Cystic fibrosis (CF) is associated with loss-of-function mutations in the CF transmembrane conductance regulator (CFTR), which regulates epithelial fluid and ion homeostasis. The CFTR cytoplasmic C-terminus interacts with a number of PDZ (PSD-95/Dlg/ZO-1) proteins that modulate its intracellular trafficking and chloride-channel activity. Among these, the CFTR-associated ligand (CAL) has a negative effect on apical-membrane expression levels of the most common disease-associated mutant {Delta}F508-CFTR, making CAL a candidate target for the treatment of CF. A selective peptide inhibitor of the CAL PDZ domain (iCAL36) has recently been developed and shown to stabilize apical expression of {Delta}F508-CFTR, enhancing net chloride-channel activity, both alone and in combination with the folding corrector corr-4a. As a basis for structural studies of the CAL-iCAL36 interaction, a purification protocol has been developed that increases the oligomeric homogeneity of the protein. Here, the cocrystallization of the complex in space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 35.9, b = 47.7, c = 97.3 {angstrom}, is reported. The crystals diffracted to 1.4 {angstrom} resolution. Based on the calculated Matthews coefficient (1.96 {angstrom}{sup 3} Da{sup -1}), it appears that the asymmetric unit contains two complexes.

  1. Osteoblast CFTR inactivation reduces differentiation and osteoprotegerin expression in a mouse model of cystic fibrosis-related bone disease.

    Directory of Open Access Journals (Sweden)

    Michael S Stalvey

    Full Text Available Low bone mass and increased fracture risk are recognized complications of cystic fibrosis (CF. CF-related bone disease (CFBD is characterized by uncoupled bone turnover--impaired osteoblastic bone formation and enhanced osteoclastic bone resorption. Intestinal malabsorption, vitamin D deficiency and inflammatory cytokines contribute to CFBD. However, epidemiological investigations and animal models also support a direct causal link between inactivation of skeletal cystic fibrosis transmembrane regulator (CFTR, the gene that when mutated causes CF, and CFBD. The objective of this study was to examine the direct actions of CFTR on bone. Expression analyses revealed that CFTR mRNA and protein were expressed in murine osteoblasts, but not in osteoclasts. Functional studies were then performed to investigate the direct actions of CFTR on osteoblasts using a CFTR knockout (Cftr-/- mouse model. In the murine calvarial organ culture assay, Cftr-/- calvariae displayed significantly less bone formation and osteoblast numbers than calvariae harvested from wildtype (Cftr+/+ littermates. CFTR inactivation also reduced alkaline phosphatase expression in cultured murine calvarial osteoblasts. Although CFTR was not expressed in murine osteoclasts, significantly more osteoclasts formed in Cftr-/- compared to Cftr+/+ bone marrow cultures. Indirect regulation of osteoclastogenesis by the osteoblast through RANK/RANKL/OPG signaling was next examined. Although no difference in receptor activator of NF-κB ligand (Rankl mRNA was detected, significantly less osteoprotegerin (Opg was expressed in Cftr-/- compared to Cftr+/+ osteoblasts. Together, the Rankl:Opg ratio was significantly higher in Cftr-/- murine calvarial osteoblasts contributing to a higher osteoclastogenesis potential. The combined findings of reduced osteoblast differentiation and lower Opg expression suggested a possible defect in canonical Wnt signaling. In fact, Wnt3a and PTH-stimulated canonical Wnt

  2. CFTR mutation analysis and haplotype associations in CF patients☆


    Cordovado, S.K.; Hendrix, M.; Greene, C.N.; Mochal, S.; Earley, M.C.; Farrell, P.M.; Kharrazi, M.; Hannon, W.H.; Mueller, P.W.


    Most newborn screening (NBS) laboratories use second-tier molecular tests for cystic fibrosis (CF) using dried blood spots (DBS). The Centers for Disease Control and Prevention’s NBS Quality Assurance Program offers proficiency testing (PT) in DBS for CF transmembrane conductance regulator (CFTR) gene mutation detection. Extensive molecular characterization on 76 CF patients, family members or screen positive newborns was performed for quality assurance. The coding, regulatory regions and por...

  3. CFTR mediates noradrenaline-induced ATP efflux from DRG neurons. (United States)

    Kanno, Takeshi; Nishizaki, Tomoyuki


    In our earlier study, noradrenaline (NA) stimulated ATP release from dorsal root ganglion (DRG) neurons as mediated via β(3) adrenoceptors linked to G(s) protein involving protein kinase A (PKA) activation, to cause allodynia. The present study was conducted to understand how ATP is released from DRG neurons. In an outside-out patch-clamp configuration from acutely dissociated rat DRG neurons, single-channel currents, sensitive to the P2X receptor inhibitor PPADS, were evoked by approaching the patch-electrode tip close to a neuron, indicating that ATP is released from DRG neurons, to activate P2X receptor. NA increased the frequency of the single-channel events, but such NA effect was not found for DRG neurons transfected with the siRNA to silence the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the immunocytochemical study using acutely dissociated rat DRG cells, CFTR was expressed in neurons alone, but not satellite cells, fibroblasts, or Schwann cells. It is concluded from these results that CFTR mediates NA-induced ATP efflux from DRG neurons as an ATP channel.

  4. Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis


    LaRusch, Jessica; Jung, Jinsei; General, Ignacio J.; Lewis, Michele D.; Park, Hyun Woo; Brand, Randall E.; Gelrud, Andres; Anderson, Michelle A.; Banks, Peter A.; Conwell, Darwin; Lawrence, Christopher; Romagnuolo, Joseph; Baillie, John; Alkaade, Samer; Cote, Gregory


    CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev ) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize tha...

  5. Cftr Modulates Wnt/β-Catenin Signaling and Stem Cell Proliferation in Murine Intestine

    Directory of Open Access Journals (Sweden)

    Ashlee M. Strubberg


    Conclusions: CF intestine shows increased ISC proliferation and Wnt/β-catenin signaling. Loss of Cftr increases pHi in ISCs, which stabilizes the plasma membrane association of the Wnt transducer Dvl, likely facilitating Wnt/β-catenin signaling. Absence of Cftr-dependent suppression of ISC proliferation in the CF intestine may contribute to increased risk for intestinal tumors.

  6. Evaluation of potential regulatory elements identified as DNase I hypersensitive sites in the CFTR gene

    DEFF Research Database (Denmark)

    Phylactides, M.; Rowntree, R.; Nuthall, H.


    hypersensitive sites (DHS) within the locus. We previously identified at least 12 clusters of DHS across the CFTR gene and here further evaluate DHS in introns 2,3,10,16,17a, 18, 20 and 21 to assess their functional importance in regulation of CFTR gene expression. Transient transfections of enhancer/reporter...

  7. Cellular chloride and bicarbonate retention alters intracellular pH regulation in Cftr KO crypt epithelium (United States)

    Walker, Nancy M.; Liu, Jinghua; Stein, Sydney R.; Stefanski, Casey D.; Strubberg, Ashlee M.


    Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), an anion channel providing a major pathway for Cl− and HCO3− efflux across the apical membrane of the epithelium. In the intestine, CF manifests as obstructive syndromes, dysbiosis, inflammation, and an increased risk for gastrointestinal cancer. Cftr knockout (KO) mice recapitulate CF intestinal disease, including intestinal hyperproliferation. Previous studies using Cftr KO intestinal organoids (enteroids) indicate that crypt epithelium maintains an alkaline intracellular pH (pHi). We hypothesized that Cftr has a cell-autonomous role in downregulating pHi that is incompletely compensated by acid-base regulation in its absence. Here, 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein microfluorimetry of enteroids showed that Cftr KO crypt epithelium sustains an alkaline pHi and resistance to cell acidification relative to wild-type. Quantitative real-time PCR revealed that Cftr KO enteroids exhibit downregulated transcription of base (HCO3−)-loading proteins and upregulation of the basolateral membrane HCO3−-unloader anion exchanger 2 (Ae2). Although Cftr KO crypt epithelium had increased Ae2 expression and Ae2-mediated Cl−/HCO3− exchange with maximized gradients, it also had increased intracellular Cl− concentration relative to wild-type. Pharmacological reduction of intracellular Cl− concentration in Cftr KO crypt epithelium normalized pHi, which was largely Ae2-dependent. We conclude that Cftr KO crypt epithelium maintains an alkaline pHi as a consequence of losing both Cl− and HCO3− efflux, which impairs pHi regulation by Ae2. Retention of Cl− and an alkaline pHi in crypt epithelium may alter several cellular processes in the proliferative compartment of Cftr KO intestine. PMID:26542396

  8. Rab4GTPase modulates CFTR function by impairing channel expression at plasma membrane

    International Nuclear Information System (INIS)

    Saxena, Sunil K.; Kaur, Simarna; George, Constantine


    Cystic fibrosis (CF), an autosomal recessive disorder, is caused by the disruption of biosynthesis or the function of a membrane cAMP-activated chloride channel, CFTR. CFTR regulatory mechanisms include recruitment of channel proteins to the cell surface from intracellular pools and by protein-protein interactions. Rab proteins are small GTPases involved in regulated trafficking controlling vesicle docking and fusion. Rab4 controls recycling events from endosome to the plasma membrane, fusion, and degradation. The colorectal cell line HT-29 natively expresses CFTR and responds to cAMP stimulation with an increase in CFTR-mediated currents. Rab4 over-expression in HT-29 cells inhibits both basal and cAMP-stimulated CFTR-mediated currents. GTPase-deficient Rab4Q67L and GDP locked Rab4S22N both inhibit channel activity, which appears characteristically different. Active status of Rab4 was confirmed by GTP overlay assay, while its expression was verified by Western blotting. The pull-down and immunoprecipitation experiments suggest that Rab4 physically interacts with CFTR through protein-protein interaction. Biotinylation with cell impermeant NHS-Sulfo-SS-Biotin implies that Rab4 impairs CFTR expression at cell surface. The enhanced cytosolic CFTR indicates that Rab4 expression restrains CFTR appearance at the cell membrane. The study suggests that Rab4 regulates the channel through multiple mechanisms that include protein-protein interaction, GTP/GDP exchange, and channel protein trafficking. We propose that Rab4 is a dynamic molecule with a significant role in CFTR function

  9. Cellular chloride and bicarbonate retention alters intracellular pH regulation in Cftr KO crypt epithelium. (United States)

    Walker, Nancy M; Liu, Jinghua; Stein, Sydney R; Stefanski, Casey D; Strubberg, Ashlee M; Clarke, Lane L


    Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), an anion channel providing a major pathway for Cl(-) and HCO3 (-) efflux across the apical membrane of the epithelium. In the intestine, CF manifests as obstructive syndromes, dysbiosis, inflammation, and an increased risk for gastrointestinal cancer. Cftr knockout (KO) mice recapitulate CF intestinal disease, including intestinal hyperproliferation. Previous studies using Cftr KO intestinal organoids (enteroids) indicate that crypt epithelium maintains an alkaline intracellular pH (pHi). We hypothesized that Cftr has a cell-autonomous role in downregulating pHi that is incompletely compensated by acid-base regulation in its absence. Here, 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein microfluorimetry of enteroids showed that Cftr KO crypt epithelium sustains an alkaline pHi and resistance to cell acidification relative to wild-type. Quantitative real-time PCR revealed that Cftr KO enteroids exhibit downregulated transcription of base (HCO3 (-))-loading proteins and upregulation of the basolateral membrane HCO3 (-)-unloader anion exchanger 2 (Ae2). Although Cftr KO crypt epithelium had increased Ae2 expression and Ae2-mediated Cl(-)/HCO3 (-) exchange with maximized gradients, it also had increased intracellular Cl(-) concentration relative to wild-type. Pharmacological reduction of intracellular Cl(-) concentration in Cftr KO crypt epithelium normalized pHi, which was largely Ae2-dependent. We conclude that Cftr KO crypt epithelium maintains an alkaline pHi as a consequence of losing both Cl(-) and HCO3 (-) efflux, which impairs pHi regulation by Ae2. Retention of Cl(-) and an alkaline pHi in crypt epithelium may alter several cellular processes in the proliferative compartment of Cftr KO intestine. Copyright © 2016 the American Physiological Society.

  10. The HDAC inhibitor SAHA does not rescue CFTR membrane expression in Cystic Fibrosis. (United States)

    Bergougnoux, Anne; Petit, Aurélie; Knabe, Lucie; Bribes, Estelle; Chiron, Raphaël; De Sario, Albertina; Claustres, Mireille; Molinari, Nicolas; Vachier, Isabelle; Taulan-Cadars, Magali; Bourdin, Arnaud


    The development of suitable Cystic Fibrosis (CF) models for preclinical bench tests of therapeutic candidates is challenging. Indeed, the validation of molecules to rescue the p.Phe508del-CFTR channel (encoded by the Cystic Fibrosis Transmembrane conductance Regulator gene carrying the p.Phe508del mutation) requires taking into account their overall effects on the epithelium. Suberoylanilide Hydroxamic Acid (SAHA), a histone deacetylase inhibitor (HDACi), was previously shown to be a CFTR corrector via proteostasis modulation in CFTR-deficient immortalized cells. Here, we tested SAHA effects on goblet cell metaplasia using an ex vivo model based on the air-liquid interface (ALI) culture of differentiated airway epithelial cells obtained by nasal scraping from CF patients and healthy controls. Ex vivo epithelium grew successfully in ALI cultures with significant rise in the expression of CFTR and of markers of airway epithelial differentiation compared to monolayer cell culture. SAHA decreased CFTR transcript and protein levels in CF and non-CF epithelia. Whereas SAHA induced lysine hyperacetylation, it did not change histone modifications at the CFTR promoter. SAHA reduced MUC5AC and MUC5B expression and inhibited goblet epithelial cell differentiation. Similar effects were obtained in CF and non-CF epithelia. All the effects were fully reversible within five days from SAHA withdrawal. We conclude that, ex vivo, SAHA modulate the structure of airway epithelia without specific effect on CFTR gene and protein suggesting that HDACi cannot be useful for CF treatment. Copyright © 2017. Published by Elsevier Ltd.

  11. The cystic fibrosis transmembrane recruiter the alter ego of CFTR as a multi-kinase anchor. (United States)

    Mehta, Anil


    This review focuses on a newly discovered interaction between protein kinases involved in cellular energetics, a process that may be disturbed in cystic fibrosis for unknown reasons. I propose a new model where kinase-mediated cellular transmission of energy provides mechanistic insight to a latent role of the cystic fibrosis transmembrane conductance regulator (CFTR). I suggest that CFTR acts as a multi-kinase recruiter to the apical epithelial membrane. My group finds that, in the cytosol, two protein kinases involved in cell energy homeostasis, nucleoside diphosphate kinase (NDPK) and AMP-activated kinase (AMPK), bind one another. Preliminary data suggest that both can also bind CFTR (function unclear). The disrupted role of this CFTR-kinase complex as 'membrane transmitter to the cell' is proposed as an alternative paradigm to the conventional ion transport mediated and CFTR/chloride-centric view of cystic fibrosis pathogenesis. Chloride remains important, but instead, chloride-induced control of the phosphohistidine content of one kinase component (NDPK, via a multi-kinase complex that also includes a third kinase, CK2; formerly casein kinase 2). I suggest that this complex provides the necessary near-equilibrium conditions needed for efficient transmission of phosphate energy to proteins controlling cellular energetics. Crucially, a new role for CFTR as a kinase controller is proposed with ionic concentration acting as a signal. The model posits a regulatory control relay for energy sensing involving a cascade of protein kinases bound to CFTR.

  12. Advancing clinical development pathways for new CFTR modulators in cystic fibrosis. (United States)

    Mayer-Hamblett, Nicole; Boyle, Michael; VanDevanter, Donald


    Cystic fibrosis (CF) is a life-shortening genetic disease affecting approximately 70,000 individuals worldwide. Until recently, drug development efforts have emphasised therapies treating downstream signs and symptoms resulting from the underlying CF biological defect: reduced function of the CF transmembrane conductance regulator (CFTR) protein. The current CF drug development landscape has expanded to include therapies that enhance CFTR function by either restoring wild-type CFTR protein expression or increasing (modulating) the function of mutant CFTR proteins in cells. To date, two systemic small-molecule CFTR modulators have been evaluated in pivotal clinical trials in individuals with CF and specific mutant CFTR genotypes that have led to regulatory review and/or approval. Advances in the discovery of CFTR modulators as a promising new class of therapies have been impressive, yet work remains to develop highly effective, disease-modifying modulators for individuals of all CF genotypes. The objectives of this review are to outline the challenges and opportunities in drug development created by systemic genotype-specific CFTR modulators, highlight the advantages of sweat chloride as an established biomarker of CFTR activity to streamline early-phase development and summarise options for later phase clinical trial designs that respond to the adoption of approved genotype-specific modulators into standard of care. An optimal development framework will be needed to move the most promising therapies efficiently through the drug development pipeline and ultimately deliver efficacious and safe therapies to all individuals with CF. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

  13. Cholesterol modulates CFTR confinement in the plasma membrane of primary epithelial cells. (United States)

    Abu-Arish, Asmahan; Pandzic, Elvis; Goepp, Julie; Matthes, Elizabeth; Hanrahan, John W; Wiseman, Paul W


    The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma-membrane anion channel that, when mutated, causes the disease cystic fibrosis. Although CFTR has been detected in a detergent-resistant membrane fraction prepared from airway epithelial cells, suggesting that it may partition into cholesterol-rich membrane microdomains (lipid rafts), its compartmentalization has not been demonstrated in intact cells and the influence of microdomains on CFTR lateral mobility is unknown. We used live-cell imaging, spatial image correlation spectroscopy, and k-space image correlation spectroscopy to examine the aggregation state of CFTR and its dynamics both within and outside microdomains in the plasma membrane of primary human bronchial epithelial cells. These studies were also performed during treatments that augment or deplete membrane cholesterol. We found two populations of CFTR molecules that were distinguishable based on their dynamics at the cell surface. One population showed confinement and had slow dynamics that were highly cholesterol dependent. The other, more abundant population was less confined and diffused more rapidly. Treatments that deplete the membrane of cholesterol caused the confined fraction and average number of CFTR molecules per cluster to decrease. Elevating cholesterol had the opposite effect, increasing channel aggregation and the fraction of channels displaying confinement, consistent with CFTR recruitment into cholesterol-rich microdomains with dimensions below the optical resolution limit. Viral infection caused the nanoscale microdomains to fuse into large platforms and reduced CFTR mobility. To our knowledge, these results provide the first biophysical evidence for multiple CFTR populations and have implications for regulation of their surface expression and channel function. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  14. Evidence that CFTR is expressed in rat tracheal smooth muscle cells and contributes to bronchodilation

    Directory of Open Access Journals (Sweden)

    Mettey Yvette


    Full Text Available Abstract Background The airway functions are profoundly affected in many diseases including asthma, chronic obstructive pulmonary disease (COPD and cystic fibrosis (CF. CF the most common lethal autosomal recessive genetic disease is caused by mutations of the CFTR gene, which normally encodes a multifunctional and integral membrane protein, the CF transmembrane conductance regulator (CFTR expressed in airway epithelial cells. Methods To demonstrate that CFTR is also expressed in tracheal smooth muscle cells (TSMC, we used iodide efflux assay to analyse the chloride transports in organ culture of rat TSMC, immunofluorescence study to localize CFTR proteins and isometric contraction measurement on isolated tracheal rings to observe the implication of CFTR in the bronchodilation. Results We characterized three different pathways stimulated by the cAMP agonist forskolin and the isoflavone agent genistein, by the calcium ionophore A23187 and by hypo-osmotic challenge. The pharmacology of the cAMP-dependent iodide efflux was investigated in detail. We demonstrated in rat TSMC that it is remarkably similar to that of the epithelial CFTR, both for activation (using three benzo [c]quinolizinium derivatives and for inhibition (glibenclamide, DPC and CFTRinh-172. Using rat tracheal rings, we observed that the activation of CFTR by benzoquinolizinium derivatives in TSMC leads to CFTRinh-172-sensitive bronchodilation after constriction with carbachol. An immunolocalisation study confirmed expression of CFTR in tracheal myocytes. Conclusion Altogether, these observations revealed that CFTR in the airways of rat is expressed not only in the epithelial cells but also in tracheal smooth muscle cells leading to the hypothesis that this ionic channel could contribute to bronchodilation.

  15. NM23 proteins: innocent bystanders or local energy boosters for CFTR? (United States)

    Muimo, Richmond; Alothaid, Hani Mm; Mehta, Anil


    NM23 proteins NDPK-A and -B bind to the cystic fibrosis (CF) protein CFTR in different ways from kinases such as PKA, CK2 and AMPK or linkers to cell calcium such as calmodulin and annexins. NDPK-A (not -B) interacts with CFTR through reciprocal AMPK binding/control, whereas NDPK-B (not -A) binds directly to CFTR. NDPK-B can activate G proteins without ligand-receptor coupling, so perhaps NDPK-B's binding influences energy supply local to a nucleotide-binding site (NBD1) needed for CFTR to function. Curiously, CFTR (ABC-C7) is a member of the ATP-binding cassette (ABC) protein family that does not obey 'clan rules'; CFTR channels anions and is not a pump, regulates disparate processes, is itself regulated by multiple means and is so pleiotropic that it acts as a hub that orchestrates calcium signaling through its consorts such as calmodulin/annexins. Furthermore, its multiple partners make CFTR dance to different tunes in different cellular and subcellular locations as it recycles from the plasma membrane to endosomes. CFTR function in airway apical membranes is inhibited by smoking which has been dubbed 'acquired CF'. CFTR alone among family members possesses a trap for other proteins that it unfurls as a 'fish-net' and which bears consensus phosphorylation sites for many protein kinases, with PKA being the most canonical. Recently, the site of CFTR's commonest mutation has been proposed as a knock-in mutant that alters allosteric control of kinase CK2 by log orders of activity towards calmodulin and other substrates after CFTR fragmentation. This link from CK2 to calmodulin that binds the R region invokes molecular paths that control lumen formation, which is incomplete in the tracheas of some CF-affected babies. Thus, we are poised to understand the many roles of NDPK-A and -B in CFTR function and, especially lumen formation, which is defective in the gut and lungs of many CF babies.

  16. A survey of detergents for the purification of stable, active human cystic fibrosis transmembrane conductance regulator (CFTR). (United States)

    Hildebrandt, Ellen; Zhang, Qinghai; Cant, Natasha; Ding, Haitao; Dai, Qun; Peng, Lingling; Fu, Yu; DeLucas, Lawrence J; Ford, Robert; Kappes, John C; Urbatsch, Ina L


    Structural knowledge of the cystic fibrosis transmembrane conductance regulator (CFTR) requires developing methods to purify and stabilize this aggregation-prone membrane protein above 1mg/ml. Starting with green fluorescent protein- and epitope-tagged human CFTR produced in mammalian cells known to properly fold and process CFTR, we devised a rapid tandem affinity purification scheme to minimize CFTR exposure to detergent in order to preserve its ATPase function. We compared a panel of detergents, including widely used detergents (maltosides, neopentyl glycols (MNG), C12E8, lysolipids, Chaps) and innovative detergents (branched alkylmaltosides, facial amphiphiles) for CFTR purification, function, monodispersity and stability. ATPase activity after reconstitution into proteoliposomes was 2-3 times higher when CFTR was purified using facial amphiphiles. ATPase activity was also demonstrated in purified CFTR samples without detergent removal using a novel lipid supplementation assay. By electron microscopy, negatively stained CFTR samples were monodisperse at low concentration, and size exclusion chromatography showed a predominance of monomer even after CFTR concentration above 1mg/ml. Rates of CFTR aggregation quantified in an electrophoretic mobility shift assay showed that detergents which best preserved reconstituted ATPase activity also supported the greatest stability, with CFTR monomer half-lives of 6-9days in MNG or Chaps, and 12-17days in facial amphiphile. Cryoelectron microscopy of concentrated CFTR in MNG or facial amphiphile confirmed mostly monomeric protein, producing low resolution reconstructions in conformity with similar proteins. These protocols can be used to generate samples of pure, functional, stable CFTR at concentrations amenable to biophysical characterization. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Side chain and backbone contributions of Phe508 to CFTR folding

    Energy Technology Data Exchange (ETDEWEB)

    Thibodeau, Patrick H.; Brautigam, Chad A.; Machius, Mischa; Thomas, Philip J. (U. of Texas-SMED)


    Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an integral membrane protein, cause cystic fibrosis (CF). The most common CF-causing mutant, deletion of Phe508, fails to properly fold. To elucidate the role Phe508 plays in the folding of CFTR, missense mutations at this position were generated. Only one missense mutation had a pronounced effect on the stability and folding of the isolated domain in vitro. In contrast, many substitutions, including those of charged and bulky residues, disrupted folding of full-length CFTR in cells. Structures of two mutant nucleotide-binding domains (NBDs) reveal only local alterations of the surface near position 508. These results suggest that the peptide backbone plays a role in the proper folding of the domain, whereas the side chain plays a role in defining a surface of NBD1 that potentially interacts with other domains during the maturation of intact CFTR.

  18. Purification and crystallization of the cystic fibrosis transmembrane conductance regulator (CFTR). (United States)

    Rosenberg, Mark F; Kamis, Alhaji Bukar; Aleksandrov, Luba A; Ford, Robert C; Riordan, John R


    The cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein that is mutated in patients suffering from cystic fibrosis. Here we report the purification and first crystallization of wild-type human CFTR. Functional characterization of the material showed it to be highly active. Electron crystallography of negatively stained two-dimensional crystals of CFTR has revealed the overall architecture of this channel for two different conformational states. These show a strong structural homology to two conformational states of another eukaryotic ATP-binding cassette transporter, P-glycoprotein. In contrast to P-glycoprotein, however, both conformational states can be observed in the presence of a nucleotide, which may be related to the role of CFTR as an ion channel rather than a transporter. The hypothesis that the two conformations could represent the "open" and "closed" states of the channel is considered.

  19. CFTR chloride channel as a molecular target of anthraquinone compounds in herbal laxatives (United States)

    Yang, Hong; Xu, Li-na; He, Cheng-yan; Liu, Xin; Fang, Rou-yu; Ma, Tong-hui


    Aim: To clarify whether CFTR is a molecular target of intestinal fluid secretion caused by the anthraquinone compounds from laxative herbal plants. Methods: A cell-based fluorescent assay to measure I− influx through CFTR chloride channel. A short-circuit current assay to measure transcellular Cl− current across single layer FRT cells and freshly isolated colon mucosa. A closed loop experiment to measure colon fluid secretion in vivo. Results: Anthraquinone compounds rhein, aloe-emodin and 1,8-dihydroxyanthraquinone (DHAN) stimulated I− influx through CFTR chloride channel in a dose-dependent manner in the presence of physiological concentration of cAMP. In the short-circuit current assay, the three compound enhanced Cl− currents in epithelia formed by CFTR-expressing FRT cells with EC50 values of 73±1.4, 56±1.7, and 50±0.5μmol/L, respectively, and Rhein also enhanced Cl− current in freshly isolated rat colonic mucosa with a similar potency. These effects were completely reversed by the CFTR selective blocker CFTRinh-172. In in vivo closed loop experiments, rhein 2 mmol/L stimulated colonic fluid accumulation that was largely blocked by CFTRinh-172. The anthraquinone compounds did not elevate cAMP level in cultured FRT cells and rat colonic mucosa, suggesting a direct effect on CFTR activity. Conclusion: Natural anthraquinone compounds in vegetable laxative drugs are CFTR potentiators that stimulated colonic chloride and fluid secretion. Thus CFTR chloride channel is a molecular target of vegetable laxative drugs. PMID:21602836

  20. A host defense mechanism involving CFTR-mediated bicarbonate secretion in bacterial prostatitis.

    Directory of Open Access Journals (Sweden)

    Chen Xie

    Full Text Available BACKGROUND: Prostatitis is associated with a characteristic increase in prostatic fluid pH; however, the underlying mechanism and its physiological significance have not been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study a primary culture of rat prostatic epithelial cells and a rat prostatitis model were used. Here we reported the involvement of CFTR, a cAMP-activated anion channel conducting both Cl(- and HCO(3(-, in mediating prostate HCO(3(- secretion and its possible role in bacterial killing. Upon Escherichia coli (E. coli-LPS challenge, the expression of CFTR and carbonic anhydrase II (CA II, along with several pro-inflammatory cytokines was up-regulated in the primary culture of rat prostate epithelial cells. Inhibiting CFTR function in vitro or in vivo resulted in reduced bacterial killing by prostate epithelial cells or the prostate. High HCO(3(- content (>50 mM, rather than alkaline pH, was found to be responsible for bacterial killing. The direct action of HCO(3(- on bacterial killing was confirmed by its ability to increase cAMP production and suppress bacterial initiation factors in E. coli. The relevance of the CFTR-mediated HCO(3(- secretion in humans was demonstrated by the upregulated expression of CFTR and CAII in human prostatitis tissues. CONCLUSIONS/SIGNIFICANCE: The CFTR and its mediated HCO(3(- secretion may be up-regulated in prostatitis as a host defense mechanism.

  1. Involvement of the Cdc42 pathway in CFTR post-translational turnover and in its plasma membrane stability in airway epithelial cells.

    Directory of Open Access Journals (Sweden)

    Romain Ferru-Clément

    Full Text Available Cystic fibrosis transmembrane conductance regulator (CFTR is a chloride channel that is expressed on the apical plasma membrane (PM of epithelial cells. The most common deleterious allele encodes a trafficking-defective mutant protein undergoing endoplasmic reticulum-associated degradation (ERAD and presenting lower PM stability. In this study, we investigated the involvement of the Cdc42 pathway in CFTR turnover and trafficking in a human bronchiolar epithelial cell line (CFBE41o- expressing wild-type CFTR. Cdc42 is a small GTPase of the Rho family that fulfils numerous cell functions, one of which is endocytosis and recycling process via actin cytoskeleton remodelling. When we treated cells with chemical inhibitors such as ML141 against Cdc42 and wiskostatin against the downstream effector N-WASP, we observed that CFTR channel activity was inhibited, in correlation with a decrease in CFTR amount at the cell surface and an increase in dynamin-dependent CFTR endocytosis. Anchoring of CFTR to the cortical cytoskeleton was then presumably impaired by actin disorganization. When we performed siRNA-mediated depletion of Cdc42, actin polymerization was not impacted, but we observed actin-independent consequences upon CFTR. Total and PM CFTR amounts were increased, resulting in greater activation of CFTR. Pulse-chase experiments showed that while CFTR degradation was slowed, CFTR maturation through the Golgi apparatus remained unaffected. In addition, we observed increased stability of CFTR in PM and reduction of its endocytosis. This study highlights the involvement of the Cdc42 pathway at several levels of CFTR biogenesis and trafficking: (i Cdc42 is implicated in the first steps of CFTR biosynthesis and processing; (ii it contributes to the stability of CFTR in PM via its anchoring to cortical actin; (iii it promotes CFTR endocytosis and presumably its sorting toward lysosomal degradation.

  2. Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles. (United States)

    Terlizzi, Vito; Castaldo, Giuseppe; Salvatore, Donatello; Lucarelli, Marco; Raia, Valeria; Angioni, Adriano; Carnovale, Vincenzo; Cirilli, Natalia; Casciaro, Rosaria; Colombo, Carla; Di Lullo, Antonella Miriam; Elce, Ausilia; Iacotucci, Paola; Comegna, Marika; Scorza, Manuela; Lucidi, Vincenzina; Perfetti, Anna; Cimino, Roberta; Quattrucci, Serena; Seia, Manuela; Sofia, Valentina Maria; Zarrilli, Federica; Amato, Felice


    The effect of complex alleles in cystic fibrosis (CF) is poorly defined for the lack of functional studies. To describe the genotype-phenotype correlation and the results of either in vitro and ex vivo studies performed on nasal epithelial cells (NEC) in a cohort of patients with CF carrying cystic fibrosis transmembrane conductance regulator ( CFTR ) complex alleles. We studied 70 homozygous, compound heterozygous or heterozygous for CFTR mutations: p.[Arg74Trp;Val201Met;Asp1270Asn], n=8; p.[Ile148Thr;Ile1023_Val1024del], n=5; p.[Arg117Leu;Leu997Phe], n=6; c.[1210-34TG[12];1210-12T[5];2930C>T], n=3; p.[Arg74Trp;Asp1270Asn], n=4; p.Asp1270Asn, n=2; p.Ile148Thr, n=6; p.Leu997Phe, n=36. In 39 patients, we analysed the CFTR gating activity on NEC in comparison with patients with CF (n=8) and carriers (n=4). Finally, we analysed in vitro the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele. The p.[Ile148Thr;Ile1023_Val1024del] caused severe CF in five compound heterozygous with a class I-II mutation. Their CFTR activity on NEC was comparable with patients with two class I-II mutations (mean 7.3% vs 6.9%). The p.[Arg74Trp;Asp1270Asn] and the p.Asp1270Asn have scarce functional effects, while p.[Arg74Trp;Val201Met;Asp1270Asn] caused mild CF in four of five subjects carrying a class I-II mutation in trans , or CFTR-related disorders (CFTR-RD) in three having in trans a class IV-V mutation. The p.[Arg74Trp;Val201Met;Asp1270Asn] causes significantly (pT] and a class I-II mutation had mild CF or CFTR-RD (gating activity: 18.5-19.0%). The effect of complex alleles partially depends on the mutation in trans . Although larger studies are necessary, the CFTR activity on NEC is a rapid contributory tool to classify patients with CFTR dysfunction. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

  3. Altered intestinal bile salt biotransformation in a cystic fibrosis (Cftr-/-) mouse model with hepato-biliary pathology. (United States)

    Bodewes, Frank A J A; van der Wulp, Mariëtte Y M; Beharry, Satti; Doktorova, Marcela; Havinga, Rick; Boverhof, Renze; James Phillips, M; Durie, Peter R; Verkade, Henkjan J


    Cftr(-/-tm1Unc) mice develop progressive hepato-biliary pathology. We hypothesize that this liver pathology is related to alterations in biliary bile hydrophobicity and bile salt metabolism in Cftr(-/-tm1Unc) mice. We determined bile production, biliary and fecal bile salt- and lipid compositions and fecal bacterial composition of C57BL/6J Cftr(-/-tm1Unc) and control mice. We found no differences between the total biliary bile salt or lipid concentrations of Cftr(-/-) and controls. Compared to controls, Cftr(-/-) mice had a ~30% higher bile production and a low bile hydrophobicity, related to a ~7 fold higher concentration of the choleretic and hydrophilic bile salt ursocholate. These findings coexisted with a significantly smaller quantity of fecal Bacteroides bacteria. Liver pathology in Cftr(-/-tm1Unc) is not related to increased bile hydrophobicity. Cftr(-/-) mice do however display a biliary phenotype characterized by increased bile production and decreased biliary hydrophobicity. Our findings suggest Cftr dependent, alterations in intestinal bacterial biotransformation of bile salts. Copyright © 2014. Published by Elsevier B.V.

  4. First functional polymorphism in CFTR promoter that results in decreased transcriptional activity and Sp1/USF binding

    International Nuclear Information System (INIS)

    Taulan, M.; Lopez, E.; Guittard, C.; Rene, C.; Baux, D.; Altieri, J.P.; DesGeorges, M.; Claustres, M.; Romey, M.C.


    Growing evidences show that functionally relevant polymorphisms in various promoters alter both transcriptional activity and affinities of existing protein-DNA interactions, and thus influence disease progression in humans. We previously reported the -94G>T CFTR promoter variant in a female CF patient in whom any known disease-causing mutation has been detected. To investigate whether the -94G>T could be a regulatory variant, we have proceeded to in silico analyses and functional studies including EMSA and reporter gene assays. Our data indicate that the promoter variant decreases basal CFTR transcriptional activity in different epithelial cells and alters binding affinities of both Sp1 and USF nuclear proteins to the CFTR promoter. The present report provides evidence for the first functional polymorphism that negatively affects the CFTR transcriptional activity and demonstrates a cooperative role of Sp1 and USF transcription factors in transactivation of the CFTR gene promoter

  5. Delta Plaza kohvik = Delta Plaza cafe

    Index Scriptorium Estoniae


    Tallinnas Pärnu mnt 141 asuva kohviku Delta Plaza sisekujundusest. Sisearhitektid Tiiu Truus ja Marja Viltrop (Stuudio Truus OÜ). Tiiu Truusi tähtsamate tööde loetelu. Büroohoone Delta Plaza arhitektid Marika Lõoke ja Jüri Okas (AB J. Okas & M. Lõoke)

  6. delta-vision (United States)

    California Natural Resource Agency — Delta Vision is intended to identify a strategy for managing the Sacramento-San Joaquin Delta as a sustainable ecosystem that would continue to support environmental...

  7. Functional interaction between CFTR and the sodium-phosphate co-transport type 2a in Xenopus laevis oocytes.

    Directory of Open Access Journals (Sweden)

    Naziha Bakouh

    Full Text Available A growing number of proteins, including ion transporters, have been shown to interact with Cystic Fibrosis Transmembrane conductance Regulator (CFTR. CFTR is an epithelial chloride channel that is involved in Cystic Fibrosis (CF when mutated; thus a better knowledge of its functional interactome may help to understand the pathophysiology of this complex disease. In the present study, we investigated if CFTR and the sodium-phosphate co-transporter type 2a (NPT2a functionally interact after heterologous expression of both proteins in Xenopus laevis oocytes.NPT2a was expressed alone or in combination with CFTR in X. laevis oocytes. Using the two-electrode voltage-clamp technique, the inorganic phosphate-induced current (IPi was measured and taken as an index of NPT2a activity. The maximal IPi for NPT2a substrates was reduced when CFTR was co-expressed with NPT2a, suggesting a decrease in its expression at the oolemna. This was consistent with Western blot analysis showing reduced NPT2a plasma membrane expression in oocytes co-expressing both proteins, whereas NPT2a protein level in total cell lysate was the same in NPT2a- and NPT2a+CFTR-oocytes. In NPT2a+CFTR- but not in NPT2a-oocytes, IPi and NPT2a surface expression were increased upon PKA stimulation, whereas stimulation of Exchange Protein directly Activated by cAMP (EPAC had no effect. When NPT2a-oocytes were injected with NEG2, a short amino-acid sequence from the CFTR regulatory domain that regulates PKA-dependent CFTR trafficking to the plasma membrane, IPi values and NPT2a membrane expression were diminished, and could be enhanced by PKA stimulation, thereby mimicking the effects of CFTR co-expression.We conclude that when both CFTR and NPT2a are expressed in X. laevis oocytes, CFTR confers to NPT2a a cAMPi-dependent trafficking to the membrane. This functional interaction raises the hypothesis that CFTR may play a role in phosphate homeostasis.

  8. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. (United States)

    LaRusch, Jessica; Jung, Jinsei; General, Ignacio J; Lewis, Michele D; Park, Hyun Woo; Brand, Randall E; Gelrud, Andres; Anderson, Michelle A; Banks, Peter A; Conwell, Darwin; Lawrence, Christopher; Romagnuolo, Joseph; Baillie, John; Alkaade, Samer; Cote, Gregory; Gardner, Timothy B; Amann, Stephen T; Slivka, Adam; Sandhu, Bimaljit; Aloe, Amy; Kienholz, Michelle L; Yadav, Dhiraj; Barmada, M Michael; Bahar, Ivet; Lee, Min Goo; Whitcomb, David C


    CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<0.0001). WNK1-SPAK pathway-activated increases in CFTR

  9. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    Jessica LaRusch


    Full Text Available CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev cause complete loss of CFTR function and result in cystic fibrosis (CF, a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002. Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005 and male infertility (OR 395, p<<0.0001. WNK1-SPAK pathway-activated increases in

  10. A New Targeted CFTR Mutation Panel Based on Next-Generation Sequencing Technology. (United States)

    Lucarelli, Marco; Porcaro, Luigi; Biffignandi, Alice; Costantino, Lucy; Giannone, Valentina; Alberti, Luisella; Bruno, Sabina Maria; Corbetta, Carlo; Torresani, Erminio; Colombo, Carla; Seia, Manuela


    Searching for mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) is a key step in the diagnosis of and neonatal and carrier screening for cystic fibrosis (CF), and it has implications for prognosis and personalized therapy. The large number of mutations and genetic and phenotypic variability make this search a complex task. Herein, we developed, validated, and tested a laboratory assay for an extended search for mutations in CFTR using a next-generation sequencing-based method, with a panel of 188 CFTR mutations customized for the Italian population. Overall, 1426 dried blood spots from neonatal screening, 402 genomic DNA samples from various origins, and 1138 genomic DNA samples from patients with CF were analyzed. The assay showed excellent analytical and diagnostic operative characteristics. We identified and experimentally validated 159 (of 188) CFTR mutations. The assay achieved detection rates of 95.0% and 95.6% in two large-scale case series of CF patients from central and northern Italy, respectively. These detection rates are among the highest reported so far with a genetic test for CF based on a mutation panel. This assay appears to be well suited for diagnostics, neonatal and carrier screening, and assisted reproduction, and it represents a considerable advantage in CF genetic counseling. Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  11. Delta antibody radioimmunoassay

    Energy Technology Data Exchange (ETDEWEB)

    Kselikova, M; Urbankova, J


    The principle and procedure are described of the radioimmunoassay of delta antibody (delta-Ab) using the ABBOTT ANTI-DELTA kit by Abbott Co. A description is given of the kit, the working procedure and the method of evaluation. The results are reported of the incidence of delta-Ab in sera of patients with viral hepatitis B, in haemophiliacs, carriers of the hepatitis B virus surface antigen (HBsAg) and blood donors. The presence was detected of delta-Ab in one HBsAg carrier. The necessity is emphasized of delta-Ab determinations in the blood of donors in view of the antibody transfer with blood and blood preparations.

  12. Analysis of cystic fibrosis gener product (CFTR) function in patients with pancreas divisum and recurrent acute pancreatitis. (United States)

    Gelrud, Andres; Sheth, Sunil; Banerjee, Subhas; Weed, Deborah; Shea, Julie; Chuttani, Ram; Howell, Douglas A; Telford, Jennifer J; Carr-Locke, David L; Regan, Meredith M; Ellis, Lynda; Durie, Peter R; Freedman, Steven D


    The mechanism by which pancreas divisum may lead to recurrent episodes of acute pancreatitis in a subset of individuals is unknown. Abnormalities of the cystic fibrosis gene product (CFTR) have been implicated in the genesis of idiopathic chronic pancreatitis. The aim of this study was to determine if CFTR function is abnormal in patients with pancreas divisum and recurrent acute pancreatitis (PD/RAP). A total of 69 healthy control subjects, 12 patients with PD/RAP, 16 obligate heterozygotes with a single CFTR mutation, and 95 patients with cystic fibrosis were enrolled. CFTR function was analyzed by nasal transepithelial potential difference testing in vivo. The outcomes of the PD/RAP patients following endoscopic and surgical treatments were concomitantly analyzed. Direct measurement of CFTR function in nasal epithelium in response to isoproterenol demonstrated that the values for PD/RAP were intermediate between those observed for healthy controls and cystic fibrosis patients. The median value was 13 mV for PD/RAP subjects, which was statistically different from healthy controls (22 mV, p= 0.001) and cystic fibrosis pancreatic sufficient (-1 mV, p < 0.0001) and pancreatic insufficient (-3 mV, p < 0.0001) patients. These results suggest a link between CFTR dysfunction and recurrent acute pancreatitis in patients with pancreas divisum and may explain why a subset of patients with pancreas divisum develops recurrent acute pancreatitis. Copyright 2004 American College of Gastroenterology

  13. Delta hedging strategies comparison

    DEFF Research Database (Denmark)

    De Giovanni, Domenico; Ortobelli, S.; Rachev, S.T.


    In this paper we implement dynamic delta hedging strategies based on several option pricing models. We analyze different subordinated option pricing models and we examine delta hedging costs using ex-post daily prices of S&P 500. Furthermore, we compare the performance of each subordinated model...

  14. Connectivity in river deltas (United States)

    Passalacqua, P.; Hiatt, M. R.; Sendrowski, A.


    Deltas host approximately half a billion people and are rich in ecosystem diversity and economic resources. However, human-induced activities and climatic shifts are significantly impacting deltas around the world; anthropogenic disturbance, natural subsidence, and eustatic sea-level rise are major causes of threat to deltas and in many cases have compromised their safety and sustainability, putting at risk the people that live on them. In this presentation, I will introduce a framework called Delta Connectome for studying connectivity in river deltas based on different representations of a delta as a network. Here connectivity indicates both physical connectivity (how different portions of the system interact with each other) as well as conceptual (pathways of process coupling). I will explore several network representations and show how quantifying connectivity can advance our understanding of system functioning and can be used to inform coastal management and restoration. From connectivity considerations, the delta emerges as a leaky network that evolves over time and is characterized by continuous exchanges of fluxes of matter, energy, and information. I will discuss the implications of connectivity on delta functioning, land growth, and potential for nutrient removal.

  15. CFTR-dependent chloride efflux in cystic fibrosis mononuclear cells is increased by ivacaftor therapy. (United States)

    Guerra, Lorenzo; D'Oria, Susanna; Favia, Maria; Castellani, Stefano; Santostasi, Teresa; Polizzi, Angela M; Mariggiò, Maria A; Gallo, Crescenzio; Casavola, Valeria; Montemurro, Pasqualina; Leonetti, Giuseppina; Manca, Antonio; Conese, Massimo


    The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiator ivacaftor (Kalydeco®) improves clinical outcome in G551D cystic fibrosis (CF) patients. Here, we have investigated whether ivacaftor has a clinical impact on non-G551D gating mutations and function of circulating leukocytes as well. Seven patients were treated with ivacaftor and evaluated at baseline, and at 1-3 and 6 months. Besides clinical and systemic inflammatory parameters, circulating mononuclear cells (MNC) were evaluated for CFTR-dependent chloride efflux by spectrofluorimetry, neutrophils for oxidative burst by cytofluorimetry and HVCN1 mRNA expression by real time PCR. Ivacaftor determined a significant decrease in sweat chloride concentrations at all time points during treatment. Body mass index (BMI), FEV 1 , and FVC showed an increasing trend. While C-reactive protein decreased significantly at 2 months, the opposite behavior was noticed for circulating monocytes. CFTR activity in MNC was found to increase significantly at 3 and 6 months. Neutrophil oxidative burst peaked at 2 months and then decreased to baseline. HVCN1 mRNA expression was significantly higher than baseline at 1-3 months and decreased after 6 months of treatment. The chloride efflux in MNC correlated positively with both FEV 1 and FVC. On the other hand, sweat chloride correlated positively with CRP and WBC, and negatively with both respiratory function tests. A cluster analysis confirmed that sweat chloride, FEV 1 , FVC, BMI, and MNC chloride efflux behaved as a single entity over time. In patients with non-G551D mutations, ivacaftor improved both chloride transport in sweat ducts and chloride efflux in MNC, that is, functions directly imputed to CFTR. © 2017 Wiley Periodicals, Inc.

  16. Stimulation of Intestinal Cl- Secretion Through CFTR by Caffeine Intake in Salt-Sensitive Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Xiao Wei


    Full Text Available Background/Aims: High salt consumption is a major risk factor for hypertension, and sodium homeostasis is regulated by both intestinal sodium absorption and urinary sodium excretion. Chronic caffeine intake has been reported to attenuate salt-sensitive hypertension by promoting urinary sodium excretion; however, its exact role in intestinal sodium absorption remains unknown. Here, we investigated whether and how chronic caffeine consumption antagonizes salt-sensitive hypertension by inhibiting intestinal sodium absorption. Methods: Dahl salt-sensitive rats were fed 8% NaCl chow and 0.1% caffeine in their drinking water for 15 days. The blood pressure and fecal sodium content were measured. The effect of caffeine on the movement of Cl- in enterocyte cells was determined with the Ussing chamber assay. Results: Rats that were treated with caffeine displayed significantly lower mean blood pressure and higher fecal sodium content than the controls. Consistent with these findings, caffeine intake decreased fluid absorption by the intestine in the fluid perfusion experiment. Further, the results from the Ussing chamber assay indicated that caffeine promoted Cl- secretion through enterocyte apical cystic fibrosis transmembrane conductance regulator (CFTR, and thus inhibited sodium absorption. Moreover, depletion of cAMP or inhibition of CFTR completely abolished the effect of caffeine on Cl- secretion. Conclusion: The results indicate that chronic caffeine consumption reduces sodium absorption by promoting CFTR-mediated Cl- secretion in the intestine, which contributes to the anti-hypertensive effect of caffeine in salt-sensitive rats.

  17. CFTR-dependent defect in alternatively-activated macrophages in cystic fibrosis. (United States)

    Tarique, Abdullah A; Sly, Peter D; Holt, Patrick G; Bosco, Anthony; Ware, Robert S; Logan, Jayden; Bell, Scott C; Wainwright, Claire E; Fantino, Emmanuelle


    The role of the macrophages in cystic fibrosis (CF) lung disease has been poorly studied. We hypothesized that alternatively activated M2 macrophages are abnormal in CF lung disease. Blood samples were collected from adults (n=13) children (n=27) with CF on admission for acute pulmonary exacerbation and when clinically stable. Monocytes were differentiated into macrophages and polarized into classical (M1) and alternatively-activated (M2) phenotypes, function determined ex-vivo and compared with healthy controls. In the absence of functional cystic fibrosis trans-membrane conductance regulator (CFTR), either naturally in patients with CF or induced with CFTR inhibitors, monocyte-derived macrophages do not respond to IL-13/IL-4, fail to polarize into M2s associated with a post-transcriptional failure to produce and express IL-13Rα1 on the macrophage surface Polarization to the M1 phenotype was unaffected. CFTR-dependent imbalance of macrophage phenotypes and functions could contribute to the exaggerated inflammatory response seen in CF lung disease. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  18. Antibodies to the CFTR modulate the turgor pressure of guard cell protoplasts via slow anion channels. (United States)

    Leonhardt, N; Bazin, I; Richaud, P; Marin, E; Vavasseur, A; Forestier, C


    The plasma membrane guard cell slow anion channel is a key element at the basis of water loss control in plants allowing prolonged osmolite efflux necessary for stomatal closure. This channel has been extensively studied by electrophysiological approaches but its molecular identification is still lacking. Recently, we described that this channel was sharing some similarities with the mammalian ATP-binding cassette protein, cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel [Leonhardt, N. et al. (1999) Plant Cell 11, 1141-1151]. Here, using the patch-clamp technique and a bioassay, consisting in the observation of the change in guard cell protoplasts volume, we demonstrated that a functional antibody raised against the mammalian CFTR prevented ABA-induced guard cell protoplasts shrinking and partially inhibited the slow anion current. Moreover, this antibody immunoprecipitated a polypeptide from guard cell protein extracts and immunolabeled stomata in Vicia faba leaf sections. These results indicate that the guard cell slow anion channel is, or is closely controlled by a polypeptide, exhibiting one epitope shared with the mammalian CFTR.

  19. A new compound heterozygous CFTR mutation in a Chinese family with cystic fibrosis. (United States)

    Xie, Yingjun; Huang, Xueqiong; Liang, Yujian; Xu, Lingling; Pei, Yuxin; Cheng, Yucai; Zhang, Lidan; Tang, Wen


    Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians but is rarer in the Chinese population, because mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To elucidate the causative role of a novel compound heterozygous mutation of CF. In this study, clinical samples were obtained from two siblings with recurrent airway infections, clubbed fingers, salt-sweat and failure to gain weight in a non-consanguineous Chinese family. Next-generation sequencing was performed on the 27 coding exons of CFTR in both children, with confirmation by Sanger sequencing. Next-generation sequencing showed the same compound heterozygous CFTR mutation (c.865A>T p.Arg289X and c.3651_3652insAAAT p.Tyr1219X) in both children. As this mutation is consistent with the clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that the CF phenotype is caused by compound heterozygosity for c.865A>T and c.3651_3652insAAAT. As c865A>T is not currently listed in the "Cystic Fibrosis Mutation Database", this information about CF in a Chinese population is of interest. © 2015 John Wiley & Sons Ltd.

