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Sample records for delta f508 mutation

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

    Energy Technology Data Exchange (ETDEWEB)

    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)

    2010-07-19

    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.

  2. Frequency of the deltaF508 mutation in 108 cystic fibrosis patients in São Paulo: comparison with reported Brazilian data Freqüência da mutação deltaF508 em 108 pacientes com fibrose cística de São Paulo: comparação com dados de estudos brasileiros

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    Thelma Suely Okay

    2005-04-01

    Full Text Available PURPOSE: To analyze the frequency of the delta F508 (deltaF508 deletion mutation in 108 unrelated cystic fibrosis patients and compare the results with the previously reported data for Brazilian patients. Cystic fibrosis is the leading cause of genetic disease in Caucasians, and the deltaF508 deletion is the most common mutation associated with the disease. METHOD: The frequency of the deltaF508 mutation was assessed by means of a polymerase chain reaction (PCR followed by detection in 8% silver-stained polyacrylamide gels. RESULTS: Twenty-three of 108 patients (21.3% were homozygous for the deltaF508 deletion, 50 were heterozygous (46.3%, and the remaining 35 (32.4% were non-carriers. In terms of alleles, there were 96 mutated (96/216 or 44.45% and 120 wild-type ones (120/216 or 55.5%. CONCLUSION: The 44.45% of affected alleles that were found is higher than the 33% first described in 1993, but slightly lower than the 48% recently reported. Moreover, our data corroborated the idea that the frequency of the deltaF508 mutation is lower in Brazil in comparison to that found in studies carried out in Europe and North American (circa 70.0%, probably due to increased racial miscegenation. These findings must be taken into account before any genetic screening of the population is proposed in Brazil.OBJETIVO: Analisar a freqüência da mutação delta F508 (deltaF508 em 108 pacientes não aparentados, com fibrose cística e comparou os resultados com os dados de outros estudos brasileiros. A fibrose cística (CF constitui a doença genética mais comum em populações caucasianas, sendo a deltaF508 a mais freqüente dentre as mutações relacionadas à doença. MÉTODO: A freqüência da deltaF508 foi analisada por meio da Reação em Cadeia da Polimerase (PCR seguida de detecção em géis de poliacrilamida a 8%. RESULTADOS: Vinte e três dos 108 pacientes foram homozigotos para a mutação (21,3%, 50 foram heterozigotos (46,3% e os 35 restantes n

  3. DeltaF508 heterozygosity in cystic fibrosis and susceptibility to asthma

    DEFF Research Database (Denmark)

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

    1998-01-01

    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....

  4. Identification of natural coumarin compounds that rescue defective DeltaF508-CFTR chloride channel gating.

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    Xu, Li-Na; Na, Wan-Li; Liu, Xin; Hou, Shu-Guang; Lin, Sen; Yang, Hong; Ma, Tong-Hui

    2008-08-01

    1. Deletion of phenylalanine at position 508 (DeltaF508) of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is the most common mutation causing cystic fibrosis (CF). Effective pharmacological therapy of CF caused by the DeltaF508-CFTR mutation requires the rescue of both intracellular processing and channel gating defects. 2. We identified a class of natural coumarin compounds that can correct the defective DeltaF508-CFTR chloride channel gating by screening a collection of 386 single natural compounds from Chinese medicinal herbs. Screening was performed with an iodide influx assay in Fischer rat thyroid epithelial cells coexpressing DeltaF508-CFTR and an iodide-sensitive fluorescent indicator (YFP-H148Q/I152L). 3. Dose-dependent potentiation of defective DeltaF508-CFTR chloride channel gating by five coumarin compounds was demonstrated by the fluorescent iodide influx assay and confirmed by an Ussing chamber short-circuit current assay. Activation was fully abolished by the specific CFTR inhibitor CFTR(inh)-172. Two potent compounds, namely imperatorin and osthole, have activation K(d) values of approximately 10 micromol/L, as determined by the short-circuit current assay. The active coumarin compounds do not elevate intracellular cAMP levels. Activation of DeltaF508-CFTR by the coumarin compounds requires cAMP agonist, suggesting direct interaction with the mutant CFTR molecule. Kinetics analysis indicated rapid activation of DeltaF508-CFTR by the coumarin compounds, with half-maximal activation of CFTR activators may represent a new class of natural lead compounds for the development of pharmacological therapies for CF caused by the DeltaF508 mutation.

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

    DEFF Research Database (Denmark)

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

    1998-01-01

    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. A truncated CFTR protein rescues endogenous DeltaF508-CFTR and corrects chloride transport in mice.

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    Cormet-Boyaka, Estelle; Hong, Jeong S; Berdiev, Bakhram K; Fortenberry, James A; Rennolds, Jessica; Clancy, J P; Benos, Dale J; Boyaka, Prosper N; Sorscher, Eric J

    2009-11-01

    Cystic fibrosis (CF) is most frequently associated with deletion of phenylalanine at position 508 (DeltaF508) in the CF transmembrane conductance regulator (CFTR) protein. The DeltaF508-CFTR mutant protein exhibits a folding defect that affects its processing and impairs chloride-channel function. This study aimed to determine whether CFTR fragments approximately half the size of wild-type CFTR and complementary to the portion of CFTR bearing the mutation can specifically rescue the processing of endogenous DeltaF508-CFTR in vivo. cDNA encoding CFTR fragments were delivered to human airway epithelial cells and mice harboring endogenous DeltaF508-CFTR. Delivery of small CFTR fragments, which do not act as chloride channels by themselves, rescue DeltaF508-CFTR. Therefore, we can speculate that the presence of the CFTR fragment, which does not harbor a mutation, might facilitate intermolecular interactions. The rescue of CFTR was evident by the restoration of chloride transport in human CFBE41o- bronchial epithelial cells expressing DeltaF508-CFTR in vitro. More important, nasal administration of an adenovirus expressing a complementary CFTR fragment restored some degree of CFTR activity in the nasal airways of DeltaF508 homozygous mice in vivo. These findings identify complementary protein fragments as a viable in vivo approach for correcting disease-causing misfolding of plasma membrane proteins.

  7. Mammalian osmolytes and S-nitrosoglutathione promote Delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) protein maturation and function.

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    Howard, Marybeth; Fischer, Horst; Roux, Jeremie; Santos, Bento C; Gullans, Steven R; Yancey, Paul H; Welch, William J

    2003-09-12

    In cystic fibrosis, the absence of functional CFTR results in thick mucous secretions in the lung and intestines, as well as pancreatic deficiency. Although expressed at high levels in the kidney, mutations in CFTR result in little or no apparent kidney dysfunction. In an effort to understand this phenomenon, we analyzed Delta F508 CFTR maturation and function in kidney cells under conditions that are common to the kidney, namely osmotic stress. Kidney cells were grown in culture and adapted to 250 mM NaCl and 250 mM urea. High performance liquid chromatography analysis of lysates from kidney cells adapted to these conditions identified an increase in the cellular osmolytes glycerophosphorylcholine, myo-inositol, sorbitol, and taurine. In contrast to isoosmotic conditions, hyperosmotic stress led to the proper folding and processing of Delta F508 CFTR. Furthermore, three of the cellular osmolytes, when added individually to cells, proved effective in promoting the proper folding and processing of the Delta F508 CFTR protein in both epithelial and fibroblast cells. Whole-cell patch clamping of osmolyte-treated cells showed that Delta F508 CFTR had trafficked to the plasma membrane and was activated by forskolin. Encouraged by these findings, we looked at other features common to the kidney that may impact Delta F508 maturation and function. Interestingly, a small molecule, S-nitrosoglutathione, which is a substrate for gamma glutamyltranspeptidase, an abundant enzyme in the kidney, likewise promoted Delta F508 CFTR maturation and function. S-Nitrosoglutathione-corrected Delta F508 CFTR exhibited a shorter half-life as compared with wild type CFTR. These results demonstrate the feasibility of a small molecule approach as a therapeutic treatment in promoting Delta F508 CFTR maturation and function and suggest that an additional treatment may be required to stabilize Delta F508 CFTR protein once present at the plasma membrane. Finally, our observations may help to

  8. Delta F508 testing of the DNA bank of the Royal Manchester Children's Hospital.

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    Schwarz, M J; Super, M; Wallis, C; Beighton, P; Newton, C; Heptinstall, L E; Summers, C; Markham, A; Hambleton, G; Webb, K W

    1990-09-01

    Details of haplotype and delta F508 status from various populations represented in the cystic fibrosis (CF) DNA bank of the Royal Manchester Children's Hospital are provided, together with information on the association of genotype and clinical status. Clinical details and DNA analyses from native English in the North-West and South-West of England (Bath), from Lancashire Pakistani families and from Afrikaans Namibian families are compared. A 78.5% incidence of delta F508 has been found in English families. Compound heterozygotes with CF and only one delta F508 gene have an increased likelihood of having milder disease, with less Pseudomonas isolated from sputum and relatively more showing either no regular respiratory pathogens or colonisation with Staphylococcus. There is also a relative increase in meconium ileus in these compound heterozygotes. The diagnosis of CF may be in doubt in some subjects negative for delta F508. Some of the Bath families have unusual haplotypes for an English population and a compound heterozygote delta F508/delta I507 has been found. There is evidence from metD analysis of the founder effect in the Afrikaans Namibian families, who have a high delta F508 incidence.

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

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    Adrian W R Serohijos

    2008-02-01

    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

  10. Genetic Inhibition of the Ubiquitin Ligase Rnf5 Attenuates Phenotypes Associated to F508del Cystic Fibrosis Mutation

    NARCIS (Netherlands)

    V. Tomati (Valeria); E. Sondo (Elvira); A. Armirotti (Andrea); E. Caci (Emanuela); E. Pesce (Emanuela); M. Marini (Monica); A. Gianotti (Ambra); Y. Ju Jeon (Young); M. Cilli (Michele); A. Pistorio (Angela); L. Mastracci (Luca); R. Ravazzolo (Roberto); B.J. Scholte (Bob); Z. Ronai (Ze'ev); L.J.V. Galietta (Luis J. V.); N. Pedemonte (Nicoletta)

    2015-01-01

    textabstractCystic fibrosis (CF) is caused by mutations in the CFTR chloride channel. Deletion of phenylalanine 508 (F508del), the most frequent CF mutation, impairs CFTR trafficking and gating. F508del-CFTR mistrafficking may be corrected by acting directly on mutant CFTR itself or by modulating ex

  11. Calumenin contributes to ER-Ca(2+) homeostasis in bronchial epithelial cells expressing WT and F508del mutated CFTR and to F508del-CFTR retention.

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    Philippe, Réginald; Antigny, Fabrice; Buscaglia, Paul; Norez, Caroline; Huguet, Florentin; Castelbou, Cyril; Trouvé, Pascal; Becq, Frédéric; Frieden, Maud; Férec, Claude; Mignen, Olivier

    2017-03-01

    Cystic Fibrosis (CF) is the most frequent fatal genetic disease in Caucasian populations. Mutations in the chloride channel CF Transmembrane Conductance Regulator (CFTR) gene are responsible for functional defects of the protein and multiple associated dysregulations. The most common mutation in patients with CF, F508del-CFTR, causes defective CFTR protein folding. Thus minimal levels of the receptor are expressed at the cell surface as the mutated CFTR is retained in the endoplasmic reticulum (ER) where it correlates with defective calcium (Ca(2+)) homeostasis. In this study, we discovered that the Ca(2+) binding protein Calumenin (CALU) is a key regulator in the maintenance of ER-Ca(2+) calcium homeostasis in both wild type and F508del-CFTR expressing cells. Calumenin modulates SERCA pump activity without drastically affecting ER-Ca(2+) concentration. In addition, reducing Calumenin expression in CF cells results in a partial restoration of CFTR activity, highlighting a potential function of Calumenin in CFTR maturation. These findings demonstrate a pivotal role for Calumenin in CF cells, providing insights into how modulation of Calumenin expression or activity may be used as a potential therapeutic tool to correct defects in F508del-CFTR.

  12. The CFTR trafficking mutation F508del inhibits the constitutive activity of SLC26A9.

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    Bertrand, Carol A; Mitra, Shalini; Mishra, Sanjay K; Wang, Xiaohui; Zhao, Yu; Pilewski, Joseph M; Madden, Dean R; Frizzell, Raymond A

    2017-03-30

    Several members of the SLC26A family of anion transporters associate with CFTR, forming complexes in which CFTR and SLC26A functions are reciprocally regulated. This association is thought to be facilitated by PDZ scaffolding interactions. CFTR has been shown to be positively regulated by NHERF-1, and negatively regulated by CAL in airway epithelia. However, it's unclear which PDZ-domain protein(s) interact with SLC26A9, a SLC26A family member found in airway epithelia. We have previously shown that primary, human bronchial epithelia (HBE) from non-CF donors exhibit constitutive anion secretion attributable to SLC26A9. However, constitutive anion secretion is absent in HBE from CF donors. We examined whether changes in SLC26A9 constitutive activity could be attributed to a loss of CFTR trafficking, and what role PDZ interactions played. HEK293 co-expressing SLC26A9 with the trafficking mutant F508del CFTR exhibited a significant reduction in constitutive current compared to cells co-expressing SLC26A9 and wt CFTR. We found that SLC26A9 exhibits complex glycosylation when co-expressed with F508del CFTR, but its expression at the plasma membrane is decreased. SLC26A9 interacted with both NHERF-1 and CAL, and its interaction with both significantly increased with co-expression of wt CFTR. However, co-expression with F508del CFTR only increased SLC26A9's interaction with CAL. Mutation of SLC26A9's PDZ motif decreased this association with CAL, and restored its constitutive activity. Correcting aberrant F508del CFTR trafficking in CF HBE with corrector VX-809 also restored SLC26A9 activity. We conclude that when SLC26A9 is co-expressed with F508del CFTR, its trafficking defect leads to a PDZ motif-sensitive intracellular retention of SLC26A9.