  20. Longevity and plasticity of CFTR provide an argument for noncanonical SNP organization in hominid DNA.

    Directory of Open Access Journals (Sweden)

    Aubrey E Hill

    Full Text Available Like many other ancient genes, the cystic fibrosis transmembrane conductance regulator (CFTR has survived for hundreds of millions of years. In this report, we consider whether such prodigious longevity of an individual gene--as opposed to an entire genome or species--should be considered surprising in the face of eons of relentless DNA replication errors, mutagenesis, and other causes of sequence polymorphism. The conventions that modern human SNP patterns result either from purifying selection or random (neutral drift were not well supported, since extant models account rather poorly for the known plasticity and function (or the established SNP distributions found in a multitude of genes such as CFTR. Instead, our analysis can be taken as a polemic indicating that SNPs in CFTR and many other mammalian genes may have been generated--and continue to accrue--in a fundamentally more organized manner than would otherwise have been expected. The resulting viewpoint contradicts earlier claims of 'directional' or 'intelligent design-type' SNP formation, and has important implications regarding the pace of DNA adaptation, the genesis of conserved non-coding DNA, and the extent to which eukaryotic SNP formation should be viewed as adaptive.

  1. The Niger Delta Crisis

    African Journals Online (AJOL)



    Sep 28, 2013 ... Department of History & International Studies, Delta State University, Abraka,. Nigeria. .... democracy implies popular power. That is ... Okonta (2006:5) draws attention to Anna Zalik's treatise called 'Petro-Vio- lence' and ...

  2. Delta agent (Hepatitis D) (United States)

    ... this page: // Hepatitis D (Delta agent) To use the sharing features on this page, please enable JavaScript. Hepatitis D is a viral infection caused by the ...

  3. Delta 2.0

    DEFF Research Database (Denmark)

    Skott, Jeppe; Skott, Charlotte Krog; Jess, Kristine

    DELTA 2.0 er en ny og helt opdateret udgave af Delta, der i ti år været brugt i matematiklærernes grund-, efter- og videreuddannelse. DELTA 2.0 er seriens almene fagdidaktik. Der er også fagdidaktiske overvejelser i de øvrige bøger i serien, men de er knyttet til specifikt matematisk indhold. DELTA...... 2.0 behandler mere generelle matematikdidaktiske problemstillinger såsom læringsteoretiske overvejelser i forbindelse med matematik, centrale aspekter af det at undervise i matematik og digitale teknologier som værktøj til at støtte elevers faglige læring af matematik....

  4. Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis. (United States)

    Ockenga, J; Stuhrmann, M; Ballmann, M; Teich, N; Keim, V; Dörk, T; Manns, M P


    We investigated whether mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and cationic trypsinogen gene are associated with recurrent acute, or chronic idiopathic pancreatitis. Twenty patients with idiopathic pancreatitis (11 women, nine men; mean age, 30 yr) were studied for the presence of a CFTR mutation by screening the genomic DNA for more than 30 mutations and variants in the CFTR gene. Selected mutations of the cationic trypsinogen gene were screened by Afl III restriction digestion or by a mutation-specific polymerase chain reaction (PCR). In each patient exons 1, 2, and 3 of the cationic trypsinogen gene were sequenced. Patients with a CFTR mutation underwent evaluation of further functional electrophysiological test (intestinal current measurement). No mutation of the cationic trypsinogen gene was detected. A CFTR mutation was detected in 6/20 (30.0%) patients. Three patients (15.0%) had a cystic fibrosis (CF) mutation on one chromosome (deltaF508, I336K, Y1092X), which is known to cause phenotypical severe cystic fibrosis. One patient was heterozygous for the 5T allele. In addition, two possibly predisposing CFTR variants (R75Q, 1716G-->A) were detected on four patients, one of these being a compound heterozygous for the missense mutation I336K and R75Q. No other family member (maternal I336K; paternal R75Q; sister I1336K) developed pancreatitis. An intestinal current measurement in rectum samples of patients with a CFTR mutation revealed no CF-typical constellations. CFTR mutations are associated with recurrent acute, or chronic idiopathic pancreatitis, whereas mutations of the cationic trypsinogen mutation do not appear to be a frequent pathogenetic factor.

  5. Crystallographic and single-particle analyses of native- and nucleotide-bound forms of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. (United States)

    Awayn, N H; Rosenberg, M F; Kamis, A B; Aleksandrov, L A; Riordan, J R; Ford, R C


    Cystic fibrosis, one of the major human inherited diseases, is caused by defects in the CFTR (cystic fibrosis transmembrane conductance regulator), a cell-membrane protein. CFTR acts as a chloride channel which can be opened by ATP. Low-resolution structural studies of purified recombinant human CFTR are described in the present paper. Localization of the C-terminal decahistidine tag in CFTR was achieved by Ni2+-nitriloacetate nanogold labelling, followed by electron microscopy and single-particle analysis. The presence of the gold label appears to improve the single-particle-alignment procedure. Projection structures of CFTR from two-dimensional crystals analysed by electron crystallography displayed two alternative conformational states in the presence of nucleotide and nanogold, but only one form of the protein was observed in the quiescent (nucleotide-free) state.

  6. S737F is a new CFTR mutation typical of patients originally from the Tuscany region in Italy. (United States)

    Terlizzi, Vito; Di Lullo, Antonella Miriam; Comegna, Marika; Centrone, Claudia; Pelo, Elisabetta; Castaldo, Giuseppe; Raia, Valeria; Braggion, Cesare


    An increasing number of patients have been described as having a number of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) variants for which it lacks a clear genotype-phenotype correlation. We assesses the clinical features of patients bearing the S737F (p.Ser737Phe) CFTR missense variant and evaluated the residual function of CFTR protein on nasal epithelial cells (NEC). A retrospective database was performed from individuals homozygous or compound heterozygous for the S737F variant followed in the Cystic Fibrosis (CF) Centre of Florence. We performed a nasal brushing in cooperating patients and compared the results with those of patients followed in the pediatric CF Centre of Naples. 9/295 (3%) subjects carrying at least S737F CFTR variant on one allele were identified. Patients were diagnosed in 7/9 cases by newborn screening and in two cases for dehydration with hypochloremic metabolic alkalosis; at diagnosis sweat chloride levels (SCL) were in the pathological range in only one case. After a mean follow up of 8,6 years (range 0,5-15,8), SCL were in the pathological range in 8/9 cases (mean age at CF diagnosis: 1,5 years), all patients were pancreatic sufficiency and respiratory function was normal. The gating activity on NEC was 15.6% and 12.7% in two patients compound heterozygous for W1282X and DelE22_24, while it was ranged between 6,2% and 9,8% in CF patients. S737F is a CFTR mutation associated to hypochloremic alkalosis in childhood, mild CF phenotype in teenage years and a residual function of CFTR protein.

  7. An immortal cell line to study the role of endogenous CFTR in electrolyte absorption. (United States)

    Bell, C L; Quinton, P M


    The intact human reabsorptive sweat duct (RD) has been a reliable model for investigations of the functional role of "endogenous" CFTR (cystic fibrosis transmembrane conductance regulator) in normal and abnormal electrolyte absorptive function. But to overcome the limitations imposed by the use of fresh, intact tissue, we transformed cultured RD cells using the chimeric virus Ad5/SV40 1613 ori-. The resultant cell line, RD2(NL), has remained differentiated forming a polarized epithelium that expressed two fundamental components of absorption, a cAMP activated Cl- conductance (GCl) and an amiloride-sensitive Na+ conductance (GNa). In the unstimulated state, there was a low level of transport activity; however, addition of forskolin (10(-5) M) significantly increased the Cl- diffusion potential (Vt) generated by a luminally directed Cl- gradient from -15.3 +/- 0.7 mV to -23.9 +/- 1.1 mV, n = 39; and decreased the transepithelial resistance (Rt) from 814.8 +/- 56.3 omega.cm2 to 750.5 +/- 47.5 omega.cm2, n = 39, (n = number of cultures). cAMP activation, anion selectivity (Cl- > I- > gluconate), and a dependence upon metabolic energy (metabolic poisoning inhibited GCl), all indicate that the GCl expressed in RD2(NL) is in fact CFTR-GCl. The presence of an apical amiloride-sensitive GNa was shown by the amiloride (10(-5) M) inhibition of GNa as indicated by a reduction of Vt and equivalent short circuit current by 78.0 +/- 3.1% and 77.9 +/- 2.6%, respectively, and an increase in Rt by 7.2 +/- 0.8%, n = 36. In conclusion, the RD2(NL) cell line presents the first model system in which CFTR-GCl is expressed in a purely absorptive tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Women of Niger Delta

    African Journals Online (AJOL)

    Religion Dept

    The Indispensability of Women in Conflict Resolution in the Niger Delta ... The situation leads to a shift in gender roles with a dramatic increase in the number of women .... organization is to work in partnership with the Nigerian Government and the .... that “women are the impartial arbitrators in family or clan disputes or.

  9. Conservative Delta Hedging (United States)


    an exact method for converting such intervals into arbitrage based prices of financial derivatives or industrial or contractual options. We call this...procedure conservative delta hedging . As existing procedures are of an ad hoc nature, the proposed approach will permit an institution’s man agement a greater oversight of its exposure to risk.

  10. Restoration of CFTR Activity in Ducts Rescues Acinar Cell Function and Reduces Inflammation in Pancreatic and Salivary Glands of Mice. (United States)

    Zeng, Mei; Szymczak, Mitchell; Ahuja, Malini; Zheng, Changyu; Yin, Hongen; Swaim, William; Chiorini, John A; Bridges, Robert J; Muallem, Shmuel


    Sjögren's syndrome and autoimmune pancreatitis are disorders with decreased function of salivary, lacrimal glands, and the exocrine pancreas. Nonobese diabetic/ShiLTJ mice and mice transduced with the cytokine BMP6 develop Sjögren's syndrome and chronic pancreatitis and MRL/Mp mice are models of autoimmune pancreatitis. Cystic fibrosis transmembrane conductance regulator (CFTR) is a ductal Cl -  channel essential for ductal fluid and HCO 3 - secretion. We used these models to ask the following questions: is CFTR expression altered in these diseases, does correction of CFTR correct gland function, and most notably, does correcting ductal function correct acinar function? We treated the mice models with the CFTR corrector C18 and the potentiator VX770. Glandular, ductal, and acinar cells damage, infiltration, immune cells and function were measured in vivo and in isolated duct/acini. In the disease models, CFTR expression is markedly reduced. The salivary glands and pancreas are inflamed with increased fibrosis and tissue damage. Treatment with VX770 and, in particular, C18 restored salivation, rescued CFTR expression and localization, and nearly eliminated the inflammation and tissue damage. Transgenic overexpression of CFTR exclusively in the duct had similar effects. Most notably, the markedly reduced acinar cell Ca 2+ signaling, Orai1, inositol triphosphate receptors, Aquaporin 5 expression, and fluid secretion were restored by rescuing ductal CFTR. Our findings reveal that correcting ductal function is sufficient to rescue acinar cell function and suggests that CFTR correctors are strong candidates for the treatment of Sjögren's syndrome and pancreatitis. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  11. Mystery of the delta(980)

    International Nuclear Information System (INIS)

    Cahn, R.N.; Landshoff, P.V.


    The apparent conflict between the dominance of the decay delta->etaπ in D->deltaπ and its absence in iota->deltaπ is analyzed. Explicit models are presented in which the nearby Kanti K threshold plays an important role in resolving the conflict. (orig.)

  12. Development of allele-specific multiplex PCR to determine the length of poly-T in intron 8 of CFTR

    Directory of Open Access Journals (Sweden)

    Neng Chen


    Full Text Available Cystic fibrosis transmembrane conductance regulator (CFTR gene mutation analysis has been implemented for Cystic Fibrosis (CF carrier screening, and molecular diagnosis of CF and congenital bilateral absence of the vas deferens (CBAVD. Although poly-T allele analysis in intron 8 of CFTR is required when a patient is positive for R117H, it is not recommended for routine carrier screening. Therefore, commercial kits for CFTR mutation analysis were designed either to mask the poly-T allele results, unless a patient is R117H positive, or to have the poly-T analysis as a standalone reflex test using the same commercial platform. There are other standalone assays developed to detect poly-T alleles, such as heteroduplex analysis, High Resolution Melting (HRM curve analysis, allele-specific PCR (AS-PCR and Sanger sequencing. In this report, we developed a simple and easy-to-implement multiplex AS-PCR assay using unlabeled standard length primers, which can be used as a reflex or standalone test for CFTR poly-T track analysis. Out of 115 human gDNA samples tested, results from our new AS-PCR matched to the previous known poly-T results or results from Sanger sequencing.

  13. Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis. (United States)

    Bremer, Lindsay A; Blackman, Scott M; Vanscoy, Lori L; McDougal, Kathryn E; Bowers, Amanda; Naughton, Kathleen M; Cutler, David J; Cutting, Garry R


    Cystic fibrosis (CF), the most common lethal single gene disorder in Caucasians, is due to mutations in the CFTR gene. Twin and sibling analysis indicates that modifier genes, rather than allelic variation in CFTR, are responsible for most of the variability in severity of lung disease, the major cause of mortality in CF patients. We used a family-based approach to test for association between lung function and two functional SNPs (rs1800469, '-509' and rs1982073, 'codon 10') in the 5' region of transforming growth factor-beta1 (TGFB1), a putative CF modifier gene. Quantitative transmission disequilibrium testing of 472 CF patient-parent-parent trios revealed that both TGFB1 SNPs showed significant transmission distortion when patients were stratified by CFTR genotype. Although lung function and nutritional status are correlated in CF patients, there was no evidence of association between the TGFB1 SNPs and variation in nutritional status. Additional tagging SNPs (rs8179181, rs2278422, rs8110090, rs4803455 and rs1982072) that capture most of the diversity in TGFB1 were also typed but none showed association with variation in lung function. However, a haplotype composed of the -509 C and codon 10 T alleles along with the C allele of the 3' SNP rs8179181 was highly associated with increased lung function in patients grouped by CFTR genotype. These results demonstrate that TGFB1 is a modifier of CF lung disease and reveal a previously unrecognized beneficial effect of TGFB1 variants upon the pulmonary phenotype.

  14. Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility (United States)

    Lin, Hui; Li, Rui-Rui; Liang, Zong-Lai; Gao, Yuan; Yang, Zhao; He, Dong-Fang; Lin, Amy; Mo, Hui; Lu, Yu-Jing; Li, Meng-Jing; Kong, Wei; Chung, Ka Young; Yi, Fan; Li, Jian-Yuan; Qin, Ying-Ying; Li, Jingxin; Thomsen, Alex R B; Kahsai, Alem W; Chen, Zi-Jiang; Xu, Zhi-Gang; Liu, Mingyao


    Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility. PMID:29393851

  15. DELTAS: A new Global Delta Sustainability Initiative (Invited) (United States)

    Foufoula-Georgiou, E.


    Deltas are economic and environmental hotspots, food baskets for many nations, home to a large part of the world population, and hosts of exceptional biodiversity and rich ecosystems. Deltas, being at the land-water interface, are international, regional, and local transport hubs, thus providing the basis for intense economic activities. Yet, deltas are deteriorating at an alarming rate as 'victims' of human actions (e.g. water and sediment reduction due to upstream basin development), climatic impacts (e.g. sea level rise and flooding from rivers and intense tropical storms), and local exploration (e.g. sand or aggregates, groundwater and hydrocarbon extraction). Although many efforts exist on individual deltas around the world, a comprehensive global delta sustainability initiative that promotes awareness, science integration, data and knowledge sharing, and development of decision support tools for an effective dialogue between scientists, managers and policy makers is lacking. Recently, the international scientific community proposed to establish the International Year of Deltas (IYD) to serve as the beginning of such a Global Delta Sustainability Initiative. The IYD was proposed as a year to: (1) increase awareness and attention to the value and vulnerability of deltas worldwide; (2) promote and enhance international and regional cooperation at the scientific, policy, and stakeholder level; and (3) serve as a launching pad for a 10-year committed effort to understand deltas as complex socio-ecological systems and ensure preparedness in protecting and restoring them in a rapidly changing environment. In this talk, the vision for such an international coordinated effort on delta sustainability will be presented as developed by a large number of international experts and recently funded through the Belmont Forum International Opportunities Fund. Participating countries include: U.S., France, Germany, U.K., India, Japan, Netherlands, Norway, Brazil, Bangladesh

  16. Incidence and Carrier Frequency of CFTR Gene Mutations in Pregnancies With Echogenic Bowel in Nova Scotia and Prince Edward Island. (United States)

    Miller, Michelle E; Allen, Victoria M; Brock, Jo-Ann K


    Fetal echogenic bowel (echogenic bowel) is associated with cystic fibrosis (CF), with a reported incidence ranging from 1% to 13%. Prenatal testing for CF in the setting of echogenic bowel can be done by screening parental or fetal samples for pathogenic CFTR variants. If only one pathogenic variant is identified, sequencing of the CFTR gene can be undertaken, to identify a second pathogenic variant not covered in the standard screening panel. Full gene sequencing, however, also introduces the potential to identify variants of uncertain significance (VUSs) that can create counselling challenges and cause parental anxiety. To provide accurate counselling for families in the study population, the incidence of CF associated with echogenic bowel and the carrier frequency of CFTR variants were investigated. All pregnancies for which CF testing was undertaken for the indication of echogenic bowel (from Nova Scotia and Prince Edward Island) were identified (January 2007-July 2017). The CFTR screening and sequencing results were reviewed, and fetal outcomes related to CF were assessed. A total of 463 pregnancies with echogenic bowel were tested. Four were confirmed to be affected with CF, giving an incidence of 0.9% in this cohort. The carrier frequency of CF among all parents in the cohort was 5.0% (1 in 20); however, when excluding parents of affected fetuses, the carrier frequency for the population was estimated at 4.1% (1 in 25). CFTR gene sequencing identified an additional VUS in two samples. The incidence of CF in pregnancies with echogenic bowel in Nova Scotia and Prince Edward Island is 0.9%, with an estimated population carrier frequency of 4.1%. These results provide the basis for improved counselling to assess the risk of CF in the pregnancy, after parental carrier screening, using Bayesian probability. Counselling regarding VUSs should be undertaken before gene sequencing. Copyright © 2017 Society of Obstetricians and Gynaecologists of Canada. Published by

  17. Thermodynamic study of the native and phosphorylated regulatory domain of the CFTR

    Energy Technology Data Exchange (ETDEWEB)

    Marasini, Carlotta, E-mail: [Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Via De Marini 6, 16149 Genova (Italy); Galeno, Lauretta; Moran, Oscar [Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Via De Marini 6, 16149 Genova (Italy)


    Highlights: Black-Right-Pointing-Pointer CFTR mutations produce cystic fibrosis. Black-Right-Pointing-Pointer Chloride transport depends on the regulatory domain phosphorylation. Black-Right-Pointing-Pointer Regulatory domain is intrinsically disordered. Black-Right-Pointing-Pointer Secondary structure and protein stability change upon phosphorylation. -- Abstract: The regulatory domain (RD) of the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein in cystic fibrosis, is the region of the channel that regulates the CFTR activity with multiple phosphorylation sites. This domain is an intrinsically disordered protein, characterized by lack of stable or unique tertiary structure. The disordered character of a protein is directly correlated with its function. The flexibility of RD may be important for its regulatory role: the continuous conformational change may be necessary for the progressive phosphorylation, and thus activation, of the channel. However, the lack of a defined and stable structure results in a considerable limitation when trying to in build a unique molecular model for the RD. Moreover, several evidences indicate significant structural differences between the native, non-phosphorylated state, and the multiple phosphorylated state of the protein. The aim of our work is to provide data to describe the conformations and the thermodynamic properties in these two functional states of RD. We have done the circular dichroism (CD) spectra in samples with a different degree of phosphorylation, from the non-phosphorylated state to a bona fide completely phosphorylated state. Analysis of CD spectra showed that the random coil and {beta}-sheets secondary structure decreased with the polypeptide phosphorylation, at expenses of an increase of {alpha}-helix. This observation lead to interpret phosphorylation as a mechanism favoring a more structured state. We also studied the thermal denaturation curves of the protein in the two

  18. Thermodynamic study of the native and phosphorylated regulatory domain of the CFTR

    International Nuclear Information System (INIS)

    Marasini, Carlotta; Galeno, Lauretta; Moran, Oscar


    Highlights: ► CFTR mutations produce cystic fibrosis. ► Chloride transport depends on the regulatory domain phosphorylation. ► Regulatory domain is intrinsically disordered. ► Secondary structure and protein stability change upon phosphorylation. -- Abstract: The regulatory domain (RD) of the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein in cystic fibrosis, is the region of the channel that regulates the CFTR activity with multiple phosphorylation sites. This domain is an intrinsically disordered protein, characterized by lack of stable or unique tertiary structure. The disordered character of a protein is directly correlated with its function. The flexibility of RD may be important for its regulatory role: the continuous conformational change may be necessary for the progressive phosphorylation, and thus activation, of the channel. However, the lack of a defined and stable structure results in a considerable limitation when trying to in build a unique molecular model for the RD. Moreover, several evidences indicate significant structural differences between the native, non-phosphorylated state, and the multiple phosphorylated state of the protein. The aim of our work is to provide data to describe the conformations and the thermodynamic properties in these two functional states of RD. We have done the circular dichroism (CD) spectra in samples with a different degree of phosphorylation, from the non-phosphorylated state to a bona fide completely phosphorylated state. Analysis of CD spectra showed that the random coil and β-sheets secondary structure decreased with the polypeptide phosphorylation, at expenses of an increase of α-helix. This observation lead to interpret phosphorylation as a mechanism favoring a more structured state. We also studied the thermal denaturation curves of the protein in the two conditions, monitoring the changes of the mean residue ellipticity measured at 222 nm as a function of temperature

  19. The importance of functional tests to assess the effect of a new CFTR variant when genotype-phenotype correlation is not possible. (United States)

    Hinzpeter, Alexandre; Reboul, Marie-Pierre; Callebaut, Isabelle; Zordan, Cécile; Costes, Bruno; Guichoux, Julie; Iron, Albert; Lacombe, Didier; Martin, Natacha; Arveiler, Benoit; Fanen, Pascale; Fergelot, Patricia; Girodon, Emmanuelle


    In vitro functional tests aimed to investigate CFTR dysfunction appear critical to help elucidate the functional impact of new variants of uncertain clinical significance and solve inconclusive cases, especially in early deceased newborns.

  20. Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Are Associated with Chronic Pancreatitis in Patients without Cystic Fibrosis (United States)

    Schneider, Alexander; LaRusch, Jessica; Sun, Xiumei; Aloe, Amy; Lamb, Janette; Hawes, Robert; Cotton, Peter; Brand, Randall E.; Anderson, Michelle A.; Money, Mary E.; Banks, Peter A.; Lewis, Michele D.; Baillie, John; Sherman, Stuart; DiSario, James; Burton, Frank R.; Gardner, Timothy B.; Amann, Stephen T.; Gelrud, Andres; George, Ryan; Kassabian, Sirvart; Martinson, Jeremy; Slivka, Adam; Yadav, Dhiraj; Oruc, Nevin; Barmada, M. Michael; Frizzell, Raymond; Whitcomb, David C.


    Background & Aims Idiopathic chronic pancreatitis (ICP) is a complex inflammatory disorder associated with multiple genetic and environmental factors. In individuals without cystic fibrosis (CF), variants of CFTR that inhibit bicarbonate conductance but maintain chloride conductance might selectively impair secretion of pancreatic juice, leading to trypsin activation and pancreatitis. We investigated whether sequence variants in the gene encoding the pancreatic secretory trypsin inhibitor, SPINK1, further increase the risk of pancreatitis in these patients. Methods We screened patients with ICP (sporadic or familial) and controls for variants in SPINK1 associated with chronic pancreatitis (CP) risk (in exon 3) and in all 27 exons of CFTR. The final study group included 53 patients with sporadic ICP, 27 probands with familial ICP, and 150 unrelated controls, plus 503 controls for limited genotyping. CFTR wild-type (wt) and p.R75Q were cloned and expressed in HEK293 cells and relative conductances of HCO3− and Cl− were measured. Results SPINK1 variants were identified in 36% of subjects and 3% controls (odds ratio [OR]=16.5). One variant of CFTR that has not been associated with CF, p.R75Q, was found in 16% of subjects and 5.4% controls (OR=3.4). Co-inheritance of CFTR p.R75Q and SPINK1 variants occurred in 8.75% of patients and 0.15% controls (OR=62.5). Patch-clamp recordings of cells that expressed CFTR p.R75Q demonstrated normal chloride currents but significantly reduced bicarbonate currents (P=0.0001). Conclusions The CFTR variant p.R75Q causes a selective defect in bicarbonate conductance and increases risk for pancreatitis. Co-inheritance of CF-associated, and some not associated, CFTR variants with SPINK1 variants significantly increase risk of ICP. PMID:20977904

  1. Gap Junctions Are Involved in the Rescue of CFTR-Dependent Chloride Efflux by Amniotic Mesenchymal Stem Cells in Coculture with Cystic Fibrosis CFBE41o- Cells

    Directory of Open Access Journals (Sweden)

    Annalucia Carbone


    Full Text Available We previously found that human amniotic mesenchymal stem cells (hAMSCs in coculture with CF immortalised airway epithelial cells (CFBE41o- line, CFBE on Transwell® filters acquired an epithelial phenotype and led to the expression of a mature and functional CFTR protein. In order to explore the role of gap junction- (GJ- mediated intercellular communication (GJIC in this rescue, cocultures (hAMSC : CFBE, 1 : 5 ratio were studied for the formation of GJIC, before and after silencing connexin 43 (Cx43, a major component of GJs. Functional GJs in cocultures were inhibited when the expression of the Cx43 protein was downregulated. Transfection of cocultures with siRNA against Cx43 resulted in the absence of specific CFTR signal on the apical membrane and reduction in the mature form of CFTR (band C, and in parallel, the CFTR-dependent chloride channel activity was significantly decreased. Cx43 downregulation determined also a decrease in transepithelial resistance and an increase in paracellular permeability as compared with control cocultures, implying that GJIC may regulate CFTR expression and function that in turn modulate airway epithelium tightness. These results indicate that GJIC is involved in the correction of CFTR chloride channel activity upon the acquisition of an epithelial phenotype by hAMSCs in coculture with CF cells.

  2. Gap Junctions Are Involved in the Rescue of CFTR-Dependent Chloride Efflux by Amniotic Mesenchymal Stem Cells in Coculture with Cystic Fibrosis CFBE41o- Cells. (United States)

    Carbone, Annalucia; Zefferino, Roberto; Beccia, Elisa; Casavola, Valeria; Castellani, Stefano; Di Gioia, Sante; Giannone, Valentina; Seia, Manuela; Angiolillo, Antonella; Colombo, Carla; Favia, Maria; Conese, Massimo


    We previously found that human amniotic mesenchymal stem cells (hAMSCs) in coculture with CF immortalised airway epithelial cells (CFBE41o- line, CFBE) on Transwell® filters acquired an epithelial phenotype and led to the expression of a mature and functional CFTR protein. In order to explore the role of gap junction- (GJ-) mediated intercellular communication (GJIC) in this rescue, cocultures (hAMSC : CFBE, 1 : 5 ratio) were studied for the formation of GJIC, before and after silencing connexin 43 (Cx43), a major component of GJs. Functional GJs in cocultures were inhibited when the expression of the Cx43 protein was downregulated. Transfection of cocultures with siRNA against Cx43 resulted in the absence of specific CFTR signal on the apical membrane and reduction in the mature form of CFTR (band C), and in parallel, the CFTR-dependent chloride channel activity was significantly decreased. Cx43 downregulation determined also a decrease in transepithelial resistance and an increase in paracellular permeability as compared with control cocultures, implying that GJIC may regulate CFTR expression and function that in turn modulate airway epithelium tightness. These results indicate that GJIC is involved in the correction of CFTR chloride channel activity upon the acquisition of an epithelial phenotype by hAMSCs in coculture with CF cells.

  3. Les vésicules extracellulaires comme vecteurs de macromolécules bioactives : modèle du transporteur ABCC7 (CFTR) et application à la biothérapie de la mucoviscidose


    Vituret , Cyrielle


    Cystic fibrosis is a genetic disease in which its prognosis depends on the lung damage. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), resulting in a dysfunctional CFTR protein normally located at the plasma membrane of epithelial cells. This thesis is a study of a novel therapeutic approach to use extracellular vesicles (EVs), microvesicles and exosomes, as transfer vectors for CFTR mRNA and protein to target cells. The proof of concept for ...

  4. Fifteen-year follow-up of pulmonary function in individuals heterozygous for the cystic fibrosis phenylalanine-508 deletion

    DEFF Research Database (Denmark)

    Dahl, Morten; Nordestgaard, B G; Lange, P


    In a cross-sectional study, we previously showed that cystic fibrosis phenylalanine-508 deletion (DeltaF508) heterozygosity may be overrepresented among individuals with asthma.......In a cross-sectional study, we previously showed that cystic fibrosis phenylalanine-508 deletion (DeltaF508) heterozygosity may be overrepresented among individuals with asthma....

  5. Cystic fibrosis transmembrane conductance regulator gene mutations: do they play a role in the aetiology of allergic bronchopulmonary aspergillosis? (United States)

    Eaton, T E; Weiner Miller, P; Garrett, J E; Cutting, G R


    Previous work suggests that cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations may be implicated in the aetiology of allergic bronchopulmonary aspergilosis (ABPA). To compare the frequency of CF gene mutations in asthmatics with ABPA of varying severity with asthmatics who were skin prick test (SPT)-positive to Aspergillus fumigatus (Af) without evidence of ABPA and asthmatics SPT-negative to Af. Thirty-one Caucasian patients with ABPA were identified, together with asthmatics SPT positive to Af without evidence of ABPA (n = 23) and SPT negative to Af (n = 28). Genomic DNA was tested for 16 CF mutations accounting for approximately 85% of CF alleles in Caucasian New Zealanders. Four (12.9%) ABPA patients were found to be carriers of a CF mutation (DeltaF508 n = 3, R117H n = 1), one (4.3%) asthmatic SPT positive to Af without ABPA (DeltaF508), and one (3.6%) asthmatic SPT negative to Af (R117H). All patients with a CF mutation had normal sweat chloride (< 40 mM). There was no significant difference between the frequency of CF mutations in the ABPA patients and asthmatics without ABPA. However, the frequency of CF mutations in the ABPA patients was significantly different (P = 0.0125) to the expected carrier rate in the general population. These results lend further support to a possible link between CF mutations and ABPA.

  6. Thermostatted delta f

    International Nuclear Information System (INIS)

    Krommes, J.A.


    The delta f simulation method is revisited. Statistical coarse-graining is used to rigorously derive the equation for the fluctuation delta f in the particle distribution. It is argued that completely collisionless simulation is incompatible with the achievement of true statistically steady states with nonzero turbulent fluxes because the variance of the particle weights w grows with time. To ensure such steady states, it is shown that for dynamically collisionless situations a generalized thermostat or W-stat may be used in lieu of a full collision operator to absorb the flow of entropy to unresolved fine scales in velocity space. The simplest W-stat can be implemented as a self-consistently determined, time-dependent damping applied to w. A precise kinematic analogy to thermostatted nonequilibrium molecular dynamics (NEMD) is pointed out, and the justification of W-stats for simulations of turbulence is discussed. An extrapolation procedure is proposed such that the long-time, steady-state, collisionless flux can be deduced from several short W-statted runs with large effective collisionality, and a numerical demonstration is given

  7. People of the Delta

    Energy Technology Data Exchange (ETDEWEB)

    Gregoire, L.


    The potential impacts of both global warming and the $16 billion Mackenzie pipeline project on communities in the Mackenzie Delta were discussed. A consortium of oil and gas developers is now planning to exploit the natural gas reserves located near the mouth of the Delta, whose largest town is Inuvik. The project is expected to place a significant burden on the resources and infrastructure of the town, which currently has a population of 6000. The community, comprised of a diverse international population and an Inuit majority, is largely in favour of the pipeline project. The Inuvialuit people have invested a significant amount of time to ensure that the project, which was stalled due to land claims in 1977, benefits their communities. Public hearings are now being held to consider the potential environmental and socio-economic impacts of the project. Separate hearings are also being held to consider the project's design. The pipeline project includes 3 natural gas production facilities, a gas-processing facility, a pipeline gathering system, a 480 km natural gas liquids pipeline to the Northwest Territories, and a 1220 km natural gas pipeline to northern Alberta. The pipeline will be buried to minimize environmental impacts. The project is expected to create 8200 jobs at the height of its construction. However, communities located near the site of the natural gas reserves, such as the town of Tuktoyaktuk are now threatened by soil erosion that has been attributed to global warming. 21 figs.

  8. Phenotypic expressions of CCR5-Delta 32/Delta 32 homozygosity

    NARCIS (Netherlands)

    Nguyen, GT; Carrington, M; Beeler, JA; Dean, M; Aledort, LM; Blatt, PM; Cohen, AR; DiMichele, D; Eyster, ME; Kessler, CM; Konkle, B; Leissinger, C; Luban, N; O'Brien, SJ; Goedert, JJ; O'Brien, TR


    Objective: As blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1, we examined whether the CCR5-Delta 32/Delta 32 homozygous genotype has phenotypic expressions other than those related to HIV-1. Design: Study subjects were white homosexual men or men with hemophilia

  9. Peat compaction in deltas : implications for Holocene delta evolution

    NARCIS (Netherlands)

    van Asselen, S.


    Many deltas contain substantial amounts of peat, which is the most compressible soil type. Therefore, peat compaction potentially leads to high amounts of subsidence in deltas. The main objective of this research was to quantify subsidence due to peat compaction in Holocene fluvial-deltaic settings

  10. Sweat chloride and immunoreactive trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis. (United States)

    Castellani, Carlo; Tridello, Gloria; Tamanini, Anna; Assael, Baroukh M


    Newborns with raised immunotrypsinogen levels who have non-pathological sweat chloride values and carry two cystic fibrosis transmembrane regulator ( CFTR ) mutations of which at least one is not acknowledged to be cystic fibrosis (CF)-causing are at risk of developing clinical manifestations consistent with CFTR-related disorders or even CF. It is not known whether newborns with similar genotypes and normal immunoreactive trypsinogen (IRT) may share the same risk. This study found that newborns with these characteristics and normal IRT have lower sweat chloride values than those with raised IRT (p=0.007). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

  11. Intra-individual biological variation in sweat chloride concentrations in CF, CFTR dysfunction, and healthy pediatric subjects. (United States)

    Cirilli, Natalia; Raia, Valeria; Rocco, Ilaria; De Gregorio, Fabiola; Tosco, Antonella; Salvadori, Laura; Sepe, Angela Ornella; Buzzetti, Roberto; Minicuci, Nadia; Castaldo, Giuseppe


    The sweat test is one of the main diagnostic tools used in newborn screening programs and as a confirmatory test, in case of suspect of Cystic Fibrosis (CF). Since sweat chloride (Cl) concentration is also considered an appropriate parameter to explore the efficacy of CFTR modulators in clinical trials, it is crucial to evaluate the biological variability of this test in healthy and pathological conditions. The aim of this pilot study was to determine the intra-individual biological variability of sweat Cl, both in healthy individuals and CF patients and to assess its correlation with diet, season, and menstrual cycle. Thirty-five out of 36 selected subjects (6-18 years) were enrolled by 2 CF care centers and assigned to 3 cohorts: CF, CFTR-related disorder (CFTR-RD) and healthy volunteers. Each participant was subjected to eight sweat tests in different conditions and time of the year. Data were analyzed using linear mixed effects models for repeated measures, taking also into account intra-individual correlations. We observed a high intra-individual variability of sweat Cl, with the lowest mean CV% values among CF patients (20.21 in CF, 29.74 in CFTR-RD, and 31.15 in healthy subjects). Gender and diet had no influence on sweat Cl variability, nor had pubertal age and menstrual phase. Results of this pilot study confirmed that sweat Cl variability is high in CF patients, although non-CF individuals displayed even higher mean CV% values. Season significantly influenced sweat test values only in CF patients, likely due to changes in their hydration status. © 2018 Wiley Periodicals, Inc.

  12. Analysis of the CFTR gene in Venezuelan cystic fibrosis patients, identification of six novel cystic fibrosis-causing genetic variants


    Sánchez, Karen; De Mendonca,Elizabeth; Matute,Xiorama; Chaustre,Ismenia; Villalon,Marlene; Takiff,Howard


    Karen Sánchez,1 Elizabeth de Mendonca,1 Xiorama Matute,2 Ismenia Chaustre,2 Marlene Villalón,3 Howard Takiff4 1Unit of Genetic and Forensic Studies, Venezuelan Institute for Scientific Research (IVIC), 2Hospital JM de los Ríos, 3Hospital José Ignacio Baldo, Algodonal, National Reference Unit, 4Laboratory of Molecular Genetics, Venezuelan Institute for Scientific Research (IVIC), Caracas, Venezuela. Abstract: The mutations in the CFTR gene found in ...

  13. Comparison of vectorial ion transport in primary murine airway and human sinonasal air-liquid interface cultures, models for studies of cystic fibrosis, and other airway diseases. (United States)

    Zhang, Shaoyan; Fortenberry, James A; Cohen, Noam A; Sorscher, Eric J; Woodworth, Bradford A


    The purpose of this study was to compare vectorial ion transport within murine trachea, murine nasal septa, and human sinonasal cultured epithelium. Our hypothesis is that murine septal epithelium, rather than trachea, will more closely mimic the electrophysiology properties of human sinonasal epithelium. Epithelium from murine trachea, murine septa, and human sinonasal tissue were cultured at an air-liquid interface to confluence and full differentiation. A limited number of homozygous dF508 epithelia were also cultured. Monolayers were mounted in modified Ussing chambers to investigate pharmacologic manipulation of ion transport. The change in forskolin-stimulated current (delta-I(SC), expressed as micro-A/cm(2)) in murine septal (n = 19; 16.84 +/- 2.09) and human sinonasal (n = 18; 12.15 +/- 1.93) cultures was significantly increased over murine tracheal cultures (n = 15; 6.75 +/- 1.35; p = 0.035 and 0.0005, respectively). Forskolin-stimulated I(SC) was inhibited by the specific cystic fibrosis transmembrane regulator (CFTR) inhibitor INH-172 (5 microM). No forskolin-stimulated I(SC) was shown in cultures of dF508 homozygous murine septal epithelium (n = 3). Murine septal I(SC) was largely inhibited by amiloride (12.03 +/- 0.66), whereas human sinonasal cultures had a very limited response (0.70 +/- 0.47; p < 0.0001). The contribution of CFTR to stimulated chloride current as measured by INH-172 was highly significantly different between all groups (murine septa, 19.51 +/- 1.28; human sinonasal, 11.12 +/- 1.58; murine trachea, 4.85 +/- 0.49; p < 0.0001). Human sinonasal and murine septal epithelial cultures represent a useful model for studying CFTR activity and may provide significant advantages over lower airway tissues for investigating upper and lower respiratory pathophysiology.

  14. Analysis of the CFTR gene in Venezuelan cystic fibrosis patients, identification of six novel cystic fibrosis-causing genetic variants. (United States)

    Sánchez, Karen; de Mendonca, Elizabeth; Matute, Xiorama; Chaustre, Ismenia; Villalón, Marlene; Takiff, Howard


    The mutations in the CFTR gene found in patients with cystic fibrosis (CF) have geographic differences, but there are scant data on their prevalence in Venezuelan patients. This study determined the frequency of common CFTR gene mutations in a group of Venezuelan patients with CF. The 27 exons of the CFTR gene from 110 Venezuelan patients in the National CF Program were amplified and sequenced. A total of 36 different mutations were identified, seven with frequencies greater than 1%: p.Phe508del (27.27%), p.Gly542* (3.18%), c.2988+1G>A (3.18%), p.Arg334Trp (1.36%), p.Arg1162* (1.36%), c.1-8G>C (1.36%), and p.[Gly628Arg;Ser1235Arg](1.36). In 40% of patients, all with a clinical diagnosis of CF, no mutations were found. This report represents the largest cohort of Venezuelan patients with CF ever examined, and includes a wider mutation panel than has been previously studied in this population. Mutations common in Southern European populations predominate, and several new mutations were discovered, but no mutations were found in 40% of the cohort.

  15. Prevalence of DF508, G551D, G542X, and R553X mutations among cystic fibrosis patients in the North of Brazil

    Directory of Open Access Journals (Sweden)

    Araújo F.G. de


    Full Text Available Cystic fibrosis (CF is the most common genetic disease among Caucasians and is rare among sub-Saharan Africans. The Brazilian population is not ethnically homogeneous but it is the result of three-way ethnic admixture of Europeans, Africans and Amerindians in varying proportions, depending on the region. In the present study, we investigated 33 patients who had been diagnosed and are currently under treatment for CF at the University Hospital João de Barros Barreto, Belém, Pará State. The molecular analysis for G542X, G551D and R553X mutations was performed by PCR followed by RFLP using BstNI, HincII and MboI, respectively, in polyacrylamide gel eletrophoresis and stained with AgNO3. ThedeltaF508 mutation (a deletion of 3 bp was only analyzed by polyacrylamide gel electrophoresis and stained with AgNO3. Each sample was analyzed for regions of interest in the CFTR gene using amplified by PCR and specific primers. The deltaF508 and G551D mutations presented frequencies of 22.7 and 3%, respectively. In 74.3% of the remaining patients, none of the mutations investigated was found. The present study characterized in a sample of patients with an established clinical diagnosis of CF (asthma, repeated bronchopneumonia, disorders of nutritional status, etc. the most frequent mutation ( deltaF508 in the North region of Brazil and is also the first report of the G551D mutation. In spite of the wide spectrum of CF mutations and the heterogeneous ethnic origin of the Amazon population, the molecular diagnosis is a helpful additional tool for the diagnosis and treatment of CF patients.

  16. Challenges, Approaches and Experiences from Asian Deltas and the Rhine-Meuse Delta : Regional Training Workshop on Delta Planning and Management

    NARCIS (Netherlands)

    Wosten, J.H.M.; Douven, W.; Long Phi, H.; Fida Abdullah Khan, M.


    River delta's, like the Mekong Delta (Vietnam), Ganges-Brahmaputra Delta (Bangladesh), Ayeyarwady Delta (Myanmar), Nile (Egypt) and Ciliwung Delta (Indonesia) are developing rapidly and are characterised by large-scale urbanisation and industrialization processes. They are facing serious planning

  17. Mida pakub Delta? / Teele Kurm

    Index Scriptorium Estoniae

    Kurm, Teele


    Politsei- ja Piirivalveamet võtab kasutusele ühise Siseministeeriumi infotehnoloogia- ja arenduskeskuse ning Webmedia AS koostööna loodud dokumendihaldussüsteemi Delta. Kust sai Delta oma nime? Projekti "Dokumendihaldussüsteemi juurutamine Siseministeeriumi haldusalas" eesmärgid

  18. Delta isobars in neutron stars

    Directory of Open Access Journals (Sweden)

    Pagliara Giuseppe


    Full Text Available The appearance of delta isobars in beta-stable matter is regulated by the behavior of the symmetry energy at densities larger than saturation density. We show that by taking into account recent constraints on the density derivative of the symmetry energy and the theoretical and experimental results on the excitations of delta isobars in nuclei, delta isobars are necessary ingredients for the equations of state used for studying neutron stars. We analyze the effect of the appearance of deltas on the structure of neutron stars: as in the case of hyperons, matter containing delta is too soft for allowing the existence of 2M⊙ neutron stars. Quark stars on the other hand, could reach very massive configurations and they could form from a process of conversion of hadronic stars in which an initial seed of strangeness appears through hyperons.

  19. Conserved allosteric hot spots in the transmembrane domains of cystic fibrosis transmembrane conductance regulator (CFTR) channels and multidrug resistance protein (MRP) pumps. (United States)

    Wei, Shipeng; Roessler, Bryan C; Chauvet, Sylvain; Guo, Jingyu; Hartman, John L; Kirk, Kevin L


    ATP-binding cassette (ABC) transporters are an ancient family of transmembrane proteins that utilize ATPase activity to move substrates across cell membranes. The ABCC subfamily of the ABC transporters includes active drug exporters (the multidrug resistance proteins (MRPs)) and a unique ATP-gated ion channel (cystic fibrosis transmembrane conductance regulator (CFTR)). The CFTR channel shares gating principles with conventional ligand-gated ion channels, but the allosteric network that couples ATP binding at its nucleotide binding domains (NBDs) with conformational changes in its transmembrane helices (TMs) is poorly defined. It is also unclear whether the mechanisms that govern CFTR gating are conserved with the thermodynamically distinct MRPs. Here we report a new class of gain of function (GOF) mutation of a conserved proline at the base of the pore-lining TM6. Multiple substitutions of this proline promoted ATP-free CFTR activity and activation by the weak agonist, 5'-adenylyl-β,γ-imidodiphosphate (AMP-PNP). TM6 proline mutations exhibited additive GOF effects when combined with a previously reported GOF mutation located in an outer collar of TMs that surrounds the pore-lining TMs. Each TM substitution allosterically rescued the ATP sensitivity of CFTR gating when introduced into an NBD mutant with defective ATP binding. Both classes of GOF mutations also rescued defective drug export by a yeast MRP (Yor1p) with ATP binding defects in its NBDs. We conclude that the conserved TM6 proline helps set the energy barrier to both CFTR channel opening and MRP-mediated drug efflux and that CFTR channels and MRP pumps utilize similar allosteric mechanisms for coupling conformational changes in their translocation pathways to ATP binding at their NBDs. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


    Directory of Open Access Journals (Sweden)

    ȘOVĂILĂ Florin


    Full Text Available 3D printing is a very used process in industry, the generic name being “rapid prototyping”. The essential advantage of a 3D printer is that it allows the designers to produce a prototype in a very short time, which is tested and quickly remodeled, considerably reducing the required time to get from the prototype phase to the final product. At the same time, through this technique we can achieve components with very precise forms, complex pieces that, through classical methods, could have been accomplished only in a large amount of time. In this paper, there are presented the stages of a 3D model execution, also the physical achievement after of a Delta 3D printer after the model.

  1. Novel CFTR missense mutations in Brazilian patients with congenital absence of vas deferens: counseling issues Mutações novas no gene CFTR de pacientes brasileiros portadores de agenesia dos vasos deferentes: dificuldades no aconselhamento

    Directory of Open Access Journals (Sweden)

    Patricia de Campos Pieri


    Full Text Available PURPOSE: Screening for mutations in the entire Cystic Fibrosis gene (CFTR of Brazilian infertile men with congenital absence of vas deferens, in order to prevent transmission of CFTR mutations to offspring with the use of assisted reproductive technologies. METHOD: Specific polymerase chain reaction (PCR primers were designed to each of the 27 exons and splicing sites of interest followed by single strand conformational polymorphism and Heteroduplex Analysis (SSCP-HA in precast 12.5% polyacrylamide gels at 7ºC and 20ºC. Fragments with abnormal SSCP migration pattern were sequenced. RESULTS: Two novel missense mutations (S753R and G149W were found in three patients (two brothers together with the IVS8-5T allele in hetrozygosis. CONCLUSION: The available screenings for CF mutations do not include the atypical mutations associated to absence of vas deferens and thus, when these tests fail to find mutations, there is still a genetic risk of affected children with the help of assisted reproduction. We recommend the screening of the whole CFTR gene for these infertile couples, as part of the work-up before assisted reproduction.OBJETIVO: Pesquisar mutações em toda a extensão do gene que causa a Fibrose Cística (CFTR de homens brasileiros inférteis por agenesia congênita dos vasos deferentes, com a finalidade de prevenir a transmissão de mutações em CFTR à prole com o uso das tecnologias de reprodução assistida. MÉTODOS: Foram desenhados oligonucleotídeos específicos para realização de reação de polimerização em cadeia (PCR para cada um dos 27 exons e sítios de processamento de interesse no gene CFTR. O PCR foi seguido pela técnica de SSCP-HA (polimorfismos de conformação no DNA de fita simples e na formação de heteroduplexes em géis pré-fabricados de poliacrilamida a 12,5% em duas temperaturas, 7ºC e 20ºC. Os fragmentos com padrão alterado na migração do SSCP foram submetidos a seqüenciamento automatizado

  2. Funciones de los canales iónicos CFTR y ENAC en la fibrosis quística

    Directory of Open Access Journals (Sweden)

    Alejandra G. Palma


    Full Text Available La fibrosis quística se debe a la ausencia o defecto del canal transmembrana regulador de la fibrosis quística (CFTR, un canal de cloruro codificado en el gen cftr que juega un papel clave en la homeostasis del agua e iones. El CFTR es activado por el AMPc y se localiza en las membranas apicales y basolaterales de las vías aéreas, intestino y glándulas exocrinas. Una de sus funciones primarias en los pulmones es mantener la capa de líquido superficial a través de su función de canal y regular el canal epitelial de sodio sensible al amiloride (ENaC. Se han identificado más de 1900 mutaciones en el gen cftr. La enfermedad se caracteriza por secreciones viscosas en las glándulas exocrinas y por niveles elevados de cloruro de sodio en el sudor. En la fibrosis quística el CFTR no funciona y el ENaC está desregulado; el resultado es un aumento en la reabsorción de sodio y agua con la formación de un líquido viscoso. En las glándulas sudoríparas tanto el Na+ como el Cl- se retienen en el lumen causando una pérdida de electrolitos durante la sudoración y el NaCl se elimina al sudor. Así, los niveles elevados de NaCl son la base del test del sudor inducido por pilocarpina, un método de diagnóstico para la enfermedad. En esta revisión se discuten los movimientos de Cl- y Na+ en las glándulas sudoríparas y pulmón así como el papel del ENaC en la patogénesis de la enfermedad.

  3. Microparticle-mediated transfer of the viral receptors CAR and CD46, and the CFTR channel in a CHO cell model confers new functions to target cells.

    Directory of Open Access Journals (Sweden)

    Gaëlle Gonzalez

    Full Text Available Cell microparticles (MPs released in the extracellular milieu can embark plasma membrane and intracellular components which are specific of their cellular origin, and transfer them to target cells. The MP-mediated, cell-to-cell transfer of three human membrane glycoproteins of different degrees of complexity was investigated in the present study, using a CHO cell model system. We first tested the delivery of CAR and CD46, two monospanins which act as adenovirus receptors, to target CHO cells. CHO cells lack CAR and CD46, high affinity receptors for human adenovirus serotype 5 (HAdV5, and serotype 35 (HAdV35, respectively. We found that MPs derived from CHO cells (MP-donor cells constitutively expressing CAR (MP-CAR or CD46 (MP-CD46 were able to transfer CAR and CD46 to target CHO cells, and conferred selective permissiveness to HAdV5 and HAdV35. In addition, target CHO cells incubated with MP-CD46 acquired the CD46-associated function in complement regulation. We also explored the MP-mediated delivery of a dodecaspanin membrane glycoprotein, the CFTR to target CHO cells. CFTR functions as a chloride channel in human cells and is implicated in the genetic disease cystic fibrosis. Target CHO cells incubated with MPs produced by CHO cells constitutively expressing GFP-tagged CFTR (MP-GFP-CFTR were found to gain a new cellular function, the chloride channel activity associated to CFTR. Time-course analysis of the appearance of GFP-CFTR in target cells suggested that MPs could achieve the delivery of CFTR to target cells via two mechanisms: the transfer of mature, membrane-inserted CFTR glycoprotein, and the transfer of CFTR-encoding mRNA. These results confirmed that cell-derived MPs represent a new class of promising therapeutic vehicles for the delivery of bioactive macromolecules, proteins or mRNAs, the latter exerting the desired therapeutic effect in target cells via de novo synthesis of their encoded proteins.

  4. The ichthyotoxic alga Chattonella marina induces Na+, K+-ATPase, and CFTR proteins expression in fish gill chloride cells in vivo

    International Nuclear Information System (INIS)

    Tang, Janet Y.M.; Wong, Chris K.C.; Au, Doris W.T.


    Our previous studies demonstrated that the ichthyotoxic Chattonella marina stimulated proliferation of branchial chloride cell (CC) and induced osmotic distress akin to hyperactive elimination of ions in fish (Rhabdosargus sarba). To ascertain the in vivo effects of C. marina on key CC ion transporters, the localization and expression of Na + , K + -ATPase (NKA) and cystic fibrosis transmembrane conductance regulator (CFTR) proteins in response to C. marina exposure were investigated, using a quantitative immunocytochemical approach. The polarized distributions of NKA (α subunit) and CFTR proteins in branchial CCs of R. sarba remained unchanged under C. marina exposure. However, significant inductions of these two ion-transporters were detected in CCs of fish after 6 h exposure. By real-time PCR, no significant changes in gill NKA and CFTR mRNA expressions were detected, suggesting a post-transcriptional pathway is likely involved in regulating the ion transporters abundance. This study is the first to demonstrate the in vivo effects of harmful algal toxin on NKA and CFTR protein expressions in gill transepithelial cells. Taken together, an augmentation of branchial CCs together with hyper-stimulation of NKA and CFTR in CCs attribute to the rapid development of osmotic distress in C. marina susceptible fish

  5. Fast delta Hadamard transform

    International Nuclear Information System (INIS)

    Fenimore, E.E.; Weston, G.S.


    In many fields (e.g., spectroscopy, imaging spectroscopy, photoacoustic imaging, coded aperture imaging) binary bit patterns known as m sequences are used to encode (by multiplexing) a series of measurements in order to obtain a larger throughput. The observed measurements must be decoded to obtain the desired spectrum (or image in the case of coded aperture imaging). Decoding in the past has used a technique called the fast Hadamard transform (FHT) whose chief advantage is that it can reduce the computational effort from N 2 multiplies of N log 2 N additions or subtractions. However, the FHT has the disadvantage that it does not readily allow one to sample more finely than the number of bits used in the m sequence. This can limit the obtainable resolution and cause confusion near the sample boundaries (phasing errors). Both 1-D and 2-D methods (called fast delta Hadamard transforms, FDHT) have been developed which overcome both of the above limitations. Applications of the FDHT are discussed in the context of Hadamard spectroscopy and coded aperture imaging with uniformly redundant arrays. Special emphasis has been placed on how the FDHT can unite techniques used by both of these fields into the same mathematical basis

  6. Energy deposition by delta rays

    International Nuclear Information System (INIS)

    Weigand, F.C.; Braby, L.A.


    Monte Carlo calculations for proton tracks were extended to projectile with more complex electronic structures which add additional delta ray production processes. An experimental apparatus was used to detect gas gain and resolution for H 2+ and 3 He ++

  7. Niger Delta Development Commission and Sustainable ...

    African Journals Online (AJOL)

    Niger Delta Development Commission and Sustainable Development of Niger Delta Region of Nigeria: The Case of Rivers State. Goddey Wilson. Abstract. The study is on Niger Delta Development Commission and sustainable development of Niger Delta region of Nigeria, the case of Rivers State. The main objective of the ...

  8. $\\delta$-Expansion at Finite Temperature


    Ramos, Rudnei O.


    We apply the $\\delta$-expansion perturbation scheme to the $\\lambda \\phi^{4}$ self-interacting scalar field theory in 3+1 D at finite temperature. In the $\\delta$-expansion the interaction term is written as $\\lambda (\\phi^{2})^{ 1 + \\delta}$ and $\\delta$ is considered as the perturbation parameter. We compute within this perturbative approach the renormalized mass at finite temperature at a finite order in $\\delta$. The results are compared with the usual loop-expansion at finite temperature.

  9. Mercury toxicity in the shark (Squalus acanthias) rectal gland: apical CFTR chloride channels are inhibited by mercuric chloride. (United States)

    Ratner, Martha A; Decker, Sarah E; Aller, Stephen G; Weber, Gerhard; Forrest, John N


    In the shark rectal gland, basolateral membrane proteins have been suggested as targets for mercury. To examine the membrane polarity of mercury toxicity, we performed experiments in three preparations: isolated perfused rectal glands, primary monolayer cultures of rectal gland epithelial cells, and Xenopus oocytes expressing the shark cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. In perfused rectal glands we observed: (1) a dose-dependent inhibition by mercury of forskolin/3-isobutyl-1-methylxanthine (IBMX)-stimulated chloride secretion; (2) inhibition was maximal when mercury was added before stimulation with forskolin/IBMX; (3) dithiothrietol (DTT) and glutathione (GSH) completely prevented inhibition of chloride secretion. Short-circuit current (Isc) measurements in monolayers of rectal gland epithelial cells were performed to examine the membrane polarity of this effect. Mercuric chloride inhibited Isc more potently when applied to the solution bathing the apical vs. the basolateral membrane (23 +/- 5% and 68 +/- 5% inhibition at 1 and 10 microM HgCl2 in the apical solution vs. 2 +/- 0.9% and 14 +/- 5% in the basolateral solution). This inhibition was prevented by pre-treatment with apical DTT or GSH; however, only the permeant reducing agent DTT reversed mercury inhibition when added after exposure. When the shark rectal gland CFTR channel was expressed in Xenopus oocytes and chloride conductance was measured by two-electrode voltage clamping, we found that 1 microM HgCl2 inhibited forskolin/IBMX conductance by 69.2 +/- 2.0%. We conclude that in the shark rectal gland, mercury inhibits chloride secretion by interacting with the apical membrane and that CFTR is the likely site of this action. Copyright 2006 Wiley-Liss, Inc.

  10. Anaerobic Transformation of Furfural by Methanococcus deltae (Delta)LH (United States)

    Belay, N.; Boopathy, R.; Voskuilen, G.


    Methanococcus deltae (Delta)LH was grown on H(inf2)-CO(inf2) in the presence of various concentrations of furfural. Furfural at higher concentrations, namely, 20 and 25 mM, inhibited growth of this organism. At concentration of 5 and 10 mM, no inhibition of growth was observed. The other methanogens in this study were not inhibited by 10 mM furfural. Among the methanogens tested, M. deltae was capable of transforming furfural, whereas Methanobacterium thermoautotrophicum Marburg, Methanosarcina barkeri 227, Methanococcus thermolithotrophicus, and Methanobrevibacter ruminantium lacked this capability. One hundred percent removal of furfural was observed within 48 h of incubation in M. deltae cultures. The end product observed during furfural metabolism was furfuryl alcohol. An almost stoichiometric amount of furfuryl alcohol was produced by M. deltae. This transformation is likely to be of value in the detoxification of furfural and in its ultimate conversion to methane and CO(inf2) by anaerobic digestion. PMID:16535618

  11. Genomic sequencing in cystic fibrosis newborn screening: what works best, two-tier predefined CFTR mutation panels or second-tier CFTR panel followed by third-tier sequencing? (United States)

    Currier, Robert J; Sciortino, Stan; Liu, Ruiling; Bishop, Tracey; Alikhani Koupaei, Rasoul; Feuchtbaum, Lisa


    PurposeThe purpose of this study was to model the performance of several known two-tier, predefined mutation panels and three-tier algorithms for cystic fibrosis (CF) screening utilizing the ethnically diverse California population.MethodsThe cystic fibrosis transmembrane conductance regulator (CFTR) mutations identified among the 317 CF cases in California screened between 12 August 2008 and 18 December 2012 were used to compare the expected CF detection rates for several two- and three-tier screening approaches, including the current California approach, which consists of a population-specific 40-mutation panel followed by third-tier sequencing when indicated.ResultsThe data show that the strategy of using third-tier sequencing improves CF detection following an initial elevated immunoreactive trypsinogen and detection of only one mutation on a second-tier panel.ConclusionIn a diverse population, the use of a second-tier panel followed by third-tier CFTR gene sequencing provides a better detection rate for CF, compared with the use of a second-tier approach alone, and is an effective way to minimize the referrals of CF carriers for sweat testing. Restricting screening to a second-tier testing to predefined mutation panels, even broad ones, results in some missed CF cases and demonstrates the limited utility of this approach in states that have diverse multiethnic populations.

  12. Two Salt Bridges Differentially Contribute to the Maintenance of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channel Function* (United States)

    Cui, Guiying; Freeman, Cody S.; Knotts, Taylor; Prince, Chengyu Z.; Kuang, Christopher; McCarty, Nael A.


    Previous studies have identified two salt bridges in human CFTR chloride ion channels, Arg352-Asp993 and Arg347-Asp924, that are required for normal channel function. In the present study, we determined how the two salt bridges cooperate to maintain the open pore architecture of CFTR. Our data suggest that Arg347 not only interacts with Asp924 but also interacts with Asp993. The tripartite interaction Arg347-Asp924-Asp993 mainly contributes to maintaining a stable s2 open subconductance state. The Arg352-Asp993 salt bridge, in contrast, is involved in stabilizing both the s2 and full (f) open conductance states, with the main contribution being to the f state. The s1 subconductance state does not require either salt bridge. In confirmation of the role of Arg352 and Asp993, channels bearing cysteines at these sites could be latched into a full open state using the bifunctional cross-linker 1,2-ethanediyl bismethanethiosulfonate, but only when applied in the open state. Channels remained latched open even after washout of ATP. The results suggest that these interacting residues contribute differently to stabilizing the open pore in different phases of the gating cycle. PMID:23709221

  13. Four new Delta Scuti stars (United States)

    Schutt, R. L.


    Four new Delta Scuti stars are reported. Power, modified into amplitude, spectra, and light curves are used to determine periodicities. A complete frequency analysis is not performed due to the lack of a sufficient time base in the data. These new variables help verify the many predictions that Delta Scuti stars probably exist in prolific numbers as small amplitude variables. Two of these stars, HR 4344 and HD 107513, are possibly Am stars. If so, they are among the minority of variable stars which are also Am stars.

  14. Clusters of Cl- channels in CFTR-expressing em>Sf>9 cells switch spontaneously between slow and fast gating modes

    DEFF Research Database (Denmark)

    Larsen, Erik Hviid; Price, E. M.; Gabriel, S. E.


    channel. Excised outside-out patches of CFTR-infected and forskolin-stimulated cells exhibited wave-like gating kinetics of well-resolved current transitions. All-point Gaussian distributions revealed contributions from several (five to nine) identical channels. Such channels, in excised outside...

  15. Purinergic regulation of CFTR and Ca2+ -activated Cl- channels and K+ channels in human pancreatic duct epithelium

    DEFF Research Database (Denmark)

    Wang, Jing; Haanes, Kristian A; Novak, Ivana


    mutated CFTR, basolateral ATP and UTP had negligible effects. In addition to Cl(-) transport in Capan-1 cells, the effects of 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (DC-EBIO) and clotrimazole indicated functional expression of the intermediate conductance K(+) channels (IK, KCa3...

  16. PDE5 Inhibitors As Potential Tools In The Treatment Of Cystic Fibrosis

    Directory of Open Access Journals (Sweden)

    Sabrina eNoel


    Full Text Available Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF, there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5 inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF.

  17. Novel short chain fatty acids restore chloride secretion in cystic fibrosis

    International Nuclear Information System (INIS)

    Nguyen, Toan D.; Kim, Ug-Sung; Perrine, Susan P.


    Phenylalanine deletion at position 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508-CFTR), the most common mutation in cystic fibrosis (CF), causes a misfolded protein exhibiting partial chloride conductance and impaired trafficking to the plasma membrane. 4-Phenylbutyrate corrects defective ΔF508-CFTR trafficking in vitro, but is not clinically efficacious. From a panel of short chain fatty acid derivatives, we showed that 2,2-dimethyl-butyrate (ST20) and α-methylhydrocinnamic acid (ST7), exhibiting high oral bioavailability and sustained plasma levels, correct the ΔF508-CFTR defect. Pre-incubation (≥6 h) of CF IB3-1 airway cells with ≥1 mM ST7 or ST20 restored the ability of 100 μM forskolin to stimulate an 125 I - efflux. This efflux was fully inhibited by NPPB, DPC, or glibenclamide, suggesting mediation through CFTR. Partial inhibition by DIDS suggests possible contribution from an additional Cl - channel regulated by CFTR. Thus, ST7 and ST20 offer treatment potential for CF caused by the ΔF508 mutation

  18. Hydrological and Climatic Significance of Martian Deltas (United States)

    Di Achille, G.; Vaz, D. A.


    We a) review the geomorphology, sedimentology, and mineralogy of the martian deltas record and b) present the results of a quantitative study of the hydrology and sedimentology of martian deltas using modified version of terrestrial model Sedflux.

  19. Adaptive delta management : Roots and branches

    NARCIS (Netherlands)

    Timmermans, J.S.; Haasnoot, M.; Hermans, L.M.; Kwakkel, J.H.; Rutten, M.M.; Thissen, W.A.H.


    Deltas are generally recognized as vulnerable to climate change and therefore a salient topic in adaptation science. Deltas are also highly dynamic systems viewed from physical (erosion, sedimentation, subsidence), social (demographic), economic (trade), infrastructures (transport, energy,

  20. Adaptive Delta Management : Roots and Branches

    NARCIS (Netherlands)

    Timmermans, Jos; Haasnoot, Marjolijn; Hermans, Leon; Kwakkel, Jan H.; Rutten, Maarten; Thissen, Wil A.H.; Mynett, Arthur


    Deltas are generally recognized as vulnerable to climate change and therefore a salient topic in adaptation science. Deltas are also highly dynamic systems viewed from physical (erosion, sedimentation, subsidence), social (demographic), economic (trade), infrastructures (transport, energy,

  1. Delta Vegetation and Land Use [ds292 (United States)

    California Natural Resource Agency — Vegetation and land use are mapped for the approximately 725,000 acres constituting the Legal Delta portion of the Sacramento and San Joaquin River Delta area....

  2. Delta Scuti variables. Lecture 6

    International Nuclear Information System (INIS)

    Cox, A.N.


    The class of variables near or on the upper main sequence, the delta Scuti variables, are not only the usual ones about the masses, radii, and luminosities, but also the age, rotation, element diffusion to change the surface layer composition, the occurance of convection and the presence of radial and nonradial pulsation modes

  3. about the Dirac Delta Function(?)

    Indian Academy of Sciences (India)

    V Balakrishnan is in the. Department of ... and sweet as befits this impatient age. It said (in its en- ... to get down to real work by shutting down the system and reverting to ... the Dirac delta function" - but do note the all-important question mark in ...

  4. Variation in leaf water delta D and delta 18O values during the evapotranspiration process

    International Nuclear Information System (INIS)

    Leopoldo, P.R.; Foloni, L.L.


    A theoretical model was developed to evaluate leaf water delta D and delta 18 O variation in relation to: leaf temperature, relative humidity converted to leaf temperature and delta D and delta 18 O values of atmospheric water vapour and soil water. (M.A.C.) [pt

  5. An analytical framework for strategic delta planning

    NARCIS (Netherlands)

    Seijger, C.; Douven, W.; Halsema, van G.; Hermans, L.; Evers, J.; Phi, H.L.; Khan, M.F.; Brunner, J.; Pols, L.; Ligtvoet, W.; Koole, S.; Slager, K.; Vermoolen, M.S.; Hasan, S.; Thi Minh Hoang, Vo


    Sectoral planning on water, agriculture and urban development has not been able to prevent increased flood risks and environmental degradation in many deltas. Governments conceive strategic delta planning as a promising planning approach and develop strategic delta plans. Such plans are linked to

  6. Delta Semantics Defined By Petri Nets

    DEFF Research Database (Denmark)

    Jensen, Kurt; Kyng, Morten; Madsen, Ole Lehrmann

    and the possibility of using predicates to specify state changes. In this paper a formal semantics for Delta is defined and analysed using Petri nets. Petri nets was chosen because the ideas behind Petri nets and Delta concide on several points. A number of proposals for changes in Delta, which resulted from...

  7. Cystic fibrosis transmembrane regulator haplotypes in households of patients with cystic fibrosis. (United States)

    Furgeri, Daniela Tenório; Marson, Fernando Augusto Lima; Correia, Cyntia Arivabeni Araújo; Ribeiro, José Dirceu; Bertuzzo, Carmen Sílvia


    Nearly 2000 mutations in the cystic fibrosis transmembrane regulator (CFTR) gene have been reported. The F508del mutation occurs in approximately 50-65% of patients with cystic fibrosis (CF). However, molecular diagnosis is not always possible. Therefore, silent polymorphisms can be used to label the mutant allele in households of patients with CF. To verify the haplotypes of four polymorphisms at the CFTR locus in households of patients with CF for pre-fertilization, pre-implantation, and prenatal indirect mutation diagnosis to provide better genetic counseling for families and patients with CF and to associate the genotypes/haplotypes with the F508del mutation screening. GATT polymorphism analysis was performed using direct polymerase chain reaction amplification, and the MP6-D9, TUB09 and TUB18 polymorphism analyses were performed using restriction fragment length polymorphism. Nine haplotypes were found in 37 CFTR alleles, and of those, 24 were linked with the F508del mutation and 13 with other CFTR mutations. The 6 (GATT), C (MP6-D9), G (TUB09), and C (TUB18) haplotypes showed the highest prevalence (48%) of the mutant CFTR allele and were linked to the F508del mutation (64%). In 43% of households analyzed, at least one informative polymorphism can be used for the indirect diagnostic test. CFTR polymorphisms are genetic markers that are useful for identifying the mutant CFTR alleles in households of patients with CF when it is not possible to establish the complete CFTR genotype. Moreover, the polymorphisms can be used for indirect CFTR mutation identification in cases of pre-fertilization, pre-implantation and prenatal analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Future Change to Tide-Influenced Deltas (United States)

    Nienhuis, Jaap H.; Hoitink, A. J. F. (Ton); Törnqvist, Torbjörn E.


    Tides tend to widen deltaic channels and shape delta morphology. Here we present a predictive approach to assess a priori the effect of fluvial discharge and tides on deltaic channels. We show that downstream channel widening can be quantified by the ratio of the tide-driven discharge and the fluvial discharge, along with a second metric representing flow velocities. A test of our new theory on a selection of 72 deltas globally shows good correspondence to a wide range of environments, including wave-dominated deltas, river-dominated deltas, and alluvial estuaries. By quantitatively relating tides and fluvial discharge to delta morphology, we offer a first-order prediction of deltaic change that may be expected from altered delta hydrology. For example, we expect that reduced fluvial discharge in response to dam construction will lead to increased tidal intrusion followed by enhanced tide-driven sediment import into deltas, with implications for navigation and other human needs.

  9. A large-scale study of the random variability of a coding sequence: a study on the CFTR gene. (United States)

    Modiano, Guido; Bombieri, Cristina; Ciminelli, Bianca Maria; Belpinati, Francesca; Giorgi, Silvia; Georges, Marie des; Scotet, Virginie; Pompei, Fiorenza; Ciccacci, Cinzia; Guittard, Caroline; Audrézet, Marie Pierre; Begnini, Angela; Toepfer, Michael; Macek, Milan; Ferec, Claude; Claustres, Mireille; Pignatti, Pier Franco


    Coding single nucleotide substitutions (cSNSs) have been studied on hundreds of genes using small samples (n(g) approximately 100-150 genes). In the present investigation, a large random European population sample (average n(g) approximately 1500) was studied for a single gene, the CFTR (Cystic Fibrosis Transmembrane conductance Regulator). The nonsynonymous (NS) substitutions exhibited, in accordance with previous reports, a mean probability of being polymorphic (q > 0.005), much lower than that of the synonymous (S) substitutions, but they showed a similar rate of subpolymorphic (q < 0.005) variability. This indicates that, in autosomal genes that may have harmful recessive alleles (nonduplicated genes with important functions), genetic drift overwhelms selection in the subpolymorphic range of variability, making disadvantageous alleles behave as neutral. These results imply that the majority of the subpolymorphic nonsynonymous alleles of these genes are selectively negative or even pathogenic.

  10. Astrometric Observation of Delta Cepheus (United States)

    Warren, Naomi; Wilson, Betsie; Estrada, Chris; Crisafi, Kim; King, Jackie; Jones, Stephany; Salam, Akash; Warren, Glenn; Collins, S. Jananne; Genet, Russell


    Members of a Cuesta College astronomy research seminar used a manually-controlled 10-inch Newtonian Reflector telescope to determine the separation and position angle of the binary star Delta Cepheus. It was observed on the night of Saturday, October 29, 2011, at Star Hill in Santa Margarita, California. Their values of 40.2 arc seconds and 192.4 degrees were similar to those reported in the WDS (1910).

  11. Impact of the CFTR-potentiator ivacaftor on airway microbiota in cystic fibrosis patients carrying a G551D mutation.

    Directory of Open Access Journals (Sweden)

    Cédric Bernarde

    Full Text Available Airway microbiota composition has been clearly correlated with many pulmonary diseases, and notably with cystic fibrosis (CF, an autosomal genetic disorder caused by mutation in the CF transmembrane conductance regulator (CFTR. Recently, a new molecule, ivacaftor, has been shown to re-establish the functionality of the G551D-mutated CFTR, allowing significant improvement in lung function.The purpose of this study was to follow the evolution of the airway microbiota in CF patients treated with ivacaftor, using quantitative PCR and pyrosequencing of 16S rRNA amplicons, in order to identify quantitative and qualitative changes in bacterial communities. Three G551D children were followed up longitudinally over a mean period of more than one year covering several months before and after initiation of ivacaftor treatment.129 operational taxonomy units (OTUs, representing 64 genera, were identified. There was no significant difference in total bacterial load before and after treatment. Comparison of global community composition found no significant changes in microbiota. Two OTUs, however, showed contrasting dynamics: after initiation of ivacaftor, the relative abundance of the anaerobe Porphyromonas 1 increased (p<0.01 and that of Streptococcus 1 (S. mitis group decreased (p<0.05, possibly in relation to the anti-Gram-positive properties of ivacaftor. The anaerobe Prevotella 2 correlated positively with the pulmonary function test FEV-1 (r=0.73, p<0.05. The study confirmed the presumed positive role of anaerobes in lung function.Several airway microbiota components, notably anaerobes (obligate or facultative anaerobes, could be valuable biomarkers of lung function improvement under ivacaftor, and could shed light on the pathophysiology of lung disease in CF patients.

  12. The CFTR Met 470 allele is associated with lower birth rates in fertile men from a population isolate.

    Directory of Open Access Journals (Sweden)

    Gülüm Kosova


    Full Text Available Although little is known about the role of the cystic fibrosis transmembrane regulator (CFTR gene in reproductive physiology, numerous variants in this gene have been implicated in etiology of male infertility due to congenital bilateral absence of the vas deferens (CBAVD. Here, we studied the fertility effects of three CBAVD-associated CFTR polymorphisms, the (TGm and polyT repeat polymorphisms in intron 8 and Met470Val in exon 10, in healthy men of European descent. Homozygosity for the Met470 allele was associated with lower birth rates, defined as the number of births per year of marriage (P = 0.0029. The Met470Val locus explained 4.36% of the phenotypic variance in birth rate, and men homozygous for the Met470 allele had 0.56 fewer children on average compared to Val470 carrier men. The derived Val470 allele occurs at high frequencies in non-African populations (allele frequency = 0.51 in HapMap CEU, whereas it is very rare in African population (Fst = 0.43 between HapMap CEU and YRI. In addition, haplotypes bearing Val470 show a lack of genetic diversity and are thus longer than haplotypes bearing Met470 (measured by an integrated haplotype score [iHS] of -1.93 in HapMap CEU. The fraction of SNPs in the HapMap Phase2 data set with more extreme Fst and iHS measures is 0.003, consistent with a selective sweep outside of Africa. The fertility advantage conferred by Val470 relative to Met470 may provide a selective mechanism for these population genetic observations.

  13. Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus. (United States)

    Smith, Emily M; Lajoie, Bryan R; Jain, Gaurav; Dekker, Job


    Three-dimensional genome structure plays an important role in gene regulation. Globally, chromosomes are organized into active and inactive compartments while, at the gene level, looping interactions connect promoters to regulatory elements. Topologically associating domains (TADs), typically several hundred kilobases in size, form an intermediate level of organization. Major questions include how TADs are formed and how they are related to looping interactions between genes and regulatory elements. Here we performed a focused 5C analysis of a 2.8 Mb chromosome 7 region surrounding CFTR in a panel of cell types. We find that the same TAD boundaries are present in all cell types, indicating that TADs represent a universal chromosome architecture. Furthermore, we find that these TAD boundaries are present irrespective of the expression and looping of genes located between them. In contrast, looping interactions between promoters and regulatory elements are cell-type specific and occur mostly within TADs. This is exemplified by the CFTR promoter that in different cell types interacts with distinct sets of distal cell-type-specific regulatory elements that are all located within the same TAD. Finally, we find that long-range associations between loci located in different TADs are also detected, but these display much lower interaction frequencies than looping interactions within TADs. Interestingly, interactions between TADs are also highly cell-type-specific and often involve loci clustered around TAD boundaries. These data point to key roles of invariant TAD boundaries in constraining as well as mediating cell-type-specific long-range interactions and gene regulation. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  14. Deformation characteristics of {delta} phase in the delta-processed Inconel 718 alloy

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, H.Y., E-mail: [Institute of Metal Research, Chinese Academy of Sciences, Shenyang 110016 (China); Zhang, S.H., E-mail: [Institute of Metal Research, Chinese Academy of Sciences, Shenyang 110016 (China); Cheng, M. [Institute of Metal Research, Chinese Academy of Sciences, Shenyang 110016 (China); Li, Z.X. [Beijing Institute of Aeronautica1 Materials, Beijing 100095 (China)


    The hot working characteristics of {delta} phase in the delta-processed Inconel 718 alloy during isothermal compression deformation at temperature of 950 deg. C and strain rate of 0.005 s{sup -1}, were studied by using optical microscope, scanning electron microscope and quantitative X-ray diffraction technique. The results showed that the dissolution of plate-like {delta} phase and the precipitation of spherical {delta} phase particles coexisted during the deformation, and the content of {delta} phase decreased from 7.05 wt.% to 5.14 wt.%. As a result of deformation breakage and dissolution breakage, the plate-like {delta} phase was spheroidized and transferred to spherical {delta} phase particles. In the center with largest strain, the plate-like {delta} phase disappeared and spherical {delta} phase appeared in the interior of grains and grain boundaries.

  15. Migration in Deltas: An Integrated Analysis (United States)

    Nicholls, Robert J.; Hutton, Craig W.; Lazar, Attila; Adger, W. Neil; Allan, Andrew; Arto, Inaki; Vincent, Katharine; Rahman, Munsur; Salehin, Mashfiqus; Sugata, Hazra; Ghosh, Tuhin; Codjoe, Sam; Appeaning-Addo, Kwasi


    Deltas and low-lying coastal regions have long been perceived as vulnerable to global sea-level rise, with the potential for mass displacement of exposed populations. The assumption of mass displacement of populations in deltas requires a comprehensive reassessment in the light of present and future migration in deltas, including the potential role of adaptation to influence these decisions. At present, deltas are subject to multiple drivers of environmental change and often have high population densities as they are accessible and productive ecosystems. Climate change, catchment management, subsidence and land cover change drive environmental change across all deltas. Populations in deltas are also highly mobile, with significant urbanization trends and the growth of large cities and mega-cities within or adjacent to deltas across Asia and Africa. Such migration is driven primarily by economic opportunity, yet environmental change in general, and climate change in particular, are likely to play an increasing direct and indirect role in future migration trends. The policy challenges centre on the role of migration within regional adaptation strategies to climate change; the protection of vulnerable populations; and the future of urban settlements within deltas. This paper reviews current knowledge on migration and adaptation to environmental change to discern specific issues pertinent to delta regions. It develops a new integrated methodology to assess present and future migration in deltas using the Volta delta in Ghana, Mahanadi delta in India and Ganges-Brahmaputra-Meghna delta across India and Bangladesh. The integrated method focuses on: biophysical changes and spatial distribution of vulnerability; demographic changes and migration decision-making using multiple methods and data; macro-economic trends and scenarios in the deltas; and the policies and governance structures that constrain and enable adaptation. The analysis is facilitated by a range of

  16. Tides Stabilize Deltas until Humans Interfere (United States)

    Hoitink, T.; Zheng Bing, W.; Vermeulen, B.; Huismans, Y.; Kastner, K.


    Despite global concerns about river delta degradation caused by extraction of natural resources, sediment retention by reservoirs and sea-level rise, human activity in the world's largest deltas intensifies. In this review, we argue that tides tend to stabilize deltas until humans interfere. Under natural circumstances, delta channels subject to tides are more stable than their fluvial-dominated counterparts. The oscillatory tidal flow counteracts the processes responsible for bank erosion, which explains why unprotected tidal channels migrate only slowly. Peak river discharges attenuate the tides, which creates storage space to accommodate the extra river discharge during extreme events and as a consequence, reduce flood risk. With stronger tides, the river discharge is being distributed more evenly over the various branches in a delta, preventing silting up of smaller channels. Human interference in deltas is massive. Storm surge barriers are constructed, new land is being reclaimed and large-scale sand excavation takes place, to collect building material. Evidence from deltas around the globe shows that in human-controlled deltas the tidal motion often plays a destabilizing role. In channels of the Rhine-Meuse Delta, some 100 scour holes are identified, which relates to the altered tidal motion after completion of a storm surge barrier. Sand mining has led to widespread river bank failures in the tidally-influenced Mekong Delta. The catastrophic flood event in the Gauges-Brahmaputra Delta by Cyclone Aila, which caused the inundation of an embanked polder area for over two years, was preceded by river bank erosion at the mouths of formal tidal channels that were blocked by the embankment. Efforts to predict the developments of degrading deltas are few. Existing delta models are capable of reproducing expanding deltas, which is essentially a matter of simulating the transport of sediment from source in a catchment to the sink in a delta. Processes of soil

  17. Future Deltas Utrecht University research focus area: towards sustainable management of sinking deltas (United States)

    Stouthamer, E.; van Asselen, S.


    Deltas are increasingly under pressure from human impact and climate change. To deal with these pressures that threat future delta functioning, we need to understand interactions between physical, biological, chemical and social processes in deltas. This requires an integrated approach, in which knowledge on natural system functioning is combined with knowledge on spatial planning, land and water governance and legislative frameworks. In the research focus area Future Deltas of Utrecht University an interdisciplinary team from different research groups therefore works together. This allows developing integrated sustainable and resilient delta management strategies, which is urgently needed to prevent loss of vital delta services.

  18. COMMD1 regulates the delta epithelial sodium channel ({delta}ENaC) through trafficking and ubiquitination

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Tina; Ke, Ying; Ly, Kevin [Department of Physiology, University of Otago, P.O. Box 913, Dunedin 9054 (New Zealand); McDonald, Fiona J., E-mail: [Department of Physiology, University of Otago, P.O. Box 913, Dunedin 9054 (New Zealand)


    Highlights: {yields} The COMM domain of COMMD1 mediates binding to {delta}ENaC. {yields} COMMD1 reduces the cell surface population of {delta}ENaC. {yields} COMMD1 increases the population of {delta}ENaC-ubiquitin. {yields} Both endogenous and transfected {delta}ENaC localize with COMMD1 and transferrin suggesting they are located in early/recycling endosomes. -- Abstract: The delta subunit of the epithelial sodium channel ({delta}ENaC) is a member of the ENaC/degenerin family of ion channels. {delta}ENaC is distinct from the related {alpha}-, {beta}- and {gamma}ENaC subunits, known for their role in sodium homeostasis and blood pressure control, as {delta}ENaC is expressed in brain neurons and activated by external protons. COMMD1 (copper metabolism Murr1 domain 1) was previously found to associate with and downregulate {delta}ENaC activity. Here, we show that COMMD1 interacts with {delta}ENaC through its COMM domain. Co-expression of {delta}ENaC with COMMD1 significantly reduced {delta}ENaC surface expression, and led to an increase in {delta}ENaC ubiquitination. Immunocytochemical and confocal microscopy studies show that COMMD1 promoted localization of {delta}ENaC to the early/recycling endosomal pool where the two proteins were localized together. These results suggest that COMMD1 downregulates {delta}ENaC activity by reducing {delta}ENaC surface expression through promoting internalization of surface {delta}ENaC to an intracellular recycling pool, possibly via enhanced ubiquitination.

  19. Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations. (United States)

    Pompei, Fiorenza; Ciminelli, Bianca Maria; Bombieri, Cristina; Ciccacci, Cinzia; Koudova, Monika; Giorgi, Silvia; Belpinati, Francesca; Begnini, Angela; Cerny, Milos; Des Georges, Marie; Claustres, Mireille; Ferec, Claude; Macek, Milan; Modiano, Guido; Pignatti, Pier Franco


    An average of about 1700 CFTR (cystic fibrosis transmembrane conductance regulator) alleles from normal individuals from different European populations were extensively screened for DNA sequence variation. A total of 80 variants were observed: 61 coding SNSs (results already published), 13 noncoding SNSs, three STRs, two short deletions, and one nucleotide insertion. Eight DNA variants were classified as non-CF causing due to their high frequency of occurrence. Through this survey the CFTR has become the most exhaustively studied gene for its coding sequence variability and, though to a lesser extent, for its noncoding sequence variability as well. Interestingly, most variation was associated with the M470 allele, while the V470 allele showed an 'extended haplotype homozygosity' (EHH). These findings make us suggest a role for selection acting either on the M470V itself or through an hitchhiking mechanism involving a second site. The possible ancient origin of the V allele in an 'out of Africa' time frame is discussed.

  20. The Niger Delta Amnesty Program

    Directory of Open Access Journals (Sweden)

    Benjamin A. Okonofua


    Full Text Available The armed conflict between militias and government forces in Nigeria’s Niger Delta region has spanned for more than two decades, defying all solutions. A disarmament, demobilization, and reintegration (DDR program was established in August 2015 in effort to end the violence and has remained in place. It is a radically different approach from past approaches that displayed zero tolerance to all political challenges to oil production or the allocation of oil profits. The approach appeared to be immediately successful in that it forced a ceasefire, engaged militants in planned programs to rehabilitate and reintegrate them into civilian society, and opened up the oil wells (many of which had been shut due to the crisis with the effect of increasing government revenue, which depends 85% on oil exports. Yet, few studies have attempted to understand the dynamics within the country that are responsible for the design and implementation of this broad policy shift or to understand whether and how the current initiative is able to end the conflict and institute peace beyond the short term. This study, therefore, is important because it provides a critical perspective that anticipates and explains emerging issues with the Niger Delta Amnesty Program, which have implications for DDR adaptation and implementation all over the world. Ultimately, the research demonstrates how the DDR program both transforms the Niger Delta conflict and becomes embroiled in intense contestations not only about the mechanism for transforming the targeted population but also whether and how the program incorporates women who are being deprioritized by the program.

  1. Penelope Delta, recently discovered writer




    The aim of this article is to present a Greek writer, Penelope Delta. This writer has recently come up in the field of the studies of the Greek literature and, although thereare neither many translations of her works in foreign languages nor many theses or dissertations, she was chosen for the great interest for her works. Her books have been read by many generations, so she is considered a classical writer of Modern Greek Literature. The way she uses the Greek language, the unique characters...

  2. Climate change and the Delta (United States)

    Dettinger, Michael; Anderson, Jamie; Anderson, Michael L.; Brown, Larry R.; Cayan, Daniel; Maurer, Edwin P.


    Anthropogenic climate change amounts to a rapidly approaching, “new” stressor in the Sacramento–San Joaquin Delta system. In response to California’s extreme natural hydroclimatic variability, complex water-management systems have been developed, even as the Delta’s natural ecosystems have been largely devastated. Climate change is projected to challenge these management and ecological systems in different ways that are characterized by different levels of uncertainty. For example, there is high certainty that climate will warm by about 2°C more (than late-20th-century averages) by mid-century and about 4°C by end of century, if greenhouse-gas emissions continue their current rates of acceleration. Future precipitation changes are much less certain, with as many climate models projecting wetter conditions as drier. However, the same projections agree that precipitation will be more intense when storms do arrive, even as more dry days will separate storms. Warmer temperatures will likely enhance evaporative demands and raise water temperatures. Consequently, climate change is projected to yield both more extreme flood risks and greater drought risks. Sea level rise (SLR) during the 20th century was about 22cm, and is projected to increase by at least 3-fold this century. SLR together with land subsidence threatens the Delta with greater vulnerabilities to inundation and salinity intrusion. Effects on the Delta ecosystem that are traceable to warming include SLR, reduced snowpack, earlier snowmelt and larger storm-driven streamflows, warmer and longer summers, warmer summer water temperatures, and water-quality changes. These changes and their uncertainties will challenge the operations of water projects and uses throughout the Delta’s watershed and delivery areas. Although the effects of climate change on Delta ecosystems may be profound, the end results are difficult to predict, except that native species will fare worse than invaders. Successful

  3. Endoplasmic Reticulum-Targeted Subunit Toxins Provide a New Approach to Rescue Misfolded Mutant Proteins and Revert Cell Models of Genetic Diseases.

    Directory of Open Access Journals (Sweden)

    Humaira Adnan

    Full Text Available Many germ line diseases stem from a relatively minor disturbance in mutant protein endoplasmic reticulum (ER 3D assembly. Chaperones are recruited which, on failure to correct folding, sort the mutant for retrotranslocation and cytosolic proteasomal degradation (ER-associated degradation-ERAD, to initiate/exacerbate deficiency-disease symptoms. Several bacterial (and plant subunit toxins, retrograde transport to the ER after initial cell surface receptor binding/internalization. The A subunit has evolved to mimic a misfolded protein and hijack the ERAD membrane translocon (dislocon, to effect cytosolic access and cytopathology. We show such toxins compete for ERAD to rescue endogenous misfolded proteins. Cholera toxin or verotoxin (Shiga toxin containing genetically inactivated (± an N-terminal polyleucine tail A subunit can, within 2-4 hrs, temporarily increase F508delCFTR protein, the major cystic fibrosis (CF mutant (5-10x, F508delCFTR Golgi maturation (<10x, cell surface expression (20x and chloride transport (2x in F508del CFTR transfected cells and patient-derived F508delCFTR bronchiolar epithelia, without apparent cytopathology. These toxoids also increase glucocerobrosidase (GCC in N370SGCC Gaucher Disease fibroblasts (3x, another ERAD-exacerbated misfiling disease. We identify a new, potentially benign approach to the treatment of certain genetic protein misfolding diseases.

  4. Genetic pattern of cystic fibrosis patients in Azeri Turkish population

    Directory of Open Access Journals (Sweden)

    Morteza Jabarpoor-Bonyadi


    Conclusion ― These findings indicate high frequency of consanguinity marriage in this area. A low frequency of the ∆F508 mutation and detection 32 mutations reflect a heterogeneous spectrum of the mutations in this ethnic group. Further examinations are necessary on CFTR gene and affect these items on on age, sex and mortality.

  5. From Natural to Design River Deltas (United States)

    Giosan, Liviu


    Productive and biologically diverse, deltaic lowlands attracted humans since prehistory and may have spurred the emergence of the first urban civilizations. Deltas continued to be an important nexus for economic development across the world and are currently home for over half a billion people. But recently, under the double whammy of sea level rise and inland sediment capture behind dams, they have become the most threatened coastal landscape. Here I will address several deceptively simple questions to sketch some unexpected answers using example deltas from across the world from the Arctic to the Tropics, from the Danube to the Indus, Mississippi to Godavari and Krishna, Mackenzie to Yukon. What is a river delta? What is natural and what is not in a river delta? Are the geological and human histories of a delta important for its current management? Is maintaining a delta the same to building a new one? Can we design better deltas than Nature? These answers help us see clearly that survival of deltas in the next century depends on human intervention and is neither assured nor simple to address or universally applicable. Empirical observations on the hydrology, geology, biology and biochemistry of deltas are significantly lagging behind modeling capabilities endangering the applicability of numerical-based reconstruction solutions and need to be ramped up significantly and rapidly across the world.

  6. [Frequency of the most common mutations of the CFTR gene in peruvian patients with cystic fibrosis using the ARMS-PCR technique]. (United States)

    Aquino, Ruth; Protzel, Ana; Rivera, Juan; Abarca, Hugo; Dueñas, Milagros; Nestarez, Cecilia; Purizaga, Nestor; Diringer, Benoit


    To determine the frequency of the ten most common mutations of the CFTR gene reported in Latin Americausing amplification-refractory mutation system-polymerase chain reaction (ARMS-PCR) in patients with cystic fibrosis (CF) in two referral hospitals in Peru during the year 2014. The frequency of the ten most common mutations of the CFTR gene was assessed in patients of the Hospital Nacional Edgardo Rebagliati Martins and the Instituto Nacional de Salud del Niño, both located in Lima, Peru. Blood samples were collected from 36 patients with CF, and the ARMS-PCR technique was used to determine the presence of these mutations. The study group included 73.5% of patients with a known diagnosis of CF in the country when the study was carried out. ARMS-PCR allowed three of the mutations to be identified in a combined 30.6% of the alleles from patients with CF, and 64.9% of the mutated alleles were not identified. The mutations found were p.Phe508del (22,2%), p.Gly542* (6,9%), and p.Arg1162* (1,4%). There is significant variability in both the frequency and type of mutations present in our study population and in what has been reported in other Latin American countries. It is necessary to perform studies that use complete sequencing technology for the CFTR gene to identify other mutations present in our population.

  7. An analytical framework for strategic delta planning : negotiating consent for long-term sustainable delta development

    NARCIS (Netherlands)

    Seijger, C.; Douven, W; Hermans, L.M.; Evers, J.; Phi, H. L.; Brunner, J.; Pols, L.; Ligtvoet, W.; Koole, S.; Slager, K.; Vermoolen, M.S.; Hasan, S.; Hoang, V. T M; van Halsema, G


    Sectoral planning on water, agriculture and urban development has not been able to prevent increased flood risks and environmental degradation in many deltas. Governments conceive strategic delta planning as a promising planning approach and develop strategic delta plans. Such plans are linked to

  8. Mutating the Conserved Q-loop Glutamine 1291 Selectively Disrupts Adenylate Kinase-dependent Channel Gating of the ATP-binding Cassette (ABC) Adenylate Kinase Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Reduces Channel Function in Primary Human Airway Epithelia. (United States)

    Dong, Qian; Ernst, Sarah E; Ostedgaard, Lynda S; Shah, Viral S; Ver Heul, Amanda R; Welsh, Michael J; Randak, Christoph O


    The ATP-binding cassette (ABC) transporter cystic fibrosis transmembrane conductance regulator (CFTR) and two other non-membrane-bound ABC proteins, Rad50 and a structural maintenance of chromosome (SMC) protein, exhibit adenylate kinase activity in the presence of physiologic concentrations of ATP and AMP or ADP (ATP + AMP ⇆ 2 ADP). The crystal structure of the nucleotide-binding domain of an SMC protein in complex with the adenylate kinase bisubstrate inhibitor P(1),P(5)-di(adenosine-5') pentaphosphate (Ap5A) suggests that AMP binds to the conserved Q-loop glutamine during the adenylate kinase reaction. Therefore, we hypothesized that mutating the corresponding residue in CFTR, Gln-1291, selectively disrupts adenylate kinase-dependent channel gating at physiologic nucleotide concentrations. We found that substituting Gln-1291 with bulky side-chain amino acids abolished the effects of Ap5A, AMP, and adenosine 5'-monophosphoramidate on CFTR channel function. 8-Azidoadenosine 5'-monophosphate photolabeling of the AMP-binding site and adenylate kinase activity were disrupted in Q1291F CFTR. The Gln-1291 mutations did not alter the potency of ATP at stimulating current or ATP-dependent gating when ATP was the only nucleotide present. However, when physiologic concentrations of ADP and AMP were added, adenylate kinase-deficient Q1291F channels opened significantly less than wild type. Consistent with this result, we found that Q1291F CFTR displayed significantly reduced Cl(-) channel function in well differentiated primary human airway epithelia. These results indicate that a highly conserved residue of an ABC transporter plays an important role in adenylate kinase-dependent CFTR gating. Furthermore, the results suggest that adenylate kinase activity is important for normal CFTR channel function in airway epithelia. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Entropy and optimality in river deltas (United States)

    Tejedor, Alejandro; Longjas, Anthony; Edmonds, Douglas A.; Zaliapin, Ilya; Georgiou, Tryphon T.; Rinaldo, Andrea; Foufoula-Georgiou, Efi


    The form and function of river deltas is intricately linked to the evolving structure of their channel networks, which controls how effectively deltas are nourished with sediments and nutrients. Understanding the coevolution of deltaic channels and their flux organization is crucial for guiding maintenance strategies of these highly stressed systems from a range of anthropogenic activities. To date, however, a unified theory explaining how deltas self-organize to distribute water and sediment up to the shoreline remains elusive. Here, we provide evidence for an optimality principle underlying the self-organized partition of fluxes in delta channel networks. By introducing a suitable nonlocal entropy rate (nER) and by analyzing field and simulated deltas, we suggest that delta networks achieve configurations that maximize the diversity of water and sediment flux delivery to the shoreline. We thus suggest that prograding deltas attain dynamically accessible optima of flux distributions on their channel network topologies, thus effectively decoupling evolutionary time scales of geomorphology and hydrology. When interpreted in terms of delta resilience, high nER configurations reflect an increased ability to withstand perturbations. However, the distributive mechanism responsible for both diversifying flux delivery to the shoreline and dampening possible perturbations might lead to catastrophic events when those perturbations exceed certain intensity thresholds.

  10. A Modal Logic for Abstract Delta Modeling

    NARCIS (Netherlands)

    F.S. de Boer (Frank); M. Helvensteijn (Michiel); J. Winter (Joost)


    htmlabstractAbstract Delta Modeling is a technique for implementing (software) product lines. Deltas are put in a partial order which restricts their application and are then sequentially applied to a core product in order to form specific products in the product line. In this paper we explore the

  11. Tidal controls on river delta morphology

    NARCIS (Netherlands)

    Hoitink, A.J.F.; Wang, Z.B.; Vermeulen, B.; Huismans, Y.; Kästner, K.


    River delta degradation has been caused by extraction of natural resources, sediment retention by reservoirs, and sea-level rise. Despite global concerns about these issues, human activity in the world's largest deltas intensifies. Harbour development, construction of flood defences, sand mining and

  12. Tidal controls on river delta morphology

    NARCIS (Netherlands)

    Hoitink, A.J.F.; Wang, Zhengbing; Vermeulen, B.; Huismans, Y; Kästner, K

    River delta degradation has been caused by extraction of natural resources, sediment retention by reservoirs, and sea-level rise. Despite global concerns about these issues, human activity in the world’s largest deltas intensifies. Harbour development, construction of flood defences, sand mining and

  13. Floating City IJmeer : Accelerator for Delta Technology

    NARCIS (Netherlands)

    De Graaf, R.; Fremouw, M.; Van Bueren, B.; Czapiewska, K.; Kuijper, M.


    Climate change, sea level rise, population growth and ongoing urbanization result in higher vulnerability of the Rhine delta because it will result in increased flooding frequency, increasing investments and increased use of water, energy and other resources. The Rhine Delta also faces strong

  14. Entendiendo Delta desde las Humanidades

    Directory of Open Access Journals (Sweden)

    José Calvo Tello


    Full Text Available Stylometry is one of the research areas in greater development within Digital Humanities. However, few studies have worked until recently with texts in Spanish and even less so from Spanish-speaking countries. The aim of this paper is to present in Spanish, and without prior statistical knowledge from the reader, one of the main methods used in stylometry, the measure of textual distance Burrows’ Delta. This paper explains this measure using a very small corpus of proverbs and then checks the results in a corpus of Spanish novels. Both data and Python scripts are available to the community through GitHub, commented step by step so that you can play and visualize each step.

  15. EEHG at FLASH and DELTA

    Energy Technology Data Exchange (ETDEWEB)

    Molo, Robert; Hoener, Markus; Huck, Holger; Hacker, Kirsten; Khan, Shaukat; Schick, Andreas; Ungelenk, Peter; Zeinalzadeh, Maryam [Center for Synchrotron Radiation (DELTA), TU Dortmund University (Germany); Meulen, Peter van der; Salen, Peter [Stockholm University (Sweden); Angelova Hamberg, Gergana; Ziemann, Volker [Uppsala University (Sweden)


    The echo-enabled harmonic generation (EEHG) scheme utilizes two modulators with two magnetic chicanes in order to generate an electron density modulation with high harmonic content. In contrast to free-electron lasers (FEL) based on self-amplified spontaneous emission (SASE), the radiation of an EEHG FEL has better longitudinal coherence and is naturally synchronized with an external laser, which is advantageous for pump-probe applications. At the free-electron laser in Hamburg (FLASH), an EEHG experiment is currently under preparation. The short-pulse facility at DELTA (a 1.5-GeV synchrotron light source operated by the TU Dortmund University) based on coherent harmonic generation (CHG) will be upgraded using the EEHG technique in order to reach shorter wavelengths.

  16. Growth laws for delta crevasses in the Mississippi River Delta: observations and modeling (United States)

    Yocum, T. A.; Georgiou, I. Y.


    River deltas are accumulations of sedimentary deposits delivered by rivers via a network of distributary channels. Worldwide they are threatened by environmental changes, including subsidence, global sea level rise and a suite of other local factors. In the Mississippi River Delta (MRD) these impacts are exemplified, and have led to proposed solutions to build land that include sediment diversions, thereby reinitiating the delta cycle. While economically efficient, there are too few analogs of small deltas aside from laboratory studies, numerical modeling studies, theoretical approaches, and limited field driven observations. Anthropogenic crevasses in the modern delta are large enough to overcome limitations of laboratory deltas, and small enough to allow for "rapid" channel and wetland development, providing an ideal setting to investigate delta development mechanics. Crevasse metrics were obtained using a combination of geospatial tools, extracting key parameters (bifurcation length and width, channel order and depth) that were non-dimensionalized and compared to river-dominated delta networks previously studied. Analysis showed that most crevasses in the MRD appear to obey delta growth laws and delta allometry relationships, suggesting that crevasses do exhibit similar planform metrics to larger Deltas; the distance to mouth bar versus bifurcation order demonstrated to be a very reasonable first order estimate of delta-top footprint. However, some crevasses exhibited different growth metrics. To better understand the hydrodynamic and geomorphic controls governing crevasse evolution in the MRD, we assess delta dynamics via a suite of field observations and numerical modeling in both well-established and newly constructed crevasses. Our analysis suggests that delta development is affected by the relative influence of external (upstream and downstream) and internal controls on the hydrodynamic and sediment transport patterns in these systems.

  17. A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators. (United States)

    Ponzano, Stefano; Nigrelli, Giulia; Fregonese, Laura; Eichler, Irmgard; Bertozzi, Fabio; Bandiera, Tiziano; Galietta, Luis J V; Papaluca, Marisa


    In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000-2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers ( e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended. Copyright ©ERS 2018.