  13. Búsqueda de la mutación delta F508 y análisis de dos polimorfismos de nucleótido único en el gen CFTR, en una muestra de población general de Valparaíso, Chile

    OpenAIRE

    Vera L,Alejandra; Henríquez-Roldán, Carlos F; González R,Francisco J; Molina F,Graciela

    2005-01-01

    Background: The Cystic Fibrosis (CF) carrier rate in Chile was estimated to be 1/40. CF is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Delta F508 mutation is the most common in CF patients in Chile and worldwide. Delta F508 has linkage disequilibrium with two Single Nucleotide Polymorphisms (SNP), often used to define the haplotypic frameworks of CF mutations. Aim: To know the frequency of the delta F508 mutation and to establish the SNPs, M470V...

  14. Cystic fibrosis in Afro-Brazilians: XK haplotypes analysis supports the European origin of p.F508del mutation.

    Science.gov (United States)

    de Souza, D A S; Faucz, F R; de Alexandre, R B; Santana, M A; de Souza, E L S; Reis, F J C; Pereira-Ferrari, L; Sotomaior, V S; Culpi, L; Phillips, J A; Raskin, S

    2017-02-01

    Cystic fibrosis (CF) is a common autosomal recessive disorder, being the p.F508del the most frequent mutation. Also, a nearby restriction fragment length polymorphism (RFLP) named XK (KM19 and XV2C) is non-randomly associated with specific CF alleles. Our aim was to analyze the occurrence of the p.F508del mutation and XK haplotypes in Afro-Brazilians CF patients and controls, since these data is available for the other two main ethnic groups found in Brazil (Euro-Brazilians and Brazilian Amerindians), contributing for the whole comprehension of these haplotypes in the Brazilian population. A total of 103 patients and 54 controls were studied. PCR and PCR-RFLP methodologies were used to identify the presence of the p.F508del and the XK haplotype in the subjects. The combined data show that 84.2% of p.F508del mutation is associated with haplotype B and only 15.8% with haplotype A; no other haplotypes were found to be associated with this mutation. Our data suggest that the occurrence of p.F508del mutation and haplotype B in Afro-Brazilian patients occurs probably due to admixture with Euro-descendants. Therefore this mutation and haplotype could be used as a admixture marker.

  15. Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation.

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    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

    2014-01-01

    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.

  16. Cost-effective one-step PCR amplification of cystic fibrosis delta F508 fragment in a single cell for preimplantation genetic diagnosis.

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    Tsai, Y H

    1999-11-01

    The combination of in vitro fertilization (IVF) with PCR technologies enables diagnosis of single gene defects for preimplantation genetic diagnosis. This has been accomplished by two-step nested PCR, or PEP-PCR followed by nested PCR processes. To improve the detection of single cell genetic defects, the lysate of a single lymphocyte, with or without cystic fibrosis DeltaF508 mutation (CFDeltaF508), was incubated in a higher ionic strength solution containing mercaptoethanol prior to the addition of primers to the denatured cellular DNA. A single cell in 5 microl lysis buffer was incubated at 65 degrees C for 15 min, cooled, and neutralized with an equal volume of neutralizing buffer. A 5 microl aliquot of a solution X containing 50 mM MgCl(2), 1 M NaCl, and 10 mM mercaptoethanol was added to the neutralized cell lysate, followed by incubation at 93 degrees C for 15 min. The step was crucial to the successful amplification of CFDeltaF508 DNA fragment. The incubation of cell lysate in solution with the high level of sulphydryl reducing agent and a high ionic strength of about 0.45, at 93 degrees C for 15 min, might denature many chromatin-binding proteins and also ensure the complete dissociation of dsDNA. After the addition of PCR mix, the resulting reaction mixture still contained a sufficient level of sulphydryl reducing agent and 0.135 total ionic strength. This might reduce significantly the interference of various protein factors with DNA, and favour the primer-template annealing. The efficient initial annealing of the primers to target DNA sequences would facilitate PCR amplification efficacy. In conclusion, in more than 80 single cells tested (apart from one) the CFDeltaF508 defect was successfully demonstrated with the present protocol (>99 per cent), without using fluorescent primers and expensive automatic instrumentation.

  17. PCR-heteroduplex by grouping: Rapid screening carrier method for cystic fibrosis F508del mutation in Colombia.

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    Lina Manuela Jay

    2009-11-01

    Full Text Available Background: Cystic fibrosis (CF is the most frequent autosomal recessive disorder in the Caucasian population with an incidence of 1 in 2,500 newborns. More than 1,300 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR gene that causes CF have been described. However, mutation F508del is the most common mutation in different populations around the world. Objective: To develop a fast, reliable and low-cost technique to screen carriers and affected individuals for the F508del mutation. This kind of analysis will have an impact on genetic counselling to decrease the incidence of new cases, in the early diagnosis and instauration of appropriate treatment to decrease morbidity and mortality associated to CF in Colombia. Methods: The reliability of the PCR-heteroduplex by grouping technique by analysis of 400 blood spot samples from asymptomatic CF patients was defined. Results: Using PCR-heteroduplex by grouping technique 100% efficiency, reproducibility and specificity and 92%sensitivity were found. Conclusions: The sensitivity and reproducibility of the PCR-heteroduplex by grouping technique up to pooling of 10 samples were demonstrated. This kind of analysis could be used in heterozygotes and affected screening programs.

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

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    Liping He

    2012-11-01

    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.

  19. Reduced expression of Tis7/IFRD1 protein in murine and human cystic fibrosis airway epithelial cell models homozygous for the F508del-CFTR mutation.

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    Blanchard, Elise; Marie, Solenne; Riffault, Laure; Bonora, Monique; Tabary, Olivier; Clement, Annick; Jacquot, Jacky

    2011-08-01

    12-O-tetradecanoyl phorbol-13-acetate-induced sequence 7/interferon related development regulator 1 (Tis7/IFRD1) has been recently identified as a modifier gene in lung inflammatory disease severity in patients with cystic fibrosis (CF), based upon its capacity to regulate inflammatory activities in neutrophils. In CF patients, the F508del mutation in the Cftr gene encoding a chloride channel, the CF transmembrane conductance regulator (CFTR) in airway epithelial cells results in an exaggerated inflammatory response of these cells. At present, it is unknown whether the Tis7/IFRD1 gene product is expressed in airway epithelial cells. We therefore investigated the possibility there is an intrinsic alteration in Tis7/IFRD1 protein level in cells lacking CFTR function in tracheal homogenates of F508del-CFTR mice and in a F508del-CFTR human bronchial epithelial cell line (CFBE41o(-) cells). When Tis7/IFRD1 protein was detectable, trachea from F508del-CFTR mice showed a reduction in the level of Tis7/IFRD1 protein compared to wild-type control littermates. A significant reduction of IFRD1 protein level was found in CFBE41o(-) cells compared to normal bronchial epithelial cells 16HBE14o(-). Surprisingly, messenger RNA level of IFRD1 in CFBE41o(-) cells was found elevated. Treating CFBE41o(-) cells with the antioxidant glutathione rescued the IFRD1 protein level closer to control level and also reduced the pro-inflammatory cytokine IL-8 release. This work provides evidence for the first time of reduced level of IFRD1 protein in murine and human F508del-CFTR airway epithelial cell models, possibly mediated in response to oxidative stress which might contribute to the exaggerated inflammatory airway response observed in CF patients homozygous for the F508del mutation.

  20. 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

    2012-12-01

    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

  1. Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

    OpenAIRE

    De Stefano, Daniela; Villella, Valeria R.; Esposito, Speranza; Tosco, Antonella; Sepe, Angela; Gregorio, Fabiola De; Salvadori, Laura; Grassia, Rosa; Leone, Carlo A; Rosa, Giuseppe De; Maria C Maiuri; Pettoello-Mantovani, Massimo; Guido, Stefano; Bossi, Anna; Zolin, Anna

    2014-01-01

    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 CftrF508del homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-app...

  2. Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations.

    Science.gov (United States)

    Dekkers, Johanna F; Van Mourik, Peter; Vonk, Annelotte M; Kruisselbrink, Evelien; Berkers, Gitte; de Winter-de Groot, Karin M; Janssens, Hettie M; Bronsveld, Inez; van der Ent, Cornelis K; de Jonge, Hugo R; Beekman, Jeffrey M

    2016-09-01

    The potentiator VX-770 (ivacaftor/KALYDECO™) targets defective gating of CFTR and has been approved for treatment of cystic fibrosis (CF) subjects carrying G551D, S1251N or one of 8 other mutations. Still, the current potentiator treatment does not normalize CFTR-dependent biomarkers, indicating the need for development of more effective potentiator strategies. We have recently pioneered a functional CFTR assay in primary rectal organoids and used this model to characterize interactions between VX-770, genistein and curcumin, the latter 2 being natural food components with established CFTR potentiation capacities. Results indicated that all possible combinations of VX-770, genistein and curcumin synergistically repaired CFTR-dependent forskolin-induced swelling of organoids with CFTR-S1251N or CFTR-G551D, even under suboptimal CFTR activation and compounds concentrations, conditions that may predominate in vivo. Genistein and curcumin also enhanced forskolin-induced swelling of F508del homozygous organoids that were treated with VX-770 and the prototypical CFTR corrector VX-809. These results indicate that VX-770, genistein and curcumin in double or triple combinations can synergize in restoring CFTR-dependent fluid secretion in primary CF cells and support the use of multiple potentiators for treatment of CF.

  3. Mitochondrial DNA genetic diversity and LCT-13910 and deltaF508 CFTR alleles typing in the medieval sample from Poland.

    Science.gov (United States)

    Płoszaj, T; Jerszyńska, B; Jędrychowska-Dańska, K; Lewandowska, M; Kubiak, D; Grzywnowicz, K; Masłowska, A; Witas, H W

    2015-06-01

    We attempted to confirm the resemblance of a local medieval population and to reconstruct their contribution to the formation of the modern Polish population at the DNA level. The HVR I mtDNA sequence and two nuclear alleles, LCT-13910C/T SNP and deltaF508 CFTR, were chosen as markers since the distribution of selected nuclear alleles varies among ethnic groups. A total of 47 specimens were selected from a medieval cemetery in Cedynia (located in the western Polish lowland). Regarding the HVR I profile, the analyzed population differed from the present-day population (P = 0.045, F(st) = 0.0103), in contrast to lactase persistence (LP) based on the LCT-13910T allele, thus indicating the lack of notable frequency changes of this allele during the last millennium (P = 0.141). The sequence of the HVR I mtDNA fragment allowed to identify six major haplogroups including H, U5, T, K, and HV0 within the medieval population of Cedynia which are common in today's central Europe. An analysis of haplogroup frequency and its comparison with modern European populations shows that the studied medieval population is more closely related to Finno-Ugric populations than to the present Polish population. Identification of less common haplogroups, i.e., Z and U2, both atypical of the modern Polish population and of Asian origin, provides evidence for some kind of connections between the studied and foreign populations. Furthermore, a comparison of the available aDNA sequences from medieval Europe suggests that populations differed from one another and a number of data from other locations are required to find out more about the features of the medieval gene pool profile.

  4. Decoding F508del Misfolding in Cystic Fibrosis

    Directory of Open Access Journals (Sweden)

    Xiaodong Robert Wang

    2014-05-01

    Full Text Available The functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR, a plasma membrane chloride channel, leads to the development of cystic fibrosis. The deletion of a phenylalanine at residue 508 (F508del is the most common cause of CFTR misfolding leading to the disease. The F508del misfolding originates in the first nucleotide-binding domain (NBD1, which induces a global conformational change in CFTR through NBD1’s interactions with other domains. Such global misfolding produces a mutant chloride channel that is impaired in exocytic trafficking, peripheral stability, and channel gating. The nature and atomic details of F508del misfolding have been subject to extensive research during the past decade. Current data support a central role for NBD1 in F508del misfolding and rescue. Many cis-acting NBD1 second-site mutations rescue F508del misfolding in the context of full-length CFTR. While some of these mutations appear to specifically counteract the F508del-induced misfolding, others release certain inherent conformational constraints of the human wild-type CFTR. Several small-molecule correctors were recently found to act on key interdomain interfaces of F508del CFTR. Potential rational approaches have been proposed in an attempt to develop highly effective small molecule modulators that improve the cell surface functional expression of F508del CFTR.

  5. Carrier frequency of F508del mutation of cystic fibrosis in medical students from Universidad del Rosario, Bogotá, Colombia.

    Directory of Open Access Journals (Sweden)

    Heidi Eliana Mateus

    2009-11-01

    Full Text Available Introducción: La fibrosis quística es la enfermedad letal autosómica recesiva más frecuente en caucásicos, donde su incidencia es de 1 en 2000 nacidos vivos. Se debe a mutaciones en el gen CFTR, de las cuales la más frecuente es la F508del presente en 66% de los enfermos y en 1 de cada 25 personas sanas de origen caucásico. Objetivo: Identificar la tasa de portadores de la mutación F508del en una muestra de estudiantes de la Facultad de Medicina de la Universidad del Rosario. Materiales y métodos: Se determinó la presencia de la mutación F508del mediante PCR y análisis de heterodúplex en 110 estudiantes de IV y VII semestre de la Facultad de Medicina. Resultados: Se obtuvieron 4 heterocigotos para la mutación F508del, es decir, una frecuencia de portadores de 1 en 27 estudiantes. Conclusiones: La frecuencia de portadores de esta mutación en la población analizada es considerable, e indica que hay un alto número de personas en riesgo de heredar la enfermedad y que deben recibir asesoramiento genético. Es necesario aumentar el tamaño de la muestra para obtener datos representativos de la población colombiana.