  18. Influence of different organic fertilizers on quality parameters and the delta(15)N, delta(13)C, delta(2)H, delta(34)S, and delta(18)O values of orange fruit (Citrus sinensis L. Osbeck). (United States)

    Rapisarda, Paolo; Camin, Federica; Fabroni, Simona; Perini, Matteo; Torrisi, Biagio; Intrigliolo, Francesco


    To investigate the influence of different types of fertilizers on quality parameters, N-containing compounds, and the delta(15)N, delta(13)C, delta(2)H, delta (34)S, and delta(18)O values of citrus fruit, a study was performed on the orange fruit cv. 'Valencia late' (Citrus sinensis L. Osbeck), which was harvested in four plots (three organic and one conventional) located on the same farm. The results demonstrated that different types of organic fertilizers containing the same amount of nitrogen did not effect important changes in orange fruit quality parameters. The levels of total N and N-containing compounds such as synephrine in fruit juice were not statistically different among the different treatments. The delta(15)N values of orange fruit grown under fertilizer derived from animal origin as well as from vegetable compost were statistically higher than those grown with mineral fertilizer. Therefore, delta(15)N values can be used as an indicator of citrus fertilization management (organic or conventional), because even when applied organic fertilizers are of different origins, the natural abundance of (15)N in organic citrus fruit remains higher than in conventional ones. These treatments also did not effect differences in the delta(13)C, delta(2)H, delta(34)S, and delta(18)O values of fruit.

  19. Resveratrol enhances airway surface liquid depth in sinonasal epithelium by increasing cystic fibrosis transmembrane conductance regulator open probability.

    Directory of Open Access Journals (Sweden)

    Shaoyan Zhang

    Full Text Available Chronic rhinosinusitis engenders enormous morbidity in the general population, and is often refractory to medical intervention. Compounds that augment mucociliary clearance in airway epithelia represent a novel treatment strategy for diseases of mucus stasis. A dominant fluid and electrolyte secretory pathway in the nasal airways is governed by the cystic fibrosis transmembrane conductance regulator (CFTR. The objectives of the present study were to test resveratrol, a strong potentiator of CFTR channel open probability, in preparation for a clinical trial of mucociliary activators in human sinus disease.Primary sinonasal epithelial cells, immortalized bronchoepithelial cells (wild type and F508del CFTR, and HEK293 cells expressing exogenous human CFTR were investigated by Ussing chamber as well as patch clamp technique under non-phosphorylating conditions. Effects on airway surface liquid depth were measured using confocal laser scanning microscopy. Impact on CFTR gene expression was measured by quantitative reverse transcriptase polymerase chain reaction.Resveratrol is a robust CFTR channel potentiator in numerous mammalian species. The compound also activated temperature corrected F508del CFTR and enhanced CFTR-dependent chloride secretion in human sinus epithelium ex vivo to an extent comparable to the recently approved CFTR potentiator, ivacaftor. Using inside out patches from apical membranes of murine cells, resveratrol stimulated an ~8 picosiemens chloride channel consistent with CFTR. This observation was confirmed in HEK293 cells expressing exogenous CFTR. Treatment of sinonasal epithelium resulted in a significant increase in airway surface liquid depth (in µm: 8.08+/-1.68 vs. 6.11+/-0.47,control,p<0.05. There was no increase CFTR mRNA.Resveratrol is a potent chloride secretagogue from the mucosal surface of sinonasal epithelium, and hydrates airway surface liquid by increasing CFTR channel open probability. The foundation for a

  20. Tidal controls on river delta morphology (United States)

    Hoitink, A. J. F.; Wang, Z. B.; Vermeulen, B.; Huismans, Y.; Kästner, K.


    River delta degradation has been caused by extraction of natural resources, sediment retention by reservoirs, and sea-level rise. Despite global concerns about these issues, human activity in the world’s largest deltas intensifies. Harbour development, construction of flood defences, sand mining and land reclamation emerge as key contemporary factors that exert an impact on delta morphology. Tides interacting with river discharge can play a crucial role in the morphodynamic development of deltas under pressure. Emerging insights into tidal controls on river delta morphology suggest that--despite the active morphodynamics in tidal channels and mouth bar regions--tidal motion acts to stabilize delta morphology at the landscape scale under the condition that sediment import during low flows largely balances sediment export during high flows. Distributary channels subject to tides show lower migration rates and are less easily flooded by the river because of opposing non-linear interactions between river discharge and the tide. These interactions lead to flow changes within channels, and a more uniform distribution of discharge across channels. Sediment depletion and rigorous human interventions in deltas, including storm surge defence works, disrupt the dynamic morphological equilibrium and can lead to erosion and severe scour at the channel bed, even decades after an intervention.

  1. Rise and Fall of one of World's largest deltas; the Mekong delta in Vietnam (United States)

    Minderhoud, P. S. J.; Eslami Arab, S.; Pham, H. V.; Erkens, G.; van der Vegt, M.; Oude Essink, G.; Stouthamer, E.; Hoekstra, P.


    The Mekong delta is the third's largest delta in the world. It is home to almost 20 million people and an important region for the food security in South East Asia. As most deltas, the Mekong delta is the dynamic result of a balance of sediment supply, sea level rise and subsidence, hosting a system of fresh and salt water dynamics. Ongoing urbanization, industrialization and intensification of agricultural practices in the delta, during the past decades, resulted in growing domestic, agricultural and industrial demands, and have led to a dramatic increase of fresh water use. Since the year 2000, the amount of fresh groundwater extracted from the subsurface increased by 500%. This accelerated delta subsidence as the groundwater system compacts, with current sinking rates exceeding global sea level rise up to an order of magnitude. These high sinking rates have greatly altered the sediment budget of the delta and, with over 50% of the Mekong delta surface elevated less than 1 meter above sea level, greatly increase vulnerability to flooding and storm surges and ultimately, permanent inundation. Furthermore, as the increasingly larger extractions rapidly reduce the fresh groundwater reserves, groundwater salinization subsequently increases. On top of that, dry season low-flows by the Mekong river cause record salt water intrusion in the delta's estuarine system, creating major problems for rice irrigation. We present the work of three years research by the Dutch-Vietnamese `Rise and Fall' project on land subsidence and salinization in both groundwater and surface water in the Vietnamese Mekong delta.

  2. Delta Electroproduction in 12-C

    Energy Technology Data Exchange (ETDEWEB)

    McLauchlan, Steven [Univ. of Glasgow, Scotland (United Kingdom)


    The Δ-nucleus potential is a crucial element in the understanding of the nuclear system. Previous electroexcitation measurements in the delta region reported a Q2 dependence of the Δ mass indicating that this potential is dependent on the momentum of the Δ. Such a dependence is not observed for protons and neutrons in the nuclear medium. This thesis presents the experimental study of the electroexcitation of the Δ resonance in 12C, performed using the high energy electron beam at the Thomas Jefferson National Accelerator Facility, and the near 4π acceptance detector CLAS that enables the detection of the full reaction final state. Inclusive, semi inclusive, and exclusive cross sections were measured with an incident electron beam energy of 1.162GeV over the Q2 range 0.175-0.475 (GeV/c)2. A Q2 dependence of the Δ mass was only observed in the exclusive measurements indicating that the Δ-nucleus potential is affected by the momentum of the Δ.

  3. Applicability and Efficiency of NGS in Routine Diagnosis: In-Depth Performance Analysis of a Complete Workflow for CFTR Mutation Analysis.

    Directory of Open Access Journals (Sweden)

    Adrien Pagin

    Full Text Available Actually, about 2000 sequence variations have been documented in the CFTR gene requiring extensive and multi-step genetic testing in the diagnosis of cystic fibrosis and CFTR-related disorders. We present a two phases study, with validation and performance monitoring, of a single experiment methodology based on multiplex PCR and high throughput sequencing that allows detection of all variants, including large rearrangements, affecting the coding regions plus three deep intronic loci.A total of 340 samples, including 257 patients and 83 previously characterized control samples, were sequenced in 17 MiSeq runs and analyzed with two bioinformatic pipelines in routine diagnostic conditions. We obtained 100% coverage for all the target regions in every tested sample.We correctly identified all the 87 known variants in the control samples and successfully confirmed the 62 variants identified among the patients without observing false positive results. Large rearrangements were identified in 18/18 control samples. Only 17 patient samples showed false positive signals (6.6%, 12 of which showed a borderline result for a single amplicon. We also demonstrated the ability of the assay to detect allele specific dropout of amplicons when a sequence variation occurs at a primer binding site thus limiting the risk for false negative results.We described here the first NGS workflow for CFTR routine analysis that demonstrated equivalent diagnostic performances compared to Sanger sequencing and multiplex ligation-dependent probe amplification. This study illustrates the advantages of NGS in term of scalability, workload reduction and cost-effectiveness in combination with an improvement of the overall data quality due to the simultaneous detection of SNVs and large rearrangements.

  4. Molecular mechanisms of reduced glutathione transport: role of the MRP/CFTR/ABCC and OATP/SLC21A families of membrane proteins

    International Nuclear Information System (INIS)

    Ballatori, Nazzareno; Hammond, Christine L.; Cunningham, Jennifer B.; Krance, Suzanne M.; Marchan, Rosemarie


    The initial step in reduced glutathione (GSH) turnover in all mammalian cells is its transport across the plasma membrane into the extracellular space; however, the mechanisms of GSH transport are not clearly defined. GSH export is required for the delivery of its constituent amino acids to other tissues, detoxification of drugs, metals, and other reactive compounds of both endogenous and exogenous origin, protection against oxidant stress, and secretion of hepatic bile. Recent studies indicate that some members of the multidrug resistance-associated protein (MRP/CFTR or ABCC) family of ATP-binding cassette (ABC) proteins, as well as some members of the organic anion transporting polypeptide (OATP or SLC21A) family of transporters contribute to this process. In particular, five of the 12 members of the MRP/CFTR family appear to mediate GSH export from cells namely, MRP1, MRP2, MRP4, MRP5, and CFTR. Additionally, two members of the OATP family, rat Oatp1 and Oatp2, have been identified as GSH transporters. For the Oatp1 transporter, efflux of GSH may provide the driving force for the uptake of extracellular substrates. In humans, OATP-B and OATP8 do not appear to transport GSH; however, other members of this family have yet to be characterized in regards to GSH transport. In yeast, the ABC proteins Ycf1p and Bpt1p transport GSH from the cytosol into the vacuole, whereas Hgt1p mediates GSH uptake across the plasma membrane. Because transport is a key step in GSH homeostasis and is intimately linked to its biological functions, GSH export proteins are likely to modulate essential cellular functions

  5. Legal Delta Boundary, 2001, DWR [ds586 (United States)

    California Natural Resource Agency — The original topographic maps containing the drawn delta border were scanned from the Department of Water Resources. Images were registered to 1:24,000 USGS DRG's in...

  6. sheltered creeks in Niger Delta, Nigeria

    African Journals Online (AJOL)



    Mar 18, 2015 ... 273 and 115,000 barrels, respectively, making the delta. *Corresponding author. .... content was transferred to savillex digestion bombs and concen- trated hydrochloric ... metals (Zn, Pb and Cu) by flame atomic absorption.

  7. South Local Government Area, Delta S

    African Journals Online (AJOL)


    environs, Aniocha- South Local Government Area of Delta State, Nigeria was carried out with a view to determining the ... supply for physical industrial development to achieve maximum human .... the Schlumberger O' Neil software package.

  8. Delta-nucleus dynamics: proceedings of symposium

    Energy Technology Data Exchange (ETDEWEB)

    Lee, T.S.H.; Geesaman, D.F.; Schiffer, J.P. (eds.)


    The appreciation of the role in nuclear physics of the first excited state of the nucleon, the delta, has grown rapidly in the past decade. The delta resonance dominates nuclear reactions induced by intermediate energy pions, nucleons, and electromagnetic probes. It is also the most important non-nucleonic degree of freedom needed to resolve many fundamental problems encountered in the study of low-energy nuclear phenomena. Clearly, a new phase of nuclear physics has emerged and conventional thinking must be extended to account for this new dimension of nuclear dynamics. The most challenging problem we are facing is how a unified theory can be developed to describe dynamics at all energies. In exploring this new direction, it is important to have direct discussions among researchers with different viewpoints. Separate entries were prepared for the 49 papers presented. (WHK)

  9. Damped Oscillator with Delta-Kicked Frequency (United States)

    Manko, O. V.


    Exact solutions of the Schrodinger equation for quantum damped oscillator subject to frequency delta-kick describing squeezed states are obtained. The cases of strong, intermediate, and weak damping are investigated.

  10. On the origin of delta spots

    International Nuclear Information System (INIS)

    Tang, F.


    Mount Wilson sunspot drawings from 1966 through 1980 were used in conjunction with Hα filtergrams from Big Bear Solar Observatory to examine the origin of delta spots, spots with bipolar umbrae within one penumbra. Of the six cases we studied, five were formed by the union of non-paired spots. They are either shoved into one another by two neighboring growing bipoles or by a new spot born piggy-back style on an existing spot of opposite polarity. Proper motions of the growing spots take on curvilinear paths around one another to avoid a collision. This is the shear motion observed in delta spots (Tanaka, 1979). In the remaining case, the delta spot was formed by spots that emerged as a pair. Our findings indicate no intrinsic differences in the formation or the behavior between delta spots of normal magnetic configuration. (orig.)

  11. 2016 Rose Ojowhoh Delta State Polytechnic, Ozoro

    African Journals Online (AJOL)


    The study examined staff development and library services in academic libraries in Bayelsa and Delta States. ... academic libraries, whose responsibility will be to cater for the development of staff in all ramifications. ..... Human resource.


    African Journals Online (AJOL)


    federal government, the Niger Delta communities claim that they are entitled to ... instability, macroeconomic challenges, inconsistent policy regimes to ..... continues they cannot threaten the stability of the country nor affect its continued.

  13. Astrobee Periodic Technical Review (PTR) Delta 3 (United States)

    Provencher, Christopher; Smith, Marion F.; Smith, Ernest Everett; Bualat, Maria Gabriele; Barlow, Jonathan Spencer


    Astrobee is a free flying robot for the inside of the International Space Station (ISS). The Periodic Technical Review (PTR) delta 3 is the final design review of the system presented to stakeholders.

  14. Frecuencia de las mutaciones más comunes del gen CFTR en pacientes peruanos con fibrosis quística mediante la técnica ARMS-PCR


    Aquino, Ruth; Protzel, Ana; Rivera, Juan; Abarca, Hugo; Dueñas, Milagros; Nestarez, Cecilia; Purizaga, Nestor; Diringer, Benoit


    Objetivos. Determinar la frecuencia de las diez mutaciones más comúnmente reportadas en América Latina del gen CFTR mediante Sistema de Mutación Refractario a la amplificación por PCR (ARMS-PCR) en los pacientes con fibrosis quística (FQ) de dos instituciones hospitalarias de referencia en el Perú durante el año 2014. Materiales y métodos. Se evaluó la frecuencia de las diez comúnmente reportadas más comúnmente reportadas del gen CFTR en los pacientes del Hospital Nacional Edgardo Rebagliati ...

  15. Migration in Vulnerable Deltas: A Research Strategy (United States)

    Hutton, C.; Nicholls, R. J.; Allan, A.


    C. Hutton1, & R. J. Nicholls1, , 1 University of Southampton, University Road, Southampton, Hampshire, United Kingdom, SO17 1BJ. cwh@geodata., deltas contain 500 million people and with rising sea levels often linked to large number of forced migrants are expected in the coming century. However, migration is already a major process in deltas, such as the growth of major cities such as Dhaka and Kolkata. Climate and environmental change interacts with a range of catchment and delta level drivers, which encompass a nexus of sea-level rise, storms, freshwater and sediment supply from the catchment, land degradation, subsidence, agricultural loss and socio-economic stresses. DECCMA (Deltas, Vulnerability and Climate Change: Migration and Adaptation/CARRIA) is investigating migration in the Ganges-Brahmaputra-Meghna (GBM), Mahanadi and Volta Deltas, including the influence of climate change. The research will explore migration from a range of perspectives including governance and stakeholder analysis, demographic analysis, household surveys of sending and receiving areas, macro-economic analysis, and hazards and hotspot analysis both historically and into the future. Migration under climate change will depend on other adaptation in the deltas and this will be examined. Collectively, integrated analysis will be developed to examine migration, other adaptation and development pathways with a particular focus on the implications for the poorest. This will require the development of input scenarios, including expert-derived exogenous scenarios (e.g., climate change) and endogenous scenarios of the delta developed in a participatory manner. This applied research will facilitate decision support methods for the development of deltas under climate change, with a focus on migration and other adaptation strategies.

  16. A novel mouse PKC{delta} splice variant, PKC{delta}IX, inhibits etoposide-induced apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jung D. [School of Biological Sciences, University of Ulsan, Ulsan (Korea, Republic of); Seo, Kwang W. [Department of Internal Medicines, Ulsan University Hospital and School of Medicine, University of Ulsan, Ulsan (Korea, Republic of); Lee, Eun A.; Quang, Nguyen N. [School of Biological Sciences, University of Ulsan, Ulsan (Korea, Republic of); Cho, Hong R. [Department of Surgery, Ulsan University Hospital and School of Medicine, University of Ulsan, Ulsan (Korea, Republic of); Biomedical Research Center, Ulsan University Hospital and School of Medicine, University of Ulsan, Ulsan (Korea, Republic of); Kwon, Byungsuk, E-mail: [School of Biological Sciences, University of Ulsan, Ulsan (Korea, Republic of); Biomedical Research Center, Ulsan University Hospital and School of Medicine, University of Ulsan, Ulsan (Korea, Republic of)


    Highlights: {yields} A novel PKC{delta} isoform, named PKC{delta}IX, that lacks the C1 domain and the ATP-binding site is ubiquitously expressed. {yields} PKC{delta}IX inhibits etoposide-induced apoptosis. {yields} PKC{delta}IX may function as an endogenous dominant negative isoform for PKC{delta}. -- Abstract: Protein kinase C (PKC) {delta} plays an important role in cellular proliferation and apoptosis. The catalytic fragment of PKC{delta} generated by caspase-dependent cleavage is essential for the initiation of etoposide-induced apoptosis. In this study, we identified a novel mouse PKC{delta} isoform named PKC{delta}IX (Genebank Accession No. (HQ840432)). PKC{delta}IX is generated by alternative splicing and is ubiquitously expressed, as seen in its full-length PKC{delta}. PKC{delta}IX lacks the C1 domain, the caspase 3 cleavage site, and the ATP binding site but preserves an almost intact c-terminal catalytic domain and a nuclear localization signal (NLS). The structural characteristics of PKC{delta}IX provided a possibility that this PKC{delta} isozyme functions as a novel dominant-negative form for PKC{delta} due to its lack of the ATP-binding domain that is required for the kinase activity of PKC{delta}. Indeed, overexpression of PKC{delta}IX significantly inhibited etoposide-induced apoptosis in NIH3T3 cells. In addition, an in vitro kinase assay showed that recombinant PKC{delta}IX protein could competitively inhibit the kinase activity of PKC{delta}. We conclude that PKC{delta}IX can function as a natural dominant-negative inhibitor of PKC{delta}in vivo.

  17. Delta infection evidenced by radioimmunoanalysis in selected collectives

    Energy Technology Data Exchange (ETDEWEB)

    Kselikova, M; Horejsi, J; Urbankova, J


    The presence of the Delta agent within the population was tested by means of the Delta-antibody radioimmunoassay using competitive kits of the firms ABBOTT (ABBOTT-ANTI-DELTA) and SORIN (AB-DELTAK). The Delta-antibody was found in 3.2% HBV patients, 5% HBsAg carriers, and in 20.8% of specific anti-Hbs-immunoglobulin. In hemophiliacs and blood donors no Delta-antibody was seen.

  18. Delta infection evidenced by radioimmunoanalysis in selected collectives

    International Nuclear Information System (INIS)

    Kselikova, M.; Horejsi, J.; Urbankova, J.


    The presence of the Delta agent within the population was tested by means of the Delta-antibody radioimmunoassay using competitive kits of the firms ABBOTT (ABBOTT-ANTI-DELTA) and SORIN (AB-DELTAK). The Delta-antibody was found in 3.2% HBV patients, 5% HBsAg carriers, and in 20.8% of specific anti-Hbs-immunoglobulin. In hemophiliacs and blood donors no Delta-antibody was seen. (author)

  19. Growth laws for sub-delta crevasses in the Mississippi River Delta (United States)

    Yocum, T. A.; Georgiou, I. Y.; Straub, K. M.


    River deltas are threatened by environmental change, including subsidence, global sea level rise, reduced sediment inputs and other local factors. In the Mississippi River Delta (MRD) these impacts are exemplified, and have led to proposed solutions to build land that include sediment diversions to reinitiate the delta cycle. Deltas were studied extensively using numerical models, theoretical and conceptual frameworks, empirical scaling relationships, laboratory models and field observations. But predicting the future of deltas relies on field observations where for most deltas data are still lacking. Moreover, empirical and theoretical scaling laws may be influenced by the data used to develop them, while laboratory deltas may be influenced by scaling issues. Anthropogenic crevasses in the MRD are large enough to overcome limitations of laboratory deltas, and small enough to allow for rapid channel and wetland development, providing an ideal setting to investigate delta development mechanics. Here we assessed growth laws of sub-delta crevasses (SDC) in the MRD, in two experimental laboratory deltas (LD - weakly and strongly cohesive) and compared them to river dominated deltas worldwide. Channel and delta geometry metrics for each system were obtained using geospatial tools, bathymetric datasets, sediment size, and hydrodynamic observations. Results show that SDC follow growth laws similar to large river dominated deltas, with the exception of some that exhibit anomalous behavior with respect to the frequency and distance to a bifurcation and the fraction of wetted delta shoreline (allometry metrics). Most SDC exhibit a systematic decrease of non-dimensional channel geometries with increased bifurcation order, indicating that channels are adjusting to decreased flow after bifurcations occur, and exhibit linear trends for land allometry and width-depth ratio, although geometries decrease more rapidly per bifurcation order. Measured distance to bifurcations in SDC

  20. Houtman Abrolhos Isotope (delta 18O, delta 13C) Data for 1795 to 1994 (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — DESCRIPTION: VARIABLES AND UNITS: Column #1: core depth in mm Column #2: delta C-13 vs V-PDB Column #3: delta O-18 vs V-PDB Column #4: assigned date in years A.D....

  1. The Enabling Delta Life Initiative - Global Programme of Action on Deltas - Programme description

    NARCIS (Netherlands)

    Driel, van W.F.; Skyllerstedt, S.; Wosten, J.H.M.


    Being ‘hotspots’ of human activity with generally high population densities, deltas are vulnerable to changes induced by a range of driving forces, both natural and anthropogenic. In addition to already existing challenges, uncertainty of the possible impacts of climate change, low lying deltas

  2. Holocene evolution of a wave-dominated fan-delta: Godavari delta, India (United States)

    Saito, Y.; Nageswara Rao, K.; Nagakumar, K.; Demudu, G.; Rajawat, A.; Kubo, S.; Li, Z.


    The Godavari delta is one of the world's largest wave-dominated deltas. The Godavari River arises in the Western Ghats near the west coast of India and drains an area of about 3.1x10^5 km^2, flowing about 1465 km southeast across the Indian peninsula to the Bay of Bengal. The Godavari delta consists of a gentle seaward slope from its apex (12 m elevation) at Rajahmundry and a coastal beach-ridge plain over a distance of about 75 km and covers ~5200 km^2 as a delta plain. The river splits into two major distributary channels, the Gautami and the Vasishta, at a barrage constructed in the mid-1800s. The coastal environment of the deltaic coast is microtidal (~1 m mean tidal range) and wave-dominated (~1.5 m mean wave height in the June-September SW monsoon season, ~0.8 m in the NE monsoon season). Models of the Holocene evolution of the Godavari delta have changed from a zonal progradation model (e.g. Nageswara Rao & Sadakata, 1993) to a truncated cuspate delta model (Nageswara Rao et al., 2005, 2012). Twelve borehole cores (340 m total length), taken in the coastal delta plain during 2010-2013, yielded more than 100 C-14 dates. Sediment facies and C-14 dates from these and previous cores and remote-sensing data support a new delta evolution model. The Holocene coastal delta plain is divided into two parts by a set of linear beach ridges 12-14 km landward from the present shoreline in the central part of the delta. The location of the main depocenter (lobe) has shifted during the Holocene from 1) the center to 2) the west, 3) east, 4) center, 5) west, and 6) east. The linear beach ridges separate the first three from the last three stages. These lobe shifts are controlled by river channel shifts near the apex. Just as the current linear shoreline of the central part of the delta and the concave-up nearshore topography are the result of coastal erosion of a cuspate delta, the linear beach ridges indicate a former eroded shoreline. An unconformity within the deltaic

  3. Open source integrated modeling environment Delta Shell (United States)

    Donchyts, G.; Baart, F.; Jagers, B.; van Putten, H.


    In the last decade, integrated modelling has become a very popular topic in environmental modelling since it helps solving problems, which is difficult to model using a single model. However, managing complexity of integrated models and minimizing time required for their setup remains a challenging task. The integrated modelling environment Delta Shell simplifies this task. The software components of Delta Shell are easy to reuse separately from each other as well as a part of integrated environment that can run in a command-line or a graphical user interface mode. The most components of the Delta Shell are developed using C# programming language and include libraries used to define, save and visualize various scientific data structures as well as coupled model configurations. Here we present two examples showing how Delta Shell simplifies process of setting up integrated models from the end user and developer perspectives. The first example shows coupling of a rainfall-runoff, a river flow and a run-time control models. The second example shows how coastal morphological database integrates with the coastal morphological model (XBeach) and a custom nourishment designer. Delta Shell is also available as open-source software released under LGPL license and accessible via

  4. QCD in the {delta}-regime

    Energy Technology Data Exchange (ETDEWEB)

    Bietenholz, W. [Universidad Nacional Autonoma de Mexico, Mexico City (Mexico). Inst. de Ciencias Nucleares; Cundy, N. [Seoul National Univ. (Korea, Republic of). Lattice Gauge Theory Research Center; Goeckeler, M. [Regensburg Univ. (Germany). Inst. fuer Theoretische Physik; Horsley, R.; Zanotti, J.M. [Edinburgh Univ. (United Kingdom). School of Physics; Nakamura, Y. [Tsukuba Univ., Ibaraki (Japan). Center for Computational Sciences; Pleiter, D. [Deutsches Elektronen-Synchrotron (DESY), Zeuthen (Germany); Rakow, P.E.L. [Liverpool Univ. (United Kingdom). Theoretical Physics Div.; Schierholz, G. [Regensburg Univ. (Germany). Inst. fuer Theoretische Physik; Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)


    The {delta}-regime of QCD is characterised by light quarks in a small spatial box, but a large extent in (Euclidean) time. In this setting a specific variant of chiral perturbation theory - the {delta}-expansion - applies, based on a quantum mechanical treatment of the quasi onedimensional system. In particular, for vanishing quark masses one obtains a residual pion mass M{sup R}{sub {pi}}, which has been computed to the third order in the {delta}-expansion. A comparison with numerical measurements of this residual mass allows for a new determination of some Low Energy Constants, which appear in the chiral Lagrangian. We first review the attempts to simulate 2-flavour QCD directly in the {delta}-regime. This is very tedious, but results compatible with the predictions for M{sup R}{sub {pi}} have been obtained. Then we show that an extrapolation of pion masses measured in a larger volume towards the {delta}-regime leads to good agreement with the theoretical predictions. From those results, we also extract a value for the (controversial) sub-leading Low Energy Constant anti l{sub 3}. (orig.)

  5. Combinatorial effects of genistein and sex-steroids on the level of cystic fibrosis transmembrane regulator (CFTR), adenylate cyclase (AC) and cAMP in the cervix of ovariectomised rats. (United States)

    Salleh, Naguib; Ismail, Nurain; Muniandy, Sekaran; Korla, Praveen Kumar; Giribabu, Nelli


    The combinatorial effects of genistein and estrogen (E) or estrogen plus progesterone (E+P) on CFTR, AC and cAMP levels in cervix were investigated. Ovariectomised adult female rats received 50 or 100mg/kg/day genistein with E or E followed by E+P [E+(E+P)] for seven consecutive days. Cervixes were harvested and analyzed for CFTR mRNA levels by Real-time PCR. Distribution of AC and CFTR proteins in endocervix were observed by immunohistochemistry. Levels of cAMP were measured by enzyme-immunoassay. Molecular docking predicted interaction between genistein and AC. Our results indicate that levels of CFTR, AC and cAMP in cervix of rats receiving genistein plus E were higher than E-only treatment (pcervix of E and E+(E+P)-treated rats by genistein could affect the cervical secretory function which could influence the female reproductive processes. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. El plan del delta - Holanda

    Directory of Open Access Journals (Sweden)

    Editorial, Equipo


    Full Text Available Holland is very poor in land resources. Hence its development has been directed towards intensive industrialization and maximum agricultural exploitation. The western part of the country is below sea level and is occupied by 65 percent of the population. Originally the coast consisted of a number of islands, estuaries and slight elevations. Man has transformed this coastline, first making a number of artificial lakes, or polders, and then converting these into fertile districts. These projects protect the soil by means of dykes, which require careful conservation, but even so violent floods are not infrequent. One of the difficult problems involved in this vast enterprise is the complex system of water supply, lines of communication and flow of the rivers into the sea along the estuary zone. This zone is on the south west, and to protect it a National Commission has been set up. After careful study, it was decided that the best defense against the violence of the sea would consist in closing off the inroads of the sea into the continental coastline. The set of hydraulic projects which constitutes this plan for the improvement of the sea defences will take 25 years to fulfil. The general project is highly ambitious and includes both maritime, road and structural works, in which there is a variety of stonework constructions. This paper describes, in brief outline, the main contents of the 11 headings into which the general construction project has been subdivided. In addition, this is supplemented with information on the projects which are already initiated and on the constructional procedure that is being adopted. Of these latter projects, the Nabla bridge is of particular interest. It is situated on the delta. It is made in prestressed concrete, and consists of 17 spans, of 60 length each. This enormous structure, in addition to its great length, and supporting a 22.8 ms wide roadway, is subjected to the tremendous forces 11» of the sea on one

  7. Large old trees influence patterns of delta13C and delta15N in forests. (United States)

    Weber, Pascale; Bol, Roland; Dixon, Liz; Bardgett, Richard D


    Large old trees are the dominant primary producers of native pine forest, but their influence on spatial patterns of soil properties and potential feedback to tree regeneration in their neighbourhood is poorly understood. We measured stable isotopes of carbon (delta(13)C) and nitrogen (delta(15)N) in soil and litter taken from three zones of influence (inner, middle and outer zone) around the trunk of freestanding old Scots pine (Pinus sylvestris L.) trees, to determine the trees' influence on below-ground properties. We also measured delta(15)N and delta(13)C in wood cores extracted from the old trees and from regenerating trees growing within their three zones of influence. We found a significant and positive gradient in soil delta(15)N from the inner zone, nearest to the tree centre, to the outer zone beyond the tree crown. This was probably caused by the higher input of (15)N-depleted litter below the tree crown. In contrast, the soil delta(13)C did not change along the gradient of tree influence. Distance-related trends, although weak, were visible in the wood delta(15)N and delta(13)C of regenerating trees. Moreover, the wood delta(15)N of small trees showed a weak negative relationship with soil N content in the relevant zone of influence. Our results indicate that large old trees control below-ground conditions in their immediate surroundings, and that stable isotopes might act as markers for the spatial and temporal extent of these below-ground effects. John Wiley & Sons, Ltd

  8. Hepatitis delta genotypes in chronic delta infection in the northeast of Spain (Catalonia). (United States)

    Cotrina, M; Buti, M; Jardi, R; Quer, J; Rodriguez, F; Pascual, C; Esteban, R; Guardia, J


    Based on genetic analysis of variants obtained around the world, three genotypes of the hepatitis delta virus have been defined. Hepatitis delta virus variants have been associated with different disease patterns and geographic distributions. To determine the prevalence of hepatitis delta virus genotypes in the northeast of Spain (Catalonia) and the correlation with transmission routes and clinical disease, we studied the nucleotide divergence of the consensus sequence of HDV RNA obtained from 33 patients with chronic delta hepatitis (24 were intravenous drug users and nine had no risk factors), and four patients with acute self-limited delta infection. Serum HDV RNA was amplified by the polymerase chain reaction technique and a fragment of 350 nucleotides (nt 910 to 1259) was directly sequenced. Genetic analysis of the nucleotide consensus sequence obtained showed a high degree of conservation among sequences (93% of mean). Comparison of these sequences with those derived from different geographic areas and pertaining to genotypes I, II and III, showed a mean sequence identity of 92% with genotype I, 73% with genotype II and 61% with genotype III. At the amino acid level (aa 115 to 214), the mean identity was 87% with genotype I, 63% with genotype II and 56% with genotype III. Conserved regions included the RNA editing domain, the carboxyl terminal 19 amino acids of the hepatitis delta antigen and the polyadenylation signal of the viral mRNA. Hepatitis delta virus isolates in the northeast of Spain are exclusively genotype I, independently of the transmission route and the type of infection. No hepatitis delta virus subgenotypes were found, suggesting that the origin of hepatitis delta virus infection in our geographical area is homogeneous.

  9. Abraham Reef Stable Isotope Data (delta 13C, delta 18O, delta 14C) for 1635-1957 (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Site: Abraham Reef, 22ó 06'S, 153ó 00'E, Porites australiensus, Radiocarbon (delta 14C) and Stable Isotope (del 18O and del 13C) results from bi-annual samples from...

  10. Deltas on the move. Making deltas cope with the effects of climate change

    International Nuclear Information System (INIS)

    Reker, J.; Van Winden, A.; Braakhekke, W.; Vermaat, J.; Eleveld, M.; Janssen, R.; De Reus, N.; Omzigt, N.


    This scoping study is the first phase of a study aimed at: (a) providing knowledge on the potential of a system-based approach to deal with the effects of climate change as an alternative for the more traditional technical measures such as dams, dikes and surge barriers. This should be shown for both rich and poor countries and should address hydrological, ecological as well as socio-economic aspects; and (b) identifying the potential to market these results worldwide. To reach these objectives four research steps are defined: (1) to make an inventory of deltas: their vulnerability to the effects of climate change; (2) development of indicators for successful use of a system-based approach; (3) to provide an overview of the potential of soft measures for these deltas; (4) to select a number of deltas with potential for marketing system-based measures and the development of strategies to link economic and ecological objectives. This scoping study addresses step 1 only. The results from step 1 will be used as a starting point for steps 2 and 3. The outputs of this scoping study are threefold: a background report (this report); a flyer with a brief description of the findings; a website with information on delta's and how these may be affected by climate change. The scoping study will roughly outline which deltas are still functioning in a more or less natural manner - or could be (re)developed in that direction - and thus would be good candidates for a system-based approach. Chapter 2 gives a description of the geomorphological and ecological processes in a delta. In addition, those aspects of climate change that can have an effect on deltas are described. The third chapter deals with human interventions in deltas and whether or not they fit within a system-based approach. In a system-based approach, as presented in Chapter 4, natural processes are given free reign where possible. Chapter 5 shows how available data on deltas could be used in such a system

  11. AAV exploits subcellular stress associated with inflammation, endoplasmic reticulum expansion, and misfolded proteins in models of cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    Jarrod S Johnson


    Full Text Available Barriers to infection act at multiple levels to prevent viruses, bacteria, and parasites from commandeering host cells for their own purposes. An intriguing hypothesis is that if a cell experiences stress, such as that elicited by inflammation, endoplasmic reticulum (ER expansion, or misfolded proteins, then subcellular barriers will be less effective at preventing viral infection. Here we have used models of cystic fibrosis (CF to test whether subcellular stress increases susceptibility to adeno-associated virus (AAV infection. In human airway epithelium cultured at an air/liquid interface, physiological conditions of subcellular stress and ER expansion were mimicked using supernatant from mucopurulent material derived from CF lungs. Using this inflammatory stimulus to recapitulate stress found in diseased airways, we demonstrated that AAV infection was significantly enhanced. Since over 90% of CF cases are associated with a misfolded variant of Cystic Fibrosis Transmembrane Conductance Regulator (ΔF508-CFTR, we then explored whether the presence of misfolded proteins could independently increase susceptibility to AAV infection. In these models, AAV was an order of magnitude more efficient at transducing cells expressing ΔF508-CFTR than in cells expressing wild-type CFTR. Rescue of misfolded ΔF508-CFTR under low temperature conditions restored viral transduction efficiency to that demonstrated in controls, suggesting effects related to protein misfolding were responsible for increasing susceptibility to infection. By testing other CFTR mutants, G551D, D572N, and 1410X, we have shown this phenomenon is common to other misfolded proteins and not related to loss of CFTR activity. The presence of misfolded proteins did not affect cell surface attachment of virus or influence expression levels from promoter transgene cassettes in plasmid transfection studies, indicating exploitation occurs at the level of virion trafficking or processing. Thus

  12. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. (United States)

    Alton, Eric W F W; Armstrong, David K; Ashby, Deborah; Bayfield, Katie J; Bilton, Diana; Bloomfield, Emily V; Boyd, A Christopher; Brand, June; Buchan, Ruaridh; Calcedo, Roberto; Carvelli, Paula; Chan, Mario; Cheng, Seng H; Collie, D David S; Cunningham, Steve; Davidson, Heather E; Davies, Gwyneth; Davies, Jane C; Davies, Lee A; Dewar, Maria H; Doherty, Ann; Donovan, Jackie; Dwyer, Natalie S; Elgmati, Hala I; Featherstone, Rosanna F; Gavino, Jemyr; Gea-Sorli, Sabrina; Geddes, Duncan M; Gibson, James S R; Gill, Deborah R; Greening, Andrew P; Griesenbach, Uta; Hansell, David M; Harman, Katharine; Higgins, Tracy E; Hodges, Samantha L; Hyde, Stephen C; Hyndman, Laura; Innes, J Alastair; Jacob, Joseph; Jones, Nancy; Keogh, Brian F; Limberis, Maria P; Lloyd-Evans, Paul; Maclean, Alan W; Manvell, Michelle C; McCormick, Dominique; McGovern, Michael; McLachlan, Gerry; Meng, Cuixiang; Montero, M Angeles; Milligan, Hazel; Moyce, Laura J; Murray, Gordon D; Nicholson, Andrew G; Osadolor, Tina; Parra-Leiton, Javier; Porteous, David J; Pringle, Ian A; Punch, Emma K; Pytel, Kamila M; Quittner, Alexandra L; Rivellini, Gina; Saunders, Clare J; Scheule, Ronald K; Sheard, Sarah; Simmonds, Nicholas J; Smith, Keith; Smith, Stephen N; Soussi, Najwa; Soussi, Samia; Spearing, Emma J; Stevenson, Barbara J; Sumner-Jones, Stephanie G; Turkkila, Minna; Ureta, Rosa P; Waller, Michael D; Wasowicz, Marguerite Y; Wilson, James M; Wolstenholme-Hogg, Paul


    Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0.9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with, number NCT01621867. Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3.7%, 95% CI 0.1-7.3; p=0.046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in

  13. The Economic Dimensions of the Niger Delta Ethnic Conflicts (Pp ...

    African Journals Online (AJOL)


    1970, the price of international oil stepped upwards following the Middle. Eastern Yom Kippur .... Over the years, the pleas of the Niger Delta people for accommodation are ignored or .... In a labour surplus region like the Niger Delta, budget.

  14. Conceptualizing delta forms and processes in Arctic coastal environments

    DEFF Research Database (Denmark)

    Bendixen, Mette; Kroon, Aart


    Climate warming in the Arctic directly causes two opposite changes in Arctic coastal systems: increased melt-water discharge through rivers induces extra influx of sediments and extended open water season increases wave impact which reworks and erodes the shores. A shoreline change analysis along...... and popped up as hotspots. The Tuapaat delta and Skansen delta showed large progradation rates (1.5 and 7m/yr) and migration of the adjacent barriers and spits. The dynamic behavior at the delta mouths was mainly caused by classic delta channel lobe switching at one delta (Tuapaat), and by a breach...... of the fringing spit at the other delta (Skansen). The longshore and cross-shore transports are responsible for reworking the sediment with a result of migrating delta mouths and adjacent subaqueous mouth bars. Seaward progradation of the deltas is limited due to the steep nature of the bathymetry in Disko Bay...

  15. Binding energies of two deltas bound states

    International Nuclear Information System (INIS)

    Sato, Hiroshi; Saito, Koichi.


    Bound states of the two-deltas system are investigated by employing the realistic one boson exchange potential. It is found that there exist many bound states in each isospin channel and also found that the tensor interaction plays important role in producing these bound states. Relationship between these bound states and dibaryon resonances is discussed. (J.P.N.)

  16. Solubility of hydrogen in delta iron

    International Nuclear Information System (INIS)

    Shapovalov, V.I.; Trofimenko, V.V.


    The solubility of hydrogen in iron (less than 0.002 % impurities) at temperatures of 800-1510 deg C and a pressure of 100 atm was measured. The heat of solution of hydrogen in delta-Fe, equal to 73 kJ/g-atom, is by far greater than the corresponding values for α- and γ-Fe

  17. Applications of Dirac's Delta Function in Statistics (United States)

    Khuri, Andre


    The Dirac delta function has been used successfully in mathematical physics for many years. The purpose of this article is to bring attention to several useful applications of this function in mathematical statistics. Some of these applications include a unified representation of the distribution of a function (or functions) of one or several…

  18. Managing flood risks in the Mekong Delta

    NARCIS (Netherlands)

    Hoang, Long Phi; Biesbroek, Robbert; Tri, Van Pham Dang; Kummu, Matti; Vliet, van Michelle T.H.; Leemans, Rik; Kabat, Pavel; Ludwig, Fulco


    Climate change and accelerating socioeconomic developments increasingly challenge flood-risk management in the Vietnamese Mekong River Delta—a typical large, economically dynamic and highly vulnerable delta. This study identifies and addresses the emerging challenges for flood-risk management.

  19. Bioluminescent hydrocarbonclastic bacteria of the Niger Delta ...

    African Journals Online (AJOL)

    Utilization of three petroleum hydrocarbons (Mobil SAE 40 Engine Oil, Diesel and Bonny light Crude Oil) by four bioluminescent bacteria (Vibrio harveyi, V. fisheri, Photobacterium leiognathi and P. Phosphoreum isolated from the Bonny estuary in the Niger Delta, Nigeria was investigated. Microbial utilization was monitored ...

  20. The Delta Team: Empowering Adolescent Girls. (United States)

    Hood, Marian White


    In response to adolescent girls' concerns about teen violence, rumors, grooming, careers, and equity, four women teachers and a woman administrator at a Maryland middle school developed the Delta Program. The program provides positive learning experiences, teaches social skills and conflict management techniques, empowers girls through mentoring…

  1. delta. -isobars and photodisintegration at intermediate energies

    Energy Technology Data Exchange (ETDEWEB)

    Suzumura, Jun-ichi; Futami, Yasuhiko [Science Univ. of Tokyo, Noda, Chiba (Japan). Faculty of Science and Technology


    The dynamics of the peak considered to be due to the two-nucleon process in the reaction /sup 9/Be(gamma, p) anything is investigated with the quasi-deuteron model. We show that the process is dominated by a two-nucleon mechanism with pion and rho-meson exchange through virtual delta-isobar formation (author).

  2. Morphodynamics of a cyclic prograding delta: the Red River, Vietnam

    NARCIS (Netherlands)

    Maren, D.S. van


    River deltas are inhabited by over 60% of the world population, and are, consequently, of paramount agricultural and economical importance. They constitute unique wetland envi ronments which gives river deltas ecological importance as well. Additionally, many deltas contain large accumulations of

  3. Environmental challenges in Nigeria's Delta Region and Agriculture ...

    African Journals Online (AJOL)

    The paper discussed the environmental challenges in the Niger-Delta region of Nigeria with emphasis on the impacts on agricultural production. It thus discussed the concepts of Niger-Delta, Environmental pollution, Niger-Delta crises and Agriculture. The paper posits that there are positive relationships between these ...

  4. deltaPlotR: An R Package for Di?erential Item Functioning Analysis with Ango? s Delta Plot


    David Magis; Bruno Facon


    Angoff's delta plot is a straightforward and not computationally intensive method to identify differential item functioning (DIF) among dichotomously scored items. This approach was recently improved by proposing an optimal threshold selection and by considering several item purification processes. Moreover, to support practical DIF analyses with the delta plot and these improvements, the R package deltaPlotR was also developed. The purpose of this paper is twofold: to outline the delta plot ...

  5. cGMP inhibition of type 3 phosphodiesterase is the major mechanism by which C-type natriuretic peptide activates CFTR in the shark rectal gland (United States)

    De Jonge, Hugo R.; Tilly, Ben C.; Hogema, Boris M.; Pfau, Daniel J.; Kelley, Catherine A.; Kelley, Megan H.; Melita, August M.; Morris, Montana T.; Viola, Ryan M.


    The in vitro perfused rectal gland of the dogfish shark (Squalus acanthias) and filter-grown monolayers of primary cultures of shark rectal gland (SRG) epithelial cells were used to analyze the signal transduction pathway by which C-type natriuretic peptide (CNP) stimulates chloride secretion. CNP binds to natriuretic receptors in the basolateral membrane, elevates cellular cGMP, and opens cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels in the apical membrane. CNP-provoked chloride secretion was completely inhibitable by the nonspecific protein kinase inhibitor staurosporine and the PKA inhibitor H89 but insensitive to H8, an inhibitor of type I and II isoforms of cGMP-dependent protein kinase (cGKI and cGKII). CNP-induced secretion could not be mimicked by nonhydrolyzable cGMP analogs added alone or in combination with the protein kinase C activator phorbolester, arguing against a role for cGK or for cGMP-induced PKC signaling. We failed to detect a dogfish ortholog of cGKII by molecular cloning and affinity chromatography. However, inhibitors of the cGMP-inhibitable isoform of phosphodiesterase (PDE3) including milrinone, amrinone, and cilostamide but not inhibitors of other PDE isoenzymes mimicked the effect of CNP on chloride secretion in perfused glands and monolayers. CNP raised cGMP and cAMP levels in the SRG epithelial cells. This rise in cAMP as well as the CNP and amrinone-provoked chloride secretion, but not the rise in cGMP, was almost completely blocked by the Gαi-coupled adenylyl cyclase inhibitor somatostatin, arguing against a role for cGMP cross-activation of PKA in CNP action. These data provide molecular, functional, and pharmacological evidence for a CNP/cGMP/PDE3/cAMP/PKA signaling cascade coupled to CFTR in the SRG. PMID:24259420

  6. Delta-nucleus dynamics: proceedings of symposium

    International Nuclear Information System (INIS)

    Lee, T.S.H.; Geesaman, D.F.; Schiffer, J.P.


    The appreciation of the role in nuclear physics of the first excited state of the nucleon, the delta Δ(1232), has grown rapidly in the past decade. The delta resonance dominates nuclear reactions induced by intermediate energy pions, nucleons, and electromagnetic probes. It is also the most important non-nucleonic degree of freedom needed to resolve many fundamental problems encountered in the study of low-energy nuclear phenomena. Clearly, a new phase of nuclear physics has emerged and conventional thinking must be extended to account for this new dimension of nuclear dynamics. The most challenging problem we are facing is how a unified theory can be developed to describe Δ-nucleus dynamics at all energies. In exploring this new direction, it is important to have direct discussions among researchers with different viewpoints. Separate entries were prepared for the 49 papers presented

  7. Inhibition of cortiocosteroidogenesis by delta-9-tetrahydrocannabinol. (United States)

    Warner, W; Harris, L S; Carchman, R A


    ACTH, cholera toxin, cyclic AMP but not pregnenolone-induced steroidogenesis in Y-1 functional mouse adrenal tumor cells was significantly inhibited by delta-9-tetrahydrocannabinol, cannabidiol, and cannabinol. The inhibition of steroidogenesis could not be correlated with a general depression in cell function or viability. The data suggest that cannabinoids inhibit corticosteroidogenesis at a site between the synthesis of cAMP and of pregnenolone.

  8. Determination of the positions and residues of the. delta. /sup + +/ and. delta. /sup 0/ poles. [Phase shifts,coulomb corrections

    Energy Technology Data Exchange (ETDEWEB)

    Vasan, S S [Carnegie-Mellon Univ., Pittsburgh, Pa. (USA). Dept. of Physics


    The poles and the associated residues in the ..pi..N P/sub 33/ amplitude corresponding to the resonances + +/ and 0/ are determined by fitting the ..pi../sup +/p and ..pi../sup -/p hadronic phase shifts from the Carter 73 analysis. The + +/ and 0/ pole positions are determined also from the nuclear phase shifts, these being the phase shifts made up of the hadronic phase shifts plus the Coulomb corrections. The pole positions obtained from the two sets of phase shifts are different, the differences being larger in the case of the + +/.

  9. Adaptive Delta Management: cultural aspects of dealing with uncertainty (United States)

    Timmermans, Jos; Haasnoot, Marjolijn; Hermans, Leon; Kwakkel, Jan


    Deltas are generally recognized as vulnerable to climate change and therefore a salient topic in adaptation science. Deltas are also highly dynamic systems viewed from physical (erosion, sedimentation, subsidence), social (demographic), economic (trade), infrastructures (transport, energy, metropolization) and cultural (multi-ethnic) perspectives. This multi-faceted dynamic character of delta areas warrants the emergence of a branch of applied adaptation science, Adaptive Delta Management, which explicitly focuses on climate adaptation of such highly dynamic and deeply uncertain systems. The application of Adaptive Delta Management in the Dutch Delta Program and its active international dissemination by Dutch professionals results in the rapid dissemination of Adaptive Delta Management to deltas worldwide. This global dissemination raises concerns among professionals in delta management on its applicability in deltas with cultural conditions and historical developments quite different from those found in the Netherlands and the United Kingdom where the practices now labelled as Adaptive Delta Management first emerged. This research develops an approach and gives a first analysis of the interaction between the characteristics of different approaches in Adaptive Delta Management and their alignment with the cultural conditions encountered in various delta's globally. In this analysis, first different management theories underlying approaches to Adaptive Delta Management as encountered in both scientific and professional publications are identified and characterized on three dimensions: The characteristics dimensions used are: orientation on today, orientation on the future, and decision making (Timmermans, 2015). The different underlying management theories encountered are policy analysis, strategic management, transition management, and adaptive management. These four management theories underlying different approaches in Adaptive Delta Management are connected to

  10. Delta count-rate monitoring system

    International Nuclear Information System (INIS)

    Van Etten, D.; Olsen, W.A.


    A need for a more effective way to rapidly search for gamma-ray contamination over large areas led to the design and construction of a very sensitive gamma detection system. The delta count-rate monitoring system was installed in a four-wheel-drive van instrumented for environmental surveillance and accident response. The system consists of four main sections: (1) two scintillation detectors, (2) high-voltage power supply amplifier and single-channel analyzer, (3) delta count-rate monitor, and (4) count-rate meter and recorder. The van's 6.5-kW generator powers the standard nuclear instrument modular design system. The two detectors are mounted in the rear corners of the van and can be run singly or jointly. A solid-state bar-graph count-rate meter mounted on the dashboard can be read easily by both the driver and passenger. A solid-state strip chart recorder shows trends and provides a permanent record of the data. An audible alarm is sounded at the delta monitor and at the dashboard count-rate meter if a detected radiation level exceeds the set background level by a predetermined amount

  11. The sensitivity of the ESA DELTA model (United States)

    Martin, C.; Walker, R.; Klinkrad, H.