  6. Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain.

    Science.gov (United States)

    Odolczyk, Norbert; Fritsch, Janine; Norez, Caroline; Servel, Nathalie; da Cunha, Melanie Faria; Bitam, Sara; Kupniewska, Anna; Wiszniewski, Ludovic; Colas, Julien; Tarnowski, Krzysztof; Tondelier, Danielle; Roldan, Ariel; Saussereau, Emilie L; Melin-Heschel, Patricia; Wieczorek, Grzegorz; Lukacs, Gergely L; Dadlez, Michal; Faure, Grazyna; Herrmann, Harald; Ollero, Mario; Becq, Frédéric; Zielenkiewicz, Piotr; Edelman, Aleksander

    2013-10-01

    The deletion of Phe508 (ΔF508) in the first nucleotide binding domain (NBD1) of CFTR is the most common mutation associated with cystic fibrosis. The ΔF508-CFTR mutant is recognized as improperly folded and targeted for proteasomal degradation. Based on molecular dynamics simulation results, we hypothesized that interaction between ΔF508-NBD1 and housekeeping proteins prevents ΔF508-CFTR delivery to the plasma membrane. Based on this assumption we applied structure-based virtual screening to identify new low-molecular-weight compounds that should bind to ΔF508-NBD1 and act as protein-protein interaction inhibitors. Using different functional assays for CFTR activity, we demonstrated that in silico-selected compounds induced functional expression of ΔF508-CFTR in transfected HeLa cells, human bronchial CF cells in primary culture, and in the nasal epithelium of homozygous ΔF508-CFTR mice. The proposed compounds disrupt keratin8-ΔF508-CFTR interaction in ΔF508-CFTR HeLa cells. Structural analysis of ΔF508-NBD1 in the presence of these compounds suggests their binding to NBD1. We conclude that our strategy leads to the discovery of new compounds that are among the most potent correctors of ΔF508-CFTR trafficking defect known to date.

  7. RNA Interference Screen to Identify Kinases That Suppress Rescue of ΔF508-CFTR.

    Science.gov (United States)

    Trzcińska-Daneluti, Agata M; Chen, Anthony; Nguyen, Leo; Murchie, Ryan; Jiang, Chong; Moffat, Jason; Pelletier, Lawrence; Rotin, Daniela

    2015-06-01

    Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the Cystic fibrosis transmembrane conductance regulator (CFTR). ΔF508-CFTR, the most common disease-causing CF mutant, exhibits folding and trafficking defects and is retained in the endoplasmic reticulum, where it is targeted for proteasomal degradation. To identify signaling pathways involved in ΔF508-CFTR rescue, we screened a library of endoribonuclease-prepared short interfering RNAs (esiRNAs) that target ∼750 different kinases and associated signaling proteins. We identified 20 novel suppressors of ΔF508-CFTR maturation, including the FGFR1. These were subsequently validated by measuring channel activity by the YFP halide-sensitive assay following shRNA-mediated knockdown, immunoblotting for the mature (band C) ΔF508-CFTR and measuring the amount of surface ΔF508-CFTR by ELISA. The role of FGFR signaling on ΔF508-CFTR trafficking was further elucidated by knocking down FGFRs and their downstream signaling proteins: Erk1/2, Akt, PLCγ-1, and FRS2. Interestingly, inhibition of FGFR1 with SU5402 administered to intestinal organoids (mini-guts) generated from the ileum of ΔF508-CFTR homozygous mice resulted in a robust ΔF508-CFTR rescue. Moreover, combination of SU5402 and VX-809 treatments in cells led to an additive enhancement of ΔF508-CFTR rescue, suggesting these compounds operate by different mechanisms. Chaperone array analysis on human bronchial epithelial cells harvested from ΔF508F508-CFTR transplant patients treated with SU5402 identified altered expression of several chaperones, an effect validated by their overexpression or knockdown experiments. We propose that FGFR signaling regulates specific chaperones that control ΔF508-CFTR maturation, and suggest that FGFRs may serve as important targets for therapeutic intervention for the treatment of CF.

  8. F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.

    Science.gov (United States)

    Pankow, Sandra; Bamberger, Casimir; Calzolari, Diego; Martínez-Bartolomé, Salvador; Lavallée-Adam, Mathieu; Balch, William E; Yates, John R

    2015-12-24

    Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (∆F508 CFTR) is the major cause of cystic fibrosis, one of the most common inherited childhood diseases. The mutated CFTR anion channel is not fully glycosylated and shows minimal activity in bronchial epithelial cells of patients with cystic fibrosis. Low temperature or inhibition of histone deacetylases can partly rescue ∆F508 CFTR cellular processing defects and function. A favourable change of ∆F508 CFTR protein-protein interactions was proposed as a mechanism of rescue; however, CFTR interactome dynamics during temperature shift and inhibition of histone deacetylases are unknown. Here we report the first comprehensive analysis of the CFTR and ∆F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, we identify 638 individual high-confidence CFTR interactors and discover a ∆F508 deletion-specific interactome, which is extensively remodelled upon rescue. Detailed analysis of the interactome remodelling identifies key novel interactors, whose loss promote ∆F508 CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. Our results demonstrate that global remodelling of ∆F508 CFTR interactions is crucial for rescue, and provide comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508.

  9. Targeting F508del-CFTR to develop rational new therapies for cystic fibrosis

    Institute of Scientific and Technical Information of China (English)

    Zhi-wei CAI; Jia LIU; Hong-yu LI; David N SHEPPARD

    2011-01-01

    The mutation F508del is the commonest cause of the genetic disease cystic fibrosis (CF). CF disrupts the function of many organs in the body, most notably the lungs, by perturbing salt and water transport across epithelial surfaces. F508del causes harm in two principal ways. First,the mutation prevents delivery of the cystic fibrosis transmembrane conductance regulator (CFTR) to its correct cellular location,the apical(lumen-facing) membrane of epithelial cells. Second, F508del perturbs the Cl- channel function of CFTR by disrupting channel gating. Here, we discuss the development of rational new therapies for CF that target F508del-CFTR.We highlight how structural studies provide new insight into the role of F508 in the regulation of channel gating by cycles of ATP binding and hydrolysis. We emphasize the use of high-throughput screening to identify lead compounds for therapy development.These compounds include CFTR correctors that restore the expression of F508del-CFTR at the apical membrane of epithelial cells and CFTR potentiators that rescue the F508del-CFTR gating defect. Initial results from clinical trials of CFTR correctors and potentiators augur well for the development of small molecule therapies that target the root cause of CF: mutations in CFTR.

  10. The ΔF508-CFTR mutation inhibits wild-type CFTR processing and function when co-expressed in human airway epithelia and in mouse nasal mucosa

    Directory of Open Access Journals (Sweden)

    Tucker Torry A

    2012-09-01

    Full Text Available Abstract Background Rescue or correction of CFTR function in native epithelia is the ultimate goal of CF therapeutics development. Wild-type (WT CFTR introduction and replacement is also of particular interest. Such therapies may be complicated by possible CFTR self-assembly into an oligomer or multimer. Results Surprisingly, functional CFTR assays in native airway epithelia showed that the most common CFTR mutant, ΔF508-CFTR (ΔF-CFTR, inhibits WT-CFTR when both forms are co-expressed. To examine more mechanistically, both forms of CFTR were transfected transiently in varying amounts into IB3-1 CF human airway epithelial cells and HEK-293 human embryonic kidney cells null for endogenous CFTR protein expression. Increasing amounts of ΔF-CFTR inhibited WT-CFTR protein processing and function in CF human airway epithelial cells but not in heterologous HEK-293 cells. Stably expressed ΔF-CFTR in clones of the non-CF human airway epithelial cell line, CALU-3, also showed reduction in cAMP-stimulated anion secretion and in WT-CFTR processing. An ultimate test of this dominant negative-like effect of ΔF-CFTR on WT-CFTR was the parallel study of two different CF mouse models: the ΔF-CFTR mouse and the bitransgenic CFTR mouse corrected in the gut but null in the lung and airways. WT/ΔF heterozygotes had an intermediate phenotype with regard to CFTR agonist responses in in vivo nasal potential difference (NPD recordings and in Ussing chamber recordings of short-circuit current (ISC in vitro on primary tracheal epithelial cells isolated from the same mice. In contrast, CFTR bitransgenic +/− heterozygotes had no difference in their responses versus +/+ wild-type mice. Conclusions Taken altogether, these data suggest that ΔF-CFTR and WT-CFTR co-assemble into an oligomeric macromolecular complex in native epithelia and share protein processing machinery and regulation at the level of the endoplasmic reticulum (ER. As a consequence, ΔF-CFTR slows WT

  11. Unravelling druggable signalling networks that control F508del-CFTR proteostasis.

    Science.gov (United States)

    Hegde, Ramanath Narayana; Parashuraman, Seetharaman; Iorio, Francesco; Ciciriello, Fabiana; Capuani, Fabrizio; Carissimo, Annamaria; Carrella, Diego; Belcastro, Vincenzo; Subramanian, Advait; Bounti, Laura; Persico, Maria; Carlile, Graeme; Galietta, Luis; Thomas, David Y; Di Bernardo, Diego; Luini, Alberto

    2015-12-23

    Cystic fibrosis (CF) is caused by mutations in CF transmembrane conductance regulator (CFTR). The most frequent mutation (F508del-CFTR) results in altered proteostasis, that is, in the misfolding and intracellular degradation of the protein. The F508del-CFTR proteostasis machinery and its homeostatic regulation are well studied, while the question whether 'classical' signalling pathways and phosphorylation cascades might control proteostasis remains barely explored. Here, we have unravelled signalling cascades acting selectively on the F508del-CFTR folding-trafficking defects by analysing the mechanisms of action of F508del-CFTR proteostasis regulator drugs through an approach based on transcriptional profiling followed by deconvolution of their gene signatures. Targeting multiple components of these signalling pathways resulted in potent and specific correction of F508del-CFTR proteostasis and in synergy with pharmacochaperones. These results provide new insights into the physiology of cellular proteostasis and a rational basis for developing effective pharmacological correctors of the F508del-CFTR defect.

  12. Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Bruce A Stanton

    Full Text Available P. aeruginosa is an opportunistic pathogen that chronically infects the lungs of 85% of adult patients with Cystic Fibrosis (CF. Previously, we demonstrated that P. aeruginosa reduced wt-CFTR Cl secretion by airway epithelial cells. Recently, a new investigational drug VX-809 has been shown to increase F508del-CFTR Cl secretion in human bronchial epithelial (HBE cells, and, in combination with VX-770, to increase FEV1 (forced expiratory volume in 1 second by an average of 3-5% in CF patients homozygous for the F508del-CFTR mutation. We propose that P. aeruginosa infection of CF lungs reduces VX-809 + VX-770- stimulated F508del-CFTR Cl secretion, and thereby reduces the clinical efficacy of VX-809 + VX-770.F508del-CFBE cells and primary cultures of CF-HBE cells (F508del/F508del were exposed to VX-809 alone or a combination of VX-809 + VX-770 for 48 hours and the effect of P. aeruginosa on F508del-CFTR Cl secretion was measured in Ussing chambers. The effect of VX-809 on F508del-CFTR abundance was measured by cell surface biotinylation and western blot analysis. PAO1, PA14, PAK and 6 clinical isolates of P. aeruginosa (3 mucoid and 3 non-mucoid significantly reduced drug stimulated F508del-CFTR Cl secretion, and plasma membrane F508del-CFTR.The observation that P. aeruginosa reduces VX-809 and VX-809 + VX-770 stimulated F508del CFTR Cl secretion may explain, in part, why VX-809 + VX-770 has modest efficacy in clinical trials.

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

    Science.gov (United States)

    Veit, Guido; Oliver, Kathryn; Apaja, Pirjo M; Perdomo, Doranda; Bidaud-Meynard, Aurélien; Lin, Sheng-Ting; Guo, Jingyu; Icyuz, Mert; Sorscher, Eric J; Hartman Iv, John L; Lukacs, Gergely L

    2016-05-01

    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.

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

    Directory of Open Access Journals (Sweden)

    Guido Veit

    2016-05-01

    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.

  15. Manipulating proteostasis to repair the F508del-CFTR defect in cystic fibrosis.

    Science.gov (United States)

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

    2016-12-01

    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.

  16. Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression.

    Science.gov (United States)

    Veit, Guido; Avramescu, Radu G; Perdomo, Doranda; Phuan, Puay-Wah; Bagdany, Miklos; Apaja, Pirjo M; Borot, Florence; Szollosi, Daniel; Wu, Yu-Sheng; Finkbeiner, Walter E; Hegedus, Tamas; Verkman, Alan S; Lukacs, Gergely L

    2014-07-23

    Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ΔF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ΔF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ΔF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ΔF508-CFTR density and function. VX-770-induced destabilization of ΔF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of ΔF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF.