    Long-term debris environment models play a vital role in furthering our understanding of the future debris environment, and in aiding the determination of a strategy to preserve the Earth orbital environment for future use. By their very nature these models have to make certain assumptions to enable informative future projections to be made. Examples of these assumptions include the projection of future traffic, including launch and explosion rates, and the methodology used to simulate break-up events. To ensure a sound basis for future projections, and consequently for assessing the effectiveness of various mitigation measures, it is essential that the sensitivity of these models to variations in key assumptions is examined. The DELTA (Debris Environment Long Term Analysis) model, developed by QinetiQ for the European Space Agency, allows the future projection of the debris environment throughout Earth orbit. Extensive analyses with this model have been performed under the auspices of the ESA Space Debris Mitigation Handbook and following the recent upgrade of the model to DELTA 3.0. This paper draws on these analyses to present the sensitivity of the DELTA model to changes in key model parameters and assumptions. Specifically the paper will address the variation in future traffic rates, including the deployment of satellite constellations, and the variation in the break-up model and criteria used to simulate future explosion and collision events.

  12. Understanding delta-sigma data converters

    CERN Document Server

    Pavan, Shanti; Temes, Gabor C


    This new edition introduces novel analysis and design techniques for delta-sigma (ΔΣ) converters in physical and conceptual terms, and includes new chapters that explore developments in the field over the last decade. This book explains the principles and operation of delta-sigma analog-to-digital converters (ADCs) in physical and conceptual terms in accordance with the most recent developments in the field. The interest of ΔΣ converter designers has shifted significantly over the past decade, due to many new applications for data converters at the far ends of the frequency spectrum. Continuous-time delta-sigma A/D converters with GHz clocks, of both lowpass and bandpass types, are required for wireless applications. At the other extreme, multiplexed ADCs with very narrow (sometimes 10 Hz wide) signal bandwidths, but very high accuracy are needed in the interfaces of biomedical and environmental sensors. To reflect the changing eeds of designers, the second edition includes significant new material on bo...

  13. Formation of conjugated delta8,delta10-double bonds by delta12-oleic-acid desaturase-related enzymes: biosynthetic origin of calendic acid. (United States)

    Cahoon, E B; Ripp, K G; Hall, S E; Kinney, A J


    Divergent forms of the plant Delta(12)-oleic-acid desaturase (FAD2) have previously been shown to catalyze the formation of acetylenic bonds, epoxy groups, and conjugated Delta(11),Delta(13)-double bonds by modification of an existing Delta(12)-double bond in C(18) fatty acids. Here, we report a class of FAD2-related enzymes that modifies a Delta(9)-double bond to produce the conjugated trans-Delta(8),trans-Delta(10)-double bonds found in calendic acid (18:3Delta(8trans,10trans,12cis)), the major component of the seed oil of Calendula officinalis. Using an expressed sequence tag approach, cDNAs for two closely related FAD2-like enzymes, designated CoFADX-1 and CoFADX-2, were identified from a C. officinalis developing seed cDNA library. The deduced amino acid sequences of these polypeptides share 40-50% identity with those of other FAD2 and FAD2-related enzymes. Expression of either CoFADX-1 or CoFADX-2 in somatic soybean embryos resulted in the production of calendic acid. In embryos expressing CoFADX-2, calendic acid accumulated to as high as 22% (w/w) of the total fatty acids. In addition, expression of CoFADX-1 and CoFADX-2 in Saccharomyces cerevisiae was accompanied by calendic acid accumulation when induced cells were supplied exogenous linoleic acid (18:2Delta(9cis,12cis)). These results are thus consistent with a route of calendic acid synthesis involving modification of the Delta(9)-double bond of linoleic acid. Regiospecificity for Delta(9)-double bonds is unprecedented among FAD2-related enzymes and further expands the functional diversity found in this family of enzymes.

  14. Biomass co-firing for Delta Electricity

    International Nuclear Information System (INIS)



    Electricity generator Delta Electricity has implemented a biomass co-firing program at its Vales Point power station on the Central Coast to reduce its reliance on coal and emissions of CO 2 . The program comprises two parts: direct co-firing with coal of up to 5% biomass; and development of Continuous Biomass Converter (CBC) technology with the Crucible Group to remove technology constraints and enable much higher rates of biomass co-firing. It is talking industrial scale tests. Delta increased biomass co-firing in 2013/14 to 32,000 tonnes, up from just 3,000 tonnes the previous year, and conducted biochar co-firing trials at a rate equivalent to 400,000 tonnes per annum to demonstrate the potential of CBC technology. It reduced CO 2 emissions in 2013/14 by more than 32,000 tonnes. 'Legislation and regulations define biomass as renewable,' said Delta Electricity sustainability manager Justin Flood. 'By preferring biomass over coal, the carbon in the coal is not burnt and remains locked up.' One biomass source is wood waste that would normally go to landfill, but the primary driver of Delta's recent increase in co-firing is sawmill residues. 'Previously there was a higher value market for the residues for paper pulp. However, when that market evaporated the timber industry was left with a sizable problem in terms of what to do with its residues and the loss of revenue,' said Flood. The way greenhouse gas accounting is conducted in Australia, with carbon emissions based on site activities, makes it difficult to undertake a life cycle assessment of the program. 'However, some of the international studies looking at this issue have concluded that the net carbon emissions of the biomass system are significantly lower than the coal system because of the uptake of carbon during biomass growth,' said Flood. Delta identified two challenges, sourcing the feedstock and that biomass conversion to electricity is slightly less

  15. Nuclease-mediated double-strand break (DSB) enhancement of small fragment homologous recombination (SFHR) gene modification in human-induced pluripotent stem cells (hiPSCs). (United States)

    Sargent, R Geoffrey; Suzuki, Shingo; Gruenert, Dieter C


    Recent developments in methods to specifically modify genomic DNA using sequence-specific endonucleases and donor DNA have opened the door to a new therapeutic paradigm for cell and gene therapy of inherited diseases. Sequence-specific endonucleases, in particular transcription activator-like (TAL) effector nucleases (TALENs), have been coupled with polynucleotide small/short DNA fragments (SDFs) to correct the most common mutation in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene, a 3-base-pair deletion at codon 508 (delF508), in induced pluripotent stem (iPS) cells. The studies presented here describe the generation of candidate TALENs and their co-transfection with wild-type (wt) CFTR-SDFs into CF-iPS cells homozygous for the delF508 mutation. Using an allele-specific PCR (AS-PCR)-based cyclic enrichment protocol, clonal populations of corrected CF-iPS cells were isolated and expanded.

  16. Improved γ-linolenic acid production in Mucor circinelloides by homologous overexpressing of delta-12 and delta-6 desaturases. (United States)

    Zhang, Yao; Luan, Xiao; Zhang, Huaiyuan; Garre, Victoriano; Song, Yuanda; Ratledge, Colin


    γ-Linolenic acid (GLA) is important because of its nutritional value and medicinal applications. Although the biosynthetic pathways of some plant and microbial GLA have been deciphered, current understanding of the correlation between desaturases and GLA synthesis in oleaginous fungi is incomplete. In previous work, we found that a large amount of oleic acid (OA) had not been converted to linoleic acid (LA) or GLA in Mucor circinelloides CBS 277.49, which may be due to inadequate activities of the delta-12 or delta-6 desaturases, and thus leading to the accumulation of OA and LA. Thus, it is necessary to explore the main contributing factor during the process of GLA biosynthesis in M. circinelloides. To enhance GLA production in M. circinelloides, homologous overexpression of delta-12 and two delta-6 desaturases (named delta-6-1 and delta-6-2, respectively) were analyzed. When delta-6 desaturase were overexpressed in M. circinelloides, up to 43% GLA was produced in the total fatty acids, and the yield of GLA reached 180 mg/l, which were, respectively, 38 and 33% higher than the control strain. These findings revealed that delta-6 desaturase (especially for delta-6-1 desaturase) plays an important role in GLA synthesis by M. circinelloides. The strain overexpressing delta-6-1 desaturase may have potential application in microbial GLA production.

  17. Synoptic Lithostratigraphy of The Niger Delta

    International Nuclear Information System (INIS)

    Nwajide, C.S.


    The Tertiary Niger Delta is stratigraphically framed by the Dahomey, Anambra, Abakaliki, Afikpo and Calabar Flank basins. From the apex at Onitsha a fluvial plain splays southwards and translates progressively into a freshwater swamp, succeeded by a mangrove swamp belt. Along the coast is a strip of wave-washed barrier bars indented by large estuaries, fronted by submerged moth bars. Habitation in the delta is on levees, point bars, and barrier bars. These landforms provided the firm salients for buildings the ports that facilitated international trade from the pre-colonial times.There are four lithofacies-clean, pebbly, and muddy sandstones, and mudstones. Their subdivision, based on sedimentary structures, textures and fossil content yields twenty reservoir and seven nonreservoir classes. Their environments of deposition, identified using facies associations, fall into fluvial, wave-and tide-dominated, marginal, and shallow marine, with localised canyons incised into the delta front and filled with deeper marine facies.The reservoirs are composed of 70 90% quartz, 4 15% feldspar, and 3 13% clay matrix, with minor mica, bioclasts, carbonaceous debris, glauconite, and heavy minerals. Grain size varies from very fine to coarse and pebbly, implying the presence of sands of varying textural and compositional maturities. Silica, K-feldspar, and carbonates constitute the cements.Porosity in the reservoirs has remained about the same as at deposition due to low mechanical compaction occasioned by shallow burial. Meteoric water-flushed progradational sequence are characterised by cementation with quartz and kaolinite. In contrast, marine water-flushed transgressive sands show grain coating illite-smectite, chlorite and K-feldspar overgrowths


    Directory of Open Access Journals (Sweden)

    Ionica SOARE


    Full Text Available Purpose - the purpose of this paper is to evaluate the rural areas has market size and forecast its development as an economic activity. The present paper aims at analyzing the rural areas has in Danube Delta. In an enviable BAs which have responsibility for their particular isolated, such as the Danube Delta and the Danube that used, fishing and rural areas has the main activities that provide jobs and income sources for local populations. Design/methodology/approach - A survey was administered to customers’ rural hostel accommodation in Danube Delta. Descriptive statistics method was mainly adopted to calculate the mean with standard deviation of entry assumes variable, and to examine the different levels of consumers' awareness. The index values of product familiarity, the ratio between entries assumes product's familiarity value and the average value. Findings - the research results show hash has rural consumers have different perception and accomplished through behaviour. The information channels of brand hash mainly from friends, relatives and neighbours, so word of mouth spreading is very important for a brand. Women show a higher sensitivity in health and are currently operating the propensity than referred to follow the recommendations for nutrition. Research limitations/implications - This item is intended to synthesize developments and challenges," on June 13th rural market growth has. The results of this paper should be considered tentatively until has also features replicated by larger has rural consumers. Originality/value - members of rural areas has consumer's behavior would improve marketing and the development of rural areas has products, in order to reduce consumer confusion.

  19. Stratigraphy and Evolution of Delta Channel Deposits, Jezero Crater, Mars (United States)

    Goudge, T. A.; Mohrig, D.; Cardenas, B. T.; Hughes, C. M.; Fassett, C. I.


    The Jezero impact crater hosted an open-basin lake that was active during the valley network forming era on early Mars. This basin contains a well exposed delta deposit at the mouth of the western inlet valley. The fluvial stratigraphy of this deposit provides a record of the channels that built the delta over time. Here we describe observations of the stratigraphy of the channel deposits of the Jezero western delta to help reconstruct its evolution.

  20. Tracks, spurs, blobs and delta-rays

    International Nuclear Information System (INIS)

    Magee, J.L.; Chatterjee, A.


    The track of a high-energy particle is the collection of all transient species created by the particle in the total degradation of its energy. Visible electron tracks are called delta rays. A microscopic description of the track with all its knocked-out electrons leads to spurs, blobs, and short tracks. Energy deposition criteria for these three track entities are 6 to 100 eV, 100 to 500 eV, and 500 eV to 5 keV, respectively

  1. The situation in the Niger Delta

    International Nuclear Information System (INIS)

    Vitalis, E.


    An energy issue for the United States and a political challenge for Europe, Nigeria is experiencing growing instability and is on the verge of civil war; the ecosystem and the population of the Niger Delta are the main victims. The State, corrupt, is powerless to contain the rising violence and redistribute the proceeds of oil sales. It is high time for oil-consuming countries, starting with the United States, to concern themselves with stabilizing the region. Europe must contribute to the lasting development of this country. (author)

  2. Airway epithelial cell exposure to distinct e-cigarette liquid flavorings reveals toxicity thresholds and activation of CFTR by the chocolate flavoring 2,5-dimethypyrazine. (United States)

    Sherwood, Cara L; Boitano, Scott


    that the increases in ion conductance evoked by 2,5-dimethylpyrazine were largely attributed to a protein kinase A-dependent (PKA) activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Data from our high-capacity screening assays demonstrates that individual e-cigarette liquid flavoring chemicals vary in their cytotoxicity profiles and that some constituents evoke a cellular physiological response on their own independent of cell death. The activation of CFTR by 2,5-dimethylpyrazine may have detrimental consequences for airway surface liquid homeostasis in individuals that use e-cigarettes habitually.

  3. Adaptive delta management: a comparison between the Netherlands and Bangladesh Delta Program

    NARCIS (Netherlands)

    Zevenbergen, Chris; Khan, Shah Alam; Alphen, van Jos; Terwisscha van Scheltinga, Catharien; Veerbeek, William


    In the Netherlands, the central government, water authorities, provinces and municipalities are working together on a new Delta Program on Flood Risk Management and Fresh Water Supply (DP). Its primary goal is to protect the Netherlands against floods and ensure the availability of fresh water, now

  4. Tidal modulated flow and sediment flux through Wax Lake Delta distributary channels: Implications for delta development

    Directory of Open Access Journals (Sweden)

    K. Hanegan


    Full Text Available In this study, a Delft3D model of the Wax Lake Delta was developed to simulate flow and sediment flux through delta distributary channels. The model was calibrated for tidal constituents as well as velocity and sediment concentration across channel transects. The calibrated model was then used to simulate full spring–neap tidal cycles under constant low flow upstream boundary conditions, with grain size variation in suspended load represented using two sediment fractions. Flow and sediment flux results through distributary channel cross-sections were examined for spatial and temporal variability with the goal of characterizing the role of tides in sediment reworking and delta development. The Wax Lake Delta has prograded through channel extension, river mouth bar deposition, and channel bifurcation. Here we show that tidal modulation of currents influences suspended sand transport, and spatial acceleration through distributary channels at low tides is sufficient to suspend sand in distal reaches during lower flows. The basinward-increasing transport capacity in distributary channels indicates that erosive channel extension could be an important process, even during non-flood events.

  5. Delta Plaza kohvik = The Delta Plaza Café / Margit Mutso

    Index Scriptorium Estoniae

    Mutso, Margit, 1966-


    Tallinnas Pärnu mnt. 141 asuva kohviku Delta Plaza sisekujundusest. Sisearhitektid Tiiu Truus ja Marja Viltrop (Stuudio Truus OÜ). Hoone arhitektid Jüri Okas ja Marika Lõoke (AB J. Okas & M. Lõoke). Žürii liikme Mait Summataveti arvamus kohvikust

  6. Studying medium effects with the optimized {delta} expansion

    Energy Technology Data Exchange (ETDEWEB)

    Krein, G [Instituto de Fisica Teorica (IFT), Sao Paulo, SP (Brazil); Menezes, D P [Santa Catarina Univ., Florianopolis, SC (Brazil). Dept. de Fisica; Nielsen, M [Sao Paulo Univ., SP (Brazil). Inst. de Fisica; Pinto, M B [Montpellier-2 Univ., 34 (France). Lab. de Physique Mathematique


    The possibility of using the optimized {delta} expansion for studying medium effects on hadronic properties in quark or nuclear matter is investigated. The {delta} expansion is employed to study density effects with two commonly used models in hadron and nuclear physics, the Nambu-Jona-Lasinio model for the dynamical chiral symmetry breaking and the Walecka model for the equation of state of nuclear matter. The results obtained with the {delta} expansion are compared to those obtained with the traditional Hartree-Fock approximation. Perspectives for using the {delta} expansion in other field theoretic models in hadron and nuclear physics are discussed. (author). 17 refs, 9 figs.

  7. Optimality and self-organization in river deltas (United States)

    Tejedor, A.; Longjas, A.; Edmonds, D. A.; Zaliapin, I. V.; Georgiou, T. T.; Rinaldo, A.; Foufoula-Georgiou, E.


    Deltas are nourished by channel networks, whose connectivity constrains, if not drives, the evolution, functionality and resilience of these systems. Understanding the coevolution of deltaic channels and their flux organization is crucial for guiding maintenance strategies of these highly stressed systems from a range of anthropogenic activities. However, in contrast to tributary channel networks, to date, no theory has been proposed to explain how deltas self-organize to distribute water and sediment to the delta top and the shoreline. Here, we hypothesize the existence of an optimality principle underlying the self-organized partition of fluxes in delta channel networks. Specifically, we hypothesize that deltas distribute water and sediment fluxes on a given delta topology such as to maximize the diversity of flux delivery to the shoreline. By introducing the concept of nonlocal Entropy Rate (nER) and analyzing ten field deltas in diverse environments, we present evidence that supports our hypothesis, suggesting that delta networks achieve dynamically accessible maxima of their nER. Furthermore, by analyzing six simulated deltas using the Delf3D model and following their topologic and flux re-organization before and after major avulsions, we further study the evolution of nER and confirm our hypothesis. We discuss how optimal flux distributions in terms of nER, when interpreted in terms of resilience, are configurations that reflect an increased ability to withstand perturbations.

  8. Upper-division student difficulties with the Dirac delta function

    Directory of Open Access Journals (Sweden)

    Bethany R. Wilcox


    Full Text Available The Dirac delta function is a standard mathematical tool that appears repeatedly in the undergraduate physics curriculum in multiple topical areas including electrostatics, and quantum mechanics. While Dirac delta functions are often introduced in order to simplify a problem mathematically, students still struggle to manipulate and interpret them. To characterize student difficulties with the delta function at the upper-division level, we examined students’ responses to traditional exam questions and a standardized conceptual assessment, and conducted think-aloud interviews. Our analysis was guided by an analytical framework that focuses on how students activate, construct, execute, and reflect on the Dirac delta function in the context of problem solving in physics. Here, we focus on student difficulties using the delta function to express charge distributions in the context of junior-level electrostatics. Common challenges included invoking the delta function spontaneously, translating a description of a charge distribution into a mathematical expression using delta functions, integrating 3D or non-Cartesian delta function expressions, and recognizing that the delta function can have units. We also briefly discuss implications of these difficulties for instruction.

  9. Is acute recurrent pancreatitis in children a precursor of chronic pancreatitis? A long-term follow-up study of 93 cases. (United States)

    Poddar, Ujjal; Yachha, Surender K; Borkar, Vibhor; Srivastava, Anshu


    In view of paucity of literature we analyzed our experience of acute recurrent pancreatitis (ARP) to study clinical profile and long-term outcome. Over 13 years, 93 consecutive children (≤18 years) diagnosed to have ARP were included in this study. Magnetic resonance cholangiopancreatography was done at baseline and on follow-up. Common mutations for serine-protease-inhibitor (SPINK1 N34S), protease inhibitor (PRSS1 R122S) and cystic fibrosis transmembrane conductance regulator (CFTR deltaF508, 5T) were studied in 22 idiopathic cases. The median age of the children with ARP was 13 (10-14.5) years, 53 were males. Etiology included biliary in 14 (15%), pancreas divisum in 6 (7%), others in 3 (3.5%) and idiopathic in the remaining 70 (75%). SPINK1 mutation was found in 10/22 (45%) cases. Over a median follow-up of 25.5 (8.25-48) months, 37 (42%) of 88 (5 lost to follow-up) developed chronic pancreatitis (CP). On multivariate analysis idiopathic etiology (petiology and presence of genetic mutations. Hence, patients with ARP should be kept on regular follow-up to detect CP. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  10. Mutations in CFTR gene and clinical correlation in Argentine patients with congenital bilateral absence of the vas deferens Correlación de las características clínicas con mutaciones del gen CFTR en pacientes argentinos con ausencia bilateral congénita de vasos deferentes

    Directory of Open Access Journals (Sweden)

    Estrella M Levy


    Full Text Available Congenital bilateral absence of the vas deferens (CBAVD is a form of male infertility in which mutations in the cystic fibrosis transmembrane conductance regulator (CFTR gene have been identified. Here we identify different mutations of CFTR and the poly-T variant of intron 8 (IVS8 in Argentine patients and analyze sweat test values and clinical characteristic related to Cystic Fibrosis (CF. For counseling purposes the two most frequent mutations in Argentine CF population: DF508 and G542X were screened in wives. In all cases, it was possible to reduce the risk of CF/CBAVD descendants in these couples because none of the mutation were found in the 36 samples. Eight patients (23% showed abnormal chloride values (> 60 mmol/l. A second group of 6 patients (18% had borderline values of sweat chloride (40-59 mmol/l. We defined another group with 6 patients (18%, with normal sweat chloride levels (30-39 mmo/l and a fourth group of 14 (41% patients with sweat chloride below 30 mmol/l. DF508, the most frequent CF mutation in the Argentine population, was found on 15 of the 72 chromosomes (21%, R117H mutation was detected on 2 of 62 chromosomes (3%. Only one R347P allele was found on 28 chromosomes analyzed (2%. On a sample of 27 patients, IVS8 analysis showed a frequency of 6/56 chromosomes (11% of 5T allele. Even though these findings present an improvement in the detection of mutations related to clinical correlations in Argentine CBAVD population, the search for other common and uncommon mutations should be continued.La ausencia bilateral congénita de vasos deferentes (CBAVD es una forma de infertilidad masculina en la que se han identificado mutaciones en el gen de la conductancia transmembrana de la fibrosis quística (CFTR. Hemos estudiado en pacientes argentinos diferentes mutaciones en el CFTR y la variante poli T del intron 8 (IVS8 y analizado los valores de test del sudor y las características clínicas relacionadas a la Fibrosis Qu

  11. Catalyzing action towards the sustainability of deltas: deltas as integrated socio-ecological systems and sentinels of regional and global change (United States)

    Foufoula-Georgiou, E.; Tessler, Z. D.; Brondizio, E.; Overeem, I.; Renaud, F.; Sebesvari, Z.; Nicholls, R. J.; Anthony, E.


    Deltas are highly dynamic and productive environments: they are food baskets of the world, home to biodiverse and rich ecosystems, and they play a central role in food and water security. However, they are becoming increasingly vulnerable to risks arising from human activities, land subsidence, regional water management, global sea-level rise, and climate extremes. Our Belmont Forum DELTAS project (BF-DELTAS: Catalyzing actions towards delta sustainability) encompasses an international network of interdisciplinary research collaborators with focal areas in the Mekong, Ganges Brahmaputra, and the Amazon deltas. The project is organized around five main modules: (1) developing an analytical framework for assessing delta vulnerability and scenarios of change (Delta-SRES), (2) developing an open-acess, science-based integrative modeling framework for risk assessment and decision support (Delta-RADS), (3) developing tools to support quantitative mapping of the bio-physical and socio-economic environments of deltas and consolidate bio-physical and social data within shared data repositories (Delta-DAT), (4) developing Global Delta Vulnerability Indices (Delta-GDVI) that capture current and projected scenarios for major deltas around the world , and (5) collaborating with regional stakeholders to put the science, modeling, and data into action (Delta-ACT). In this talk, a research summary will be presented on three research domains around which significant collaborative work was developed: advancing biophysical classification of deltas, understanding deltas as coupled socio-ecological systems, and analyzing and informing social and environmental vulnerabilities in delta regions.

  12. Superconducting bandpass delta-sigma modulator

    International Nuclear Information System (INIS)

    Bulzacchelli, J.F.; Lee, H.-S.; Misewich, J.A.; Ketchen, M.B.


    Bandpass delta-sigma modulators digitize narrowband signals with high dynamic range and linearity. The required sampling rate is only a few times higher than the centre frequency of the input. This paper presents a superconducting bandpass delta-sigma modulator for direct analogue-to-digital conversion of RF signals in the GHz range. The input signal is capacitively coupled to one end of a microstrip transmission line, and a single flux quantum balanced comparator quantizes the current flowing out of the other end. Quantization noise is suppressed at the quarter-wave resonance of the transmission line (about 2 GHz in our design). Circuit performance at a 20 GHz sampling rate has been studied with several long JSIM simulations. Full-scale (FS) input sensitivity is 20 mV (rms), and in-band noise is -53 dBFS and -57 dBFS over bandwidths of 39 MHz and 19.5 MHz, respectively. In-band intermodulation distortion is better than -69 dBFS. (author)

  13. In vivo metabolism of the methyl homologues of delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol and abn-delta-8-tetrahydrocannabinol in the mouse. (United States)

    Brown, N K; Harvey, D J


    Methyl-delta-8-tetrahydrocannabinol (methyl-delta-8-THC), methyl-delta-9-THC and abn-methyl-delta-8-THC were synthesized by condensation of orcinol and (1S)-cis-verbenol and were administered to male Charles River CD-1 mice. Extracted hepatic metabolites were isolated by chromatography on Sephadex LH-20 and examined by gas chromatography/mass spectrometry as trimethylsilyl (TMS), (2H9)TMS and methyl ester/TMS derivatives. In addition, metabolic fractions were reduced with lithium aluminium deuteride to convert carboxylic acids to alcohols for structural correlation. Metabolites from methyl-delta-8-THC were similar with respect to the positions substituted to those produced by higher homologues; the major metabolite was methyl-delta-8-THC-11-oic acid. abn-Methyl-delta-8-THC was metabolized in a different manner. The location of the aromatic methyl group at the position adjacent to ring fusion appeared to inhibit metabolism at C(11) to a considerable extent and also to reduce the amount of the resulting alcohol from being oxidized to a carboxylic acid. This caused other metabolic pathways to become dominant, with the result that a compound containing a hydroxy group at the gem-methyl position was the major metabolite. Hydroxylation at this position has not been confirmed with any other cannabinoid, although it is thought to result in trace concentrations of hydroxy metabolites from some compounds. Metabolism of methyl-delta-9-THC was also similar to that of the higher homologues, with the exception that less metabolism occurred at C(8) and a higher percentage of the total metabolic fraction was accounted for by the 11-oic acid metabolite. Minor metabolites were mainly dihydroxy compounds and hydroxylated derivatives of delta-9-THC-11-oic acid.

  14. Sediment and Vegetation Controls on Delta Channel Networks (United States)

    Lauzon, R.; Murray, A. B.; Piliouras, A.; Kim, W.


    Numerous factors control the patterns of distributary channels formed on a delta, including water and sediment discharge, grain size, sea level rise rates, and vegetation type. In turn, these channel networks influence the shape and evolution of a delta, including what types of plant and animal life - such as humans - it can support. Previous fluvial modeling and flume experiments, outside of the delta context, have addressed how interactions between sediment and vegetation, through their influence on lateral transport of sediment, determine what type of channel networks develops. Similar interactions likely also shape delta flow patterns. Vegetation introduces cohesion, tending to reduce channel migration rates and strengthen existing channel banks, reinforcing existing channels and resulting in localized, relatively stable flow patterns. On the other hand, sediment transport processes can result in lateral migration and frequent switching of active channels, resulting in flow resembling that of a braided stream. While previous studies of deltas have indirectly explored the effects of vegetation through the introduction of cohesive sediment, we directly incorporate key effects of vegetation on flow and sediment transport into the delta-building model DeltaRCM to explore how these effects influence delta channel network formation. Model development is informed by laboratory flume experiments at UT Austin. Here we present initial results of experiments exploring the effects of sea level rise rate, sediment grain size, vegetation type, and vegetation growth rate on delta channel network morphology. These results support the hypothesis that the ability for lateral transport of sediment to occur plays a key role in determining the evolution of delta channel networks and delta morphology.

  15. The Concentration Dependence of the (Delta)s Term in the Gibbs Free Energy Function: Application to Reversible Reactions in Biochemistry (United States)

    Gary, Ronald K.


    The concentration dependence of (delta)S term in the Gibbs free energy function is described in relation to its application to reversible reactions in biochemistry. An intuitive and non-mathematical argument for the concentration dependence of the (delta)S term in the Gibbs free energy equation is derived and the applicability of the equation to…

  16. Complex rearrangements within the human J delta-C delta/J alpha-C alpha locus and aberrant recombination between J alpha segments

    NARCIS (Netherlands)

    Baer, R.; Boehm, T.; Yssel, H.; Spits, H.; Rabbitts, T. H.


    We have examined DNA rearrangements within a 120 kb cloned region of the human T cell receptor J delta-C delta/J alpha-C alpha locus. Three types of pattern emerge from an analysis of T cell lines and clones. Firstly, cells with two rearrangements within J delta-C delta; secondly, cells with one

  17. Spatio-temporal distributions of delta18O, delta D and salinity in the Arabian Sea: Identifying processes and controls

    Digital Repository Service at National Institute of Oceanography (India)

    Deshpande, R.D; Muraleedharan, P.M.; Singh, R.L.; Kumar, B.; Rao, M.S.; Dave, M.; Sivakumar, K.U.; Gupta, S.K.

    the geographic distributions of the delta18O and S; (2) in spite of a large scatter, a statistically significant delta18O–S relationship can be identified in much of the investigated part of the AS; (3) the delta18Odelta...

  18. 78 FR 21491 - DeltaPoint Capital IV, L.P., DeltaPoint Capital IV (New York), L.P.; Notice Seeking Exemption... (United States)


    ... SMALL BUSINESS ADMINISTRATION [License No. 02/02-0662, 02/02-0661] DeltaPoint Capital IV, L.P., DeltaPoint Capital IV (New York), L.P.; Notice Seeking Exemption Under Section 312 of the Small Business Investment Act, Conflicts of Interest Notice is hereby given that DeltaPoint Capital IV, L.P. and DeltaPoint...

  19. Changes to subaqueous delta bathymetry following a high river flow event, Wax Lake Delta, LA, USA (United States)

    Whaling, A. R.; Shaw, J.


    Sediment transport capacity is increased during high river flow (flood) events which are characterized by discharges that exceed the 15 year median daily statistic. The Wax Lake Delta (WLD) in coastal Louisiana has experienced 19 of these high flow events in the past 20 years, yet the depositional patterns of single floods are rarely measured in a field-scale deltaic setting. We characterize flood deposition and erosion patterns on the subaqueous portion of the WLD by differencing two Digital Elevation Models (DEMs) constructed from bathymetric surveys before and after the third largest flood in the WLD's recorded history. The total suspended sediment discharge for the 496 day inter-survey period was 2.14x107 cubic meters measured 21 km upstream of the delta apex. The difference map showed 1.06x107 cubic meters of sediment was deposited and 8.2x106 cubic meters was eroded, yielding 2.40x106 cubic meters of net deposition in the survey area ( 79.7 km2 ). Therefore the average deposition rate was 0.061 mm/day. Channel planform remained relatively unchanged for five out of six distributary passes however Gadwall Pass experienced a maximum channel displacement of 166 m ( 1 channel width) measured from the thalweg centerline. Channel tip extension was negligible. In addition, channel displacement was not concentrated at any portion along the channel centerline. Maximum erosion occurred within channel margins and increased upstream whereas maximum deposition occurred immediately outside the channel margins. Sediment eroded from the survey area was either subsequently re-deposited or transported out of the system. Our results show that up to 77.4% of deposition in the survey area originated from sediment eroded during the flood. Surprisingly, only 11.2% of the total suspended sediment discharge was retained in the subaqueous portion of the delta after the flood. We conclude that a high flow event does not produce channel progradation. Rather, high flow causes delta

  20. Niger Delta Crisis and Security Implications for the Nation State ...

    African Journals Online (AJOL)

    The Niger Delta is the nation's treasure base, the Niger Delta provides over 80 percent of government revenue, 95 percent of export receipts, and 90 percent of ... The government should tackle the fundamental issue of basic necessities – provision of good motorable roads, pipe borne water, electricity, good hospitals, good ...

  1. Morphodynamics of the Manyema tidal delta 1 LIST OF TABLES ...

    African Journals Online (AJOL)

    Kheira Kortenbout

    Morphodynamics of the Manyema tidal delta. 1. LIST OF ... Location of Manyema Creek and its associated tidal delta platform at Kunduchi. Fig. 2. ... platform. Beachcomber. Hotel. Whitesands. Hotel. Kunduchi. Beach Hotel. Giraffe. Hotel. INDIAN. OCEAN. Mombasa. Dar es. Salaam. KUNDUCHI. KENYA. TANZANIA.

  2. Towards a Comprehensive Framework for Adaptive Delta Management

    NARCIS (Netherlands)

    Marchand, M.; Ludwig, F.


    Deltas are dynamic landforms at the boundary of land and sea, involving intricate mazes of rivers and small waterways, wetlands, estuaries and coastal barrier islands. They are home to over half a billion people. Deltas are also home to rich ecosystems, such as mangroves and marshes. They are

  3. Conflict resolution among Niger delta communities: A historical ...

    African Journals Online (AJOL)

    Conflict related issues have assumed endemic proportion in the Niger Delta. A proper assessment of the critical factors in motion must take cognizance of their historical underpinnings. Peaceful co-existence, the hallmark of conflict resolution, can be feasible in the Niger Delta, through sustainable dialogue. These, among

  4. Upper-Division Student Difficulties with the Dirac Delta Function (United States)

    Wilcox, Bethany R.; Pollock, Steven J.


    The Dirac delta function is a standard mathematical tool that appears repeatedly in the undergraduate physics curriculum in multiple topical areas including electrostatics, and quantum mechanics. While Dirac delta functions are often introduced in order to simplify a problem mathematically, students still struggle to manipulate and interpret them.…

  5. Caribbean piracy and youth restiveness in Niger delta: A ...

    African Journals Online (AJOL)

    Our aim in this paper is to make a comparative analysis of Caribbean piracy and youth restiveness in Niger Delta of Nigeria. It will not be out of place to carry out such an analysis having seen, heard or read of the ongoing chaos, insecurity in the. Niger Delta Zone in Nigeria. We have to look at the past to find out such similar

  6. 78 FR 45592 - DeltaPoint Capital IV, LP; (United States)


    ..., Suite 160, Pittsford, NY 14534. The financing was contemplated for working capital. The financing is... SMALL BUSINESS ADMINISTRATION [License No. 02/02-0662] DeltaPoint Capital IV, LP; Notice Seeking... given that DeltaPoint Capital IV, L.P., 45 East Avenue, 6th Floor, Rochester, NY 14604, Federal...

  7. Central Delta languages: An overview | Kari | Stellenbosch Papers ...

    African Journals Online (AJOL)

    This paper presents an overview of the phonology, morphology and syntax of Central Delta languages. It also provides information on the geo-linguistic, demographic and sociolinguistic situation of these languages. It notes that Central Delta languages have a 20-vowel system, which divides into two sets of 10 vowels ...

  8. Downstream hydraulic geometry of a tidally influenced river delta

    NARCIS (Netherlands)

    Sassi, M.G.; Hoitink, A.J.F.; Brye, de B.; Deleersnijder, E.


    Channel geometry in tidally influenced river deltas can show a mixed scaling behavior between that of river and tidal channel networks, as the channel forming discharge is both of river and tidal origin. We present a method of analysis to quantify the tidal signature on delta morphology, by

  9. Delta: the first pion nucleon resonance - its discovery and applications

    International Nuclear Information System (INIS)

    Nagle, D.E.


    It is attempted to recapture some of the fun and excitement of the pion-scattering work that led to the discovery of what is now called the delta particle. How significant this discovery was became apparent only gradually. That the delta is alive today and thriving at Los Alamos (as well as other places) is described

  10. Wastewater disposal at safari lodges in the Okavango Delta, Botswana

    African Journals Online (AJOL)

    Wastewater disposal at safari lodges in the Okavango Delta, Botswana. TS McCarthy, T Gumbricht, RG Stewart, D Brandt, PJ Hancox, J McCarthy, AG Duse. Abstract. Many safari lodges in the Okavango Delta obtain their water supply from boreholes in near-surface aquifers while disposing of their wastewater via ...

  11. Remote stereocontrol by sulfinyl groups: reduction of delta-ketosulfoxides. (United States)

    García Ruano, José L; Fernández-Ibáñez, M Angeles; Maestro, M Carmen; Rodríguez-Fernández, M Mercedes


    The reduction of delta-ketosulfoxides constitutes the first evidence of the efficiency of the sulfinyl group to control the stereoselectivity of 1,5-asymmetric induction processes. The use of DIBAL/Yb(OTf)3 or L-Selectride as the reducing agents provides delta-hydroxysulfoxides with the opposite configuration at the hydroxylic carbon in a highly stereoselective way.

  12. Quark sea and the. delta. I=1/2 rule

    Energy Technology Data Exchange (ETDEWEB)

    Donoghue, J F [Carnegie-Mellon Univ., Pittsburgh, Pa. (USA). Dept. of Physics; Golowich, E [Massachusetts Univ., Amherst (USA)


    The effect on nonleptonic processes of quark-antiquark pairs due to quantum chromodynamics is studied. Their presence improves agreement between theory and experiment for hyperon decays. In kaon decays a new contribution is found, but effects are still too large to be in agreement.

  13. Antinociceptive activity of Delta9-tetrahydrocannabinol non-ionic microemulsions. (United States)

    Lazzari, P; Fadda, P; Marchese, G; Casu, G L; Pani, L


    Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent of Cannabis sativa L., has been widely studied for its potential pharmaceutical application in the treatment of various diseases and disturbs. This sparingly soluble terpeno-phenolic compound is not easy to handle and to be formulated in pharmaceutical preparations. The aim of this work was to develop a stable aqueous Delta(9)-THC formulation acceptable for different ways of administration, and to evaluate the therapeutic properties of the new Delta(9)-THC based preparation for pain treatment. Due to the thermodynamic stability and advantages of microemulsion based systems, the study was focused on the identification of aqueous microemulsion based systems containing Delta(9)-THC. Oil in water Delta(9)-THC microemulsions were individuated through phase diagrams construction, using the non-ionic surfactant Solutol HS15, being this surfactant acceptable for parenteral administration in human. A selected microemulsion samples containing 0.2 wt% of Delta(9)-THC, stable up to 52 degrees C, was successfully assayed on animal models of pain. Significant antinociceptive activity has been detected by both intraperitoneal and intragastric administration of the new Delta(9)-THC pharmaceutical preparation. The effect has been highlighted in shorter time if compared to a preparation of the same active principle based on previously reported conventional preparation. 2010 Elsevier B.V. All rights reserved.

  14. An annotated list of Fishes from the Niger Delta

    NARCIS (Netherlands)

    Boeseman, M.


    At the end of November 1960, the Leiden Museum received an interesting collection of animals, mostly fishes, from the Niger delta. All specimens were collected by Mr. H. J. G. Beets, at the time employed by Shell B.P. — Delta Investigations, during the period May to August 1960, and in the region

  15. Topological Mappings via B&delta;g-Closed Sets


    Maruthamuthu, Raja; Narayanasamy, Seenivasagan; Otchanathevar, Ravi


    In this paper we introduce a new class of functions called  B&delta;g-continuous functions. We obtain several characterizations and some their properties. Also we investigate its relationship with other types of functions. Further we introduce and study a new class of functions namely B&delta;g-irresolute.

  16. Estimation of Thermal Conductivity in the North- Western Niger Delta ...

    African Journals Online (AJOL)

    Thermal conductivity estimates are computed from nineteen petroleum wells in the north-western Niger Delta, Nigeria, using a geometric mean model. Sonic and gamma-ray logs were digitised and used in the estimation of in situ conductivity. The Niger Delta is composed of three major diachronous lithostratigraphic units of ...

  17. How to deal with subsidence in the Dutch delta?

    NARCIS (Netherlands)

    Stouthamer, E.; Erkens, G.


    In many deltas worldwide subsidence still is an underestimated problem, while the threat posed by land subsidence low-lying urbanizing and urbanized deltas exceeds the threat of sea-level rise induced by climate change. Human-induced subsidence is driven by the extraction of hydrocarbons and

  18. Dousing the tension in the Niger delta through administrative agency

    African Journals Online (AJOL)

    Dousing the tension in the Niger delta through administrative agency: A programme evaluation of Niger delta development commission as an intervention regime. ... the study concludes that because of systemic constraints arising from the hegemonic interests of the dominant coalitions in the Nigerian Social formation, ...

  19. Drones on the delta | CRDI - Centre de recherches pour le ...

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

    25 nov. 2016 ... Waves wash ashore at Fuvemeh, a town in Ghana's Volta River delta that's threatened by coastal erosion and flooding. Brian Owens, Canadian Geographic. Ghana's Volta River delta is an area vulnerable to climate change, with rising seas and increasingly powerful storms driving flooding and erosion, ...

  20. Homosexuality amongst migrant oil workers in the Niger Delta ...

    African Journals Online (AJOL)

    Aims: To determine the prevalence of homosexuality among migrant oil workers in Niger Delta. Methods: A prospective questionnaire – based study was conducted among migrant oil workers in the Niger Delta region of Nigeria. The design was to determine the prevalence of homosexuality in the workers in oil workers.

  1. T gamma/delta lymphocytes in renal transplant recipients

    NARCIS (Netherlands)

    Raasveld, M. H.; Bloemena, E.; Surachno, S.; ten Berge, R. J.


    T gamma/delta lymphocytes are able to perform allospecific cytotoxicity and natural killer cytotoxicity in vitro. However, very little is known about their function in vivo. To investigate the possible involvement of T gamma/delta lymphocytes in the immune response to renal allografts, fine-needle

  2. The evolution of a subaqueous delta in the Anthropocene: A stratigraphic investigation of the Brazos River delta, TX USA (United States)

    Carlin, Joseph A.; Dellapenna, Timothy M.


    Globally, deltas are increasingly threatened by anthropogenic activities. As a result, deltas now evolve through the combined effects of natural and human-induced processes occurring throughout the fluvial-deltaic system. The Brazos River delta, located along the Texas coast in the northwestern Gulf of Mexico, and its watershed have been impacted by direct and indirect human activities since the late 19th century. This provides an opportunity to investigate how such alterations have shaped the evolution of a delta in the Anthropocene, a time when humans are drivers of geological change. Historic alteration to the delta and watershed include extensive agricultural activity, jetty construction at the mouth in the late 1890s, mouth diversion ~10 km to the southwest in 1929, and reservoir construction throughout the early and mid 20th Century. Three subaerial deltaic geometries provided the framework to connect subaerial deltaic responses, to the anthropogenic alterations, to the resulting stratigraphic characteristics observed in the subaqueous delta. This study utilized high-resolution geophysical data (swath bathymetry, side scan sonar, CHIRP subbottom profiling) on the subaqueous delta to investigate the subaqueous delta stratigraphy and infer the processes that shaped the deltaic record over time. The results showed distinct areas across the subaqueous delta that were dominated by erosion and deposition. Erosional areas corresponded to earlier growth phase depocenters being exposed at the surface, while the depositional areas corresponded to areas with the most recent growth phase depocenter overlying the earlier depocenters. These results highlight that the subaqueous depocenter has migrated westward over time, consistent with the observed changes to the subaerial delta. Additionally, the data showed that evidence for these past growth phases and depocenters may be preserved within the subaqueous delta, even after subaerial portions of the delta returned to pre

  3. Losing ground in mega-deltas: basin-scale response to existential threats to the Mekong Delta (United States)

    Arias, M. E.; Kondolf, G. M.; Schmitt, R. J. P.; Carling, P. A.; Darby, S. E.; Bizzi, S.; Castelletti, A.; Cochrane, T. A.; Gibson, S.; Kummu, M.; Oeurng, C.; Rubin, Z.; Wild, T. B.


    The Mekong Delta is, in terms of the number of livelihoods it supports, its economic importance, and in its vulnerability to climate change and sinking lands, one of the world's critically threatened mega-deltas. Livelihoods depend on the mere existence of the delta, but also on ecosystem services provided by the delta's drainage basin spanning 795,000 km2 in six abutting countries. These ecosystem services include delivery of sand required to build delta land in the face of rising sea-levels and sediment bound nutrients, provision of spawning habitat for fish that are ultimately harvested in the delta, and hydrologic regulation driving the delta's unique flood-pulse regime. However, while the delta is mainly located in Vietnam, the basin of the Mekong River is shared among China, Myanmar, Laos, Thailand, Cambodia, and Vietnam. In the context of the region's dynamic growth, individual countries are pushing their own development agendas, which include extensive dam building, in-channel sand mining, construction of dykes and canals, and groundwater pumping, all of which contribute to subsidence and erosion of the Delta. Our synthesis of recent research indicates that most of the Mekong's delta land will likely fall below sea-level by 2100 as result of these drivers, exacerbating the impacts of global climatic changes. In this context, local infrastructural projects and changes in land- and water-management may temporarily mitigate some negative effects, but do not address the existential threat to the delta as a whole. To prevent, or at least substantially postpone, the drowning of the Mekong Delta requires identification of the key drivers and immediate concerted management actions on the basin-scale to change the trajectory of subsidence and sediment deficit. A specific challenge is to find the institutional arrangements in this transnational context that could support the needed management changes and equitably distribute costs and impacts. The Mekong Delta is

  4. The role of the UPS in cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Cyr Douglas M


    Full Text Available Abstract CF is an inherited autosomal recessive disease whose lethality arises from malfunction of CFTR, a single chloride (Cl- ion channel protein. CF patients harbor mutations in the CFTR gene that lead to misfolding of the resulting CFTR protein, rendering it inactive and mislocalized. Hundreds of CF-related mutations have been identified, many of which abrogate CFTR folding in the endoplasmic reticulum (ER. More than 70% of patients harbor the ΔF508 CFTR mutation that causes misfolding of the CFTR proteins. Consequently, mutant CFTR is unable to reach the apical plasma membrane of epithelial cells that line the lungs and gut, and is instead targeted for degradation by the UPS. Proteins located in both the cytoplasm and ER membrane are believed to identify misfolded CFTR for UPS-mediated degradation. The aberrantly folded CFTR protein then undergoes polyubiquitylation, carried out by an E1-E2-E3 ubiquitin ligase system, leading to degradation by the 26S proteasome. This ubiquitin-dependent loss of misfolded CFTR protein can be inhibited by the application of ‘corrector’ drugs that aid CFTR folding, shielding it from the UPS machinery. Corrector molecules elevate cellular CFTR protein levels by protecting the protein from degradation and aiding folding, promoting its maturation and localization to the apical plasma membrane. Combinatory application of corrector drugs with activator molecules that enhance CFTR Cl- ion channel activity offers significant potential for treatment of CF patients. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb;

  5. Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux

    NARCIS (Netherlands)

    Vrins, Carlos L. J.; van der Velde, Astrid E.; van den Oever, Karin; Levels, Johannes H. M.; Huet, Stephane; Elferink, Ronald P. J. Oude; Kuipers, Folkert; Groen, Albert K.


    Peroxisome proliferator-activated receptor delta (PPAR delta) is involved in regulation of energy homeostasis. Activation of PPAR delta markedly increases fecal neutral sterol secretion, the last step in reverse cholesterol transport. This phenomenon can neither be explained by increased

  6. Measurement of delta-rays in ATLAS silicon sensors

    CERN Document Server

    The ATLAS collaboration


    In the inner detector of the ATLAS experiment at the LHC, $\\delta$-rays originating from particle interactions in the silicon sensors may cause additional hit channels. A method for identifying silicon hit clusters that are enlarged due to the emission of a $\\delta$-ray is presented. Using pp collision data the expectation is confirmed that the $\\delta$-ray production rate depends linearly on the path length of the particle in silicon, independently of layer radius and detector technology. The range of the $\\delta$-rays, which is a property of the material and should not depend on anything else, is indeed found to be constant as a function of detector layer, path length in silicon and momentum of the particle traversing the silicon. As a by-product of this analysis a method is proposed that could correct for the effect of these $\\delta$-rays, and this could be used to improve track reconstruction.

  7. (p,. pi. /sup -/) reaction and. delta. /sup + +/ components of nuclei

    Energy Technology Data Exchange (ETDEWEB)

    Kisslinger, L S; Miller, G A [Carnegie-Mellon Univ., Pittsburgh, Pa. (USA). Dept. of Physics


    The use of the (p,..pi../sup -/) reaction as a probe to determine + +/(1232) components of nuclear wave functions is examined within the framework of a model which treats baryon resonances on the same footing as nucleons. Nuclear structure properties which affect the are discussed. Estimates of cross sections, at several energies, are made for the + +/ transfer contribution as well as for the competing processes: proton charge exchange (p,n) followed by an (n,..gamma../sup -/) reaction; emission of a ..pi../sup 0/ followed by pion charge exchange (..pi../sup -/,..pi../sup 0/). Even with as small as 0.0001 the process can compete with ordinary background charge-exchange reactions.

  8. Spectral factorization using the delta operator

    DEFF Research Database (Denmark)

    Rostgaard, Morten; Poulsen, Niels Kjølstad; Ravn, Ole


    In recent years many papers have been published abouth the gamma-operator, mostly caused by the better numerical properties and the rapprochement between continuous and discrete time. A major problem within the LQG-design of a delta-based input-output relation has been how to spectral-factorize...... solution to the spectral factorization problem. The key idea is to use the gamma-operator resembled by its behavior to the differential operator....... in an efficient way. The discrete-time method of Kuccera will not be applied since numerical word-length characteristics will be poor for fast sampling rates. In this paper a new approach is considered. A new gamma-operator (Tustin operator) is introduced, in order to make an iterative and numerical stable...

  9. $\\delta N$ formalism from superpotential and holography

    CERN Document Server

    Garriga, Jaume; Vernizzi, Filippo


    We consider the superpotential formalism to describe the evolution of scalar fields during inflation, generalizing it to include the case with non-canonical kinetic terms. We provide a characterization of the attractor behaviour of the background evolution in terms of first and second slow-roll parameters (which need not be small). We find that the superpotential is useful in justifying the separate universe approximation from the gradient expansion, and also in computing the spectra of primordial perturbations around attractor solutions in the $\\delta N$ formalism. As an application, we consider a class of models where the background trajectories for the inflaton fields are derived from a product separable superpotential. In the perspective of the holographic inflation scenario, such models are dual to a deformed CFT boundary theory, with $D$ mutually uncorrelated deformation operators. We compute the bulk power spectra of primordial adiabatic and entropy cosmological perturbations, and show that the results...

  10. Head orientation prediction: delta quaternions versus quaternions. (United States)

    Himberg, Henry; Motai, Yuichi


    Display lag in simulation environments with helmet-mounted displays causes a loss of immersion that degrades the value of virtual/augmented reality training simulators. Simulators use predictive tracking to compensate for display lag, preparing display updates based on the anticipated head motion. This paper proposes a new method for predicting head orientation using a delta quaternion (DQ)-based extended Kalman filter (EKF) and compares the performance to a quaternion EKF. The proposed framework operates on the change in quaternion between consecutive data frames (the DQ), which avoids the heavy computational burden of the quaternion motion equation. Head velocity is estimated from the DQ by an EKF and then used to predict future head orientation. We have tested the new framework with captured head motion data and compared it with the computationally expensive quaternion filter. Experimental results indicate that the proposed DQ method provides the accuracy of the quaternion method without the heavy computational burden.