  17. Trimethylangelicin promotes the functional rescue of mutant F508del CFTR protein in cystic fibrosis airway cells.

    Science.gov (United States)

    Favia, Maria; Mancini, Maria T; Bezzerri, Valentino; Guerra, Lorenzo; Laselva, Onofrio; Abbattiscianni, Anna C; Debellis, Lucantonio; Reshkin, Stephan J; Gambari, Roberto; Cabrini, Giulio; Casavola, Valeria

    2014-07-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) carrying the F508del mutation is retained in endoplasmic reticulum and fails to traffic to the cell surface where it functions as a protein kinase A (PKA)-activated chloride channel. Pharmacological correctors that rescue the trafficking of F508del CFTR may overcome this defect; however, the rescued F508del CFTR still displays reduced chloride permeability. Therefore, a combined administration of correctors and potentiators of the gating defect is ideal. We recently found that 4,6,4'-trimethylangelicin (TMA), besides inhibiting the expression of the IL-8 gene in airway cells in which the inflammatory response was challenged with Pseudomonas aeruginosa, also potentiates the cAMP/PKA-dependent activation of wild-type CFTR or F508del CFTR that has been restored to the plasma membrane. Here, we demonstrate that long preincubation with nanomolar concentrations of TMA is able to effectively rescue both F508del CFTR-dependent chloride secretion and F508del CFTR cell surface expression in both primary or secondary airway cell monolayers homozygous for F508del mutation. The correction effect of TMA seems to be selective for CFTR and persisted for 24 h after washout. Altogether, the results suggest that TMA, besides its anti-inflammatory and potentiator activities, also displays corrector properties.

  18. Synonymous codon usage affects the expression of wild type and F508del CFTR.

    Science.gov (United States)

    Shah, Kalpit; Cheng, Yi; Hahn, Brian; Bridges, Robert; Bradbury, Neil A; Mueller, David M

    2015-03-27

    The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel composed of 1480 amino acids. The major mutation responsible for cystic fibrosis results in loss of amino acid residue, F508 (F508del). Loss of F508 in CFTR alters the folding pathway resulting in endoplasmic-reticulum-associated degradation. This study investigates the role of synonymous codon in the expression of CFTR and CFTR F508del in human HEK293 cells. DNA encoding the open reading frame (ORF) for CFTR containing synonymous codon replacements was expressed using a heterologous vector integrated into the genome. The results indicate that the codon usage greatly affects the expression of CFTR. While the promoter strength driving expression of the ORFs was largely unchanged and the mRNA half-lives were unchanged, the steady-state levels of the mRNA varied by as much as 30-fold. Experiments support that this apparent inconsistency is attributed to nonsense mediated decay independent of exon junction complex. The ratio of CFTR/mRNA indicates that mRNA containing native codons was more efficient in expressing mature CFTR as compared to mRNA containing synonymous high-expression codons. However, when F508del CFTR was expressed after codon optimization, a greater percentage of the protein escaped endoplasmic-reticulum-associated degradation resulting in considerable levels of mature F508del CFTR on the plasma membrane, which showed channel activity. These results indicate that codon usage has an effect on mRNA levels and protein expression, for CFTR, and likely on chaperone-assisted folding pathway, for F508del CFTR.

  19. An unexpected effect of TNF-α on F508del-CFTR maturation and function.

    Science.gov (United States)

    Bitam, Sara; Pranke, Iwona; Hollenhorst, Monika; Servel, Nathalie; Moquereau, Christelle; Tondelier, Danielle; Hatton, Aurélie; Urbach, Valérie; Sermet-Gaudelus, Isabelle; Hinzpeter, Alexandre; Edelman, Aleksander

    2015-01-01

    Cystic fibrosis (CF) is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR), which encodes a cAMP-dependent Cl (-) channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT) CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml) of F508del-CFTR-transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE) leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon TNFα is sustained, in HBE cells, for at least 24 h. The underlying mechanism of action involves a protein kinase C (PKC) signaling pathway, and occurs through insertion of vesicles containing F508del-CFTR to the plasma membrane, with TNFα behaving as a corrector molecule. In conclusion, a novel and unexpected action of TNFα has been discovered and points to the importance of systematic studies on the roles of inflammatory mediators in the maturation of abnormally folded proteins in general and in the context of CF in particular.

  20. A truncated CFTR protein rescues endogenous ΔF508-CFTR and corrects chloride transport in mice

    OpenAIRE

    Cormet-Boyaka, Estelle; Hong, Jeong S.; Berdiev, Bakhram K.; Fortenberry, James A.; Rennolds, Jessica; Clancy, J. P.; Benos, Dale J.; Boyaka, Prosper N.; Eric J Sorscher

    2009-01-01

    Cystic fibrosis (CF) is most frequently associated with deletion of phenylalanine at position 508 (ΔF508) in the CF transmembrane conductance regulator (CFTR) protein. The ΔF508-CFTR mutant protein exhibits a folding defect that affects its processing and impairs chloride-channel function. This study aimed to determine whether CFTR fragments approximately half the size of wild-type CFTR and complementary to the portion of CFTR bearing the mutation can specifically rescue the processing of end...

  1. Reduced blood pressure of CFTR-F508del carriers correlates with diminished arterial reactivity rather than circulating blood volume in mice.

    Directory of Open Access Journals (Sweden)

    Veronica A Peotta

    Full Text Available The F508del mutation of the cystic fibrosis transmembrane conductance regulator (CFTR is the most common cause of cystic fibrosis (CF. Both CF patients and F508del carriers have decreased blood pressure. While this has been attributed to salt depletion, recent studies have shown F508del expression interferes with smooth muscle cell calcium mobilization. We tested the hypothesis that carriers of the F508del mutation have lower adult blood pressures and reduced aortic contractility without a reduction in circulating blood volume. By radiotelemetry, F508del heterozygous mice had significantly lower arterial pressures than wild-type C57BL/6 controls, with the greatest effect seen at the time of dark-to-light cycle transition (mean difference of 10 mmHg. To replicate the vascular effects of sympathetic arousal, isoproterenol and epinephrine were co-infused, and F508del mice again had significantly reduced arterial pressures. Aortas isolated from F508del heterozygous mice had significantly decreased constriction to noradrenaline (0.9 ± 0.2 versus 2.9 ± 0.7 mN. Inhibition of wild-type CFTR or the inositol triphosphate receptor replicated the phenotype of F508del aortas. CFTR carrier status did not alter circulating blood volume. We conclude the CFTR-F508del mutation decreases aortic contractility and lowers arterial pressures. As a cAMP-activated chloride channel that facilitates calcium mobilization, we speculate wild-type CFTR co-activation during adrenergic receptor stimulation buffers the vasodilatory response to catecholamines, and loss of this compensatory vasoconstrictor tone may contribute to the lower arterial pressures seen in heterozygote carriers of a CFTR-F508del mutation.

  2. Potentiation of ΔF508- and G551D-CFTR-Mediated Cl- Current by Novel Hydroxypyrazolines.

    Directory of Open Access Journals (Sweden)

    Jinhong Park

    Full Text Available The most common mutation of CFTR, affecting approximately 90% of CF patients, is a deletion of phenylalanine at position 508 (F508del, ΔF508. Misfolding of ΔF508-CFTR impairs both its trafficking to the plasma membrane and its chloride channel activity. To identify small molecules that can restore channel activity of ΔF508-CFTR, we synthesized and evaluated eighteen novel hydroxypyrazoline analogues as CFTR potentiators. To elucidate potentiation activities of hydroxypyrazolines for ΔF508-CFTR, CFTR activity was measured using a halide-sensitive YFP assay, Ussing chamber assay and patch-clamp technique. Compounds 7p, 7q and 7r exhibited excellent potentiation with EC50 value <10 μM. Among the compounds, 7q (a novel CFTR potentiator, CP7q showed the highest potentiation activity with EC50 values of 0.88 ± 0.11 and 4.45 ± 0.31 μM for wild-type and ΔF508-CFTR, respectively. In addition, CP7q significantly potentiated chloride conductance of G551D-CFTR, a CFTR gating mutant; its maximal potentiation activity was 1.9 fold higher than the well-known CFTR potentiator genistein. Combination treatment with CP7q and VX-809, a corrector of ΔF508-CFTR, significantly enhanced functional rescue of ΔF508-CFTR compared with VX-809 alone. CP7q did not alter the cytosolic cAMP level and showed no cytotoxicity at the concentration showing maximum efficacy. The hydroxypyrazolines may be potential development candidates for drug therapy of cystic fibrosis.

  3. Potentiation of ΔF508- and G551D-CFTR-Mediated Cl- Current by Novel Hydroxypyrazolines.

    Science.gov (United States)

    Park, Jinhong; Khloya, Poonam; Seo, Yohan; Kumar, Satish; Lee, Ho K; Jeon, Dong-Kyu; Jo, Sungwoo; Sharma, Pawan K; Namkung, Wan

    2016-01-01

    The most common mutation of CFTR, affecting approximately 90% of CF patients, is a deletion of phenylalanine at position 508 (F508del, ΔF508). Misfolding of ΔF508-CFTR impairs both its trafficking to the plasma membrane and its chloride channel activity. To identify small molecules that can restore channel activity of ΔF508-CFTR, we synthesized and evaluated eighteen novel hydroxypyrazoline analogues as CFTR potentiators. To elucidate potentiation activities of hydroxypyrazolines for ΔF508-CFTR, CFTR activity was measured using a halide-sensitive YFP assay, Ussing chamber assay and patch-clamp technique. Compounds 7p, 7q and 7r exhibited excellent potentiation with EC50 value CFTR potentiator, CP7q) showed the highest potentiation activity with EC50 values of 0.88 ± 0.11 and 4.45 ± 0.31 μM for wild-type and ΔF508-CFTR, respectively. In addition, CP7q significantly potentiated chloride conductance of G551D-CFTR, a CFTR gating mutant; its maximal potentiation activity was 1.9 fold higher than the well-known CFTR potentiator genistein. Combination treatment with CP7q and VX-809, a corrector of ΔF508-CFTR, significantly enhanced functional rescue of ΔF508-CFTR compared with VX-809 alone. CP7q did not alter the cytosolic cAMP level and showed no cytotoxicity at the concentration showing maximum efficacy. The hydroxypyrazolines may be potential development candidates for drug therapy of cystic fibrosis.

  4. Rescue of F508del-CFTR by RXR motif inactivation triggers proteome modulation associated with the unfolded protein response.

    Science.gov (United States)

    Gomes-Alves, Patrícia; Couto, Francisco; Pesquita, Cátia; Coelho, Ana V; Penque, Deborah

    2010-04-01

    F508del-CFTR, the most common mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, disrupts intracellular trafficking leading to cystic fibrosis (CF). The trafficking defect of F508del-CFTR can be rescued by simultaneous inactivation of its four RXR motifs (4RK). Proteins involved in the F508del-CFTR trafficking defect and/or rescue are therefore potential CF therapeutic targets. We sought to identify these proteins by investigating differential proteome modulation in BHK cells over-expressing wt-CFTR, F508del-CFTR or the revertant F508del/4RK-CFTR. By 2-dimensional electrophoresis-based proteomics and western blot approaches we demonstrated that over-expression of F508del/4RK-CFTR modulates the expression of a large number of proteins, many of which are reported interactors of CFTR and/or 14-3-3 with potential roles in CFTR trafficking. GRP78/BiP, a marker of ER stress and unfolded protein response (UPR), is up-regulated in cells over-expressing either F508del-CFTR or F598del/4RK-CFTR. However, over-expression of F508del/4RK-CFTR induces the up-regulation of many other UPR-associated proteins (e.g. GRP94, PDI, GRP75/mortalin) and, interestingly, the down-regulation of proteasome components associated with CFTR degradation, such as the proteasome activator PA28 (PSME2) and COP9 signalosome (COPS5/CSN5). Moreover, the F508del-CFTR-induced proteostasis imbalance, which involves some heat shock chaperones (e.g. HSP72/Hpa2), ER-EF-hand Ca(2+)-binding proteins (calumenin) and the proteasome activator PA28 (PSME2), tends to be 'restored', i.e., in BHK cells over-expressing F508del/4RK-CFTR those proteins tend to have expression levels similar to the wild-type ones. These findings indicate that a particular cellular environment orchestrated by the UPR contributes to and/or is compatible with F508del/4RK-CFTR rescue.

  5. Lumacaftor alone and combined with ivacaftor: preclinical and clinical trial experience of F508del CFTR correction.

    Science.gov (United States)

    Brewington, John J; McPhail, Gary L; Clancy, John P

    2016-01-01

    Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR), leading to significant morbidity and mortality. CFTR is a chloride and bicarbonate channel at the epithelial cell membrane. The most common CFTR mutation is F508del, resulting in minimal CFTR at the plasma membrane. Current disease management is supportive, whereas an ultimate goal is to develop therapies to restore CFTR activity. We summarize experience with lumacaftor, a small molecule that increases F508del-CFTR levels at the plasma membrane. Lumacaftor in combination with ivacaftor, a modulator of CFTR gating defects, improves clinical outcome measures in patients homozygous for the F508del mutation. Lumacaftor represents a significant advancement in the treatment of biochemical abnormalities in CF. Further development of CFTR modulators will improve upon current therapies, although it remains unclear whether this approach will provide therapies for all CFTR mutations.

  6. miR-16 rescues F508del-CFTR function in native cystic fibrosis epithelial cells.

    Science.gov (United States)

    Kumar, P; Bhattacharyya, S; Peters, K W; Glover, M L; Sen, A; Cox, R T; Kundu, S; Caohuy, H; Frizzell, R A; Pollard, H B; Biswas, R

    2015-11-01

    Cystic fibrosis (CF) is due to mutations in the CFTR gene, which prevents correct folding, trafficking and function of the mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. The dysfunctional effect of CFTR mutations, principally the F508del-CFTR mutant, is further manifested by hypersecretion of the pro-inflammatory chemokine interleukin-8 into the airway lumen, which further contributes to morbidity and mortality. We have hypothesized that microRNA (miR)-based therapeutics could rescue the dysfunctional consequences of mutant CFTR. Here we report that a miR-16 mimic can effectively rescue F508del-CFTR protein function in airway cell lines and primary cultures, of differentiated human bronchial epithelia from F508del homozygotes, which express mutant CFTR endogenously. We also identify two other miRs, miR-1 and miR-302a, which are also active. Although miR-16 is expressed at basal comparable levels in CF and control cells, miR-1 and miR-302a are undetectable. When miR mimics are expressed in CF lung or pancreatic cells, the expression of the F508del-CFTR protein is significantly increased. Importantly, miR-16 promotes functional rescue of the cyclic AMP-activated apical F508del-CFTR chloride channel in primary lung epithelial cells from CF patients. We interpret these findings to suggest that these miRs may constitute novel targets for CF therapy.

  7. Combination of Correctors Rescue ΔF508-CFTR by Reducing Its Association with Hsp40 and Hsp27.

    Science.gov (United States)

    Lopes-Pacheco, Miquéias; Boinot, Clément; Sabirzhanova, Inna; Morales, Marcelo M; Guggino, William B; Cebotaru, Liudmila

    2015-10-16

    Correcting the processing of ΔF508-CFTR, the most common mutation in cystic fibrosis, is the major goal in the development of new therapies for this disease. Here, we determined whether ΔF508 could be rescued by a combination of small-molecule correctors, and identified the mechanism by which correctors rescue the trafficking mutant of cystic fibrosis transmembrane conductance regulator (CFTR). We transfected COS-7 cells with ΔF508, created HEK-293 stably expressing ΔF508, and utilized CFBE41o(-) cell lines stably transduced with ΔF508. As shown previously, ΔF508 expressed less protein, was unstable at physiological temperature, and rapidly degraded. When the cells were treated with the combination C18 + C4 the mature C-band was expressed at the cell surface. After treatment with C18 + C4, we saw a lower rate of protein disappearance after translation was stopped with cycloheximide. To understand how this rescue occurs, we evaluated the change in the binding of proteins involved in endoplasmic reticulum-associated degradation, such as Hsp27 (HspB1) and Hsp40 (DnaJ). We saw a dramatic reduction in binding to heat shock proteins 27 and 40 following combined corrector therapy. siRNA experiments confirmed that a reduction in Hsp27 or Hsp40 rescued CFTR in the ΔF508 mutant, but the rescue was not additive or synergistic with C4 + 18 treatment, indicating these correctors shared a common pathway for rescue involving a network of endoplasmic reticulum-associated degradation proteins.

  8. BAP31 interacts with Sec61 translocons and promotes retrotranslocation of CFTRDeltaF508 via the derlin-1 complex.

    Science.gov (United States)

    Wang, Bing; Heath-Engel, Hannah; Zhang, Donglei; Nguyen, Nhi; Thomas, David Y; Hanrahan, John W; Shore, Gordon C

    2008-06-13

    BAP31 is an endoplasmic reticulum protein-sorting factor that associates with newly synthesized integral membrane proteins and controls their fate (i.e., egress, retention, survival, or degradation). BAP31 is itself an integral membrane protein and a constituent of several large protein complexes. Here, we show that a part of the BAP31 population interacts with two components of the Sec61 preprotein translocon, Sec61beta and TRAM. BAP31 associates with the N terminus of one of its newly synthesized client proteins, the DeltaF508 mutant of CFTR, and promotes its retrotranslocation from the ER and degradation by the cytoplasmic 26S proteasome system. Depletion of BAP31 reduces the proteasomal degradation of DeltaF508 and permits a significant fraction of the surviving protein to reach the cell surface. Of note, BAP31 also associates physically and functionally with the Derlin-1 protein disclocation complex in the DeltaF508 degradation pathway. Thus, BAP31 operates at early steps to deliver newly synthesized CFTRDeltaF508 to its degradation pathway.

  9. Increasing the Endoplasmic Reticulum Pool of the F508del Allele of the Cystic Fibrosis Transmembrane Conductance Regulator Leads to Greater Folding Correction by Small Molecule Therapeutics

    Science.gov (United States)

    Chung, W. Joon; Goeckeler-Fried, Jennifer L.; Havasi, Viktoria; Chiang, Annette; Rowe, Steven M.; Plyler, Zackery E.; Hong, Jeong S.; Mazur, Marina; Piazza, Gary A.; Keeton, Adam B.; White, E. Lucile; Rasmussen, Lynn; Weissman, Allan M.; Denny, R. Aldrin; Brodsky, Jeffrey L.; Sorscher, Eric J.

    2016-01-01

    Small molecules that correct the folding defects and enhance surface localization of the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) comprise an important therapeutic strategy for cystic fibrosis lung disease. However, compounds that rescue the F508del mutant protein to wild type (WT) levels have not been identified. In this report, we consider obstacles to obtaining robust and therapeutically relevant levels of F508del CFTR. For example, markedly diminished steady state amounts of F508del CFTR compared to WT CFTR are present in recombinant bronchial epithelial cell lines, even when much higher levels of mutant transcript are present. In human primary airway cells, the paucity of Band B F508del is even more pronounced, although F508del and WT mRNA concentrations are comparable. Therefore, to augment levels of “repairable” F508del CFTR and identify small molecules that then correct this pool, we developed compound library screening protocols based on automated protein detection. First, cell-based imaging measurements were used to semi-quantitatively estimate distribution of F508del CFTR by high content analysis of two-dimensional images. We evaluated ~2,000 known bioactive compounds from the NIH Roadmap Molecular Libraries Small Molecule Repository in a pilot screen and identified agents that increase the F508del protein pool. Second, we analyzed ~10,000 compounds representing diverse chemical scaffolds for effects on total CFTR expression using a multi-plate fluorescence protocol and describe compounds that promote F508del maturation. Together, our findings demonstrate proof of principle that agents identified in this fashion can augment the level of endoplasmic reticulum (ER) resident “Band B” F508del CFTR suitable for pharmacologic correction. As further evidence in support of this strategy, PYR-41—a compound that inhibits the E1 ubiquitin activating enzyme—was shown to synergistically enhance F508del rescue by C

  10. Rescue of Murine F508del CFTR Activity in Native Intestine by Low Temperature and Proteasome Inhibitors

    NARCIS (Netherlands)

    M. Wilke (Martina); A.G. Bot (Alice); H. Jorna (Huub); B.J. Scholte (Bob); H.R. de Jonge (Hugo)

    2012-01-01

    textabstractMost patients with Cystic Fibrosis (CF) carry at least one allele with the F508del mutation, resulting in a CFTR chloride channel protein with a processing, gating and stability defect, but with substantial residual activity when correctly sorted to the apical membranes of epithelial cel

  11. Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators protect G551D but not ΔF508 CFTR from thermal instability.

    Science.gov (United States)

    Liu, Xuehong; Dawson, David C

    2014-09-01

    The G551D cystic fibrosis transmembrane conductance regulator (CFTR) mutation is associated with severe disease in ∼5% of cystic fibrosis patients worldwide. This amino acid substitution in NBD1 results in a CFTR chloride channel characterized by a severe gating defect that can be at least partially overcome in vitro by exposure to a CFTR potentiator. In contrast, the more common ΔF508 mutation is associated with a severe protein trafficking defect, as well as impaired channel function. Recent clinical trials demonstrated a beneficial effect of the CFTR potentiator, Ivacaftor (VX-770), on lung function of patients bearing at least one copy of G551D CFTR, but no comparable effect on ΔF508 homozygotes. This difference in efficacy was not surprising in view of the established difference in the molecular phenotypes of the two mutant channels. Recently, however, it was shown that the structural defect introduced by the deletion of F508 is associated with the thermal instability of ΔF508 CFTR channel function in vitro. This additional mutant phenotype raised the possibility that the differences in the behavior of ΔF508 and G551D CFTR, as well as the disparate efficacy of Ivacaftor, might be a reflection of the differing thermal stabilities of the two channels at 37 °C. We compared the thermal stability of G551D and ΔF508 CFTR in Xenopus oocytes in the presence and absence of CTFR potentiators. G551D CFTR exhibited a thermal instability that was comparable to that of ΔF508 CFTR. G551D CFTR, however, was protected from thermal instability by CFTR potentiators, whereas ΔF508 CFTR was not. These results suggest that the efficacy of VX-770 in patients bearing the G551D mutation is due, at least in part, to the ability of the small molecule to protect the mutant channel from thermal instability at human body temperature.

  12. Isoxazolopyrimidines as Novel ΔF508-CFTR Correctors.

    Science.gov (United States)

    Yu, Gui Jun; Yang, Baoxue; Verkman, A S; Kurth, Mark J

    2010-04-01

    Using a cell-based high-throughput screen, we identified isoxazolo[5,4-d]pyrimidines as novel small-molecule correctors of the cystic fibrosis mutant protein ΔF508-CFTR. 22 Isoxazolo[5,4-d]pyrimidine analogues were synthesized and tested. Synthesis of the key intermediate, 5-amino-3-arylisoxazole-4-carboxamide, was accomplished by nitrile oxide cycloaddition to (2-amino-1-cyano-2-oxoethyl)sodium. Formation of 3-arylisoxazolo-[5,4-d]pyrimidin-4(5H)-one and chlorination gave 4-chloro-3-arylisoxazolo[5,4-d]pyrimidine. Finally, functionalization at C-4 of the pyrimidine ring by nucleophilic substitution gave the targeted isoxazolo[5,4-d]pyrimidines. Six of the reported analogues had low micromolar potency for increasing halide transport in ΔF508-CFTR cells.

  13. Increased NF-κB Activity and Decreased Wnt/β-Catenin Signaling Mediate Reduced Osteoblast Differentiation and Function in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mice.

    Science.gov (United States)

    Le Henaff, Carole; Mansouri, Rafik; Modrowski, Dominique; Zarka, Mylène; Geoffroy, Valérie; Marty, Caroline; Tarantino, Nadine; Laplantine, Emmanuel; Marie, Pierre J

    2015-07-17

    The prevalent human ΔF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is associated with reduced bone formation and bone loss in mice. The molecular mechanisms by which the ΔF508-CFTR mutation causes alterations in bone formation are poorly known. In this study, we analyzed the osteoblast phenotype in ΔF508-CFTR mice and characterized the signaling mechanisms underlying this phenotype. Ex vivo studies showed that the ΔF508-CFTR mutation negatively impacted the differentiation of bone marrow stromal cells into osteoblasts and the activity of osteoblasts, demonstrating that the ΔF508-CFTR mutation alters both osteoblast differentiation and function. Treatment with a CFTR corrector rescued the abnormal collagen gene expression in ΔF508-CFTR osteoblasts. Mechanistic analysis revealed that NF-κB signaling and transcriptional activity were increased in mutant osteoblasts. Functional studies showed that the activation of NF-κB transcriptional activity in mutant osteoblasts resulted in increased β-catenin phosphorylation, reduced osteoblast β-catenin expression, and altered expression of Wnt/β-catenin target genes. Pharmacological inhibition of NF-κB activity or activation of canonical Wnt signaling rescued Wnt target gene expression and corrected osteoblast differentiation and function in bone marrow stromal cells and osteoblasts from ΔF508-CFTR mice. Overall, the results show that the ΔF508-CFTR mutation impairs osteoblast differentiation and function as a result of overactive NF-κB and reduced Wnt/β-catenin signaling. Moreover, the data indicate that pharmacological inhibition of NF-κB or activation of Wnt/β-catenin signaling can rescue the abnormal osteoblast differentiation and function induced by the prevalent ΔF508-CFTR mutation, suggesting novel therapeutic strategies to correct the osteoblast dysfunctions in cystic fibrosis.

  14. Rattlesnake Phospholipase A2 Increases CFTR-Chloride Channel Current and Corrects ∆F508CFTR Dysfunction: Impact in Cystic Fibrosis.

    Science.gov (United States)

    Faure, Grazyna; Bakouh, Naziha; Lourdel, Stéphane; Odolczyk, Norbert; Premchandar, Aiswarya; Servel, Nathalie; Hatton, Aurélie; Ostrowski, Maciej K; Xu, Haijin; Saul, Frederick A; Moquereau, Christelle; Bitam, Sara; Pranke, Iwona; Planelles, Gabrielle; Teulon, Jacques; Herrmann, Harald; Roldan, Ariel; Zielenkiewicz, Piotr; Dadlez, Michal; Lukacs, Gergely L; Sermet-Gaudelus, Isabelle; Ollero, Mario; Corringer, Pierre-Jean; Edelman, Aleksander

    2016-07-17

    Deletion of Phe508 in the nucleotide binding domain (∆F508-NBD1) of the cystic fibrosis transmembrane regulator (CFTR; a cyclic AMP-regulated chloride channel) is the most frequent mutation associated with cystic fibrosis. This mutation affects the maturation and gating of CFTR protein. The search for new high-affinity ligands of CFTR acting as dual modulators (correctors/activators) presents a major challenge in the pharmacology of cystic fibrosis. Snake venoms are a rich source of natural multifunctional proteins, potential binders of ion channels. In this study, we identified the CB subunit of crotoxin from Crotalus durissus terrificus as a new ligand and allosteric modulator of CFTR. We showed that CB interacts with NBD1 of both wild type and ∆F508CFTR and increases their chloride channel currents. The potentiating effect of CB on CFTR activity was demonstrated using electrophysiological techniques in Xenopus laevis oocytes, in CFTR-HeLa cells, and ex vivo in mouse colon tissue. The correcting effect of CB was shown by functional rescue of CFTR activity after 24-h ΔF508CFTR treatments with CB. Moreover, the presence of fully glycosylated CFTR was observed. Molecular docking allowed us to propose a model of the complex involving of the ABCβ and F1-like ATP-binding subdomains of ΔF508-NBD1. Hydrogen-deuterium exchange analysis confirmed stabilization in these regions, also showing allosteric stabilization in two other distal regions. Surface plasmon resonance competition studies showed that CB disrupts the ∆F508CFTR-cytokeratin 8 complex, allowing for the escape of ∆F508CFTR from degradation. Therefore CB, as a dual modulator of ΔF508CFTR, constitutes a template for the development of new anti-CF agents.