  11. Dependence of {delta}E effect on internal stresses in nickel: Experimental results by laser interferometry

    Energy Technology Data Exchange (ETDEWEB)

    Chicharro, J.M. [Dept. de Mecanica Aplicada e Ingenieria de Proyectos, E.T.S.I. Industriales, Universidad de Castilla-La Mancha, Avd. Camilo Jose Cela s/n, 13071 Ciudad Real (Spain)]. E-mail:; Bayon, A. [Dept. de Fisica Aplicada a los Recursos Naturales, E.T.S.I. Minas, Universidad Politecnica de Madrid, c/Rios Rosas, 21, 28003 Madrid (Spain); Salazar, F. [Dept. de Fisica Aplicada a los Recursos Naturales, E.T.S.I. Minas, Universidad Politecnica de Madrid, c/Rios Rosas, 21, 28003 Madrid (Spain)


    The speckle heterodyne interferometry is applied to the study of the dependence of Young's modulus on both the magnetic field and the internal stresses in a soft ferromagnetic material. Young's modulus is determined from the first natural longitudinal frequency of a slender magnetic rod positioned within a solenoid. Vibration of the sample is detected by an optical heterodyne system with a wide bandwidth. The samples are heated to above the Curie point and then cooled at several rates in order to induce different internal stresses. The study refers to nickel rods 10mm in diameter and 110mm in length. The grain sizes of the samples are also determined and related to changes in {delta}E.

  12. Multimode delta-E effect magnetic field sensors with adapted electrodes

    Energy Technology Data Exchange (ETDEWEB)

    Zabel, Sebastian; Fichtner, Simon; Kirchhof, Christine; Quandt, Eckhard; Faupel, Franz, E-mail: [Faculty of Engineering, Institute for Materials Science, Kiel University, Kaiserstraße 2, 24143 Kiel (Germany); Reermann, Jens; Schmidt, Gerhard [Faculty of Engineering, Institute for Electrical Engineering, Kiel University, Kaiserstraße 2, 24143 Kiel (Germany); Wagner, Bernhard [Fraunhofer Institute for Silicon Technology ISIT, Fraunhoferstraße 1, 25524 Itzehoe (Germany)


    We present an analytical and experimental study on low-noise piezoelectric thin film resonators that utilize the delta-E effect of a magnetostrictive layer to measure magnetic fields at low frequencies. Calculations from a physical model of the electromechanical resonator enable electrode designs to efficiently operate in the first and second transversal bending modes. As predicted by our calculations, the adapted electrode design improves the sensitivity by a factor of 6 and reduces the dynamic range of the sensor output by 16 dB, which significantly eases the requirements on readout electronics. Magnetic measurements show a bandwidth of 100 Hz at a noise level of about 100 pTHz{sup −0.5}.

  13. Perspectives on bay-delta science and policy (United States)

    Healey, Michael; Dettinger, Michael; Norgaard, Richard


    The State of Bay–Delta Science 2008 highlighted seven emerging perspectives on science and management of the Delta. These perspectives had important effects on policy and legislation concerning management of the Delta ecosystem and water exports. From the collection of papers that make up the State of Bay–Delta Science 2016, we derive another seven perspectives that augment those published in 2008. The new perspectives address nutrient and contaminant concentrations in Delta waters, the failure of the Delta food web to support native species, the role of multiple stressors in driving species toward extinction, and the emerging importance of extreme events in driving change in the ecosystem and the water supply. The scientific advances that underpin these new perspectives were made possible by new measurement and analytic tools. We briefly discuss some of these, including miniaturized acoustic fish tags, sensors for monitoring of water quality, analytic techniques for disaggregating complex contaminant mixtures, remote sensing to assess levee vulnerability, and multidimensional hydrodynamic modeling. Despite these new tools and scientific insights, species conservation objectives for the Delta are not being met. We believe that this lack of progress stems in part from the fact that science and policy do not incorporate sufficiently long-term perspectives. Looking forward half a century was central to the Delta Visioning process, but science and policy have not embraced this conceptual breadth. We are also concerned that protection and enhancement of the unique cultural, recreational, natural resource, and agricultural values of the Delta as an evolving place, as required by the Delta Reform Act, has received no critical study and analysis. Adopting wider and longer science and policy perspectives immediately encourages recognition of the need for evaluation, analysis, and public discourse on novel conservation approaches. These longer and wider perspectives

  14. The Atchafalaya River Delta. Report 7. Analytical Analysis of the Development of the Atchafalaya River Delta. (United States)


    responsible for the abrupt increases in subaerial delta growth. 64. Through using satellite imagery, color infrared photog- raphy, and digital current...w RO CF = HO/A/BO/(2.-D) w (HH wo (2.-D) - 1.) + O.5/AA X2 = BO m 2.m AA a HHow(D-1.) o CF AREA = (2.wAAwB~ ww2 ) im (CKI*(1. + AmBO/HOwRO) ww2 &+ CK2 a

  15. Primary production in the Delta: Then and now (United States)

    Cloern, James E.; Robinson, April; Richey, Amy; Grenier, Letitia; Grossinger, Robin; Boyer, Katharyn E.; Burau, Jon; Canuel, Elizabeth A.; DeGeorge, John F.; Drexler, Judith Z.; Enright, Chris; Howe, Emily R.; Kneib, Ronald; Mueller-Solger, Anke; Naiman, Robert J.; Pinckney, James L.; Safran, Samuel M.; Schoellhamer, David H.; Simenstad, Charles A.


    To evaluate the role of restoration in the recovery of the Delta ecosystem, we need to have clear targets and performance measures that directly assess ecosystem function. Primary production is a crucial ecosystem process, which directly limits the quality and quantity of food available for secondary consumers such as invertebrates and fish. The Delta has a low rate of primary production, but it is unclear whether this was always the case. Recent analyses from the Historical Ecology Team and Delta Landscapes Project provide quantitative comparisons of the areal extent of 14 habitat types in the modern Delta versus the historical Delta (pre-1850). Here we describe an approach for using these metrics of land use change to: (1) produce the first quantitative estimates of how Delta primary production and the relative contributions from five different producer groups have been altered by large-scale drainage and conversion to agriculture; (2) convert these production estimates into a common currency so the contributions of each producer group reflect their food quality and efficiency of transfer to consumers; and (3) use simple models to discover how tidal exchange between marshes and open water influences primary production and its consumption. Application of this approach could inform Delta management in two ways. First, it would provide a quantitative estimate of how large-scale conversion to agriculture has altered the Delta's capacity to produce food for native biota. Second, it would provide restoration practitioners with a new approach—based on ecosystem function—to evaluate the success of restoration projects and gauge the trajectory of ecological recovery in the Delta region.

  16. How Rapid Change Affects Deltas in the Arctic Region (United States)

    Overeem, I.; Bendixen, M.


    Deltas form where the river drains into the ocean. Consequently, delta depositional processes are impacted by either changes in the respective river drainage basin or by changes in the regional marine environment. In a warming Arctic region rapid change has occurred over the last few decades in both the terrestrial domain as well as in the marine domain. Important terrestrial controls include 1) change in permafrost possibly destabilizing river banks, 2) strong seasonality of river discharge due to a short melting season, 3) high sediment supply if basins are extensively glaciated, 4) lake outbursts and ice jams favoring river flooding. Whereas in the Arctic marine domain sea ice loss promotes wave and storm surge impact, and increased longshore transport. We here ask which of these factors dominate any morphological change in Arctic deltas. First, we analyze hydrological data to assess change in Arctic-wide river discharge characteristics and timing, and sea ice concentration data to map changes in sea ice regime. Based on this observational analysis we set up a number of scenarios of change. We then model hypothetical small-scale delta formation considering change in these primary controls by setting up a numerical delta model, and combining it dynamically with a permafrost model. We find that for typical Greenlandic deltas changes in river forcing due to ice sheet melt dominate the morphological change, which is corroborated by mapping of delta progradation from aerial photos and satellite imagery. Whereas in other areas, along the North Slope and the Canadian Arctic small deltas are more stable or experienced retreat. Our preliminary coupled model allows us to further disentangle the impact of major forcing factors on delta evolution in high-latitude systems.

  17. Hot deformation behavior of delta-processed superalloy 718

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Y., E-mail: [State Key Laboratory of Powder Metallurgy, Central South University, Changsha 410083 (China); School of Aeronautics and Astronautics, Central South University, Changsha 410083 (China); Shao, W.Z.; Zhen, L.; Zhang, B.Y. [School of Materials Science and Engineering, Harbin Institute of Technology, Harbin 150001 (China)


    Research highlights: {yields} The peak stress for hot deformation can be described by the Z parameter. {yields} The grain size of DRX was inversely proportional to the Z parameter. {yields} The dissolution of {delta} phases was greatly accelerated under hot deformation. {yields}The {delta} phase stimulated nucleation can serve as the main DRX mechanism. - Abstract: Flow stress behavior and microstructures during hot compression of delta-processed superalloy 718 at temperatures from 950 to 1100 deg. C with strain rates of 10{sup -3} to 1 s{sup -1} were investigated by optical microscopy (OM), electron backscatter diffraction (EBSD) technique and transmission electron microscopy (TEM). The relationship between the peak stress and the deformation conditions can be expressed by a hyperbolic-sine type equation. The activation energy for the delta-processed superalloy 718 is determined to be 467 kJ/mol. The change of the dominant deformation mechanisms leads to the decrease of stress exponent and the increase of activation energy with increasing temperature. The dynamically recrystallized grain size is inversely proportional to the Zener-Hollomon (Z) parameter. It is found that the dissolution rate of {delta} phases under hot deformation conditions is much faster than that under static conditions. Dislocation, vacancy and curvature play important roles in the dissolution of {delta} phases. The main nucleation mechanisms of dynamic recrystallization (DRX) for the delta-processed superalloy 718 include the bulging of original grain boundaries and the {delta} phase stimulated DRX nucleation, which is closely related to the dissolution behavior of {delta} phases under certain deformation conditions.

  18. Primary Production in the Delta: Then and Now

    Directory of Open Access Journals (Sweden)

    James E. Cloern


    Full Text Available doi: evaluate the role of restoration in the recovery of the Delta ecosystem, we need to have clear targets and performance measures that directly assess ecosystem function. Primary production is a crucial ecosystem process, which directly limits the quality and quantity of food available for secondary consumers such as invertebrates and fish. The Delta has a low rate of primary production, but it is unclear whether this was always the case. Recent analyses from the Historical Ecology Team and Delta Landscapes Project provide quantitative comparisons of the areal extent of 14 habitat types in the modern Delta versus the historical Delta (pre-1850. Here we describe an approach for using these metrics of land use change to: (1 produce the first quantitative estimates of how Delta primary production and the relative contributions from five different producer groups have been altered by large-scale drainage and conversion to agriculture; (2 convert these production estimates into a common currency so the contributions of each producer group reflect their food quality and efficiency of transfer to consumers; and (3 use simple models to discover how tidal exchange between marshes and open water influences primary production and its consumption. Application of this approach could inform Delta management in two ways. First, it would provide a quantitative estimate of how large-scale conversion to agriculture has altered the Delta's capacity to produce food for native biota. Second, it would provide restoration practitioners with a new approach—based on ecosystem function—to evaluate the success of restoration projects and gauge the trajectory of ecological recovery in the Delta region.


    Directory of Open Access Journals (Sweden)

    Daniel Souza LIMA

    Full Text Available ABSTRACT BACKGROUND: The Amazon region is one of the main endemic areas of hepatitis delta in the world and the only one related to the presence of genotype 3 of the delta virus. OBJECTIVE: To analyze the profile, mortality and survival of cirrhotic patients submitted to liver transplantation for chronic hepatitis delta virus and compare with those transplanted by hepatitis B virus monoinfection. METHODS: Retrospective, observational and descriptive study. From May 2002 to December 2011, 629 liver transplants were performed at the Walter Cantídio University Hospital, of which 29 patients were transplanted due to cirrhosis caused by chronic delta virus infection and 40 by hepatitis B chronic monoinfection. The variables analyzed were: age, sex, MELD score, Child-Pugh score, upper gastrointestinal bleeding and hepatocellular carcinoma occurrence before the transplantation, perioperative platelet count, mortality and survival. RESULTS: The Delta Group was younger and all came from the Brazilian Amazon Region. Group B presented a higher proportion of male patients (92.5% compared to Group D (58.6%. The occurrence of upper gastrointestinal bleeding before transplantation, MELD score, and Child-Pugh score did not show statistical differences between groups. The occurrence of hepatocellular carcinoma and mortality were higher in the hepatitis B Group. The survival in 4 years was 95% in the Delta Group and 75% in the B Group, with a statistically significant difference (P=0.034. Patients with hepatitis delta presented more evident thrombocytopenia in the pre-transplantation and in the immediate postoperative period. CONCLUSION: The hepatitis by delta virus patients who underwent liver transplantation were predominantly male, coming from the Brazilian Amazon region and with similar liver function to the hepatitis B virus patients. They had a lower incidence of hepatocellular carcinoma, more marked perioperative thrombocytopenia levels and frequent

  20. Delta Evolution at Røde Elv, Disko Island, Greenland (United States)

    Kroon, A.; Arngrimson, J.; Bendixen, M.; Sigsgaard, C.


    Ice, snow and freezing temperatures have a large impact on coastal morphodynamics in Arctic polar environments. A recent warming of the Arctic climate induces many changes along the arctic shorelines. Sea-levels are rising due to thermal expansion and due to an increased fresh water flux from the glaciers and land ice masses. At the same time, the ice coverage of the coastal waters reduces and the open water periods in summer extend. There is a strong seasonal variation with open waters and active rivers in summer and ice-covered coastal waters and inactive rivers in winter. Coastal processes by waves and tides are thus limited to the summer and early fall. Besides, there is also a strong daily variation in fluvial discharges due to the daily variations in glacier melt with maximum melt in the afternoon and minimum values at night. At the same time, the actual flux of the river to the coastal bay is influenced by the tidal phase. Low tides will enhance the transport to the delta front, while high tides will create stagnant waters over the delta plain. The delta of the Røde Elv is located in southwestern Disko Island in west Greenland. It has a relatively small (ca. 101 km2) and partly glaciated drainage basin (ca. 20%) and its sediments consist of a mixture of basaltic sands and gravels. The Røde Elv delta is located at the end of a pro-glacial and fluvial valley at about 20 km from the glacier. The shores of the delta are reworked by waves, predominantly from southwestern, southern (largest fetch, over 50 km), and southeastern directions. The environment has a micro- to meso- tidal range with a spring tidal range of 2.7 m. The morphologic changes on the delta over the last decades clearly showed a seaward extension of the delta and a periodic shift in the location of the main delta channel. In this presentation, we focus on quantification of water discharges and suspended sediment fluxes to the Røde Elv delta in western Greenland, and on the morphological

  1. Late quaternary evolution of the Orinoco Delta, Venezuela (United States)

    Warne, A.G.; Guevara, E.H.; Aslan, A.


    The modern Orinoco Delta is the latest of a series of stacked deltas that have infilled the Eastern Venezuelan Basin (EVB) since the Oligocene. During the late Pleistocene sea-level lowstand (20,000 to 16,000 yrs BP), bedrock control points at the position of the present delta apex prevented the river channel from incising as deeply as many other major river systems. Shallow seismic data indicate that the late Pleistocene Orinoco incised into the present continental shelf, where it formed a braided-river complex that transported sediment to a series of shelf-edge deltas. As sea level rose from 16,000 to 9,500 yrs BP, the Orinoco shoreline shifted rapidly landward, causing shallow-marine waves and currents to form a widespread transgressive sand unit. Decelerating sea-level rise and a warmer, wetter climate during the early Holocene (9,500 to 6,000 yrs BP) induced delta development within the relatively quiet-water environment of the EVB embayment. Sea level approached its present stand in the middle Holocene (6,000 to 3,000 yrs BP), and the Orinoco coast prograded, broadening the delta plain and infilling the EVB embayment. Significant quantities of Amazon sediment began to be transported to the Orinoco coast by littoral currents. Continued progradation in the late Holocene caused the constriction at Boca de Serpientes to alter nearshore and shelf hydrodynamics and subdivide the submarine delta into two distinct areas: the Atlantic shelf and the Gulf of Paria. The increased influence of littoral currents along the coast promoted mudcape development. Because most of the water and sediment were transported across the delta plain through the Rio Grande distributary in the southern delta, much of the central and northwestern delta plain became sediment starved, promoting widespread accumulation of peat deposits. Human impacts on the delta are mostly associated with the Volca??n Dam on Can??o Manamo. However, human activities have had relatively little effect on the

  2. Is there a self-organization principle of river deltas? (United States)

    Tejedor, Alejandro; Longjas, Anthony; Foufoula-Georgiou, Efi


    River deltas are known to possess a complex topological and flux-partitioning structure which has recently been quantified using spectral graph theory [Tejedor et al., 2015a,b]. By analysis of real and simulated deltas it has also been shown that there is promise in formalizing relationships between this topo-dynamic delta structure and the underlying delta forming processes [e.g., Tejedor et al., 2016]. The question we pose here is whether there exists a first order organizational principle behind the self-organization of river deltas and whether this principle can be unraveled from the co-evolving topo-dynamic structure encoded in the delta planform. To answer this question, we introduce a new metric, the nonlocal Entropy Rate (nER) that captures the information content of a delta network in terms of the degree of uncertainty in delivering fluxes from any point of the network to the shoreline. We hypothesize that if the "guiding principle" of undisturbed deltas is to efficiently and robustly build land by increasing the diversity of their flux pathways over the delta plane, then they would exhibit maximum nonlocal Entropy Rate at states at which geometry and flux dynamics are at equilibrium. At the same time, their nER would be non-optimal at transient states, such as before and after major avulsions during which topology and dynamics adjust to each other to reach a new equilibrium state. We will present our results for field and simulated deltas, which confirm this hypothesis and open up new ways of thinking about self-organization, complexity and robustness in river deltas. One particular connection of interest might have important implications since entropy rate and resilience are related by the fluctuation theorem [Demetrius and Manke, 2005], and therefore our results suggest that deltas might in fact self-organize to maximize their resilience to structural and dynamic perturbations. References: Tejedor, A., A. Longjas, I. Zaliapin, and E. Foufoula

  3. Holocene evolution of the western Orinoco Delta, Venezuela (United States)

    Aslan, A.; White, W.A.; Warne, A.G.; Guevara, E.H.


    The pristine nature of the Orinoco Delta of eastern Venezuela provides unique opportunities to study the geologic processes and environments of a major tropical delta. Remote-sensing images, shallow cores, and radiocarbon-dating of organic remains form the basis for describing deltaic environments and interpreting the Holocene history of the delta. The Orinoco Delta can be subdivided into two major sectors. The southeast sector is dominated by the Rio Grande-the principal distributary-and complex networks of anastomosing fluvial and tidal channels. The abundance of siliciclastic deposits suggests that fluvial processes such as over-bank flooding strongly influence this part of the delta. In contrast, the northwest sector is represented by few major distributaries, and overbank sedimentation is less widespread relative to the southeast sector. Peat is abundant and occurs in herbaceous and forested swamps that are individually up to 200 km2 in area. Northwest-directed littoral currents transport large volumes of suspended sediment and produce prominent mudcapes along the northwest coast. Mapping of surface sediments, vegetation, and major landforms identified four principal geomorphic systems within the western delta plain: (1) distributary channels, (2) interdistributary flood basins, (3) fluvial-marine transitional environments, and (4) marine-influenced coastal environments. Coring and radiocarbon dating of deltaic deposits show that the northern delta shoreline has prograded 20-30 km during the late Holocene sea-level highstand. Progradation has been accomplished by a combination of distributary avulsion and mudcape progradation. This style of deltaic progradation differs markedly from other deltas such as the Mississippi where distributary avulsion leads to coastal land loss, rather than shoreline progradation. The key difference is that the Orinoco Delta coastal zone receives prodigious amounts of sediment from northwest-moving littoral currents that transport

  4. Identification of the CFTR c.1666A>G Mutation in Hereditary Inclusion Body Myopathy Using Next-Generation Sequencing Analysis

    Directory of Open Access Journals (Sweden)

    Yan Lu


    Full Text Available Hereditary inclusion body myopathy (HIBM is a rare autosomal recessive adult onset muscle disease which affects one to three individuals per million worldwide. This disease is autosomal dominant and occurs in adulthood. Our previous study reported a new subtype of HIBM linked to the susceptibility locus at 7q22.1-31.1. The present study is aimed to identify the candidate gene responsible for the phenotype in HIBM pedigree. After multipoint linkage analysis, we performed targeted capture sequencing on 16 members and whole-exome sequencing (WES on 5 members. Bioinformatics filtering was performed to prioritize the candidate pathogenic gene variants, which were further genotyped by Sanger sequencing. Our results showed that the highest peak of LOD score (4.70 was on chromosome 7q22.1-31.1.We identified 2 and 22 candidates using targeted capture sequencing and WES respectively, only one of which as CFTRc.1666A>G mutation was well cosegregated with the HIBM phenotype. Using transcriptome analysis, we did not detect the differences of CFTR's mRNA expression in the proband compared with healthy members. Due to low incidence of HIBM and there is no other pedigree to assess, mutation was detected in three patients with duchenne muscular dystrophyn (DMD and five patients with limb-girdle muscular dystrophy (LGMD. And we found that the frequency of mutation detected in DMD and LGMD patients was higher than that of being expected in normal population. We suggested that the CFTRc.1666A>G may be a candidate marker which has strong genetic linkage with the causative gene in the HIBM family.

  5. The DELTA 181 lithium thionyl chloride battery (United States)

    Sullivan, Ralph M.; Brown, Lawrence E.; Leigh, A. P.

    In 1986, the Johns Hopkins University/Applied Physics Laboratory (JHU/APL) undertook the development of a sensor module for the DELTA 181 spacecraft, a low earth orbit (LEO) mission of less than two months duration. A large lithium thionyl chloride battery was developed as the spacecraft's primary power source, the first known such use for this technology. The exceptionally high energy density of the lithium thionyl chloride cell was the primary driver for its use, resulting in a completed battery with a specific energy density of 120 Wh/lb. Safety requirements became the primary driver shaping all aspects of the power system design and development due to concerns about the potential hazards of this relatively new, high-energy technology. However, the program was completed without incident. The spacecraft was launched on February 8, 1988, from Kennedy Space Center (KSC) with over 60,000 Wh of battery energy. It reentered on April 2, 1988, still operating after 55 days, providing a successful, practical, and visible demonstration of the use of this technology for spacecraft applications.

  6. Chiral model for nucleon and delta

    International Nuclear Information System (INIS)

    Birse, M.C.; Banerjee, M.K.


    We propose a model of the nucleon and delta based on the idea that strong QCD forces on length scales approx.0.2--1 fm result in hidden chiral SU(2) x SU(2) symmetry and that there is a separation of roles between these forces which are also responsible for binding quarks in hadrons and the forces which produce absolute confinement. This leads us to study a linear sigma model describing the interactions of quarks, sigma mesons, and pions. We have solved this model in the semiclassical (mean-field) approximation for the hedgehog baryon state. We refer to this solution as a chiral soliton. In the semiclassical approximation the hedgehog state is a linear combination of N and Δ. We project this state onto states of good spin and isospin to calculate matrix elements of various operators in these states. Our results are in reasonable agreement with the observed properties of the nucleon. The mesonic contributions to g/sub A/ and sigma(πN) are about two to three times too large, suggesting the need for quantum corrections

  7. Delta Morphodynamics Matters! Ecosystem Services, Poverty and Morphodynamic Change in the Ganges-Brahmaputra Mega-Delta (United States)

    Nicholls, R. J.; Adger, N.; Allan, A.; Darby, S. E.; Hutton, C.; Matthews, Z.; Rahman, M.; Whitehead, P. G.; Wolf, J.


    The world's deltas are probably the most vulnerable type of coastal environment, and they face multiple stresses in the coming decades. These stresses include, amongst others, local drivers due to land subsidence, population growth and urbanisation within the deltas, regional drivers due to changes in catchment management (e.g. upstream land use and dam construction), as well as global climate change impacts such as sea-level rise. At the same time, the ecosystem services of river deltas support high population densities, with around 14% of the global population inhabiting deltas. A large proportion of these people experience extremes of poverty and they are therefore severely exposed to vulnerability from environmental and ecological stress and degradation. In areas close to or below the poverty boundary, both subsistence and cash elements of the economy tend to rely disproportionately heavily on ecosystem services which underpin livelihoods. Therefore, to sustainably manage delta environments they must be viewed as complex social-environmental systems where change is only partially driven by physical drivers such as sea level rise and climate change, and human-induced development activities are also critical. Here we outline a new conceptual framework for the development of methods to understand and characterise the key drivers of change in ecosystem services that affect the environment and economic status of populous deltas, focusing specifically on the Ganges-Brahmaputra-Meghna (GBM) mega-delta. The GBM delta is characterised by densely populated coastal lowlands with significant poverty, with livelihoods supported to a large extent by natural ecosystems such as the Sunderbahns (the largest mangrove forest in the world). However, the GBM delta is under severe development pressure due to many growing cities. At present the importance of ecosystems services to poverty and livelihoods is poorly understood. This is due to due to the complexity of interactions

  8. The situation in the Niger Delta; La situation dans le delta du Niger

    Energy Technology Data Exchange (ETDEWEB)

    Vitalis, E


    An energy issue for the United States and a political challenge for Europe, Nigeria is experiencing growing instability and is on the verge of civil war; the ecosystem and the population of the Niger Delta are the main victims. The State, corrupt, is powerless to contain the rising violence and redistribute the proceeds of oil sales. It is high time for oil-consuming countries, starting with the United States, to concern themselves with stabilizing the region. Europe must contribute to the lasting development of this country. (author)

  9. The Niger Delta Avengers, Autonomous Ethnic Clans and Common ...

    African Journals Online (AJOL)

    Nneka Umera-Okeke

    therefore investigated the sudden emergence of Niger Delta Avengers ... hardship, deprivations and environmental degradation occasioned by oil pipeline .... analysis of coded materials of the library such as books, magazines, journals,.

  10. Rarotonga Radiocarbon (delta 14C) for 1950 to 1997 (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Rarotonga coral radiocarbon (14C) timeseries. Coral radiocarbon (Delta-14C) on untreated, low-speed drilled samples. Precision is +/- 4 per mil as documented by an...

  11. Novel urinary metabolite of d-delta-tocopherol in rats

    International Nuclear Information System (INIS)

    Chiku, S.; Hamamura, K.; Nakamura, T.


    A novel metabolite of d-delta-tocopherol was isolated from the urine of rats given d-3,4-[ 3 H 2 ]-delta-tocopherol intravenously. The metabolite was collected from the urine of rats given d-delta-tocopherol in the same manner as that of the labeled compound. It was found that the metabolites consisted of sulfate conjugates. The portion of the major metabolite released with sulfatase was determined to be 2,8-dimethyl-2-(2'-carboxyethyl)-6-chromanol by infrared spectra, nuclear magnetic resonance spectra, and mass spectra. The proposed structure was confirmed by comparing the analytical results with those of a synthetically derived compound. As a result of the structural elucidation of this novel metabolite, a pathway for the biological transformation of delta-tocopherol is proposed which is different from that of alpha-tocopherol. A characteristic feature of the pathway is the absence of any opening of the chroman ring throughout the sequence

  12. Environmental Law and Underdevelopment in the Niger Delta ...

    African Journals Online (AJOL)

    Environmental Law and Underdevelopment in the Niger Delta Region of Nigeria. ... is composed of many ecosystems of great economic and social importance, ... producing companies contribute to the degradation of the environment which in ...

  13. Delta-ray spectroscopy of quasi-atoms

    International Nuclear Information System (INIS)

    Kozhuharov, C.


    The spectroscopy of high energy delta-rays, emitted in collisions of very heavy ions, is studied. The ''orange''-type beta-spectrometer and the achromatic electron channel are the experimental setups. Delta ray production probabilities are studied as a function of the distance of closest approach R /SUB min/ or the impact parameter b. Coulomb ionization, ion trajectory, scaling laws, double differential cross sections, and K-X-rays information is extracted from the experiment. The dependence of delta-ray emission on the united charge number Z /SUB u/ is discussed. Asymmetric collision systems with Z x alpha approx. = 1 (delta ray spectrum from Pb→Sn collisions) are studied. Finally, very heavy collisions, such as 208 Pb + 208 Pb collisions at bombarding energy fas below the Coulomb barrier are touched upon

  14. precise delta extraction scheme for reprogramming of wireless

    African Journals Online (AJOL)


    Keywords- reprogramming; operating system, wireless sensor network, Delta. 1. INTRODUCTION ... It entails the transmission of only modified modules that are then ... higher power consumption and slow system execution are drawbacks ...

  15. Pattern of Complicated Unsafe Abortions in Niger Delta University ...

    African Journals Online (AJOL)

    Alasia Datonye

    of cases of complicated unsafe abortion managed at the. Niger Delta University ... previous termination of pregnancy and 87.3% of the patients had ... and outcome were obtained. ... life-threatening complications, post- abortion family planning.

  16. DEltas, vulnerability and Climate Change: Migration and Adaptation ...

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

    Hutton C.W.

    Stakeholder Dialogue, London, June 19th, 2014. DEltas, vulnerability and Climate. Change: Migration and Adaptation. (DECCMA). Stakeholder Dialogue. Radisson Blu Edwardian Grafton Hotel, London, UK. June 19th, 2014 ...

  17. Ecohealth Approach to Flood Recession Farming in Okavango Delta ...

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

    In the Okavango Delta, Botswana, flood-recession farming (molapu) is a lucrative but ... Moreover, some practices involved in molapu farming may pose a threat to the ... Linking research to urban planning at the ICLEI World Congress 2018.

  18. What are Pregnant Women in a Rural Niger Delta Community's ...

    African Journals Online (AJOL)


    Buchanan House, Glasgow Caledonian University Email: Caroline. ... exploratory qualitative study was carried out to identify pregnant women in a rural Niger Delta community's perceptions of ..... sometimes you stay for the whole day.

  19. Inventory Management in Delta Allied Wire Industries Limited Asaba ...

    African Journals Online (AJOL)

    A good inventory system reduces production cost and consequently increases profit. Optimum management of inventory in the Delta – Allied Wire Industries ... under review and customers' handling processes equally studied for improvement.

  20. Nucleon and delta masses in twisted mass chiral perturbation theory

    International Nuclear Information System (INIS)

    Walker-Loud, Andre; Wu, Jackson M.S.


    We calculate the masses of the nucleons and deltas in twisted mass heavy baryon chiral perturbation theory. We work to quadratic order in a power counting scheme in which we treat the lattice spacing, a, and the quark masses, m q , to be of the same order. We give expressions for the mass and the mass splitting of the nucleons and deltas both in and away from the isospin limit. We give an argument using the chiral Lagrangian treatment that, in the strong isospin limit, the nucleons remain degenerate and the delta multiplet breaks into two degenerate pairs to all orders in chiral perturbation theory. We show that the mass splitting between the degenerate pairs of the deltas first appears at quadratic order in the lattice spacing. We discuss the subtleties in the effective chiral theory that arise from the inclusion of isospin breaking

  1. Restoration of Delta Streams: A Case History and Conceptual Model

    National Research Council Canada - National Science Library

    Killgore, K. J; Hoover, Jan J; Murphy, Catherine E; Parrish, Kent D; Johnson, David R; Myers, Karen F


    .... Low water, excessive sedimentation in smaller delta streams, and the accumulation of pesticides such as DDT are the consequences of these anthropogenic disturbances resulting in dominance of tolerant fish species...

  2. LiDAR data for the Delta Area of California (United States)

    California Natural Resource Agency — LiDAR data for the Delta Area of California from the California Department of Water Resources. Bare earth grids from LiDAR.This data is in ESRI Grid format with 2...

  3. Environmental Risk Profiling of the Volta Delta, Ghana (United States)

    Nyarko, B. K.; Appeaning-Addo, K.; Amisigo, B.


    Volta Delta communities find it difficult to absorb or bear risk at different levels, because of the physical and economic impacts of environmental hazards. In this regards various agencies and organizations have in recent years launched initiatives to measure and identify risk areas with a set of indicators and indices. The theory underpinning this study is concepts of Modern Portfolio Theory (MPT). The Cox proportional hazards regression model will be used as the model for the risk profile. Finding the optimal level of environmental risk for activities in the Volta Delta considering the risk required, risk capacity and risk tolerance. Using data from different sources, an environmental risk profile was developed for the Volta Delta. The result indicates that risks are distributed across the Delta. However, areas that have government interventions, such as sea defense system and irrigation facilities have less threat. In addition wealthy areas do effectively reduce the threat of any form of disaster.

  4. Sedimentation patterns in floodplains of the Mekong Delta - Vietnam (United States)

    Van Manh, Nguyen; Merz, Bruno; Viet Dung, Nguyen; Apel, Heiko


    Quantification of floodplain sedimentation during the flood season in the Mekong Delta (MD) plays a very important role in the assessment of flood deposits for a sustainable agro-economic development. Recent studies on floodplain sedimentation in the region are restricted to small pilot sites because of the large extend of the Delta, and the complex channel. This research aims at a quantification of the sediment deposition in floodplains of the whole Mekong Delta, and to access the impacts of the upstream basin development on the sedimentation in the Delta quantitatively. To achieve this, a suspended sediment transport model is developed based on the quasi-2D hydrodynamic model of the whole Mekong Delta developed by Dung et al. (2011). The model is calibrated and validated using observed data derived from several sediment measurement campaigns in channel networks and floodplains. Measured sediment data and hydrodynamic model quantify the spatio-temporal variability of sediment depositions in different spatial units: individual dyke compartments, and the sub-regions Plain of Reeds, Long Xuyen Quadrangle and the area between Tien River and Hau River. It is shown that the distribution of sediment deposition over the delta is highly depended on the flood magnitude, that in turn drives the operation policy of flood control systems in floodplains of the Mekong Delta. Thus, the sedimentation distribution is influenced by the protection level of the dyke systems in place and the distance to the Tien River and Hau River, the main branches of the Mekong in the Delta. This corroborates the main findings derived from data analysis obtained from a small scale test site by Hung et al, (2011, 2012a). Moreover, the results obtained here underlines the importance of the main channels for the sediment transport into the floodplains, and the deposition rate in floodplains is strongly driven by the intake locations and the distance from these to the main channels as well.

  5. Studies of Louisiana's Deltas and Wetlands using SAR (United States)

    Jones, C. E.


    Sustainable coastal environments exist in delicate balance between subsidence, erosion, and sea level rise on one hand and accretion of sediment and retention of decomposing organic matter on the other. In this talk we present results from a series of studies using an airborne L-band SAR (UAVSAR) to measure changing conditions in the Mississippi River Delta and coastal wetlands of Louisiana. Change within the Mississippi River delta (MRD), which is a highly engineered environment, is contrasted to those in the Wax Lake Delta, a small, naturally evolving delta located to the west of the current-day lobe of the MRD. The UAVSAR studies provide evidence that in the MRD subsidence and erosion related to human activities are increasing risk of flooding, submergence, and land loss. These are not seen in the Wax Lake Delta, where new land is forming. We evaluate geomorphic and hydrologic changes In the Wax Lake Delta and wetlands hydrologically connected to the Wax Lake Outlet canal that are apparent on the timescales of the UAVSAR data set, which consists of both near-yearly acquisitions (2009-2016) and several series of repeat acquisitions in 2015 and 2016 capturing conditions across a tidal cycle. Using the yearly data, we observe the evolution of subaqueous channels and crevasses in the delta and changes in distributary channels within the wetlands. We use water level change derived from InSAR applied to the rapid repeat data acquired during different stages of a tidal cycle to study the natural pattern of water flux within the delta and the coastal wetlands. The studies, results, and plans for future work will be presented. This work was carried out in part at the Jet Propulsion Laboratory, California Institute of Technology, under contracts with the California Dept. of Water Resources and with the National Aeronautics and Space Administration.

  6. The Great Diversion: Danube Delta under Human Control (Invited) (United States)

    Giosan, L.


    Many deltas around the world are suffering from sediment deficits that render them unstable to current and predicted rates of sea level rise. One solution proposed to alleviate the complete or partial drowning of such deltas is the use of river diversions to increase the quantity of sediment supplied to the delta plain to support marsh accretion. We examine the results of a half century old program of diversion in the Danube delta that led to the creation of an extensive diversion channel network akin in scope and size to a natural deltaic network. Danube’s importance as a shipping route increased after the Crimean War in the 1850s; the European Danube Commission was charged with maintaining the Sulina distributary as a shipping channel until 1940s. In the same period, several canals were dug to aid fishing in lakes and bring freshwater to brackish lagoons. After World War II, Communist authorities dramatically increased the number of canals for fishing, fish-farming and reed harvesting. New data on sedimentation rates and estimates of sediment fluxes suggest that the intensive canalization in the second half of the 20th Century led to increased sediment deposition that compensated the decreasing sediment discharge linked to damming within the internal fluvial part of the delta; however, the external marine delta has become increasingly sediment starved during the same interval. We emphasize the similarities and contrasts between the “human-controlled” and natural deltaic channel networks of the Danube delta and discuss the sustainability of the delta as a sediment budget problem within a sea level rise context.

  7. Governance of ‘long term delta planning’ in Bangladesh, Vietnam and the Netherlands

    NARCIS (Netherlands)

    Staveren, van M.F.


    The Deltas in Times of Climate Change Conference II, taking place in September 2014, Rotterdam, presented a suitable occasion to discuss both delta challenges and interesting approaches to how ‘delta dynamics’ are being dealt with worldwide.1 Delta dynamics include here both environmental (including

  8. Challenges and Approaches in River Delta Planning - Annexes to report on training workshop

    NARCIS (Netherlands)

    Wosten, J.H.M.; Douven, W.; Long Phi, H.; Fida Abdullah Khan, M.


    Programme, participants and all powerpoint presentations of the Delta Alliance Training Workshop: Challenges and approaches in river delta planning, sharing experiences from SE Asian Deltas and the Rhine-Meuse Delta. 22-26 October 2012, WACC, Vietnam National University, Ho Chi Minh City, Vietnam

  9. Natural levee evolution in the Rhine-Meuse delta, the Netherlands, during the first millennium CE

    NARCIS (Netherlands)

    Pierik, H.J.; Stouthamer, E.; Cohen, K.M.


    This paper presents reconstructions on natural levee development in the Rhine-Meuse delta, the Netherlands, during the first millennium CE, covering the full delta plain. It is the first study that performs this on a delta scale, which allows seeing the delta-wide trends on levee-forming controls

  10. An integrated assessment framework for land subsidence in delta cities

    Directory of Open Access Journals (Sweden)

    T. H. M. Bucx


    Full Text Available In many delta cities land subsidence exceeds absolute sea level rise up to a factor of ten by excessive groundwater extraction related to rapid urbanization and population growth. Without change, parts of Jakarta, Ho Chi Minh City, Bangkok and numerous other delta (and coastal cities will sink below sea level. Increased flooding and also other widespread impacts of land subsidence result already in damage of billions of dollars per year. In order to gain insight in the complex, multi-sectoral aspects of subsidence, to raise awareness and to support decision making on appropriate adaptation strategies and measures, an Integrated Assessment Framework (IAF for subsidence is introduced, illustrated by several (delta case studies. Based on that a list of 10 generic key issues and possible solutions is presented in order to further develop and support a (generic approach how to deal with subsidence in current and future subsidence-prone areas. For exchange of experiences and knowledge development.on subsidence in deltas the Delta Alliance, a knowledge network of deltas worldwide, can be supportive.

  11. Sand transport, shear stress, and the building of a delta (United States)

    Wagner, W.; Miller, K. L.; Hiatt, M. R.; Mohrig, D. C.


    River deltas distribute sediment to the coastal sea through a complex branching network of channels; however, the routing and storage of this sediment in and through the delta is poorly understood. We present results from field studies of the sediment and water transport through the branching Wax Lake Delta on the coast of Louisiana. Two channels studied, Main Pass and East Pass, maintain a near-equal total partitioning of flow and sediment. However, East Pass is narrower and has higher river velocities, lower tidal velocity fluctuations, less alluvial bed cover, and more sediment flux per unit width than Main Pass. We connect these differences to small differences in the geometry of the two channels and feedbacks between these differences. We link trends in measured sediment deposits to both measured and modeled shear velocities in Wax Lake Delta's channels and open water `islands' to understand how hydrologic processes shaped the sedimentary architecture of the delta. These connections define the sediment transport and deposition regimes in the WLD. We extend the results herein to suggest that the relationships between the available sediment and shear stress determines the basic planform of the Wax Lake Delta and cross-sectional geometries of its channels.

  12. The State of Bay–Delta Science 2016: An Introduction

    Directory of Open Access Journals (Sweden)

    Michael Healey


    Full Text Available doi: State of Bay–Delta Science 2016 (SBDS is a collection of papers that summarizes the scientific understanding of the Sacramento–San Joaquin Delta, emphasizing progress made during the past decade.It builds on the first SBDS edition (Healey et al. 2008. Paper topics for this edition address the most relevant scientific issues in the Delta identified by senior scientists and managers. The topical papers cover issues ranging from contaminants in the Delta to levee stability, and from Delta food webs to recent discoveries about salmon migration. These papers are written for a scientific audience. Two additional papers, one describing the challenges of managing water and ecosystems in the Delta and another that discusses policy implications of the recent scientific findings, are written for a general audience. The papers will be published in at least two issues of San Francisco Estuary and Watershed Science and will be available as a set electronically.

  13. Metallicism and pulsation: an analysis of the delta Delphini stars

    International Nuclear Information System (INIS)

    Kurtz, D.W.


    Fine abundance analyses of seven delta Delphini stars and one delta Scuti star relative to four comparison standards are presented. Five of the delta Del stars are shown to have abundances most similar to the evolved Am stars. It is argued that these abundances are different from the classical Am star and Ap star abundances and that similarities to the Ba II star abundances are coincidental. We suggest that the anomalous abundance delta Del stars are evolved metallic line stars on the basis of their abundances, position in the β, M/sub v/ plane, inferred rotational velocities, and perhaps their binary incidence. Some of the delta Del stars are delta Scuti pulsators. We argue that pulsation and metallicism are mutually exclusive among the classical Am stars but may coexist in other stars related to the classical Am stars. A preference for the diffusion hypothesis model for the metallic line stars is stated and supported and the implications of the coexistence of pulsation and diffusion are discussed

  14. N1303K (c.3909C>G) Mutation and Splicing: Implication of Its c.[744-33GATT(6); 869+11C>T] Complex Allele in CFTR Exon 7 Aberrant Splicing (United States)

    Farhat, Raëd; Puissesseau, Géraldine; El-Seedy, Ayman; Pasquet, Marie-Claude; Adolphe, Catherine; Corbani, Sandra; Megarbané, André; Kitzis, Alain; Ladeveze, Véronique


    Cystic Fibrosis is the most common recessive autosomal rare disease found in Caucasians. It is caused by mutations on the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) that encodes a protein located on the apical membrane of epithelial cells. c.3909C>G (p.Asn1303Lys, old nomenclature: N1303K) is one of the most common worldwide mutations. This mutation has been found at high frequencies in the Mediterranean countries with the highest frequency in the Lebanese population. Therefore, on the genetic level, we conducted a complete CFTR gene screening on c.3909C>G Lebanese patients. The complex allele c.[744-33GATT(6); 869+11C>T] was always associated with the c.3909C>G mutation in cis in the Lebanese population. In cellulo splicing studies, realized by hybrid minigene constructs, revealed no impact of the c.3909C>G mutation on the splicing process, whereas the associated complex allele induces minor exon skipping. PMID:26075213

  15. How yield relates to ash content, Delta 13C and Delta 18O in maize grown under different water regimes. (United States)

    Cabrera-Bosquet, Llorenç; Sánchez, Ciro; Araus, José Luis


    Stable isotopes have proved a valuable phenotyping tool when breeding for yield potential and drought adaptation; however, the cost and technical skills involved in isotope analysis limit its large-scale application in breeding programmes. This is particularly so for Delta(18)O despite the potential relevance of this trait in C(4) crops. The accumulation of minerals (measured as ash content) has been proposed as an inexpensive way to evaluate drought adaptation and yield in C(3) cereals, but little is known of the usefulness of this measure in C(4) cereals such as maize (Zea mays). The present study investigates how yield relates to ash content, Delta(13)C and Delta(18)O, and evaluates the use of ash content as an alternative or complementary criterion to stable isotopes in assessing yield potential and drought resistance in maize. A set of tropical maize hybrids developed by CIMMYT were subjected to different water availabilities, in order to induce water stress during the reproductive stages under field conditions. Ash content and Delta(13)C were determined in leaves and kernels. In addition, Delta(18)O was measured in kernels. Water regime significantly affected yield, ash content and stable isotopes. The results revealed a close relationship between ash content in leaves and the traits informing about plant water status. Ash content in kernels appeared to reflect differences in sink-source balance. Genotypic variation in grain yield was mainly explained by the combination of ash content and Delta(18)O, whilst Delta(13)C did not explain a significant percentage of such variation. Ash content in leaves and kernels proved a useful alternative or complementary criterion to Delta(18)O in kernels for assessing yield performance in maize grown under drought conditions.

  16. Population dynamics, delta vulnerability and environmental change: comparison of the Mekong, Ganges–Brahmaputra and Amazon delta regions


    Szabo, S.; Brondizio, E.; Renaud, F.G.; Hetrick, S.; Nicholls, R.; Matthews, Z.; Tessler, Z; Tejedor, A; Sebesvari, Z; Foufoula-Georgiou, E; da Costa, S; Dearing, J.A.


    Tropical delta regions are at risk of multiple threats including relative sea level rise and human alterations, making them more and more vulnerable to extreme floods, storms, surges, salinity intrusion, and other hazards which could also increase in magnitude and frequency with a changing climate. Given the environmental vulnerability of tropical deltas, understanding the interlinkages between population dynamics and environmental change in these regions is crucial for ensuring efficient pol...

  17. Mean proloculus size, delta super(13) C and delta super(18) O variations in recent benthic foraminifera from the west coast of India and their climatic implications

    Digital Repository Service at National Institute of Oceanography (India)

    Nigam, R.; Sarkar, A.

    The interrelationship between mean proloculus size (MPS), delta super(18) O and delta super(13) C vatiations in benthic foraminiferal species Rotalidium annectens and their relation with temperature (T) and salinity (S) have been studied in samples...

  18. Differential expression of gill Na+,K+-ATPase alpha- and beta-subunits, Na+,K+,2Cl- cotransporter and CFTR anion channel in juvenile anadromous and landlocked Atlantic salmon Salmo salar

    DEFF Research Database (Denmark)

    Nilsen, Tom O.; Ebbesson, Lars O. E.; Madsen, Steffen S.


    This study examines changes in gill Na(+),K(+)-ATPase (NKA) alpha- and beta-subunit isoforms, Na(+),K(+),2Cl(-) cotransporter (NKCC) and cystic fibrosis transmembrane conductance regulator (CFTR I and II) in anadromous and landlocked strains of Atlantic salmon during parr-smolt transformation, an...

  19. Perspectives on Bay–Delta Science and Policy

    Directory of Open Access Journals (Sweden)

    Michael Healey


    Full Text Available doi: State of Bay–Delta Science 2008 highlighted seven emerging perspectives on science and management of the Delta. These perspectives had important effects on policy and legislation concerning management of the Delta ecosystem and water exports. From the collection of papers that make up the State of Bay–Delta Science 2016, we derive another seven perspectives that augment those published in 2008. The new perspectives address nutrient and contaminant concentrations in Delta waters, the failure of the Delta food web to support native species, the role of multiple stressors in driving species toward extinction, and the emerging importance of extreme events in driving change in the ecosystem and the water supply. The scientific advances that underpin these new perspectives were made possible by new measurement and analytic tools. We briefly discuss some of these, including miniaturized acoustic fish tags, sensors for monitoring of water quality, analytic techniques for disaggregating complex contaminant mixtures, remote sensing to assess levee vulnerability, and multidimensional hydrodynamic modeling. Despite these new tools and scientific insights, species conservation objectives for the Delta are not being met. We believe that this lack of progress stems in part from the fact that science and policy do not incorporate sufficiently long-term perspectives. Looking forward half a century was central to the Delta Visioning process, but science and policy have not embraced this conceptual breadth. We are also concerned that protection and enhancement of the unique cultural, recreational, natural resource, and agricultural values of the Delta as an evolving place, as required by the Delta Reform Act, has received no critical study and analysis. Adopting wider and longer science and policy perspectives immediately encourages recognition of the need for evaluation, analysis, and public discourse on

  20. Lava delta deformation as a proxy for submarine slope instability (United States)

    Di Traglia, Federico; Nolesini, Teresa; Solari, Lorenzo; Ciampalini, Andrea; Frodella, William; Steri, Damiano; Allotta, Benedetto; Rindi, Andrea; Marini, Lorenzo; Monni, Niccolò; Galardi, Emanuele; Casagli, Nicola


    The instability of lava deltas is a recurrent phenomenon affecting volcanic islands, which can potentially cause secondary events such as littoral explosions (due to interactions between hot lava and seawater) and tsunamis. It has been shown that Interferometric Synthetic Aperture Radar (InSAR) is a powerful technique to forecast the collapse of newly emplaced lava deltas. This work goes further, demonstrating that the monitoring of lava deltas is a successful strategy by which to observe the long-term deformation of subaerial-submarine landslide systems on unstable volcanic flanks. In this paper, displacement measurements derived from Synthetic Aperture Radar (SAR) imagery were used to detect lava delta instability at Stromboli volcano (Italy). Recent flank eruptions (2002-2003, 2007 and 2014) affected the Sciara del Fuoco (SdF) depression, created a "stacked" lava delta, which overlies a pre-existing scar produced by a submarine-subaerial tsunamigenic landslide that occurred on 30 December 2002. Space-borne X-band COSMO-SkyMED (CSK) and C-band SENTINEL-1A (SNT) SAR data collected between February 2010 and October 2016 were processed using the SqueeSAR algorithm. The obtained ground displacement maps revealed the differential ground motion of the lava delta in both CSK and SNT datasets, identifying a stable area (characterized by less than 2 mm/y in both datasets) within the northern sector of the SdF and an unstable area (characterized by velocity fields on the order of 30 mm/y and 160 mm/y in the CSK and SNT datasets, respectively) in the central sector of the SdF. The slope stability of the offshore part of the SdF, as reconstructed based on a recently performed multibeam bathymetric survey, was evaluated using a 3D Limit Equilibrium Method (LEM). In all the simulations, Factor of Safety (F) values between 0.9 and 1.1 always characterized the submarine slope between the coastline and -250 m a.s.l. The critical surfaces for all the search volumes corresponded to

  1. Initial isotopic geochemistry ({delta} 18 O, {delta} D) of fluids from wells of the Los Humeros, Pue., geothermal field; Geoquimica isotopica ({delta} 18 O, {delta} D) inicial de fluidos de pozos del campo geotermico de Los Humeros, Pue.

    Energy Technology Data Exchange (ETDEWEB)

    Barragan Reyes, Rosa Maria; Arellano Gomez, Victor Manuel [Instituto de Investigaciones Electricas, Gerencia de Geotermia, Cuernavaca, Morelos (Mexico)]. E-mail:; Ramirez Montes, Miguel; Tovar Aguado, Rigoberto [Comision Federal de Electricidad, Gerencia de Proyectos Geotermoelectricos, Morelia, Michoacan (Mexico)


    Isotopic data ({delta} 18 O, {delta} D) from fluids from production wells at the Los Humeros, Pue., geothermal field were analyzed to investigate the possible origin of these fluids and the dominant processes of the reservoir at its initial state. According to pre-exploitation data, it is suggested the Los Humeros reservoir fluids are made of a mixture of meteoric water of very light isotopic composition (paleo-fluids) and andesitic water. The relationship {delta} D vs {delta} 18 O from pre-exploitation data indicates the produced fluids are composed of a mixture of (at least) two fluids with distinct isotopic compositions. At the more enriched end of the mixing relationship are the isotopic compositions of the wells H-23 and H-18 (located in the southern area of the field), while the lighter fluids were found in well H-16 (originally) and then in well H-16 (repaired). It was found that the liquid phases of deep wells are more enriched in {delta} 18 O while the shallow wells present lower values, suggesting a convection process at the initial state. Based on this isotopic profile, it is considered that even the production depths of the wells H-1, H-12 and H-16 (repaired) are just about the same, but their respective isotopic compositions are quite different. The {delta} 18 O value for well H-16 (repaired) seems to be that of condensate steam, while the corresponding values for wells H-1 and H-12 fall within the value interval of the deep wells (H-23). This suggests wells H-1 and H-12 are collecting very deep fluids enriched in {delta} 18 O. These results could be useful in creating a conceptual model of the reservoir. [Spanish] Se analizaron datos isotopicos ({delta}18 O, {delta}D) de los fluidos de pozos productores del campo geotermico de Los Humeros, Pue., para investigar el posible origen de los fluidos asi como los procesos dominantes del yacimiento en su estado inicial. De acuerdo con datos previos a la explotacion, se plantea que los fluidos del yacimiento

  2. Stratigraphy and paleohydrology of delta channel deposits, Jezero crater, Mars (United States)

    Goudge, Timothy A.; Mohrig, David; Cardenas, Benjamin T.; Hughes, Cory M.; Fassett, Caleb I.


    The Jezero crater open-basin lake contains two well-exposed fluvial sedimentary deposits formed early in martian history. Here, we examine the geometry and architecture of the Jezero western delta fluvial stratigraphy using high-resolution orbital images and digital elevation models (DEMs). The goal of this analysis is to reconstruct the evolution of the delta and associated shoreline position. The delta outcrop contains three distinct classes of fluvial stratigraphy that we interpret, from oldest to youngest, as: (1) point bar strata deposited by repeated flood events in meandering channels; (2) inverted channel-filling deposits formed by avulsive distributary channels; and (3) a valley that incises the deposit. We use DEMs to quantify the geometry of the channel deposits and estimate flow depths of ∼7 m for the meandering channels and ∼2 m for the avulsive distributary channels. Using these estimates, we employ a novel approach for assessing paleohydrology of the formative channels in relative terms. This analysis indicates that the shift from meandering to avulsive distributary channels was associated with an approximately four-fold decrease in the water to sediment discharge ratio. We use observations of the fluvial stratigraphy and channel paleohydrology to propose a model for the evolution of the Jezero western delta. The delta stratigraphy records lake level rise and shoreline transgression associated with approximately continuous filling of the basin, followed by outlet breaching, and eventual erosion of the delta. Our results imply a martian surface environment during the period of delta formation that supplied sufficient surface runoff to fill the Jezero basin without major drops in lake level, but also with discrete flooding events at non-orbital (e.g., annual to decadal) timescales.

  3. Anadromous salmonids in the Delta: New science 2006–2016 (United States)

    Perry, Russell W.; Buchanan, Rebecca A.; Brandes, Patricia L.; Burau, Jon R.; Israel, Joshua A


    As juvenile salmon enter the Sacramento–SanJoaquin River Delta (“the Delta”) they disperse among its complex channel network where they are subject to channel-specific processes that affect their rate of migration, vulnerability to predation, feeding success, growth rates, and ultimately, survival. In the decades before 2006, tools available to quantify growth, dispersal, and survival of juvenile salmon in this complex channel network were limited.Fortunately, thanks to technological advances such as acoustic telemetry and chemical and structural otolith analysis, much has been learned over the past decade about the role of the Delta in the life cycle of juvenile salmon. Here, we review new science between 2006and 2016 that sheds light on how different life stages and runs of juvenile salmon grow, move, and survive in the complex channel network of the Delta. One of the most important advances during the past decade has been the widespread adoption of acoustic telemetry techniques. Use of telemetry has shed light on how survival varies among alternative migration routes and the proportion of fish that use each migration route. Chemical and structural analysis of otoliths has provided insights about when juveniles left their natal river and provided evidence of extended rearing in the brackish or saltwater regions of the Delta. New advancements in genetics now allow individuals captured by trawls to be assigned to specific runs. Detailed information about movement and survival in the Delta has spurred development of agent-based models of juvenile salmon that are coupled to hydrodynamic models. Although much has been learned, knowledge gaps remain about how very small juvenile salmon (fry and parr) use the Delta. Understanding how all life stages of juvenile salmon grow, rear, and survive in the Delta is critical for devising management strategies that support a diversity of life history strategies.

  4. Clinical applications of gamma delta T cells with multivalent immunity

    Directory of Open Access Journals (Sweden)

    Drew C Deniger


    Full Text Available Gamma delta T cells hold promise for adoptive immunotherapy because of their reactivity to bacteria, viruses, and tumors. However, these cells represent a small fraction (1-5% of the peripheral T-cell pool and require activation and propagation to achieve clinical benefit. Aminobisphosphonates specifically expand the Vgamma9Vdelta2 subset of gamma delta T cells and have been used in clinical trials of cancer where objective responses were detected. The Vgamma9Vdelta2 TCR heterodimer binds multiple ligands and results in a multivalent attack by a monoclonal T cell population. Alternatively, populations of gamma delta T cells with oligoclonal or polyclonal TCR repertoire could be infused for broad-range specificity. However, this goal has been restricted by a lack of applicable expansion protocols for non-Vgamma9Vdelta2 cells. Recent advances using immobilized antigens, agonistic monoclonal antibodies (mAbs, tumor-derived artificial antigen presenting cells (aAPC, or combinations of activating mAbs and aAPC have been successful in expanding gamma delta T cells with oligoclonal or polyclonal TCR repertoires. Immobilized MHC Class-I chain-related A was a stimulus for gamma delta T cells expressing TCRdelta1 isotypes, and plate-bound activating antibodies have expanded Vdelta1 and Vdelta2 cells ex vivo. Clinically-sufficient quantities of TCRdelta1, TCRdelta2, and TCRdelta1negTCRdelta2neg have been produced following co-culture on aAPC, and these subsets displayed differences in memory phenotype and reactivity to tumors in vitro and in vivo. Gamma delta T cells are also amenable to genetic modification as evidenced by introduction of alpha beta TCRs, chimeric antigen receptors (CARs, and drug-resistance genes. This represents a promising future for the clinical application of oligoclonal or polyclonal gamma delta T cells in autologous and allogeneic settings that builds on current trials testing the safety and efficacy of Vgamma9Vdelta2 T cells.

  5. Challenges and Approaches in Delta Planning and Management - Sharing experiences from SE Asian Deltas and the Rhine-Meuse Delta -Report on Regional Training Workshop

    NARCIS (Netherlands)

    Long Phi, H.; Fida Abdullah Khan, M.; Wosten, J.H.M.; Douven, W.


    The training workshop consisted of a balanced mix of lectures on specific delta topics, work on group assignments, group and plenary discussions, and group presentations. Due to high professional level of the participants the discussions often reached the level of a policy dialogue among equals

  6. Early detection of cystic fibrosis in newborns using radioimmunoanalysis of trypsin in drops of blood absorbed on filter paper. Final report for the period 1 July 1996 - 30 June 1997

    International Nuclear Information System (INIS)

    Menises, M.M.


    The objective was to establish the cut-off value for blood immunoreactive trypsin radioimmunoassay used in the screening program for cystic fibrosis. Ten thousand capillary blood samples were collected from newborns 48 hours after birth on Schleider and Schnell No.903 filter paper and screened for immunoreactive trypsin (IRT) using polyethylene glycol assisted double antibody radioimmunoassay. Samples with IRT values greater then 800 ng/ml were subjected to further molecular biological diagnosis by amplification of exons 10 and 11 of CFTR gene. The products were analysed for ΔF508 and G542X mutations by hybridization with specific allele probe and G551D and R553X mutations by restriction enzyme digestion and Southern Blot. One hundred and forty one patients showed IRT values of greater then 800 ng/ml. Five of them were homozygotes for mutation at and ΔF508 and one was heterozygote the disease (one allele was positive for ΔF508 and the other allele for G542X). Only one of them presented with meconium ileus and the rest were asymptomatic. None of them has value less than 1200ng/ml in the first week of life. Five heterozygote for mutation at ΔF508 was also detected using 800ng/ml as cut-off. Based on the above findings, the cut-off value is established at 1200ng/ml. This gives specificity and sensitivity of 100%. (author)

  7. Doubly truncated FosB isoform (Delta2DeltaFosB) induces osteosclerosis in transgenic mice and modulates expression and phosphorylation of Smads in osteoblasts independent of intrinsic AP-1 activity

    DEFF Research Database (Denmark)

    Sabatakos, George; Rowe, Glenn C; Kveiborg, Marie


    DeltaFosB and a further truncated isoform (Delta2DeltaFosB) that lacks known transactivation domains but, like DeltaFosB, induces increased expression of osteoblast marker genes. MATERIALS AND METHODS: To test Delta2DeltaFosB's ability to induce bone formation in vivo, we generated transgenic mice......6 expression. CONCLUSIONS: DeltaFosB's AP-1 transactivating function is not needed to induce increased bone formation, and Delta2DeltaFosB may act, at least in part, by increasing Smad1 expression, phosphorylation, and translocation to the nucleus....

  8. Preparing the Dutch delta for future droughts: model based support in the national Delta Programme (United States)

    ter Maat, Judith; Haasnoot, Marjolijn; van der Vat, Marnix; Hunink, Joachim; Prinsen, Geert; Visser, Martijn


    Keywords: uncertainty, policymaking, adaptive policies, fresh water management, droughts, Netherlands, Dutch Deltaprogramme, physically-based complex model, theory-motivated meta-model To prepare the Dutch Delta for future droughts and water scarcity, a nation-wide 4-year project, called Delta Programme, is established to assess impacts of climate scenarios and socio-economic developments and to explore policy options. The results should contribute to a national adaptive plan that is able to adapt to future uncertain conditions, if necessary. For this purpose, we followed a model-based step-wise approach, wherein both physically-based complex models and theory-motivated meta-models were used. First step (2010-2011) was to make a quantitative problem description. This involved a sensitivity analysis of the water system for drought situations under current and future conditions. The comprehensive Dutch national hydrological instrument was used for this purpose and further developed. Secondly (2011-2012) our main focus was on making an inventory of potential actions together with stakeholders. We assessed efficacy, sell-by date of actions, and reassessed vulnerabilities and opportunities for the future water supply system if actions were (not) taken. A rapid assessment meta-model was made based on the complex model. The effects of all potential measures were included in the tool. Thirdly (2012-2013), with support of the rapid assessment model, we assessed the efficacy of policy actions over time for an ensemble of possible futures including sea level rise and climate and land use change. Last step (2013-2014) involves the selection of preferred actions from a set of promising actions that meet the defined objectives. These actions are all modeled and evaluated using the complex model. The outcome of the process will be an adaptive management plan. The adaptive plan describes a set of preferred policy pathways - sequences of policy actions - to achieve targets under

  9. Hydrology and morphology of two river mouth regions (temperate Vistula Delta and subtropical Red River Delta

    Directory of Open Access Journals (Sweden)

    Zbigniew Pruszak


    Full Text Available The paper presents a comparative analysis of two different river mouths from two different geographical zones (subtropical and temperate climatic regions. One is the multi-branch and multi-spit mouth of the Red River on the Gulf of Tonkin (Vietnam, the other is the smaller delta of the river Vistula on a bay of the Baltic Sea (Poland. The analysis focuses on the similarities and differences in the hydrodynamics between these estuaries and the adjacent coastal zones, the features of sediment transport, and the long-term morphodynamics of the river outlets. Salinity and water level are also discussed, the latter also in the context of the anticipated global effect of accelerated sea level rise. The analysis shows that the climatic and environmental conditions associated with geographical zones give rise to fundamental differences in the generation and dynamic evolution of the river mouths.

  10. Community structure of spiders in coastal habitats of a Mediterranean delta region (Nestos Delta, NE Greece

    Directory of Open Access Journals (Sweden)

    S. Buchholz


    Full Text Available (pp 101-115Habitat zonation and ecology of spider assemblages have been poorly studied in Mediterranean ecosystems. A first analysis of spider assemblages in coastal habitats in the east Mediterranean area is presented. The study area is the 250 km² Nestos Delta, located in East Macedonia in the North-East of Greece. Spiders were caught in pitfall traps at 17 sites from the beginning of April to the end of June 2004. Nonparametric estimators were used to determine species richness and alpha diversity. Ordination analysis (redundancy analysis indicated four clearly separable spider species groups (salt meadows, dunes, mea-dows and floodplain forests, along a soil salinity and moisture gradient. Based on these results we discuss the habitat preferences of these spiders and include the first ecological data on several species.

  11. Geochronology of priority pollutants in sedimentation zones of the Volga and Danube delta in comparison with the Rhine delta

    International Nuclear Information System (INIS)

    Winkels, H.J.; Kroonenberg, S.B.; Lychagin, M.Y.; Marin, G.; Rusakov, G.V.; Kasimov, N.S.


    Six sediment cores were taken in sedimentation zones of the Volga river (located in the southern part of the Russian Federation) and, additionally, 6 sediment cores were taken in several lakes (sedimentation zones) in the central and western part of the Danube delta in Romania. Priority pollutants (8 metals, 7 polychlorinated biphenyls and 10 polycyclic aromatic hydrocarbons) were determined in all samples of all cores. Present-day and historical levels of pollutants since the late 1930s were established through the use of radionuclide time tracers ( 137 Cs, 134 Cs). For the persistent metals and polycyclic aromatic hydrocarbons, trends in the concentration profiles during the last 5 decades are described. Low and hardly changing concentrations of As, Cu, Zn and all studied PAHs were observed during the last five decades in the sediments of the Volga river. Recently deposited sediments show slightly increasing levels for the heavy metals Zn and Cr and As in the Volga delta. For the studied metals and PAHs, maximum concentrations were found around 1987 in the sediments of the Danube delta. Sediments deposited around 1940 and recently deposited sediments in the Danube delta showed lower pollutant levels. If the contents of heavy metals, PAHs and PCBs in the aquatic sediments in the deltas of the rivers Rhine, Danube and Volga are compared, it is clear that the Volga delta is and was the cleanest delta during the last 5 decades. Nowadays the contents of heavy metals (except Cu and Ni), PAHs and PCBs in the aquatic sediments of the river Rhine are still highest compared to the other two rivers. The recent load of heavy metals (except Cd and Zn) in the sediments of the river Danube is the highest compared to the other two rivers. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  12. The case for selection at CCR5-Delta32.

    Directory of Open Access Journals (Sweden)


    Full Text Available The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Delta32 allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Delta32 arose within the past 1,000 y and rose to its present high frequency (5%-14% in Europe as a result of strong positive selection, perhaps by such selective agents as the bubonic plague or smallpox during the Middle Ages. This hypothesis was based on several lines of evidence, including the absence of the allele outside of Europe and long-range linkage disequilibrium at the locus. We reevaluated this evidence with the benefit of much denser genetic maps and extensive control data. We find that the pattern of genetic variation at CCR5-Delta32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Delta32 allele is likely to have arisen more than 5,000 y ago. While such results can not rule out the possibility that some selection may have occurred at C-C chemokine receptor 5 (CCR5, they imply that the pattern of genetic variation seen atCCR5-Delta32 is consistent with neutral evolution. More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome.

  13. Delta Cafés (Portugal: Sustainable Business Development

    Directory of Open Access Journals (Sweden)

    Olgierd Swiatkiewicz


    Full Text Available In the case study of Delta Cafés we discuss the sustainable development of the Portuguese company and brand over the 55 years of their existence. Delta Cafés has already been analyzed in terms of marketing activity, social responsibility, management control systems, etc. In this paper, we refer to these studies, and we reach the sources, i.e. the information provided by the Delta Cafés itself. Due to the nature of the coffee market and the use of case study methodology, we start the presentation of this case from a broader context, describing the coffee market in the world and characterizing the coffee market in Portugal as well. Then we present the history of the development of the company and the brand Delta Cafés. The paper ends with concluding remarks in which we discuss the issues of social and environmental responsibility in the light of the development of Delta Cafés business and brand strategies. 

  14. The case for selection at CCR5-Delta32.

    Directory of Open Access Journals (Sweden)

    Pardis C Sabeti


    Full Text Available The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Delta32 allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Delta32 arose within the past 1,000 y and rose to its present high frequency (5%-14% in Europe as a result of strong positive selection, perhaps by such selective agents as the bubonic plague or smallpox during the Middle Ages. This hypothesis was based on several lines of evidence, including the absence of the allele outside of Europe and long-range linkage disequilibrium at the locus. We reevaluated this evidence with the benefit of much denser genetic maps and extensive control data. We find that the pattern of genetic variation at CCR5-Delta32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Delta32 allele is likely to have arisen more than 5,000 y ago. While such results can not rule out the possibility that some selection may have occurred at C-C chemokine receptor 5 (CCR5, they imply that the pattern of genetic variation seen at CCR5-Delta32 is consistent with neutral evolution. More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome.

  15. Detection of cystic fibrosis transmembrane conductance regulator ΔF508 gene mutation using a paper-based nucleic acid hybridization assay and a smartphone camera. (United States)

    Malhotra, Karan; Noor, M Omair; Krull, Ulrich J


    Diagnostic technology that makes use of paper platforms in conjunction with the ubiquitous availability of digital cameras in cellular telephones and personal assistive devices offers opportunities for development of bioassays that are cost effective and widely distributed. Assays that operate effectively in aqueous solution require further development for implementation in paper substrates, overcoming issues associated with surface interactions on a matrix that offers a large surface-to-volume ratio and constraints on convective mixing. This report presents and compares two related methods for determination of oligonucleotides that serve as indicators of cystic fibrosis, differentiating between the normal wild-type sequence, and a mutant-type sequence that has a 3-base replacement. The transduction strategy operates by selective hybridization of oligonucleotide probes that are conjugated to fluorescent quantum dots, where hybridization of target sequences causes a molecular fluorophore to approach the quantum dot and become emissive through fluorescence resonance energy transfer. Detection can rely on hybridization of a target that is labelled with Cy3 fluorophore, or in the presence of an unlabelled target when a sandwich assay format is implemented with a labelled reporter oligonucleotide. Selectivity to determine the presence of mismatched sequences involves appropriate selection of nucleotide sequences to set melt temperatures, in conjunction with control of stringency conditions using formamide as a chaotrope. It was determined that both direct and sandwich assays on paper substrates are able to distinguish between wild-type and mutant-type samples.

  16. Oxygen Nonstoichiometry and Defect Chemistry Modeling of Ce0.8Pr0.2O2-delta

    DEFF Research Database (Denmark)

    Chatzichristodoulou, Christodoulos; Hendriksen, Peter Vang


    (DeltaHPrexc=aHdelta) and a completely random distribution of defects (referred to as “delta-linear”), or a “generalized delta-linear” solution model, where the excess Gibbs energy change in the reduction reaction of the dopant linearly varies with delta (DeltaGPrexc=aGdelta). A comparison of the partial...

  17. Flipped SU(5) predicts {delta}T/T

    Energy Technology Data Exchange (ETDEWEB)

    Kyae, Bumseok [School of Physics, Korea Institute for Advanced Study, 207-43, Cheongnyangni-Dong, Dongdaemun-Gu, Seoul 130-722 (Korea, Republic of)]. E-mail:; Shafi, Qaisar [Bartol Research Institute, Department of Physics and Astronomy, University of Delaware, Newark, DE 19716 (United States)]. E-mail:


    We discuss hybrid inflation in supersymmetric flipped SU(5) model such that the cosmic microwave anisotropy {delta}T/T is essentially proportional to (M/M{sub P}){sup 2}, where M denotes the symmetry breaking scale and M{sub P} (=2.4x10{sup 18} GeV) is the reduced Planck mass. The magnitude of M determined from {delta}T/T measurements can be consistent with the value inferred from the evolution of SU(3) and SU(2) gauge couplings. In other words, one could state that flipped SU(5) predicts (more precisely 'postdicts') {delta}T/T. The scalar spectral index n{sub s}=0.993+/-0.007, the scalar to tensor ratio satisfies r-bar 10{sup -6}, while dn{sub s}/dlnk-bar 4x10{sup -4}.

  18. Fracture Analyses of Cracked Delta Eye Plates in Ship Towing (United States)

    Huang, Xiangbing; Huang, Xingling; Sun, Jizheng


    Based on fracture mechanics, a safety analysis approach is proposed for cracked delta eye plates in ship towing. The static analysis model is presented when the delta eye plate is in service, and the fracture criterion is introduced on basis of stress intensity factor, which is estimated with domain integral method. Subsequently, three-dimensional finite element analyses are carried out to obtain the effective stress intensity factors, and a case is studied to demonstrate the reasonability of the approach. The results show that the classical strength theory is not applicable to evaluate the cracked plate while fracture mechanics can solve the problem very well, and the load level, which a delta eye plate can carry on, decreases evidently when it is damaged.

  19. Implementation of an ESA delta-DOR capability (United States)

    James, Nick; Abello, Ricard; Lanucara, Marco; Mercolino, Mattia; Maddè, Roberto


    This paper describes the implementation of delta-DOR (delta-differential one-way ranging) receivers within the ESA Deep Space ground station network. Delta-DOR provides very accurate plane-of-sky measurements of spacecraft position which complement existing line-of-sight ranging and Doppler measurements. We discuss how this technique has been adapted and implemented at the two ESA deep-space ground stations using existing equipment and infrastructure. These new capabilities were added by writing new software modules for the standard ESA digital receiver (the intermediate frequency modem system—IFMS). With these upgrades the receiver has the ability to record accurately timetagged signals from up to eight IF sub-channels. These sub-channels can have bandwidths of 50 kHz-2 MHz with a sample quantization of 1-16 bits per component. The IF samples are stored locally for subsequent retrieval over a WAN by the correlator facility at ESOC.

  20. Parametrization of the. delta. residue function. [Complex functions

    Energy Technology Data Exchange (ETDEWEB)

    Vasan, S S [Carnegie-Mellon Univ., Pittsburgh, Pa. (USA). Dept. of Physics


    The complex residues at the and poles in the relevant partial-wave amplitudes provide information on the behaviour of the Regge residue function in the resonance region u>0. Attempts to incorporate this information in parametrizations of the residue by functions that are real on the real u-axis result in residues which have unsatisfactory behaviour in the region u<1GeV/sup 2/. The choice of complex functions for the trajectory and residue removes this undesirable feature and provides a better representation of the residue in the resonance region, suggesting that complex parametrizations would be better suited to Regge analyses of near-backward scattering.

  1. Effects of external influences in subsonic delta wing vortices (United States)

    Washburn, Anthony E.


    An experimental investigation was conducted to examine inconsistencies in reported studies for the vortical flow over highly-swept delta wings. A 76-deg swept delta wing was tested in three facilities with open and closed test sections and different model-support systems. The results obtained include surface oil-flow patterns, off-body laser-light-sheet flow visualization, and aerodynamic load measurements. Parameters such as the wall boundaries and model-support systems can drastically alter the loads. The effect of a high level of free-stream turbulence on the delta-wing flowfield was also examined and found to be significant. The increase in free-stream turbulence caused boundary-layer transition, unsteadiness in the vortex core positions, and altered the loads and moments.

  2. [Transport characteristics of air pollutants over the Yangtze Delta]. (United States)

    Wang, Yan; Chai, Fa-He; Wang, Yong-Hong; Liu, Ming


    Meteorological field of January, April, July and October in 2004 was obtained by running MM5 with NCEP datasets. Then we used HYSPLIT 4.8 model to calculate the backward and forward trajectories of representative cities. Distributions of trajectories and the affected areas vary with seasons. Transport current affecting Yangtze River Delta is mainly from Mongolia, North China or Northeast region, via Yellow Sea area, Shandong, Jiangsu province or Shanghai. Another important transport path is current from southwest because of the Southwest monsoon. A movement of East Asia monsoon plays an important part in the mesoscale transport of pollutants in Yangtze Delta. Winter monsoon is a main mechanism which moves the air pollutants in Yangtze Delta to South China and West Pacific ocean. Another important transport system is the subtropical anticyclone over the western Pacific Ocean which controls the east coast of our country in spring and summer. This circulation system mainly affects the inland area of our country.

  3. Dendroclimatology of the Slave River Delta, Northwest Territories, Canada (United States)

    Jarvis, S.; Buhay, W. M.; Blair, D.; Tardif, J.; Bailey, D.


    It is well documented that changing hydrological conditions impact delta ecosystems. Such changes can also affect local inhabitants who have historical connections to the area and its resources. During the summer of 2003 a multifaceted paleo-environmental project was initiated to reconstruct the frequencies of floods and droughts in the Slave River Delta (SRD), Northwest Territories, Canada. The project goal is to forecast future hydrological and ecological conditions in the SRD in light of anticipated climate change and increasing demand on water resources. With the intent of expanding the climate history of the SRD, this particular aspect of the project will employ white spruce tree-ring chronologies constructed from six sites visited within the delta. Work is currently in progress to build a master chronology estimated to span over 300 years. In addition, a climate model for the SRD is also being developed and will be highlighted.

  4. Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment.

    LENUS (Irish Health Repository)

    Rogan, Mark P


    Recent advances in basic science have greatly expanded our understanding of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR), the chloride and bicarbonate channel that is encoded by the gene, which is mutated in patients with CF. We review the structure, function, biosynthetic processing, and intracellular trafficking of CFTR and discuss the five classes of mutations and their impact on the CF phenotype. The therapeutic discussion is focused on the significant progress toward CFTR mutation-specific therapies. We review the results of encouraging clinical trials examining orally administered therapeutics, including agents that promote read-through of class I mutations (premature termination codons); correctors, which overcome the CFTR misfolding that characterizes the common class II mutation F508del; and potentiators, which enhance the function of class III or IV mutated CFTR at the plasma membrane. Long-term outcomes from successful mutation-specific treatments could finally answer the question that has been lingering since and even before the CFTR gene discovery: Will therapies that specifically restore CFTR-mediated chloride secretion slow or arrest the deleterious cascade of events leading to chronic infection, bronchiectasis, and end-stage lung disease?

  5. Dynamic controls on shallow clinoform geometry: Mekong Delta, Vietnam (United States)

    Eidam, E. F.; Nittrouer, C. A.; Ogston, A. S.; DeMaster, D. J.; Liu, J. P.; Nguyen, T. T.; Nguyen, T. N.


    Compound deltas, composed of a subaerial delta plain and subaqueous clinoform, are common termini of large rivers. The transition between clinoform topset and foreset, or subaqueous rollover point, is located at 25-40-m water depth for many large tide-dominated deltas; this depth is controlled by removal of sediment from the topset by waves, currents, and gravity flows. However, the Mekong Delta, which has been classified as a mixed-energy system, has a relatively shallow subaqueous rollover at 4-6-m depth. This study evaluates dynamical measurements and seabed cores collected in Sep 2014 and Mar 2015 to understand processes of sediment transfer across the subaqueous delta, and evaluate possible linkages to geometry. During the southwest rainy monsoon (Sep 2014), high river discharge, landward return flow under the river plume, and regional circulation patterns facilitated limited sediment flux to the topset and foreset, and promoted alongshore flux to the northeast. Net observed sediment fluxes in Sep 2014 were landward, however, consistent with hypotheses about seasonal storage on the topset. During the northeast rainy monsoon, low river discharge and wind-driven currents facilitated intense landward and southwestward fluxes of sediment. In both seasons, bed shear velocities frequently exceeded the 0.01-0.02 m/s threshold of motion for sand, even in the absence of strong wave energy. Most sediment transport occurred at water depths 4 cm/yr at energy-limited, and thus rollover depths cannot be predicted solely by bed-stress distributions. In systems like the subaqueous Mekong Delta, direction of transport may have a key impact on morphology.

  6. Structure of the [delta]-opioid receptor bound to naltrindole

    Energy Technology Data Exchange (ETDEWEB)

    Granier, Sébastien; Manglik, Aashish; Kruse, Andrew C.; Kobilka, Tong Sun; Thian, Foon Sun; Weis, William I.; Kobilka, Brian K. (Stanford-MED)


    The opioid receptor family comprises three members, the {mu}-, {delta}- and {kappa}-opioid receptors, which respond to classical opioid alkaloids such as morphine and heroin as well as to endogenous peptide ligands like endorphins. They belong to the G-protein-coupled receptor (GPCR) superfamily, and are excellent therapeutic targets for pain control. The {delta}-opioid receptor ({delta}-OR) has a role in analgesia, as well as in other neurological functions that remain poorly understood. The structures of the {mu}-OR and {kappa}-OR have recently been solved. Here we report the crystal structure of the mouse {delta}-OR, bound to the subtype-selective antagonist naltrindole. Together with the structures of the {mu}-OR and {kappa}-OR, the {delta}-OR structure provides insights into conserved elements of opioid ligand recognition while also revealing structural features associated with ligand-subtype selectivity. The binding pocket of opioid receptors can be divided into two distinct regions. Whereas the lower part of this pocket is highly conserved among opioid receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the 'message-address' model of opioid receptor pharmacology, in which distinct 'message' (efficacy) and 'address' (selectivity) determinants are contained within a single ligand. Comparison of the address region of the {delta}-OR with other GPCRs reveals that this structural organization may be a more general phenomenon, extending to other GPCR families as well.

  7. Salinity Impacts on Agriculture and Groundwater in Delta Regions (United States)

    Clarke, D.; Salehin, M.; Jairuddin, M.; Saleh, A. F. M.; Rahman, M. M.; Parks, K. E.; Haque, M. A.; Lázár, A. N.; Payo, A.


    Delta regions are attractive for high intensity agriculture due to the availability of rich sedimentary soils and of fresh water. Many of the world's tropical deltas support high population densities which are reliant on irrigated agriculture. However environmental changes such as sea level rise, tidal inundation and reduced river flows have reduced the quantity and quality of water available for successful agriculture. Additionally, anthropogenic influences such as the over abstraction of ground water and the increased use of low quality water from river inlets has resulted in the accumulation of salts in the soils which diminishes crop productivity. Communities based in these regions are usually reliant on the same water for drinking and cooking because surface water is frequently contaminated by commercial and urban pollution. The expansion of shallow tube well systems for drinking water and agricultural use over the last few decades has resulted in mobilisation of salinity in the coastal and estuarine fringes. Sustainable development in delta regions is becoming constrained by water salinity. However salinity is often studied as an independent issue by specialists working in the fields of agriculture, community water supply and groundwater. The lack of interaction between these disciplines often results in corrective actions being applied to one sector without fully assessing the effects of these actions on other sectors. This paper describes a framework for indentifying the causes and impacts of salinity in delta regions based on the source-pathway-receptor framework. It uses examples and scenarios from the Ganges-Brahmaputra-Meghna delta in Bangladesh together with field measurements and observations made in vulnerable coastal communities. The paper demonstrates the importance of creating an holistic understanding of the development and management of water resources to reduce the impact of salinity in fresh water in delta regions.

  8. Stable isotope deltas: Tiny, yet robust signatures in nature (United States)

    Brand, Willi A.; Coplen, Tyler B.


    Although most of them are relatively small, stable isotope deltas of naturally occurring substances are robust and enable workers in anthropology, atmospheric sciences, biology, chemistry, environmental sciences, food and drug authentication, forensic science, geochemistry, geology, oceanography, and paleoclimatology to study a variety of topics. Two fundamental processes explain the stable isotope deltas measured in most terrestrial systems: isotopic fractionation and isotope mixing. Isotopic fractionation is the result of equilibrium or kinetic physicochemical processes that fractionate isotopes because of small differences in physical or chemical properties of molecular species having different isotopes. It is shown that the mixing of radioactive and stable isotope end members can be modelled to provide information on many natural processes, including 14C abundances in the modern atmosphere and the stable hydrogen and oxygen isotopic compositions of the oceans during glacial and interglacial times. The calculation of mixing fractions using isotope balance equations with isotope deltas can be substantially in error when substances with high concentrations of heavy isotopes (e.g. 13C, 2H, and 18O ) are mixed. In such cases, calculations using mole fractions are preferred as they produce accurate mixing fractions. Isotope deltas are dimensionless quantities. In the International System of Units (SI), these quantities have the unit 1 and the usual list of prefixes is not applicable. To overcome traditional limitations with expressing orders of magnitude differences in isotope deltas, we propose the term urey (symbol Ur), after Harold C. Urey, for the unit 1. In such a manner, an isotope delta value expressed traditionally as−25 per mil can be written as−25 mUr (or−2.5 cUr or−0.25 dUr; the use of any SI prefix is possible). Likewise, very small isotopic differences often expressed in per meg ‘units’ are easily included (e.g. either+0.015 ‰ or+15 per meg

  9. DNA repair synthesis in human fibroblasts requires DNA polymerase delta

    International Nuclear Information System (INIS)

    Nishida, C.; Reinhard, P.; Linn, S.


    When UV-irradiated cultured diploid human fibroblasts were permeabilized with Brij-58 then separated from soluble material by centrifugation, conservative DNA repair synthesis could be restored by a soluble factor obtained from the supernatant of similarly treated HeLa cells. Extensive purification of this factor yielded a 10.2 S, 220,000-dalton polypeptide with the DNA polymerase and 3'- to 5'-exonuclease activities reported for DNA polymerase delta II. Monoclonal antibody to KB cell DNA polymerase alpha, while binding to HeLa DNA polymerase alpha, did not bind to the HeLa DNA polymerase delta. Moreover, at micromolar concentrations N2-(p-n-butylphenyl)-2'-deoxyguanosine 5'-triphosphate (BuPdGTP) and 2-(p-n-butylanilino)-2'-deoxyadenosine 5'-triphosphate (BuAdATP) were potent inhibitors of DNA polymerase alpha, but did not inhibit the DNA polymerase delta. Neither purified DNA polymerase alpha nor beta could promote repair DNA synthesis in the permeabilized cells. Furthermore, under conditions which inhibited purified DNA polymerase alpha by greater than 90%, neither monoclonal antibodies to DNA polymerase alpha, BuPdGTP, nor BuAdATP was able to inhibit significantly the DNA repair synthesis mediated by the DNA polymerase delta. Thus, it appears that a major portion of DNA repair synthesis induced by UV irradiation might be catalyzed by DNA polymerase delta. When xeroderma pigmentosum human diploid fibroblasts were utilized, DNA repair synthesis dependent upon ultraviolet light could be restored by addition of both T4 endonuclease V and DNA polymerase delta, but not by addition of either one alone

  10. Nigeria. Petroleum, pollution and poverty in the Niger Delta

    International Nuclear Information System (INIS)


    The oil industry has operated in the Niger Delta in Nigeria for more than half a century - bringing almost no benefit to the people living there. Instead, widespread and unchecked human rights violations have pushed many people deeper into poverty and deprivation, fuelled conflict and led to a pervasive sense of powerlessness and frustration. This multidimensional crisis is driven by many factors - abuses committed by the security forces and militant groups, extensive pollution of land and water, corruption, serious corporate bad practice and government neglect. Nigeria: Petroleum, pollution and poverty in the Niger Delta focuses on one dimension of the crisis: the impact of pollution and environmental damage caused by the oil industry on the human rights of those living in the Niger Delta. Many people in the oil-producing areas of the delta rely on fisheries, subsistence agriculture and associated processing industries for their livelihood. Decades of pollution and environmental damage have resulted in violations of the right to an adequate standard of living - including food and water - violations of the right to gain a living through work, and violations of the right to health. The report examines who is responsible for this situation in a context where multinational oil companies have been operating for decades. It highlights how companies take advantage of the weak regulatory systems that characterize many poor countries, and how the poorest people are often the most vulnerable to exploitation. The people of the Niger Delta have seen their human rights undermined by oil companies that their government can not - or will not - hold to account. They have been systematically denied access to information about how oil exploration and production will affect them, and are repeatedly denied access to justice. The Niger Delta provides a stark case study of the lack of accountability of a government to the people, and of multinational companies' almost total lack of

  11. Delta progradation in Greenland driven by increasing glacial mass loss

    DEFF Research Database (Denmark)

    Bendixen, Mette; Iversen, Lars Lonsmann; Bjork, Anders Anker


    imagery. We find that delta progradation was driven by high freshwater runoff from the Greenland Ice Sheet coinciding with periods of open water. Progradation was controlled by the local initial environmental conditions (that is, accumulated air temperatures above 0 degrees C per year, freshwater runoff...... of erosion and accretion along the large deltas of the main rivers in the Arctic5-7. Our results improve the understanding of Arctic coastal evolution in a changing climate, and reveal the impacts on coastal areas of increasing ice mass loss and the associated freshwater runoff and lengthening of open-water...

  12. A divergent synthesis of the delta(13)-9-isofurans. (United States)

    Taber, Douglass F; Gu, Peiming; Li, Rui


    A stereodivergent total synthesis of the Delta(13)-9-isofurans has been developed. The four core substituted tetrahydrofurans were prepared by the Sharpless asymmetric epoxidation and Sharpless asymmetric dihydroxylation followed by cascade cyclization. The relative configuration at C-8 was inverted by oxidation followed by immediate L-Selectride reduction. The relative configuration of the C-15 diastereomers was assigned by (S)-Binol/LAH/EtOH reduction of the corresponding enone. This synthesis of the Delta(13)-9-isofurans will provide sufficient material for further investigation of their biological activity.

  13. Halotolerance of Methanobacterium thermoautotrophicum delta H and Marburg.


    Ciulla, R; Clougherty, C; Belay, N; Krishnan, S; Zhou, C; Byrd, D; Roberts, M F


    Methanobacterium thermoautotrophicum delta H and Marburg were adapted to grow in medium containing up to 0.65 M NaCl. From 0.01 to 0.5 M NaCl, there was a lag before cell growth which increased with increasing external NaCl. The effect of NaCl on methane production was not significant once the cells began to grow. Intracellular solutes were monitored by nuclear magnetic resonance (NMR) spectroscopy as a function of osmotic stress. In the delta H strain, the major intracellular small organic s...

  14. Changing Course - the Baird Team Solution: a Delta for All (United States)

    Nairn, R. B.


    The Changing Course Design competition was initiated to evaluate options for re-positioning the mouth of the Mississippi River and modifying the management of the Lower Mississippi River to support the 2017 Master Plan for the Louisiana coast. This paper will present the findings of one of the selected competitors: the Baird Team and their "Delta for All" approach. A key to success in the future management of the lower Mississippi River is the development of an integrated, holistic approach to management that recognizes the need to harness the full land/wetland building and restorative potential of the river at the same time as improving flood protection and navigation. Fundamentally the Baird solution recognized the underlying geomorphic challenges of the Delta: it receives three to four times less sediment from the Mississippi River than it did historically and sea level is rising two to three times faster than it did historically and is predicted to rise much faster in the future. The result will be a smaller delta in the future. Our approach seeks to harness as close to 100% of the land building potential of the river to make the smaller future delta as large as possible. This compares to the 2012 State Master Plan which would harness approximately 50% of the land-building potential. Our approach also recognizes that the further inland new distributary mouths and associated sub-deltas are located, the greater the delta building potential. Our approach builds with the river by creating and managing new river distributaries that are opened and closed every 50 years or so to build new sub-deltas within a defined sustainable delta footprint. By placing the last outlet somewhere in the vicinity of English Turn the lower Mississippi River would become a tidal channel. These two simple concepts of harnessing 100% of the river and placing the last outlet near English Turn result in immediate and significant benefits for flood protection and navigation. Through the

  15. Mazda kiintotyövaiheiden perustaminen : Delta Auto Oy


    Schreck, Ville


    Täyden palvelun autoliikeketju Delta Auto myy ja huoltaa Kia-, Mitsubishi- ja Mazda-merkkisiä autoja paikkakuntakohtaisesti kahdessakymmenessäviidessä toimipisteessä. Opinnäytetyön tarkoituksena oli tehdä toimiva ratkaisu Mazdan työvaiheiden sekä työpakettien myyntiin Automaster-ohjelmistoon. Työvaiheet sekä ohjeajat tulevat käyttöön kaikkiin Delta Auton toimipisteisiin ympäri Suomea. Työn lähdemateriaalin sain Inchcape Motor Finland Oy:ltä, joka toimii Suomessa Mazdan maahantuojana. Tarve tä...

  16. CMOS sigma-delta converters practical design guide

    CERN Document Server

    De la Rosa, Jose M


    A comprehensive overview of Sigma-Delta Analog-to-Digital Converters (ADCs) and a practical guide to their design in nano-scale CMOS for optimal performance. This book presents a systematic and comprehensive compilation of sigma-delta converter operating principles, the new advances in architectures and circuits, design methodologies and practical considerations - going from system-level specifications to silicon integration, packaging and measurements, with emphasis on nanometer CMOS implementation. The book emphasizes practical design issues - from high-level behavioural modelling i

  17. Measurement of $\\Delta^{++}$(1232) production in hadronic Z decays

    CERN Document Server

    Abreu, P; Adye, T; Agasi, E; Ajinenko, I; Aleksan, Roy; Alekseev, G D; Allport, P P; Almehed, S; Alvsvaag, S J; Amaldi, Ugo; Amato, S; Andreazza, A; Andrieux, M L; Antilogus, P; Anykeyev, V B; Apel, W D; Arnoud, Y; Åsman, B; Augustin, J E; Augustinus, A; Baillon, Paul; Bambade, P; Barão, F; Barate, R; Bardin, Dimitri Yuri; Barker, G J; Baroncelli, A; Bärring, O; Barrio, J A; Bartl, Walter; Bates, M J; Battaglia, Marco; Baubillier, M; Baudot, J; Becks, K H; Begalli, M; Beillière, P; Belokopytov, Yu A; Benvenuti, Alberto C; Berggren, M; Bertrand, D; Bianchi, F; Bigi, M; Bilenky, S M; Billoir, P; Bloch, D; Blume, M; Blyth, S; Bocci, V; Bolognese, T; Bonesini, M; Bonivento, W; Booth, P S L; Borisov, G; Bosio, C; Bosworth, S; Botner, O; Bouquet, B; Bourdarios, C; Bowcock, T J V; Bozzo, M; Branchini, P; Brand, K D; Brenke, T; Brenner, R A; Bricman, C; Brillault, L; Brown, R C A; Brückman, P; Brunet, J M; Bugge, L; Buran, T; Burgsmüller, T; Buschmann, P; Buys, A; Caccia, M; Calvi, M; Camacho-Rozas, A J; Camporesi, T; Canale, V; Canepa, M; Cankocak, K; Cao, F; Carena, F; Carrilho, P; Carroll, L; Caso, Carlo; Castillo-Gimenez, M V; Cattai, A; Cavallo, F R; Cerrito, L; Chabaud, V; Charpentier, P; Chaussard, L; Chauveau, J; Checchia, P; Chelkov, G A; Chierici, R; Chliapnikov, P V; Chochula, P; Chorowicz, V; Cindro, V; Collins, P; Contreras, J L; Contri, R; Cortina, E; Cosme, G; Cossutti, F; Crawley, H B; Crennell, D J; Crosetti, G; Cuevas-Maestro, J; Czellar, S; Dahl-Jensen, Erik; Dahm, J; D'Almagne, B; Dam, M; Damgaard, G; Daum, A; Dauncey, P D; Davenport, Martyn; Da Silva, W; Defoix, C; Della Ricca, G; Delpierre, P A; Demaria, N; De Angelis, A; De Boeck, H; de Boer, Wim; De Brabandere, S; De Clercq, C; La Vaissière, C de; De Lotto, B; De Min, A; De Paula, L S; De Saint-Jean, C; Dijkstra, H; Di Ciaccio, Lucia; Djama, F; Dolbeau, J; Dönszelmann, M; Doroba, K; Dracos, M; Drees, J; Drees, K A; Dris, M; Dufour, Y; Dupont, F; Edsall, D M; Ehret, R; Eigen, G; Ekelöf, T J C; Ekspong, Gösta; Elsing, M; Engel, J P; Ershaidat, N; Erzen, B; Espirito-Santo, M C; Falk, E; Fassouliotis, D; Feindt, Michael; Ferrer, A; Filippas-Tassos, A; Firestone, A; Fischer, P A; Föth, H; Fokitis, E; Fontanelli, F; Formenti, F; Franek, B J; Frenkiel, P; Fries, D E C; Frodesen, A G; Frühwirth, R; Fulda-Quenzer, F; Fuster, J A; Galloni, A; Gamba, D; Gandelman, M; García, C; García, J; Gaspar, C; Gasparini, U; Gavillet, P; Gazis, E N; Gelé, D; Gerber, J P; Gibbs, M; Gokieli, R; Golob, B; Gopal, Gian P; Gorn, L; Górski, M; Guz, Yu; Gracco, Valerio; Graziani, E; Grosdidier, G; Gunnarsson, P; Günther, M; Guy, J; Haedinger, U; Hahn, F; Hahn, M; Hahn, S; Hajduk, Z; Hallgren, A; Hamacher, K; Hao, W; Harris, F J; Hedberg, V; Henriques, R P; Hernández, J J; Herquet, P; Herr, H; Hessing, T L; Higón, E; Hilke, Hans Jürgen; Hill, T S; Holmgren, S O; Holt, P J; Holthuizen, D J; Houlden, M A; Hrubec, Josef; Huet, K; Hultqvist, K; Ioannou, P; Jackson, J N; Jacobsson, R; Jalocha, P; Janik, R; Jarlskog, G; Jarry, P; Jean-Marie, B; Johansson, E K; Jönsson, L B; Jönsson, P E; Joram, Christian; Juillot, P; Kaiser, M; Kapusta, F; Karlsson, M; Karvelas, E; Katsanevas, S; Katsoufis, E C; Keränen, R; Khomenko, B A; Khovanskii, N N; King, B J; Kjaer, N J; Klein, H; Klovning, A; Kluit, P M; Köhne, J H; Köne, B; Kokkinias, P; Koratzinos, M; Kostyukhin, V; Kourkoumelis, C; Kuznetsov, O; Kramer, P H; Krammer, Manfred; Kreuter, C; Królikowski, J; Kronkvist, I J; Krumshtein, Z; Krupinski, W; Kubinec, P; Kucewicz, W; Kurvinen, K L; Lacasta, C; Laktineh, I; Lamblot, S; Lamsa, J; Lanceri, L; Lane, D W; Langefeld, P; Lapin, V; Last, I; Laugier, J P; Lauhakangas, R; Leder, Gerhard; Ledroit, F; Lefébure, V; Legan, C K; Leitner, R; Lemoigne, Y; Lemonne, J; Lenzen, Georg; Lepeltier, V; Lesiak, T; Liko, D; Lindner, R; Lipniacka, A; Lippi, I; Lörstad, B; Lokajícek, M; Loken, J G; López, J M; López-Fernandez, A; López-Aguera, M A; Loukas, D; Lutz, P; Lyons, L; Maehlum, G; Maio, A; Malychev, V; Mandl, F; Marco, J; Maréchal, B; Margoni, M; Marin, J C; Mariotti, C; Markou, A; Maron, T; Martínez-Rivero, C; Martínez-Vidal, F; Martí i García, S; Matorras, F; Matteuzzi, C; Matthiae, Giorgio; Mazzucato, M; McCubbin, M L; McKay, R; McNulty, R; Medbo, J; Meroni, C; Meyer, W T; Michelotto, M; Migliore, E; Mirabito, L; Mitaroff, Winfried A; Mjörnmark, U; Moa, T; Møller, R; Mönig, K; Monge, M R; Morettini, P; Müller, H; Mundim, L M; Murray, W J; Muryn, B; Myatt, Gerald; Naraghi, F; Navarria, Francesco Luigi; Navas, S; Negri, P; Némécek, S; Neumann, W; Neumeister, N; Nicolaidou, R; Nielsen, B S; Nieuwenhuizen, M; Nikolaenko, V; Niss, P; Nomerotski, A; Normand, Ainsley; Oberschulte-Beckmann, W; Obraztsov, V F; Olshevskii, A G; Onofre, A; Orava, Risto; Österberg, K; Ouraou, A; Paganini, P; Paganoni, M; Pagès, P; Palka, H; Papadopoulou, T D; Pape, L; Parkes, C; Parodi, F; Passeri, A; Pegoraro, M; Pernegger, H; Pernicka, Manfred; Perrotta, A; Petridou, C; Petrolini, A; Phillips, H T; Piana, G; Pierre, F; Pimenta, M; Pindo, M; Plaszczynski, S; Podobrin, O; Pol, M E; Polok, G; Poropat, P; Pozdnyakov, V; Prest, M; Privitera, P; Pukhaeva, N; Pullia, Antonio; Radojicic, D; Ragazzi, S; Rahmani, H; Rames, J; Ratoff, P N; Read, A L; Reale, M; Rebecchi, P; Redaelli, N G; Regler, Meinhard; Reid, D; Renton, P B; Resvanis, L K; Richard, F; Richardson, J; Rídky, J; Rinaudo, G; Ripp, I; Romero, A; Roncagliolo, I; Ronchese, P; Roos, L; Rosenberg, E I; Rosso, E; Roudeau, Patrick; Rovelli, T; Rückstuhl, W; Ruhlmann-Kleider, V; Ruiz, A; Rybicki, K; Rybin, A; Saarikko, H; Sacquin, Yu; Sadovskii, A; Sajot, G; Salt, J; Sánchez, J; Sannino, M; Schneider, H; Schyns, M A E; Sciolla, G; Scuri, F; Seager, P; Sedykh, Yu; Segar, A M; Seitz, A; Sekulin, R L; Shellard, R C; Siccama, I; Siegrist, P; Simonetti, S; Simonetto, F; Sissakian, A N; Sitár, B; Skaali, T B; Smadja, G; Smirnova, O G; Smith, G R; Sosnowski, R; Souza-Santos, D; Spassoff, Tz; Spiriti, E; Sponholz, P; Squarcia, S; Stanescu, C; Stapnes, Steinar; Stavitski, I; Stepaniak, K; Stichelbaut, F; Stocchi, A; Strauss, J; Strub, R; Stugu, B; Szczekowski, M; Szeptycka, M; Tabarelli de Fatis, T; Tavernet, J P; Chikilev, O G; Tilquin, A; Timmermans, J; Tkatchev, L G; Todorov, T; Toet, D Z; Tomaradze, A G; Tomé, B; Tortora, L; Tranströmer, G; Treille, D; Trischuk, W; Tristram, G; Trombini, A; Troncon, C; Tsirou, A L; Turluer, M L; Tyapkin, I A; Tyndel, M; Tzamarias, S; Überschär, B; Ullaland, O; Uvarov, V; Valenti, G; Vallazza, E; Van der Velde, C; van Apeldoorn, G W; van Dam, P; Van Doninck, W K; Van Eldik, J; Vassilopoulos, N; Vegni, G; Ventura, L; Venus, W A; Verbeure, F; Verlato, M; Vertogradov, L S; Vilanova, D; Vincent, P; Vitale, L; Vlasov, E; Vodopyanov, A S; Vrba, V; Wahlen, H; Walck, C; Waldner, F; Weierstall, M; Weilhammer, Peter; Wetherell, Alan M; Wicke, D; Wickens, J H; Wielers, M; Wilkinson, G R; Williams, W S C; Winter, M; Witek, M; Woschnagg, K; Yip, K; Yushchenko, O P; Zach, F; Zacharatou-Jarlskog, C; Zaitsev, A; Zalewska-Bak, A; Zalewski, Piotr; Zavrtanik, D; Zevgolatakos, E; Zhigunov, V P; Zimin, N I; Zito, M; Zontar, D; Zuberi, R; Zucchelli, G C; Zumerle, G


    A measurement of the \\Delta^{++}(1232) inclusive production in hadronic decays of the Z at LEP is presented, based on 1.3 million hadronic events collected~ by the DELPHI~ detector in the 1994 LEP running~ period. The DELPHI ring imaging Cherenkov counters are used for identifying hadrons. The average \\Delta^{++}(1232) multiplicity per hadronic event is 0.079 \\pm 0.015 which is more than a factor of two below the JETSET, HERWIG and UCLA model predictions. It agrees with a recently proposed universal mass dependence of particle production rates in e^{+}e^- annihilations.