  15. Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation.

    Science.gov (United States)

    De Braekeleer, M; Allard, C; Leblanc, J P; Simard, F; Aubin, G

    1997-12-01

    Cystic fibrosis (CF) has a high incidence in the French-Canadian population of Saguenay Lac-Saint-Jean (Quebec). The A455E mutation accounts for 8.3% of the CF chromosomes. This mutation was shown to be associated with a milder lung disease in the Dutch population. Twenty two CF patients distributed in 17 families and compound heterozygotes for the A455E mutation have been followed at the Clinique de Fibrose Kystique de Chicoutimi. Fourteen patients also carried the delta F508 mutation while the remaining eight patients had the 621 + 1G-->T mutation. Each patient was matched by sex and age to a patient homozygous for the delta F508 mutation. The pairs were analyzed for several clinical and laboratory variables. The A455E compound heterozygotes were diagnosed at a later age (P = 0.003) and had chloride concentrations at the sweat test lower than those homozygous for the delta F508 mutation (P = 0.007). More patients were pancreatic sufficient (P = 0.004). They had a higher Shwachman score (P = 0.001) and better pulmonary function tests (P < 0.02). CF patients compound heterozygous for the A455E mutation have a milder pancreatic and lung disease than the delta F508 homozygotes. Therefore, the A455E should be associated with a better prognosis.

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

    Science.gov (United States)

    Tripathi, Rashmi; Benz, Nathalie; Culleton, Bridget; Trouvé, Pascal; Férec, Claude

    2014-01-01

    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 IDPs and is

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

    Directory of Open Access Journals (Sweden)

    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

  18. F508del-CFTR rescue: a matter of cell stress response.

    Science.gov (United States)

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

    2013-01-01

    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.

  19. Natural Compound Curcumin-a Channel Potentiator Rather Than a Corrector of the Defective Intracellular Processing of △F508 Mutant Cystic Fibrosis Transmembrane Conductance Regulator

    Institute of Scientific and Technical Information of China (English)

    LIU Xin; GUAN Li; HE Cheng-yan; ZHANG Xiao-jing; XU Li-na; SHANG De-jing; MA Tong-hui; YANG Hong

    2008-01-01

    Cystic fibrosis(CF)is a severe genetic disease caused by the gene mutation of the cystic fibrosis transmembrane conductance regulator(CFTR)chloride channel.The most common point mutationF508,which leads to impaired intracellular processing and channel gating of CFTR, appears in about 90%CF patients.The natural compound curcumin was reported to correct the processing defect of △F508-CFTR and proposed as a potential therapeutic drug to cure CF.In the present study.we analyzed the efrect of curcumin on △F508-CFTR and demonstrated that curcumin can restore the impaired chloride conductance of △F508 mutant CFTR.The activity is rapid,reversible and cAMP-dependent.However,we couldn't reproduce the previously reported correction of the defective membrane trafficking of △F508-CFTR by curcumin.Therefore,curcumin may not be a superior lead compound for developing anti-CF drugs.

  20. Roscovitine is a proteostasis regulator that corrects the trafficking defect of F508del-CFTR by a CDK-independent mechanism.

    Science.gov (United States)

    Norez, C; Vandebrouck, C; Bertrand, J; Noel, S; Durieu, E; Oumata, N; Galons, H; Antigny, F; Chatelier, A; Bois, P; Meijer, L; Becq, F

    2014-11-01

    The most common mutation in cystic fibrosis (CF), F508del, causes defects in trafficking, channel gating and endocytosis of the CF transmembrane conductance regulator (CFTR) protein. Because CF is an orphan disease, therapeutic strategies aimed at improving mutant CFTR functions are needed to target the root cause of CF. Human CF airway epithelial cells were treated with roscovitine 100 μM for 2 h before CFTR maturation, expression and activity were examined. The mechanism of action of roscovitine was explored by recording the effect of depleting endoplasmic reticulum (ER) Ca(2+) on the F508del-CFTR/calnexin interaction and by measuring proteasome activity. Of the cyclin-dependent kinase (CDK) inhibitors investigated, roscovitine was found to restore the cell surface expression and defective channel function of F508del-CFTR in human CF airway epithelial cells. Neither olomoucine nor (S)-CR8, two very efficient CDK inhibitors, corrected F508del-CFTR trafficking demonstrating that the correcting effect of roscovitine was independent of CDK inhibition. Competition studies with inhibitors of the ER quality control (ERQC) indicated that roscovitine acts on the calnexin pathway and on the degradation machinery. Roscovitine was shown (i) to partially inhibit the interaction between F508del-CFTR and calnexin by depleting ER Ca(2+) and (ii) to directly inhibit the proteasome activity in a Ca(2+) -independent manner. Roscovitine is able to correct the defective function of F508del-CFTR by preventing the ability of the ERQC to interact with and degrade F508del-CFTR via two synergistic but CDK-independent mechanisms. Roscovitine has potential as a pharmacological therapy for CF. © 2014 The British Pharmacological Society.

  1. Synergy-based small-molecule screen using a human lung epithelial cell line yields ΔF508-CFTR correctors that augment VX-809 maximal efficacy.

    Science.gov (United States)

    Phuan, Puay-Wah; Veit, Guido; Tan, Joseph; Roldan, Ariel; Finkbeiner, Walter E; Lukacs, Gergely L; Verkman, A S

    2014-07-01

    The most prevalent cystic fibrosis transmembrane conductance regulator (CFTR) mutation causing cystic fibrosis, ΔF508, impairs folding of nucleotide binding domain (NBD) 1 and stability of the interface between NBD1 and the membrane-spanning domains. The interfacial stability defect can be partially corrected by the investigational drug VX-809 (3-[6-[[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl]amino]-3-methyl-2-pyridinyl]-benzoic acid) or the R1070W mutation. Second-generation ΔF508-CFTR correctors are needed to improve on the modest efficacy of existing cystic fibrosis correctors. We postulated that a second corrector targeting a distinct folding/interfacial defect might act in synergy with VX-809 or the R1070W suppressor mutation. A biochemical screen for ΔF508-CFTR cell surface expression was developed in a human lung epithelium-derived cell line (CFBE41o(-)) by expressing chimeric CFTRs with a horseradish peroxidase (HRP) in the fourth exofacial loop in either the presence or absence of R1070W. Using a luminescence readout of HRP activity, screening of approximately 110,000 small molecules produced nine novel corrector scaffolds that increased cell surface ∆F508-CFTR expression by up to 200% in the presence versus absence of maximal VX-809. Further screening of 1006 analogs of compounds identified from the primary screen produced 15 correctors with an EC50 VX-809 in restoring chloride permeability in ∆F508-expressing A549 cells. An aminothiazole increased chloride conductance in human bronchial epithelial cells from a ΔF508 homozygous subject beyond that of maximal VX-809. Mechanistic studies suggested that NBD2 is required for the aminothiazole rescue. Our results provide proof of concept for synergy screening to identify second-generation correctors, which, when used in combination, may overcome the "therapeutic ceiling" of first-generation correctors.

  2. Function and regulation of TRPM7, as well as intracellular magnesium content, are altered in cells expressing ΔF508-CFTR and G551D-CFTR.

    Science.gov (United States)

    Huguet, F; Calvez, M L; Benz, N; Le Hir, S; Mignen, O; Buscaglia, P; Horgen, F D; Férec, C; Kerbiriou, M; Trouvé, P

    2016-09-01

    Cystic fibrosis (CF), one of the most common fatal hereditary disorders, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene product is a multidomain adenosine triphosphate-binding cassette (ABC) protein that functions as a chloride (Cl(-)) channel that is regulated by intracellular magnesium [Mg(2+)]i. The most common mutations in CFTR are a deletion of a phenylalanine residue at position 508 (ΔF508-CFTR, 70-80 % of CF phenotypes) and a Gly551Asp substitution (G551D-CFTR, 4-5 % of alleles), which lead to decreased or almost abolished Cl(-) channel function, respectively. Magnesium ions have to be finely regulated within cells for optimal expression and function of CFTR. Therefore, the melastatin-like transient receptor potential cation channel, subfamily M, member 7 (TRPM7), which is responsible for Mg(2+) entry, was studies and [Mg(2+)]i measured in cells stably expressing wildtype CFTR, and two mutant proteins (ΔF508-CFTR and G551D-CFTR). This study shows for the first time that [Mg(2+)]i is decreased in cells expressing ΔF508-CFTR and G551D-CFTR mutated proteins. It was also observed that the expression of the TRPM7 protein is increased; however, membrane localization was altered for both ΔF508del-CFTR and G551D-CFTR. Furthermore, both the function and regulation of the TRPM7 channel regarding Mg(2+) is decreased in the cells expressing the mutated CFTR. Ca(2+) influx via TRPM7 were also modified in cells expressing a mutated CFTR. Therefore, there appears to be a direct involvement of TRPM7 in CF physiopathology. Finally, we propose that the TRPM7 activator Naltriben is a new potentiator for G551D-CFTR as the function of this mutant increases upon activation of TRPM7 by Naltriben.

  3. Structure of wild type and mutant F508del CFTR: A small-angle X-ray scattering study of the protein-detergent complexes.

    Science.gov (United States)

    Pollock, Naomi L; Satriano, Letizia; Zegarra-Moran, Olga; Ford, Robert C; Moran, Oscar

    2016-04-01

    CFTR is an anionic channel expressed in epithelia whose mutations cause cystic fibrosis. Wild (WT) and mutated (F508del) types were over-expressed in yeast, solubilised in the detergent LPG-14 and purified. The detergent-CFTR complexes were studied by SAXS techniques using a solvent of variable density. The final result of the study is the numerical value of a set of parameters: molecular mass, volume and radius of gyration, average electron density and second moment of the electron density fluctuations inside the particles. It is also shown that in the complex the centres of gravity of CFTR and of the detergent are displaced relative to each other. The analysis of these parameters led to the determination of the size and shape of the volumes occupied by protein and by detergent in the complex. WT-CFTR to be an elongated molecule (maximum diameter ∼12.4nm) which spans a flat detergent micelle. The distance distribution function, P(r) confirms that the WT-CFTR is elongated and with an inhomogeneous electronic density. The F508del-CFTR molecule is also elongated (maximum diameter ∼13.2nm), but the associated detergent micelle hides a larger surface, plausibly related to an increased exposure of hydrophobic portions of the mutated protein. The corresponding P(r) is consistent with the presence of well defined domains, probably linked by flexible regions. These differences suggest that the full-length mutant F508del-CFTR has a detectably different conformation, in contrast to the minor differences observed for the isolated F508-containing domain. We interpret the data in terms of an incomplete post-translational assembly of the protein domains.

  4. Increased efficacy of VX-809 in different cellular systems results from an early stabilization effect of F508del-CFTR.

    Science.gov (United States)

    Farinha, Carlos M; Sousa, Marisa; Canato, Sara; Schmidt, André; Uliyakina, Inna; Amaral, Margarida D

    2015-08-01

    Cystic fibrosis (CF), the most common recessive autosomal disease among Caucasians, is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to CFTR impaired plasma membrane trafficking. Therapies modulating CFTR basic defect are emerging, such as VX-809, a corrector of F508del-CFTR traffic which just succeeded in a Phase III clinical trial. We recently showed that VX-809 is additive to two other correctors (VRT-325 and compound 4a). Here, we aimed to determine whether the differential rescuing by these compounds results from cell-specific factors or rather from distinct effects at the early biogenesis and/or processing. The rescuing efficiencies of the above three correctors were first compared in different cellular models (primary respiratory cells, cystic fibrosis bronchial epithelial and baby hamster kidney [BHK] cell lines) by functional approaches: micro-Ussing chamber and iodide efflux. Next, biochemical methods (metabolic labeling, pulse-chase and immunoprecipitation) were used to determine their impact on CFTR biogenesis / processing. Functional analyses revealed that VX-809 has the greatest rescuing efficacy and that the relative efficiencies of the three compounds are essentially maintained in all three cellular models tested. Nevertheless, biochemical data show that VX-809 significantly stabilizes F508del-CFTR immature form, an effect that is not observed for C3 nor C4. VX-809 and C3 also significantly increase accumulation of immature CFTR. Our data suggest that VX-809 increases the stability of F508del-CFTR immature form at an early phase of its biogenesis, thus explaining its increased efficacy when inducing its rescue.

  5. An unexpected effect of TNF-α on F508del-CFTR maturation and function [v1; ref status: indexed, http://f1000r.es/5jf

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    Sara Bitam

    2015-07-01

    Full Text Available Cystic fibrosis (CF is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR, which encodes a cAMP-dependent Cl- channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml of F508del-CFTR-transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon TNFα is sustained, in HBE cells, for at least 24 h. The underlying mechanism of action involves a protein kinase C (PKC signaling pathway, and occurs through insertion of vesicles containing F508del-CFTR to the plasma membrane, with TNFα behaving as a corrector molecule. In conclusion, a novel and unexpected action of TNFα has been discovered and points to the importance of systematic studies on the roles of inflammatory mediators in the maturation of abnormally folded proteins in general and in the context of CF in particular.

  6. An unexpected effect of TNF-α on F508del-CFTR maturation and function [v2; ref status: indexed, http://f1000r.es/5tv

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    Sara Bitam

    2015-09-01

    Full Text Available Cystic fibrosis (CF is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR, which encodes a cAMP-dependent Cl- channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml of F508del-CFTR-transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon TNFα is sustained, in HBE cells, for at least 24 h. The underlying mechanism of action involves a protein kinase C (PKC signaling pathway, and occurs through insertion of vesicles containing F508del-CFTR to the plasma membrane, with TNFα behaving as a corrector molecule. In conclusion, a novel and unexpected action of TNFα has been discovered and points to the importance of systematic studies on the roles of inflammatory mediators in the maturation of abnormally folded proteins in general and in the context of CF in particular.

  7. Association between F508 deletion in CFTR and chronic pancreatitis risk.

    Science.gov (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

    2017-09-01

    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.

  8. Ouabain mimics low temperature rescue of F508del-CFTR in cystic fibrosis epithelial cells

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    Donglei eZhang

    2012-10-01

    Full Text Available ABSTRACT Most cases of cystic fibrosis (CF are caused by the deletion of a single phenylalanine residue at position 508 of the cystic fibrosis transmembrane conductance regulator (CFTR. The mutant F508del-CFTR is retained in the endoplasmic reticulum and degraded, but can be induced by low temperature incubation (29°C to traffic to the plasma membrane where it functions as a chloride channel. Here we show that, cardiac glycosides, at nanomolar concentrations, can partially correct the trafficking of F508del-CFTR in human CF bronchial epithelial cells (CFBE41o- and in an F508del-CFTR mouse model. Comparison of the transcriptional profiles obtained with polarized CFBE41o- cells after treatment with ouabain and by low temperature has revealed a striking similarity between the two corrector treatments that is not shared with other correctors. In summary, our study shows a novel function of ouabain and its analogues in the regulation of F508del-CFTR trafficking and suggests that compounds that mimic this low temperature correction of trafficking will provide new avenues for the development of therapeutics for CF.

  9. The primary folding defect and rescue of ΔF508 CFTR emerge during translation of the mutant domain

    NARCIS (Netherlands)

    Hoelen, H.M.; Kleizen, B.; Schmidt, A.; Richardson, J.; Charitou, P.; Braakman, L.J.; Thomas, P. J.

    2010-01-01

    In the vast majority of cystic fibrosis (CF) patients, deletion of residue F508 from CFTR is the cause of disease. F508 resides in the first nucleotide binding domain (NBD1) and its absence leads to CFTR misfolding and degradation. We show here that the primary folding defect arises during synthesis

  10. Defective fluid secretion from submucosal glands of nasal turbinates from CFTR-/- and CFTR (ΔF508F508 pigs.

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    Hyung-Ju Cho

    Full Text Available BACKGROUND: Cystic fibrosis (CF, caused by reduced CFTR function, includes severe sinonasal disease which may predispose to lung disease. Newly developed CF pigs provide models to study the onset of CF pathophysiology. We asked if glands from pig nasal turbinates have secretory responses similar to those of tracheal glands and if CF nasal glands show reduced fluid secretion. METHODOLOGY/PRINCIPAL FINDINGS: Unexpectedly, we found that nasal glands differed from tracheal glands in five ways, being smaller, more numerous (density per airway surface area, more sensitive to carbachol, more sensitive to forskolin, and nonresponsive to Substance P (a potent agonist for pig tracheal glands. Nasal gland fluid secretion from newborn piglets (12 CF and 12 controls in response to agonists was measured using digital imaging of mucus bubbles formed under oil. Secretion rates were significantly reduced in all conditions tested. Fluid secretory rates (Controls vs. CF, in pl/min/gland were as follows: 3 µM forskolin: 9.2±2.2 vs. 0.6±0.3; 1 µM carbachol: 143.5±35.5 vs. 52.2±10.3; 3 µM forskolin + 0.1 µM carbachol: 25.8±5.8 vs. CF 4.5±0.9. We also compared CF(ΔF508F508 with CFTR(-/- piglets and found significantly greater forskolin-stimulated secretion rates in the ΔF508 vs. the null piglets (1.4±0.8, n = 4 vs. 0.2±0.1, n = 7. An unexpected age effect was also discovered: the ratio of secretion to 3 µM forskolin vs. 1 µM carbachol was ∼4 times greater in adult than in neonatal nasal glands. CONCLUSIONS/SIGNIFICANCE: These findings reveal differences between nasal and tracheal glands, show defective fluid secretion in nasal glands of CF pigs, reveal some spared function in the ΔF508 vs. null piglets, and show unexpected age-dependent differences. Reduced nasal gland fluid secretion may predispose to sinonasal and lung infections.

  11. Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening

    Science.gov (United States)

    Kalid, Ori; Mense, Martin; Fischman, Sharon; Shitrit, Alina; Bihler, Hermann; Ben-Zeev, Efrat; Schutz, Nili; Pedemonte, Nicoletta; Thomas, Philip J.; Bridges, Robert J.; Wetmore, Diana R.; Marantz, Yael; Senderowitz, Hanoch

    2010-12-01

    Folding correctors of F508del-CFTR were discovered by in silico structure-based screening utilizing homology models of CFTR. The intracellular segment of CFTR was modeled and three cavities were identified at inter-domain interfaces: (1) Interface between the two Nucleotide Binding Domains (NBDs); (2) Interface between NBD1 and Intracellular Loop (ICL) 4, in the region of the F508 deletion; (3) multi-domain interface between NBD1:2:ICL1:2:4. We hypothesized that compounds binding at these interfaces may improve the stability of the protein, potentially affecting the folding yield or surface stability. In silico structure-based screening was performed at the putative binding-sites and a total of 496 candidate compounds from all three sites were tested in functional assays. A total of 15 compounds, representing diverse chemotypes, were identified as F508del folding correctors. This corresponds to a 3% hit rate, tenfold higher than hit rates obtained in corresponding high-throughput screening campaigns. The same binding sites also yielded potentiators and, most notably, compounds with a dual corrector-potentiator activity (dual-acting). Compounds harboring both activity types may prove to be better leads for the development of CF therapeutics than either pure correctors or pure potentiators. To the best of our knowledge this is the first report of structure-based discovery of CFTR modulators.

  12. Abnormal spatial diffusion of Ca2+ in F508del-CFTR airway epithelial cells

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    Becq Frédéric

    2008-10-01

    Full Text Available Abstract Background In airway epithelial cells, calcium mobilization can be elicited by selective autocrine and/or paracrine activation of apical or basolateral membrane heterotrimeric G protein-coupled receptors linked to phospholipase C (PLC stimulation, which generates inositol 1,4,5-trisphosphate (IP3 and 1,2-diacylglycerol (DAG and induces Ca2+ release from endoplasmic reticulum (ER stores. Methods In the present study, we monitored the cytosolic Ca2+ transients using the UV light photolysis technique to uncage caged Ca2+ or caged IP3 into the cytosol of loaded airway epithelial cells of cystic fibrosis (CF and non-CF origin. We compared in these cells the types of Ca2+ receptors present in the ER, and measured their Ca2+ dependent activity before and after correction of F508del-CFTR abnormal trafficking either by low temperature or by the pharmacological corrector miglustat (N-butyldeoxynojirimycin. Results We showed reduction of the inositol 1,4,5-trisphosphate receptors (IP3R dependent-Ca2+ response following both correcting treatments compared to uncorrected cells in such a way that Ca2+ responses (CF+treatment vs wild-type cells were normalized. This normalization of the Ca2+ rate does not affect the activity of Ca2+-dependent chloride channel in miglustat-treated CF cells. Using two inhibitors of IP3R1, we observed a decrease of the implication of IP3R1 in the Ca2+ response in CF corrected cells. We observed a similar Ca2+ mobilization between CF-KM4 cells and CFTR-cDNA transfected CF cells (CF-KM4-reverted. When we restored the F508del-CFTR trafficking in CFTR-reverted cells, the specific IP3R activity was also reduced to a similar level as in non CF cells. At the structural level, the ER morphology of CF cells was highly condensed around the nucleus while in non CF cells or corrected CF cells the ER was extended at the totality of cell. Conclusion These results suggest reversal of the IP3R dysfunction in F508del-CFTR epithelial

  13. Anchored PDE4 regulates chloride conductance in wild-type and ΔF508-CFTR human airway epithelia.

    Science.gov (United States)

    Blanchard, Elise; Zlock, Lorna; Lao, Anna; Mika, Delphine; Namkung, Wan; Xie, Moses; Scheitrum, Colleen; Gruenert, Dieter C; Verkman, Alan S; Finkbeiner, Walter E; Conti, Marco; Richter, Wito

    2014-02-01

    Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that impair its expression and/or chloride channel function. Here, we provide evidence that type 4 cyclic nucleotide phosphodiesterases (PDE4s) are critical regulators of the cAMP/PKA-dependent activation of CFTR in primary human bronchial epithelial cells. In non-CF cells, PDE4 inhibition increased CFTR activity under basal conditions (ΔISC 7.1 μA/cm(2)) and after isoproterenol stimulation (increased ΔISC from 13.9 to 21.0 μA/cm(2)) and slowed the return of stimulated CFTR activity to basal levels by >3-fold. In cells homozygous for ΔF508-CFTR, the most common mutation found in CF, PDE4 inhibition alone produced minimal channel activation. However, PDE4 inhibition strongly amplified the effects of CFTR correctors, drugs that increase expression and membrane localization of CFTR, and/or CFTR potentiators, drugs that increase channel gating, to reach ∼ 25% of the chloride conductance observed in non-CF cells. Biochemical studies indicate that PDE4s are anchored to CFTR and mediate a local regulation of channel function. Taken together, our results implicate PDE4 as an important determinant of CFTR activity in airway epithelia, and support the use of PDE4 inhibitors to potentiate the therapeutic benefits of CFTR correctors and potentiators.

  14. Activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and serum- and glucocorticoid-induced protein kinase 1 (SGK1) by short-chain sphingolipid C4-ceramide rescues the trafficking defect of ΔF508-cystic fibrosis transmembrane conductance regulator (ΔF508-CFTR).

    Science.gov (United States)

    Caohuy, Hung; Yang, Qingfeng; Eudy, Yvonne; Ha, Thien-An; Xu, Andrew E; Glover, Matthew; Frizzell, Raymond A; Jozwik, Catherine; Pollard, Harvey B

    2014-12-26

    Cystic fibrosis (CF) is due to a folding defect in the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, ΔF508, prevents CFTR from trafficking to the apical plasma membrane. Here we show that activation of the PDK1/SGK1 signaling pathway with C4-ceramide (C4-CER), a non-toxic small molecule, functionally corrects the trafficking defect in both cultured CF cells and primary epithelial cell explants from CF patients. The mechanism of C4-CER action involves a series of mutual autophosphorylation and phosphorylation events between PDK1 and SGK1. Detailed mechanistic studies indicate that C4-CER initially induces autophosphorylation of SGK1 at Ser(422). SGK1[Ser(P)(422)] and C4-CER coincidently bind PDK1 and permit PDK1 to autophosphorylate at Ser(241). Then PDK1[Ser(P)(241)] phosphorylates SGK1[Ser(P)(422)] at Thr(256) to generate fully activated SGK1[Ser(422), Thr(P)(256)]. SGK1[Ser(P)(422),Thr(P)(256)] phosphorylates and inactivates the E3 ubiquitin ligase Nedd4-2. ΔF508-CFTR is thus free to traffic to the plasma membrane. Importantly, C4-CER-mediated activation of both PDK1 and SGK1 is independent of the PI3K/Akt/mammalian target of rapamycin signaling pathway. Physiologically, C4-CER significantly increases maturation and stability of ΔF508-CFTR (t½ ∼10 h), enhances cAMP-activated chloride secretion, and suppresses hypersecretion of interleukin-8 (IL-8). We suggest that candidate drugs for CF directed against the PDK1/SGK1 signaling pathway, such as C4-CER, provide a novel therapeutic strategy for a life-limiting disorder that affects one child, on average, each day.

  15. Correctors of ΔF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein.

    Science.gov (United States)

    He, Lihua; Kota, Pradeep; Aleksandrov, Andrei A; Cui, Liying; Jensen, Tim; Dokholyan, Nikolay V; Riordan, John R

    2013-02-01

    Most cystic fibrosis is caused by the deletion of a single amino acid (F508) from CFTR and the resulting misfolding and destabilization of the protein. Compounds identified by high-throughput screening to improve ΔF508 CFTR maturation have already entered clinical trials, and it is important to understand their mechanisms of action to further improve their efficacy. Here, we showed that several of these compounds, including the investigational drug VX-809, caused a much greater increase (5- to 10-fold) in maturation at 27 than at 37°C (CFTR can be completely assembled and evade cellular quality control systems, while remaining thermodynamically unstable. He, L., Kota, P., Aleksandrov, A. A., Cui, L., Jensen, T., Dokholyan, N. V., Riordan, J. R. Correctors of ΔF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein.