  18. Water and nitrogen conditions affect the relationships of Delta13C and Delta18O to gas exchange and growth in durum wheat. (United States)

    Cabrera-Bosquet, Llorenç; Molero, Gemma; Nogués, Salvador; Araus, José Luis


    Whereas the effects of water and nitrogen (N) on plant Delta(13)C have been reported previously, these factors have scarcely been studied for Delta(18)O. Here the combined effect of different water and N regimes on Delta(13)C, Delta(18)O, gas exchange, water-use efficiency (WUE), and growth of four genotypes of durum wheat [Triticum turgidum L. ssp. durum (Desf.) Husn.] cultured in pots was studied. Water and N supply significantly increased plant growth. However, a reduction in water supply did not lead to a significant decrease in gas exchange parameters, and consequently Delta(13)C was only slightly modified by water input. Conversely, N fertilizer significantly decreased Delta(13)C. On the other hand, water supply decreased Delta(18)O values, whereas N did not affect this parameter. Delta(18)O variation was mainly determined by the amount of transpired water throughout plant growth (T(cum)), whereas Delta(13)C variation was explained in part by a combination of leaf N and stomatal conductance (g(s)). Even though the four genotypes showed significant differences in cumulative transpiration rates and biomass, this was not translated into significant differences in Delta(18)O(s). However, genotypic differences in Delta(13)C were observed. Moreover, approximately 80% of the variation in biomass across growing conditions and genotypes was explained by a combination of both isotopes, with Delta(18)O alone accounting for approximately 50%. This illustrates the usefulness of combining Delta(18)O and Delta(13)C in order to assess differences in plant growth and total transpiration, and also to provide a time-integrated record of the photosynthetic and evaporative performance of the plant during the course of crop growth.

  19. Stimulation of accumbal GABAA receptors inhibits delta2-, but not delta1-, opioid receptor-mediated dopamine efflux in the nucleus accumbens of freely moving rats. (United States)

    Aono, Yuri; Kiguchi, Yuri; Watanabe, Yuriko; Waddington, John L; Saigusa, Tadashi


    The nucleus accumbens contains delta-opioid receptors that may reduce inhibitory neurotransmission. Reduction in GABA A receptor-mediated inhibition of accumbal dopamine release due to delta-opioid receptor activation should be suppressed by stimulating accumbal GABA A receptors. As delta-opioid receptors are divided into delta2- and delta1-opioid receptors, we analysed the effects of the GABA A receptor agonist muscimol on delta2- and delta1-opioid receptor-mediated accumbal dopamine efflux in freely moving rats using in vivo microdialysis. Drugs were administered intracerebrally through the dialysis probe. Doses of compounds indicate total amount administered (mol) during 25-50min infusions. The delta2-opioid receptor agonist deltorphin II (25.0nmol)- and delta1-opioid receptor agonist DPDPE (5.0nmol)-induced increases in dopamine efflux were inhibited by the delta2-opioid receptor antagonist naltriben (1.5nmol) and the delta1-opioid receptor antagonist BNTX (150.0pmol), respectively. Muscimol (250.0pmol) inhibited deltorphin II (25.0nmol)-induced dopamine efflux. The GABA A receptor antagonist bicuculline (50.0pmol), which failed to affect deltorphin II (25.0nmol)-induced dopamine efflux, counteracted the inhibitory effect of muscimol on deltorphin II-induced dopamine efflux. Neither muscimol (250.0pmol) nor bicuculline (50.0 and 500.0pmol) altered DPDPE (5.0nmol)-induced dopamine efflux. The present results show that reduction in accumbal GABA A receptor-mediated inhibition of dopaminergic activity is necessary to produce delta2-opioid receptor-induced increase in accumbal dopamine efflux. This study indicates that activation of delta2- but not delta1-opioid receptors on the cell bodies and/or terminals of accumbal GABAergic interneurons inhibits GABA release and, accordingly, decreases GABA A receptor-mediated inhibition of dopaminergic terminals, resulting in enhanced accumbal dopamine efflux. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Stable Isotope (delta OXYGEN-18, Delta Deuterium, Delta CARBON-13) Dendroclimatological Studies in the Waterloo Region of Southern Ontario, Canada, Between AD 1610 and 1990. (United States)

    Buhay, William Mark

    Oxygen (delta^{18} O), hydrogen (delta^2H) and carbon (delta^{13}C) isotopes were measured in wood cellulose from elm, white pine and maple trees that grew in southwestern Ontario, Canada. The measured oxygen and hydrogen isotopic data were used for model-based reconstructions of delta^{18}{O}_{meteoric water}, mean annual temperature (MAT) and relative humidity for a period, AD 1610 to 1880, that precedes instrumental records of climate. The carbon isotope measurements were compared with the Cellulose Model inferred climate data to reveal additional environmental information. Modifications made to the Cellulose Model focused on the dynamics of oxygen and hydrogen isotopic fractionation in plants during evapotranspiration and photosynthetic assimilation. For instance, kinetic fractionation of ^{18}O was found to be predictable from theoretical considerations of leaf energy balance and boundary layer dynamics. Kinetic fractionation during evapotranspiration is sensitive to the nature of the boundary layer, which is controlled by leaf size and morphology. Generally, plants with small segmented leaves have a lower component of turbidity in the leaf boundary layer, which results in higher kinetic fractionation values, than do plants having large simple leaves and more turbulent boundary layers. Kinetic ^2H enrichment in plant leaf water can also be rationalized in terms of leaf size and morphology when an apparent temperature-dependent isotope effect, acting in opposition to evaporative enrichment, is taken into account. Accounting for this temperature -dependent isotope effect helps to: (1) reconcile hydrogen kinetic fractionation inconsistencies for different leaves; (2) explain a temperature effect previously attributed to variable biochemical fractionation during cellulose synthesis, and; (3) verify hydrogen biochemical effects in plants. This improved characterization of the oxygen and hydrogen isotopic effects in plants, using the modified Cellulose Model, helped

  1. Polarized antiquark flavor asymmetry DELTA anti u(x)-DELTA anti d(x) and the pion cloud

    CERN Document Server

    Fries, R J; Weiss, C


    The flavor asymmetry of the unpolarized antiquark distributions in the proton, anti u(x)- anti d(x)0. Using a simple chiral linear sigma model as an example, we demonstrate that in the meson cloud picture a large positive DELTA anti u(x)-DELTA anti d(x) can be obtained from pi-sigma interference contributions. This calls into question previous estimates based on rho-meson contributions alone, and indicates how the results of the meson cloud picture may be reconciled with those of quark-based models. (orig.)

  2. Functional classification of mitochondrion-rich cells in euryhaline Mozambique tilapia (Oreochromis mossambicus) embryos, by means of triple immunofluorescence staining for Na+/K+-ATPase, Na +/K+/2Cl- cotransporter and CFTR anion channel (United States)

    Hiroi, J.; McCormick, S.D.; Ohtani-Kaneko, R.; Kaneko, T.


    Mozambique tilapia Oreochromis mossambicus embryos were transferred from freshwater to seawater and vice versa, and short-term changes in the localization of three major ion transport proteins, Na+/K +-ATPase, Na+/K+/2Cl- cotransporter (NKCC) and cystic fibrosis transmembrane conductance regulator (CFTR) were examined within mitochondrion-rich cells (MRCs) in the embryonic yolk-sac membrane. Triple-color immunofluorescence staining allowed us to classify MRCs into four types: type I, showing only basolateral Na+/K +-ATPase staining; type II, basolateral Na+/K +-ATPase and apical NKCC; type III, basolateral Na+/K +-ATPase and basolateral NKCC; type IV, basolateral Na +/K+-ATPase, basolateral NKCC and apical CFTR. In freshwater, type-I, type-II and type-III cells were observed. Following transfer from freshwater to seawater, type-IV cells appeared at 12 h and showed a remarkable increase in number between 24 h and 48 h, whereas type-III cells disappeared. When transferred from seawater back to freshwater, type-IV cells decreased and disappeared at 48 h, type-III cells increased, and type-II cells, which were not found in seawater, appeared at 12 h and increased in number thereafter. Type-I cells existed consistently irrespective of salinity changes. These results suggest that type I is an immature MRC, type II is a freshwater-type ion absorptive cell, type III is a dormant type-IV cell and/or an ion absorptive cell (with a different mechanism from type II), and type IV is a seawater-type ion secretory cell. The intracellular localization of the three ion transport proteins in type-IV cells is completely consistent with a widely accepted model for ion secretion by MRCs. A new model for ion absorption is proposed based on type-II cells possessing apical NKCC.

  3. 77 FR 61592 - Arkansas Electric Cooperative Corporation; Mississippi Delta Energy Agency; Clarksdale Public... (United States)


    ... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. EL12-110-000] Arkansas Electric Cooperative Corporation; Mississippi Delta Energy Agency; Clarksdale Public Utilities Commission.... 825(h), Arkansas Electric Cooperative Corporation, Mississippi Delta Energy Agency, and its two...

  4. Profitability and constraints in the marketing of poultry birds in Delta ...

    African Journals Online (AJOL)

    Profitability and constraints in the marketing of poultry birds in Delta central agricultural zone, Delta state, Nigeria. ... Randomly selected 54 poultry bird marketers were surveyed in 5 major markets. ... EMAIL FULL TEXT EMAIL FULL TEXT

  5. Crude Oil, a Blessing and Impediment in Niger Delta Polity: Tanure ...

    African Journals Online (AJOL)

    Journal Home > Special Edition 2011 > ... Oil has constituted a physical problem to Delta State and Nigeria as a whole. ... impediment in Delta of Nigeria; Economic growth constraints, socio-political problems and Neo-colonialism; and finally,

  6. Application in Down-hole Milling Operations In Niger Delta.

    African Journals Online (AJOL)


    export terminals, 275 flow stations, 10 gas plants, 3 refineries and a massive natural ..... clear of the Niger Delta', adding that, 'The Chinese government by investing in stolen .... Development Agency (SMEDAN); to help boost the growth of both countries' ..... “The Rule of Oil: Petro-Politics and the Anatomy of an Insurgency”.

  7. Gambiense Sleeping Sickness In The Abraka Region Of Delta State ...

    African Journals Online (AJOL)

    Gambiense Sleeping Sickness In The Abraka Region Of Delta State, Nigeria: Passive Case Detection (Pcd) At The Baptist Medical Centre (BMC) Eku 1999 – 2004. ... The highest prevalence of infection was among patients aged between 26-35 years with 35.6% infection rate, 23.3 percent was recorded among those aged ...

  8. year Review of Patients on DOTS in Delta State, Nigeria

    African Journals Online (AJOL)


    1Department of Community Medicine, Delta State University Teaching ... Therapy Short-course (DOTS), DOTS plus, and the Stop TB Strategy. ... Methods: In this descriptive records review of years 2011-2015, existing data ... Treatment success rate improved from 68.3% in ..... exploration and social interventions to curb it.

  9. Delta-gamma-theta Hedging of Crude Oil Asian Options

    Directory of Open Access Journals (Sweden)

    Juraj Hruška


    Full Text Available Since Black-Scholes formula was derived, many methods have been suggested for vanilla as well as exotic options pricing. More of investing and hedging strategies have been developed based on these pricing models. Goal of this paper is to derive delta-gamma-theta hedging strategy for Asian options and compere its efficiency with gamma-delta-theta hedging combined with predictive model. Fixed strike Asian options are type of exotic options, whose special feature is that payoff is calculated from the difference of average market price and strike price for call options and vice versa for the put options. Methods of stochastic analysis are used to determine deltas, gammas and thetas of Asian options. Asian options are cheaper than vanilla options and therefore they are more suitable for precise portfolio creation. On the other hand their deltas are also smaller as well as profits. That means that they are also less risky and more suitable for hedging. Results, conducted on chosen commodity, confirm better feasibility of Asian options compering with vanilla options in sense of gamma hedging.

  10. Assessing School Facilities in Public Secondary Schools in Delta ...

    African Journals Online (AJOL)

    This study investigated school facilitates in public secondary schools in Delta State, Nigeria. The purpose of the study was to find out the state of the facilities, the types of maintenance carried out on the facilities by school administrators, the factors encouraging school facilities depreciation and the roles of school ...

  11. Monte Carlo simulations of the stability of delta-Pu

    DEFF Research Database (Denmark)

    Landa, A.; Soderlind, P.; Ruban, Andrei


    The transition temperature (T-c) for delta-Pu has been calculated for the first time. A Monte Carlo method is employed for this purpose and the effective cluster interactions are obtained from first-principles calculations incorporated with the Connolly-Williams and generalized perturbation methods...

  12. Evolution of the Niger Delta, present dynamics and the future ...

    African Journals Online (AJOL)

    Evolution of the Niger Delta is closely linked to the geodynamics related to the separation of the African and South American continents and the tectonics of the formation of the Benue Trough. Tectonic activities, climate and eustasy are the major factors responsible for transgression and regression through the entrant point ...

  13. Validity and reliability of the Delta Healthy Eating Attitudes Scale (United States)

    The objective of this study was to evaluate psychometric properties of an instrument developed to measure psychosocial factors related to the Dietary Guidelines for Americans for a nutrition intervention in the Lower Mississippi Delta (LMD). Social Cognitive Theory constructs social support (SS), s...

  14. 75 FR 56094 - Delta-Mendota Canal Intertie Project (United States)


    ... Project AGENCY: Western Area Power Administration, DOE. ACTION: Notice of Record of Decision and... maintain a new 69-kilovolt (kV) transmission line and fiber optic cable for delivery of project use power...) Delta-Mendota Canal (DMC)/California Aqueduct Intertie (Intertie) project. The Intertie, including the...

  15. Eating Habits of the Elderly in Asaba, Delta State, Nigeria ...

    African Journals Online (AJOL)

    Objectives: The study was undertaken to describe the eating habits of literate elderly in Asaba, urban city in Delta State of Nigeria. Methods: A total of 176 elderly male (62.5%) and female (37.5%) aged 50years and above who attended Medical Lectures of the Ebreme foundation for the elderly were enrolled in this study.

  16. Morphodynamics of the Manyema Tidal Delta at Kunduchi, Tanzania

    African Journals Online (AJOL)

    Keywords: Morphodynamics, Kunduchi, Manyema, shoreline change, tidal creek, tidal delta. Abstract—The prevailing northward longshore drift of beach sand on the northern part of Msasani Bay, north of Dar es Salaam, is interrupted at Kunduchi by the tidal flushing of ... Western Indian Ocean J. Mar. Sci. Vol. 11, No. 2, pp.

  17. Ibani (Niger Delta) Traditional Religion and Social Morality | Jaja ...

    African Journals Online (AJOL)

    The Ibani is of the Ijo extraction in the Niger Delta of Nigeria. The belief in a Supreme Being called Tamuno but also on multitude of deities because of the environment in which they live. They believe that these deities perform social functions that stabilize society. Ibani cosmology revolve round the tripod – God, deities and ...

  18. Interacting boson model with surface delta interaction between nucleons

    International Nuclear Information System (INIS)

    Druce, C.; Moszkowski, S.A.


    The surface delta interaction is used as an effective nucleon-nucleon interaction to investigate the structure and interaction of the bosons in the interacting boson model. The authors have obtained analytical expressions for the coefficients of a multipole expansion of the neutron-boson proton-boson interaction for the case of degenerate orbits

  19. Dynamic Balancing of Clavel’s Delta Robot

    NARCIS (Netherlands)

    van der Wijk, V.; Herder, Justus Laurens; Kecskemethy, Andres; Müller, Andreas


    The Delta robot has shown to be a useful device in many applications. Due to large accelerations however, vibrations can decrease the accuracy and performance considerably. Instead of common techniques to reduce vibrations such as damping or including waiting times in the motion cycle, this article

  20. Ethnic Minority Problems in the Niger Delta | Quaker-Dokubo ...

    African Journals Online (AJOL)

    As a conceptual background typical types of minorities and typical sources of minority conflict are outlined. A historical overview is given of the problems Niger Delta minorities have been experiencing. Their grievances and demands are highlighted, and the responses of different Nigerian governments are discussed.

  1. Perceptions, Attitudes and Practices on Schistosomiasis in Delta ...

    African Journals Online (AJOL)

    The main objective of the study reported here was to assess the knowledge, attitude/perception and practices of the people in Oshimili South and Ndokwa Northeast Local Government Areas of Delta State in Nigeria. A cross-sectional study of 400 randomly selected persons aged ≥15 years was undertaken using a uniform ...

  2. Final Narrative Report on Nursing Ethics at Delta College. (United States)

    Pfeiffer, Raymond S.

    This four-part report describes a project undertaken by Delta College to implement two required bioethics courses for nursing students: an introductory course in ethical theories and an advanced course in applications of these theories in nursing. After Part I relates how funding for the project was secured and used, Part II delineates the…

  3. The Localizing Value Of Focal Delta Slowing In Temporal Lobe ...

    African Journals Online (AJOL)

    Slow wave EEG had a higher marginal probability than neuropsychological assessment of predicting the focus, and was equally effective as other investigative methods. Conclusion These results suggest that focal temporal delta slowing is useful in the localization of epileptogenic foci. There was no discordance with the ...

  4. Practical Design of Delta-Sigma Multiple Description Audio Coding

    DEFF Research Database (Denmark)

    Leegaard, Jack Højholt; Østergaard, Jan; Jensen, Søren Holdt


    It was recently shown that delta-sigma quantization (DSQ) can be used for optimal multiple description (MD) coding of Gaussian sources. The DSQ scheme combined oversampling, prediction, and noise-shaping in order to trade off side distortion for central distortion in MD coding. It was shown that ...

  5. Evaluation Of Delta State E-Government Website | Chete ...

    African Journals Online (AJOL)

    The study evaluates Delta state government website by adopting the method used since 2001 in evaluating national government websites. The questionnaire and web survey techniques were adopted for this study. The data from the questionnaire was analyzed using statistical package for social sciences (SPSS) and the ...

  6. training needs of school inspectors for quality instruction in delta

    African Journals Online (AJOL); ... 29. Jude Ekuevugbe Omorigho, Post Primary Education Board, Asaba, Delta State, Nigeria. ... Effective communication training for school .... Decision. Inspectors. 3.12. 0.25. Important. Headmasters. 2.96. 0.11. Table 3, shows that the individual means.

  7. Atlantic humpback dolphins Sousa teuszii in the Saloum Delta ...

    African Journals Online (AJOL)

    During October and November 2015, the first systematic survey of Sousa teuszii was carried out in the Saloum Delta (Senegal, West Africa), comprising 1 617.5 km of boat-based survey coverage. Thirty sightings were recorded in the Saloum and Diomboss rivers, and along the southern coastline. Dolphins were also ...

  8. Environmental Degradation in Oil Producing Areas of Niger Delta ...

    African Journals Online (AJOL)

    Due to oil exploration and other human activities in the Niger Delta region, there is evidence of environmental degradation all over the area (Oronto, 1998). Environmental degradation is occasioned by consistent flow of industrial waste, oil spills, gas flares, fire disaster, acid rain, flooding erosion, etc., which has led to the ...

  9. Acid Rain in Niger Delta Region: Implication on Water Resources ...

    African Journals Online (AJOL)

    This research focused on the effect of acid rain on the water quality of the Niger Delta region of Nigeria. Three hundred water samples were collected: 100 water samples from rain, 100 from open wells and 100 from rivers. The water samples were analysed using the paired t-test and multiple correlation analysis to ascertain ...

  10. Adolescent Sexual and Reproductive Health in the Niger Delta ...

    African Journals Online (AJOL)

    There has been an increasing awareness of the need to pay special focus on the adolescent and their sexual and reproductive health. This article reviews the sexual and reproductive health of adolescents in the Niger Delta region (NDR) of Nigeria. The objective is to bring to focus these important issues in the region.

  11. Isospin-breaking nuclear forces with delta degrees of freedom

    International Nuclear Information System (INIS)

    Epelbaum, E.


    The leading contributions to the isospin-violating (IV) two- and three-nucleon forces in effective field theory with explicit delta degrees of freedom are discussed. Presented at the 20th Few-Body Conference, Pisa, Italy, 10-14 September 2007. (author)

  12. Experience on tangent delta norms adopted for repaired generator

    International Nuclear Information System (INIS)

    Misra, N.N.; Sood, D.K.


    The repair techniques of the generators are very crucial for avoiding prolonged forced outages. The crucial decisions based on sound knowledge and judgement becomes essential in many cases. The unit under discussions had failed on account of flash over in the Exciter end overhang windings. The failure resulted in damaged to the stator bars as well as generator core. The damaged end packets of the stator core were replaced at site. The total winding bars were removed from stator core and damaged bars were replaced with new bars. The rest of the bars were tested for tangent delta tests for reuse. Acceptance norms of 0.6% tip up from 0.2pu to 0.6pu of rated stator voltage were adopted. Some of the bars outside the acceptable limits of tangent delta were shifted close to neutral so that the standard norms of tan delta are met. This was felt necessary because lead-time for procurement of new bars was more than six months. The above-adopted norms for tangent delta will be of much use for the operating utilities. The unit under discussions was of 67.5 MW operating at 50 Hz, 0.85 pf lag and had logged 66160.46 operating hours before failure. (author)

  13. Use of Cybercafe's Services by Households in Delta State, Nigeria ...

    African Journals Online (AJOL)

    Cyber cafés' provide important public services. They provide access to wide range of information through the internet via the computer. The study is centered on the use of cyber cafés by households in Delta State. Services provided by the cyber café's were identified. The study revealed that Household with children under ...

  14. Dermal absorption of the insecticide lindane (1 delta, 2 delta, 3 beta, 4 delta, 5 delta, 6 beta-hexachlorocyclohexane) in rats and rhesus monkeys: Effect of anatomical site

    International Nuclear Information System (INIS)

    Moody, R.P.; Ritter, L.


    Dermal absorption of the insecticide lindane (1 delta, 2 delta, 3 beta, 4 delta, 5 delta, 6 beta-hexachlorocyclohexane) was determined in rats and rhesus monkeys. Lindane is in widespread use as a 1% cream or lotion scabicide formulation and as a 1% miticide shampoo for body lice control in humans. Results obtained following our in vivo dermal absorption procedure demonstrated that 18 +/- 4.1%, 34 +/- 5.2%, and 54 +/- 26.3% of the applied dose was absorbed following topical applications at a rate of 1.5 micrograms/cm2 (6.2 micrograms/100 microliters of acetone) of the 14C-labeled pesticide to 4.2-cm2 regions of the forearm (n = 8), forehead (n = 7), and palm (n = 4) of rhesus monkeys, respectively. Dose sites were washed with soapy water 24 h posttreatment. Comparative studies in rats (n = 5) dosed middorsally demonstrated 31 +/- 9.5% absorption. Statistical analysis of the 14C excretion kinetics demonstrated slower clearance of lindane from rats than monkey forearm, forehead, or palm. Intramuscular (im) injections of 14C-lindane gave 52 +/- 7.1% recovery in monkey (n = 8) and 64 +/- 5.9% in rats (n = 5), suggesting body storage of this lipophilic chemical

  15. Characterization of middle Eocene tide-influenced delta: a study ...

    Indian Academy of Sciences (India)


    Running Title: Eocene tide-influenced delta in South Cambay Basin. Manuscript. Click here to view linked References. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 .... systematic documentation of the facies types to establish the depositional environment of the .... Hazad Member consists of a number of sandstone units separated by intervening ...

  16. Schrodinger operators with delta-interactions supported on conical surfaces

    Czech Academy of Sciences Publication Activity Database

    Behrndt, J.; Exner, Pavel; Lotoreichik, V.


    Roč. 47, č. 35 (2014), s. 355202 ISSN 1751-8113 R&D Projects: GA ČR(CZ) GA14-06818S; GA MŠk 7AMB13AT010 Institutional support: RVO:61389005 Keywords : Schrödinger operator * delta potential * infinite discrete spectrum Subject RIV: BE - Theoretical Physics Impact factor: 1.583, year: 2014

  17. Amnesty in the Niger Delta: vertical movement towards self ...

    African Journals Online (AJOL)

    ... promises of infrastructure development in the region and direct payments of oil revenues to host-communities. This paper seeks to examine the recent developments vis-à-vis the government's amnesty initiative to determine if this policy has bridged the gap in the longstanding selfdetermination demands of the Niger Delta ...

  18. Childhood nutrition in the Mississippi Delta: challenges and opportunities. (United States)

    Gray, Virginia B; Byrd, Sylvia H; Fountain, Brent J; Rader, Nicole E; Frugé, Andrew D


    Childhood obesity in the USA has more than tripled in the last three decades, and the prevalence is higher in the Mississippi Delta. Insight into the social, cultural and environmental factors that influence inequity can inform efforts to mediate health disparities. Focus groups (n = 12) among parents/guardians of elementary school children (n = 44) and teachers (n = 59) in the Mississippi Delta were used to investigate barriers and facilitators of healthy eating. Transcriptions were analyzed for themes. A strong preference for junk food among children and the pervasiveness of junk foods in schools and communities were cited as barriers to healthy eating. Potential facilitators of healthy eating included desire to avoid chronic disease, effort to limit junk food consumption and school support. Despite support for efforts to improve nutrition in the Delta, participants voiced a sense of inevitability related to children's consumption of unhealthy foods. This study suggests that parents and teachers express concern related to eating habits of children, yet they experience barriers to healthy eating which contribute to a sense of disempowerment. Improving health in the Mississippi Delta requires comprehensive strategies that offer its citizens a sense of agency. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:

  19. Drones on the delta | IDRC - International Development Research ...

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


    Nov 25, 2016 ... Ghana's Volta River delta is an area vulnerable to climate change, with rising seas and increasingly powerful storms driving flooding and erosion, leaving authorities there questioning whether the best response involves solutions such as sea walls or migration. A group of researchers is using drones to ...

  20. aranthus cruentus L) in the Niger Delta Region of Nigeria

    African Journals Online (AJOL)

    ABSTRACT. Experiments were conducted in 1987 and 1988 to study the response of Amaranthus cruentus L. to flooded soils at Ekpoma, situated in-the Niger Delta Region of Nigeria. The objective of this study was to examine the effect of flooding on yield of A. Céiieiìtus. The study revealed that the negative response of the ...

  1. The Economic Dimensions of the Niger Delta Ethnic Conflicts ...

    African Journals Online (AJOL)

    This paper presents a descriptive analysis of the remote and immediate causes of the armed ethnic conflicts in the Niger Delta in Nigeria and attempts to proffer a strategic approach rather than the use of brute force in managing the conflicts. The study revealed that the underlying cause of the conflict is the prolonged ...

  2. A Signal-Interleaving Complex Bandpass Sigma-Delta Converter

    DEFF Research Database (Denmark)

    Wad, Paul Emmanuel


    Complex or quadrature Sigma-Delta converters operate on complex signals, i.e. signals consisting of a real and an imaginary component, whereas conventional converters operate only on real signals. The advantage of complex signal processing in the discrete-time domain is that the entire sampling...

  3. Towards an Ethics of the Environment in the Niger Delta

    African Journals Online (AJOL)


    and the responsibility for both human and non-human components of nature are indeed wholly ... intend to do in this work therefore is to evolve an ethics of the Niger Delta environment which ... African Research Review Vol. 4(3a) July, 2010.

  4. Fundraising processes in Nigerian Academic Libraries: The Delta ...

    African Journals Online (AJOL)

    The paper examines fundraising processes in academic libraries in Delta State. The aim is to find out the extent to which fund raising processes can help in solving funding problems in academic libraries. The descriptive research method was employed. Eleven academic libraries in Delt a State were used in this study, that ...

  5. 2009-2010 USACE Vicksburg District Lidar: Mississippi River Delta (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — LiDAR collected at 1.0 points per square meter (1.0m GSD) for the entire portion of the Mississippi River Delta in the Vicksburg District. This area was flown during...

  6. Hepatitis delta in HIV-infected individuals in Europe

    DEFF Research Database (Denmark)

    Soriano, Vincent; Grint, Daniel; Monforte, Antonellad'arminio


    BACKGROUND:: Hepatitis delta virus (HDV) infection results in the most aggressive form of chronic viral hepatitis. There is scarce information about the prevalence, epidemiology, virological profile and natural historyof hepatitis delta in HIV patients. METHODS:: From 16,597 HIV patients enrolled......-RNA was quantified using a real-time PCR method. RESULTS:: A total of 61/422 HBsAg+ carriers were anti-HDV+ (prevalence: 14.5%). Hepatitis delta predominated in intravenous drug users and for this reason in South and/or East Europe. Serum HDV-RNA was detectable in 87% of tested anti-HDV+ patients, with a median...... titer of 1.76x10¿copies/ml. Overall, delta hepatitis patients showed lower serum HBV-DNA than the rest of HBsAg+ carriers, although the inhibitory effect of HDV on HBV replication was not recognized in HBV genotype D patients.Whereas HDV was not associated with progression to AIDS, it significantly...

  7. Comparative Noise Pollution Study Of Some Major Towns In Delta ...

    African Journals Online (AJOL)

    Comparative noise pollution studies have been carried out in some major towns in Delta State, Nigeria using a PIONneer 65 noise dosimeter. The noise measurements were taken at ten points within each of the towns at an interval of 30 minutes during the peak period of the day and at the cool of the night. The results ...

  8. Delta Healthy Sprouts: Participants' Diet and Food Environment at Baseline (United States)

    Local food environments influence the nutrition and health of area residents. This baseline analysis focuses on the food environments of women who participated in the Delta Healthy Sprouts project, a randomized, controlled, comparative trial designed to test the efficacy of two Maternal, Infant, an...

  9. The Problem with the Delta Cost Project Database (United States)

    Jaquette, Ozan; Parra, Edna


    The Integrated Postsecondary Education System (IPEDS) collects data on Title IV institutions. The Delta Cost Project (DCP) integrated data from multiple IPEDS survey components into a public-use longitudinal dataset. The DCP Database was the basis for dozens of journal articles and a series of influential policy reports. Unfortunately, a flaw in…

  10. Nonlinearities in SC Delta-Sigma A/D Converters

    DEFF Research Database (Denmark)

    Steensgaard-Madsen, Jesper


    The effects of using nonlinear low-gain opamps in switched-capacitor delta-sigma modulators are analyzed. Using unconventional topologies, the state variables are made essentially uncorrelated with the input signal, hence opamp nonlinearity will cause very little harmonic distortion. Nonlinearity...

  11. Prevalence of Neonatal Jaundice on Central Hospital, Warri, Delta ...

    African Journals Online (AJOL)

    Methods: 272 babies (aged 1 – 30 days) the Neonatal Clinic of the Department of Child Health, Central Hospital, Warri, Delta State between June 2009 and June 2010 were examined daily for evidence of jaundice. Those with serum bilirubin ³15mg/100ml were subjected to additional clinical and laboratory investigations to ...

  12. Mantle electrical conductivity profile of Niger delta region

    Indian Academy of Sciences (India)

    The mantle electrical conductivity-depth profile of the Niger delta region in Nigeria has been determined using solar quiet day ionospheric current (Sq).The magnetometer data obtained in 2010 from geomagnetic stations installed in Lagos by magnetic dataset (MAGDAS) in 2008 and data from magnetometers installed in ...

  13. The Niger Delta: State Repression and Violence Nexus

    African Journals Online (AJOL)

    crosdel emuedo


    Feb 19, 2005 ... This explains its concern only with unimpeded access to crude oil at very cheap ... The people of the Niger Delta on the other hand, places premium on the concept of human ... going amnesty, over 123 hostages were taken.

  14. delta-Opioid-induced pharmacologic myocardial hibernation during cardiopulmonary resuscitation. (United States)

    Fang, Xiangshao; Tang, Wanchun; Sun, Shijie; Weil, Max Harry


    Cardiac arrest and cardiopulmonary resuscitation is an event of global myocardial ischemia and reperfusion, which is associated with severe postresuscitation myocardial dysfunction and fatal outcome. Evidence has demonstrated that mammalian hibernation is triggered by cyclic variation of a delta-opiate-like compound in endogenous serum, during which the myocardial metabolism is dramatically reduced and the myocardium tolerates the stress of ischemia and reperfusion without overt ischemic and reperfusion injury. Previous investigations also proved that the delta-opioid agonist elicited the cardioprotection in a model of regional ischemic intact heart or myocyte. Accordingly, we were prompted to search for an alternative intervention of pharmacologically induced myocardial hibernation that would result in rapid reductions of myocardial metabolism and therefore minimize the myocardial ischemic and reperfusion injury during cardiac arrest and cardiopulmonary resuscitation. Prospective, controlled laboratory study. University-affiliated research laboratory. In the series of studies performed in the established rat and pig model of cardiac arrest and cardiopulmonary resuscitation, the delta-opioid receptor agonist, pentazocine, was administered during ventricular fibrillation. : The myocardial metabolism reflected by the concentration of lactate, or myocardial tissue PCO2 and PO2, is dramatically reduced during cardiac arrest and cardiopulmonary resuscitation. These are associated with less severe postresuscitation myocardial dysfunction and longer duration of postresuscitation survival. delta-Opioid-induced pharmacologic myocardial hibernation is an option to minimize the myocardial ischemia and reperfusion injury during cardiac arrest and cardiopulmonary resuscitation.

  15. On approximation and energy estimates for delta 6-convex functions. (United States)

    Saleem, Muhammad Shoaib; Pečarić, Josip; Rehman, Nasir; Khan, Muhammad Wahab; Zahoor, Muhammad Sajid


    The smooth approximation and weighted energy estimates for delta 6-convex functions are derived in this research. Moreover, we conclude that if 6-convex functions are closed in uniform norm, then their third derivatives are closed in weighted [Formula: see text]-norm.

  16. On approximation and energy estimates for delta 6-convex functions

    Directory of Open Access Journals (Sweden)

    Muhammad Shoaib Saleem


    Full Text Available Abstract The smooth approximation and weighted energy estimates for delta 6-convex functions are derived in this research. Moreover, we conclude that if 6-convex functions are closed in uniform norm, then their third derivatives are closed in weighted L2 $L^{2}$-norm.

  17. Questioning triple rice intensification on the Vietnamese mekong delta floodplains

    NARCIS (Netherlands)

    Tran, Dung Duc; Halsema, van Gerardo; Hellegers, Petra J.G.J.; Ludwig, Fulco; Wyatt, Andrew


    Large areas of the Vietnamese Mekong Delta floodplains (VMDF) are protected by high dikes to facilitate three rice crops per year. While this has increased rice production, there is evidence that triple rice systems have negative long-term effects, both environmental and economic. Double rice

  18. The search for environmental justice in the Niger Delta and ...

    African Journals Online (AJOL)

    Right from the beginning Man has been given the privilege by his Creator to tender the earth and take dominion over his environment. But for the impoverished people of the Niger Delta region, the mainstay of Nigeria's oil wealth, the situation is ironically abysmal. The region has been the scene of protest, sometimes ...

  19. What are pregnant women in a rural Niger Delta community's ...

    African Journals Online (AJOL)

    To date, studies have sought cause and effect and have neglected the opinion of the people about what they perceive to be problematic and what they believe constitutes satisfactory maternity service provision. An exploratory qualitative study was carried out to identify pregnant women in a rural Niger Delta community's ...

  20. Production and decay properties of the delta (970) meson

    International Nuclear Information System (INIS)

    Gay, J.B.; Chaloupka, V.; Gavillet, Ph.; Hemingway, R.J.; Marzano, F.; Montanet, L.; Blokzijl, R.; Jongejans, B.; Massaro, G.G.G.; Heinen, P.M.; Metzger, W.J.; Timmermans, J.J.M.


    Using an 80 events per microbarn sample of K - p interactions at 4.2 GeV/c the production and decay properties of the delta(970) have been investigated in the following reactions: K - p→Σ + (1385)etaπ - and K - p→Σ + (1385)K 0 K - . (Auth.)

  1. Obesity and Health Risk of Children in the Mississippi Delta (United States)

    Gamble, Abigail; Waddell, Dwight; Ford, M. Allison; Bentley, John P.; Woodyard, Catherine D.; Hallam, Jeffrey S.


    Background: Mississippi (MS) Delta adults and youth report obesity rates far exceeding those of the state and nation. State law requires in-school physical activity and nutrition practices to address childhood obesity but does not require evaluation of outcomes, specifically the impact on weight-related outcomes. This paper offers 3 things: (1)…

  2. Leena delta rännujutud / Riho Västrik

    Index Scriptorium Estoniae

    Västrik, Riho, 1965-


    Reisikiri Leena jõest filmi tegeva filmimeeskonna matkast Leena jõe delta tundras, kus satuti ka 1879. aastal purjelaeval "Jeannette" põhjapoolust vallutama tulnud ameerika polaaruurija DeLongi matmispaiga ja mälestusmärgi juurde

  3. Enhancing stakeholder participation in the Niger Delta region: the ...

    African Journals Online (AJOL)

    Nigeria's indigenous people, found in the Niger Delta area, have for many years experienced developmental challenges associated with oil exploration. The region has been perennially engulfed in various forms of agitation pertaining to self-government and resource control. Over the years, attempts to solve these ...

  4. Changes in the areal extents of the Athabasca River, Birch River, and Cree Creek Deltas, 1950-2014, Peace-Athabasca Delta, Canada (United States)

    Timoney, Kevin; Lee, Peter


    Deltas form where riverborne sediment accumulates at the interface of river mouths and their receiving water bodies. Their areal extent is determined by the net effect of processes that increase their extent, such as sediment accumulation, and processes that decrease their extent, such as erosion and subsidence. Through sequential mapping and construction of river discharge and sediment histories, this study examined changes in the subaerial extents of the Cree Creek and Athabasca River Deltas (both on the Athabasca River system) and the Birch River Delta in northern Canada over the period 1950-2014. The purpose of the study was to determine how, when, and why the deltas changed in areal extent. Temporal growth patterns were similar across the Athabasca and Birch River systems indicative of a climatic signal. Little or no areal growth occurred from 1950 to 1968; moderate growth occurred between 1968 and the early to mid-1980s; and rapid growth occurred between 1992 and 2012. Factors that affected delta progradation included dredging, sediment supply, isostatic drowning, delta front bathymetry, sediment capture efficiency, and storms. In relation to sediment delivered, areal growth rates were lowest in the Athabasca Delta, intermediate in the Birch Delta, and highest in the Cree Creek Delta. Annual sediment delivery is increasing in the Cree Creek Delta; there were no significant trends in annual sediment delivery in the Birch and Athabasca Deltas. There was a lag of up to several years between sediment delivery events and progradation. Periods of delta progradation were associated with low water levels of the receiving basins. Predicted climate-change driven declines in river discharge and lake levels may accelerate delta progradation in the region. In the changing ecosystems of northeastern Alberta, inadequate monitoring of vegetation, landforms, and sediment regimes hampers the elucidation of the nature, rate, and causality of ecosystem changes.

  5. delta 6 Hexadecenoic acid is synthesized by the activity of a soluble delta 6 palmitoyl-acyl carrier protein desaturase in Thunbergia alata endosperm. (United States)

    Cahoon, E B; Cranmer, A M; Shanklin, J; Ohlrogge, J B


    delta 6 Hexadecenoic acid (16:1 delta 6) composes more than 80% of the seed oil of Thunbergia alata. Studies were conducted to determine the biosynthetic origin of the double bond of this unusual fatty acid. Assays of fractions of developing T. alata seed endosperm with [1-14C]palmitoyl (16:0)-acyl carrier protein (ACP) revealed the presence of a soluble delta 6 desaturase activity. This activity was greatest when 16:0-ACP was provided as a substrate, whereas no desaturation of the coenzyme A ester of this fatty acid was detected. In addition, delta 6 16:0-ACP desaturase activity in T. alata endosperm extracts was dependent on the presence of ferredoxin and molecular oxygen and was stimulated by catalase. To further characterize this enzyme, a cDNA encoding a diverged acyl-ACP desaturase was isolated from a T. alata endosperm cDNA library using polymerase chain reaction with degenerate oligonucleotides corresponding to conserved amino acid sequences in delta 9 stearoyl (18:0)- and delta 4 16:0-ACP desaturases. The primary structure of the mature peptide encoded by this cDNA shares 66% identity with the mature castor delta 9 18:0-ACP desaturase and 57% identity with the mature coriander delta 4 16:0-ACP desaturase. Extracts of Escherichia coli that express the T. alata cDNA catalyzed the delta 6 desaturation of 16:0-ACP. These results demonstrate that 16:1 delta 6 in T. alata endosperm is formed by the activity of a soluble delta 6 16:0-ACP desaturase that is structurally related to the delta 9 18:0- and delta 4 16:0-ACP desaturases. Implications of this work to an understanding of active site structures of acyl-ACP desaturases are discussed.



    Ezenwafor, J. I.; Onokpaunu, Michel O.; Nna-Emmanuel, Sarah W.


    The need for wide utilization of social media marketing for entrepreneurial development in Delta State necessitated this study which sought to determine how competent practicing entrepreneurs are for their use in Delta State. One research question guided the study. A survey research design was adopted. The population consisted of 200 entrepreneurs in Delta North Senatorial District of Delta State. A validated 22 item on a 5-point rating scale questionnaire was used for data collection. Mean a...

  7. Differential entrainment of neuroelectric delta oscillations in developmental dyslexia.

    Directory of Open Access Journals (Sweden)

    Fruzsina Soltész

    Full Text Available Oscillatory entrainment to the speech signal is important for language processing, but has not yet been studied in developmental disorders of language. Developmental dyslexia, a difficulty in acquiring efficient reading skills linked to difficulties with phonology (the sound structure of language, has been associated with behavioural entrainment deficits. It has been proposed that the phonological 'deficit' that characterises dyslexia across languages is related to impaired auditory entrainment to speech at lower frequencies via neuroelectric oscillations (<10 Hz, 'temporal sampling theory'. Impaired entrainment to temporal modulations at lower frequencies would affect the recovery of the prosodic and syllabic structure of speech. Here we investigated event-related oscillatory EEG activity and contingent negative variation (CNV to auditory rhythmic tone streams delivered at frequencies within the delta band (2 Hz, 1.5 Hz, relevant to sampling stressed syllables in speech. Given prior behavioural entrainment findings at these rates, we predicted functionally atypical entrainment of delta oscillations in dyslexia. Participants performed a rhythmic expectancy task, detecting occasional white noise targets interspersed with tones occurring regularly at rates of 2 Hz or 1.5 Hz. Both groups showed significant entrainment of delta oscillations to the rhythmic stimulus stream, however the strength of inter-trial delta phase coherence (ITC, 'phase locking' and the CNV were both significantly weaker in dyslexics, suggestive of weaker entrainment and less preparatory brain activity. Both ITC strength and CNV amplitude were significantly related to individual differences in language processing and reading. Additionally, the instantaneous phase of prestimulus delta oscillation predicted behavioural responding (response time for control participants only.

  8. Oil and Security in Nigeria: The Niger Delta Crisis | Owolabi | Africa ...

    African Journals Online (AJOL)

    This paper examines oil and security in Nigeria, with special reference to the crisis-ravaged Niger Delta. Its focus on the Niger Delta and its festering crisis stems from that region's critical importance to Nigeria. As the nation's treasure base, the Niger Delta provides over 80 percent of government revenues, 95 percent of ...

  9. The coastal system of the Volta delta, Ghana : Strategies and opportunities for development

    NARCIS (Netherlands)

    Roest, Lambertus W.M.


    The Volta delta is a very dynamic environment, forming the interface between the Volta river and the Atlantic ocean. The delta is a home for many communities, settled both at the shorelines and more inland. Furthermore the delta provides great natural values and a habitat for many species.

  10. Contrasting morphodynamics in alluvial fans and fan deltas: effect of the downstream boundary

    NARCIS (Netherlands)

    Dijk, M. van; Kleinhans, M.G.; Postma, G.; Kraal, E.


    Alluvial fans and fan deltas can, in principle, have exactly the same upstream conditions, but fan deltas by definition have ponding water at their downstream boundary. This ponding creates effects on the autogenic behaviour of fan deltas, such as backwater adaptation, mouth bars and backward

  11. Challenges and Approaches in River Delta Planning - report on training workshop

    NARCIS (Netherlands)

    Wosten, J.H.M.; Douven, W.; Long Phi, H.; Fida Abdullah Khan, M.


    River delta’s, like the Mekong Delta (Vietnam), Ganges-Brahmaputra Delta (Bangladesh), Irrawady (Myanmar) and Ciliwung Delta (Indonesia) are developing rapidly and characterized by large-scale urbanization and industrialization processes. They are facing serious planning challenges related to issues

  12. T-cell receptor gamma delta bearing cells in normal human skin

    NARCIS (Netherlands)

    Bos, J. D.; Teunissen, M. B.; Cairo, I.; Krieg, S. R.; Kapsenberg, M. L.; Das, P. K.; Borst, J.


    T-cell antigen receptors (TCR) are divided into common alpha beta and less common gamma delta types. In the murine skin, TCR gamma delta+ cells have been reported to form the great majority of epidermal T lymphocytes. We have examined the relative contribution of TCR alpha beta+ and TCR gamma delta+

  13. A new identification method for energetic ion {delta}E-E telescopes

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Cesar [Departamento de Fisica, Universidad de Alcala, 28871 Alcala de Henares, Madrid (Spain); Institut fuer Experimentelle und Angewandte Physik, Christian-Albrechts, Universitaet zu Kiel, 24118 Kiel (Germany); Bronchalo, Enrique [Departamento de Fisica, Universidad de Alcala, 28871 Alcala de Henares, Madrid (Spain); Departamento de Fisica y Arquitectura de Computadores, Universidad Miguel Hernandez, Avda. Universidad s/n, 03202 Elche, Alicante (Spain)], E-mail:; Medina, Jose [Departamento de Fisica, Universidad de Alcala, 28871 Alcala de Henares, Madrid (Spain)


    A new ion identification method for {delta}E-E telescopes is presented. The method works by counting data points under {delta}E(E) curves on {delta}E-E diagrams. These curves are obtained by simulating the telescope response to a flux of energetic ions. The method is checked against three published methods applied to several experimental data sets.

  14. Remote Sensing Monitoring Methods for Detecting Invasive Weed Coverage in Delta Waterways and Bay Marshlands (United States)

    Potter, Christopher


    This presentation is part of the Independent Science Board of the State of California Delta Stewardship Council brown bag seminar series on the "How the Delta is Monitored", followed with a panel discussion. Various remote sensing approaches for aquatic vegetation will be reviewed. Key research and application issues with remote sensing monitoring in the Delta will be addressed.

  15. Effect of delta wing on the particle flow in a novel gas supersonic separator

    DEFF Research Database (Denmark)

    Wen, Chuang; Yang, Yan; Walther, Jens Honore


    The present work presents numerical simulations of the complex particle motion in a supersonic separator with a delta wing located in the supersonic flow. The effect of the delta wing on the strong swirling flow is analysed using the Discrete Particle Method. The results show that the delta wings...

  16. Grain-size sorting in grainflows at the lee side of deltas

    NARCIS (Netherlands)

    Kleinhans, M.G.


    The sorting of sediment mixtures at the lee slope of deltas (at the angle of repose) is studied with experiments in a narrow, deep flume with subaqueous Gilbert-type deltas using varied flow conditions and different sediment mixtures. Sediment deposition and sorting on the lee slope of the delta

  17. Plant delta 15N correlates with the transpiration efficiency of nitrogen acquisition in tropical trees. (United States)

    Cernusak, Lucas A; Winter, Klaus; Turner, Benjamin L


    Based upon considerations of a theoretical model of (15)N/(14)N fractionation during steady-state nitrate uptake from soil, we hypothesized that, for plants grown in a common soil environment, whole-plant delta(15)N (deltaP) should vary as a function of the transpiration efficiency of nitrogen acquisition (F(N)/v) and the difference between deltaP and root delta(15)N (deltaP - deltaR). We tested these hypotheses with measurements of several tropical tree and liana species. Consistent with theoretical expectations, both F(N)/v and deltaP - deltaR were significant sources of variation in deltaP, and the relationship between deltaP and F(N)/v differed between non-N(2)-fixing and N(2)-fixing species. We interpret the correlation between deltaP and F(N)/v as resulting from variation in mineral nitrogen efflux-to-influx ratios across plasma membranes of root cells. These results provide a simple explanation of variation in delta(15)N of terrestrial plants and have implications for understanding nitrogen cycling in ecosystems.

  18. Implications for future survival of delta smelt from four climate change scenarios for the Sacramento–San Joaquin Delta, California (United States)

    Brown, Larry R.; Bennett, William A.; Wagner, R. Wayne; Morgan-King, Tara; Knowles, Noah; Feyrer, Frederick; Schoellhamer, David H.; Stacey, Mark T.; Dettinger, Mike


    Changes in the position of the low salinity zone, a habitat suitability index, turbidity, and water temperature modeled from four 100-year scenarios of climate change were evaluated for possible effects on delta smelt Hypomesus transpacificus, which is endemic to the Sacramento–San Joaquin Delta. The persistence of delta smelt in much of its current habitat into the next century appears uncertain. By mid-century, the position of the low salinity zone in the fall and the habitat suitability index converged on values only observed during the worst droughts of the baseline period (1969–2000). Projected higher water temperatures would render waters historically inhabited by delta smelt near the confluence of the Sacramento and San Joaquin rivers largely uninhabitable. However, the scenarios of climate change are based on assumptions that require caution in the interpretation of the results. Projections like these provide managers with a useful tool for anticipating long-term challenges to managing fish populations and possibly adapting water management to ameliorate those challenges.

  19. 78 FR 22911 - Delta Air Lines, Inc., Reservation Sales and Customer Care Call Center, Seatac, WA; Delta Air... (United States)


    ... DEPARTMENT OF LABOR Employment and Training Administration [TA-W-82,197; TA-W-82,197A] Delta Air... requested administrative reconsideration of the negative determination regarding workers' eligibility to... threatened with total or partial separation from employment on the date of certification through two years...

  20. Unexpected {delta}{sup 18}O and {delta}{sup 2}H Variability of Groundwater in the Eastern Paris Basin

    Energy Technology Data Exchange (ETDEWEB)

    Gourcy, L.; Petelet-Giraud, E. [BRGM Service EAU, Orleans (France)


    The Paris Basin covers about one-third of the total surface area of France. In 2009, two campaigns sampling 25 boreholes tapping Tertiary aquifers were carried out in the Basin. These aquifers are recharged at a similar altitude and the groundwater age is too young to have registered climate change. In the past, regional studies included the use of isotopes to understand groundwater origin and dynamics. Both {delta}{sup 18}O and {delta}{sup 2}H as well as ages (CFC/SF{sub 6)} and chemical components were determined in all collected samples. A noticeable stable isotope 'anomaly' appears in the south-western part of the Basin, where the average {delta}{sup 18}O and {delta}{sup 2}H values are more depleted and do not fit the pattern given by the continental effect in this area. A regional particularity of the spatial distribution of such isotopes in precipitation may be possible, but should be confirmed by additional work. (author)