  16. The calpain, caspase 12, caspase 3 cascade leading to apoptosis is altered in F508del-CFTR expressing cells.

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    Mathieu Kerbiriou

    Full Text Available In cystic fibrosis (CF, the most frequent mutant variant of the cystic fibrosis transmembrane conductance regulator (CFTR, F508del-CFTR protein, is misfolded and retained in the endoplasmic reticulum (ER. We previously showed that the unfolded protein response (UPR may be triggered in CF. Since prolonged UPR activation leads to apoptosis via the calcium-calpain-caspase-12-caspase-3 cascade and because apoptosis is altered in CF, our aim was to compare the ER stress-induced apoptosis pathway between wild type (Wt and F508del-CFTR expressing cells. Here we show that the calcium-calpain-caspase-12-caspase-3 cascade is altered in F508del-CFTR expressing cells. We propose that this alteration is involved in the altered apoptosis triggering observed in CF.

  17. The analysis of some CFTR gene mutations in a small group of cf patients from southern part of Romania

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    Lucian GAVRILA

    2009-05-01

    Full Text Available Cystic fibrosis is the most common hereditary disease in European descendant populations, with prevalencedepending on ethnic groups studied. In contrast to other European countries, there is little information regarding the frequency ofCFTR mutations for the Southern part of Romania. The aim of this study was to test the presence of nine CFTR mutations in CFpatients from the Southern part of Romania, using complementary analysis methods. We investigated a group of unrelated CFpatients (n=19 and, when possible, their voluntary parents (n=15. We observed that the most frequently worldwide CF mutation,delta F508, was present in 17 of our patients (89.5% in homozygous (n=7 or heterozygous (n=10 condition and absent in 2 cases(10.5%. This mutation was also detected in ten parents, seven of them (100% have homozygous children and three (37.5%have heterozygous children for delta F508 mutation. None of the G542X, S549N, G551D, R553X, R560T, S1255X, W1282X andN1303K mutations have been detected in the samples from patients or parents. Our results are partially similar with those reportedin neighbouring countries where the delta F508 is the most common mutation detected and the frequency of R560T, S549N, G551D andS1255X mutations is near zero. The enlargement of this study could give a better result regarding the spectrum of CFTR mutationsin Romanian patients with CF.

  18. SYVN1, NEDD8, and FBXO2 Proteins Regulate ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitin-mediated Proteasomal Degradation.

    Science.gov (United States)

    Ramachandran, Shyam; Osterhaus, Samantha R; Parekh, Kalpaj R; Jacobi, Ashley M; Behlke, Mark A; McCray, Paul B

    2016-12-02

    We previously reported that delivery of a microRNA-138 mimic or siRNA against SIN3A to cultured cystic fibrosis (ΔF508F508) airway epithelia partially restored ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR)-mediated cAMP-stimulated Cl(-) conductance. We hypothesized that dissecting this microRNA-138/SIN3A-regulated gene network would identify individual proteins contributing to the rescue of ΔF508-CFTR function. Among the genes in the network, we rigorously validated candidates using functional CFTR maturation and electrolyte transport assays in polarized airway epithelia. We found that depletion of the ubiquitin ligase SYVN1, the ubiquitin/proteasome system regulator NEDD8, or the F-box protein FBXO2 partially restored ΔF508-CFTR-mediated Cl(-) transport in primary cultures of human cystic fibrosis airway epithelia. Moreover, knockdown of SYVN1, NEDD8, or FBXO2 in combination with corrector compound 18 further potentiated rescue of ΔF508-CFTR-mediated Cl(-) conductance. This study provides new knowledge of the CFTR biosynthetic pathway. It suggests that SYVN1 and FBXO2 represent two distinct multiprotein complexes that may degrade ΔF508-CFTR in airway epithelia and identifies a new role for NEDD8 in regulating ΔF508-CFTR ubiquitination.

  19. ΔF508 CFTR surface stability is regulated by DAB2 and CHIP-mediated ubiquitination in post-endocytic compartments.

    Science.gov (United States)

    Fu, Lianwu; Rab, Andras; Tang, Li ping; Bebok, Zsuzsa; Rowe, Steven M; Bartoszewski, Rafal; Collawn, James F

    2015-01-01

    The ΔF508 mutant form of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR) that is normally degraded by the ER-associated degradative pathway can be rescued to the cell surface through low-temperature (27°C) culture or small molecular corrector treatment. However, it is unstable on the cell surface, and rapidly internalized and targeted to the lysosomal compartment for degradation. To understand the mechanism of this rapid turnover, we examined the role of two adaptor complexes (AP-2 and Dab2) and three E3 ubiquitin ligases (c-Cbl, CHIP, and Nedd4-2) on low-temperature rescued ΔF508 CFTR endocytosis and degradation in human airway epithelial cells. Our results demonstrate that siRNA depletion of either AP-2 or Dab2 inhibits ΔF508 CFTR endocytosis by 69% and 83%, respectively. AP-2 or Dab2 depletion also increases the rescued protein half-life of ΔF508 CFTR by ~18% and ~91%, respectively. In contrast, the depletion of each of the E3 ligases had no effect on ΔF508 CFTR endocytosis, whereas CHIP depletion significantly increased the surface half-life of ΔF508 CFTR. To determine where and when the ubiquitination occurs during ΔF508 CFTR turnover, we monitored the ubiquitination of rescued ΔF508 CFTR during the time course of CFTR endocytosis. Our results indicate that ubiquitination of the surface pool of ΔF508 CFTR begins to increase 15 min after internalization, suggesting that CFTR is ubiquitinated in a post-endocytic compartment. This post-endocytic ubiquination of ΔF508 CFTR could be blocked by either inhibiting endocytosis, by siRNA knockdown of CHIP, or by treating cells with the CFTR corrector, VX-809. Our results indicate that the post-endocytic ubiquitination of CFTR by CHIP is a critical step in the peripheral quality control of cell surface ΔF508 CFTR.

  20. ΔF508 CFTR surface stability is regulated by DAB2 and CHIP-mediated ubiquitination in post-endocytic compartments.

    Directory of Open Access Journals (Sweden)

    Lianwu Fu

    Full Text Available The ΔF508 mutant form of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR that is normally degraded by the ER-associated degradative pathway can be rescued to the cell surface through low-temperature (27°C culture or small molecular corrector treatment. However, it is unstable on the cell surface, and rapidly internalized and targeted to the lysosomal compartment for degradation. To understand the mechanism of this rapid turnover, we examined the role of two adaptor complexes (AP-2 and Dab2 and three E3 ubiquitin ligases (c-Cbl, CHIP, and Nedd4-2 on low-temperature rescued ΔF508 CFTR endocytosis and degradation in human airway epithelial cells. Our results demonstrate that siRNA depletion of either AP-2 or Dab2 inhibits ΔF508 CFTR endocytosis by 69% and 83%, respectively. AP-2 or Dab2 depletion also increases the rescued protein half-life of ΔF508 CFTR by ~18% and ~91%, respectively. In contrast, the depletion of each of the E3 ligases had no effect on ΔF508 CFTR endocytosis, whereas CHIP depletion significantly increased the surface half-life of ΔF508 CFTR. To determine where and when the ubiquitination occurs during ΔF508 CFTR turnover, we monitored the ubiquitination of rescued ΔF508 CFTR during the time course of CFTR endocytosis. Our results indicate that ubiquitination of the surface pool of ΔF508 CFTR begins to increase 15 min after internalization, suggesting that CFTR is ubiquitinated in a post-endocytic compartment. This post-endocytic ubiquination of ΔF508 CFTR could be blocked by either inhibiting endocytosis, by siRNA knockdown of CHIP, or by treating cells with the CFTR corrector, VX-809. Our results indicate that the post-endocytic ubiquitination of CFTR by CHIP is a critical step in the peripheral quality control of cell surface ΔF508 CFTR.

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

    Science.gov (United States)

    Dhooghe, Barbara; Bouckaert, Charlotte; Capron, Arnaud; Wallemacq, Pierre; Leal, Teresinha; Noel, Sabrina

    2015-01-01

    ABSTRACT 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. PMID:26092868

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

    Directory of Open Access Journals (Sweden)

    Barbara Dhooghe

    2015-07-01

    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.

  3. Cystic fibrosis mutations in French Canadians: three CFTR mutations are relatively frequent in a Quebec population with an elevated incidence of cystic fibrosis.

    Science.gov (United States)

    Rozen, R; De Braekeleer, M; Daigneault, J; Ferreira-Rajabi, L; Gerdes, M; Lamoureux, L; Aubin, G; Simard, F; Fujiwara, T M; Morgan, K

    1992-02-01

    The French-Canadian population in the Saguenay-Lac St. Jean region of northeastern Quebec has an elevated frequency of cystic fibrosis (CF). The average incidence of cystic fibrosis was 1 in 891 births and the prevalence of CF carriers was estimated to be 1 in 15. We tested for 10 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 133 French-Canadian CF families from Quebec. Ninety-one families were from the Saguenay-Lac St. Jean region and 42 families were referred from other regions of Quebec. We detected the CFTR mutation in 93 and 92% of the CF chromosomes in the Saguenay-Lac St. Jean and the major-urban Quebec families, respectively. The two groups of French-Canadian families were significantly different for the proportions of CFTR mutations. The three most common mutations in the Saguenay-Lac St. Jean families were delta F508 (58%), 621 + 1G----T (23%), and A455E (8%); and in the major-urban Quebec families were delta F508 (71%), 711 + 1G----T (9%), and 621 + 1G----T (5%). These results provide evidence for the role of founder effect in the elevated incidence of cystic fibrosis in the Saguenay-Lac St. Jean population.

  4. Dehydrocostuslactone, a sesquiterpene lactone activates wild-type and ΔF508 mutant CFTR chloride channel.

    Science.gov (United States)

    Wang, Xue; Zhang, Yao-Fang; Yu, Bo; Yang, Shuang; Luan, Jian; Liu, Xin; Yang, Hong

    2013-01-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) represents the main cAMP-activated Cl⁻ channel expressed in the apical membrane of serous epithelial cells. Both deficiency and overactivation of CFTR may cause fluid and salt secretion related diseases. The aim of this study was to identify natural compounds that are able to stimulate wild-type (wt) and ΔF508 mutant CFTR channel activities in CFTR-expressing Fischer rat thyroid (FRT) cells. We found that dehydrocostuslactone [DHC, (3aS, 6aR, 9aR, 9bS)-decahydro-3,6,9-tris (methylene) azuleno [4,5-b] furan-2(3H)-one)] dose dependently potentiates both wt and ΔF508 mutant CFTR-mediated iodide influx in cell-based fluorescent assays and CFTR-mediated Cl⁻ currents in short-circuit current studies, and the activations could be reversed by the CFTR inhibitor CFTRinh-172. Maximal CFTR-mediated apical Cl⁻ current secretion in CFTR-expressing FRT cells was stimulated by 100 μM DHC. Determination of intracellular cAMP content showed that DHC modestly but significantly increased cAMP level in FRT cells, but cAMP elevation effects contributed little to DHC-stimulated iodide influx. DHC also stimulated CFTR-mediated apical Cl⁻ current secretion in FRT cells expressing ΔF508-CFTR. Subsequent studies demonstrated that activation of CFTR by DHC is forskolin dependent. DHC represents a new class of CFTR potentiators that may have therapeutic potential in CFTR-related diseases.

  5. Deep resequencing of CFTR in 762 F508del homozygotes reveals clusters of non-coding variants associated with cystic fibrosis disease traits

    Science.gov (United States)

    Vecchio-Pagán, Briana; Blackman, Scott M; Lee, Melissa; Atalar, Melis; Pellicore, Matthew J; Pace, Rhonda G; Franca, Arianna L; Raraigh, Karen S; Sharma, Neeraj; Knowles, Michael R; Cutting, Garry R

    2016-01-01

    Extensive phenotypic variability is commonly observed in individuals with Mendelian disorders, even among those with identical genotypes in the disease-causing gene. To determine whether variants within and surrounding CFTR contribute to phenotypic variability in cystic fibrosis (CF), we performed deep sequencing of CFTR in 762 patients homozygous for the common CF-causing variant, F508del. In phase 1, ~200 kb encompassing CFTR and extending 10 kb 5′ and 5 kb 3′ of the gene was sequenced in 486 F508del homozygotes selected from the extremes of sweat chloride concentration. In phase 2, a 510 kb region, which included the entire topologically associated domain of CFTR, was sequenced in 276 F508del homozygotes drawn from extremes of lung function. An additional 163 individuals who carried F508del and a different CF-causing variant were sequenced to inform haplotype construction. Region-based burden testing of both common and rare variants revealed seven regions of significance (α=0.01), five of which overlapped known regulatory elements or chromatin interactions. Notably, the −80 kb locus known to interact with the CFTR promoter was associated with variation in both CF traits. Haplotype analysis revealed a single rare recombination event (1.9% frequency) in intron 15 of CFTR bearing the F508del variant. Otherwise, the majority of F508del chromosomes were markedly similar, consistent with a single origin of the F508del allele. Together, these high-resolution variant analyses of the CFTR locus suggest a role for non-coding regulatory motifs in trait variation among individuals carrying the common CF allele. PMID:27917292

  6. S-palmitoylation regulates biogenesis of core glycosylated wild-type and F508del CFTR in a post-ER compartment.

    Science.gov (United States)

    McClure, Michelle L; Wen, Hui; Fortenberry, James; Hong, Jeong S; Sorscher, Eric J

    2014-04-15

    Defects in CFTR (cystic fibrosis transmembrane conductance regulator) maturation are central to the pathogenesis of CF (cystic fibrosis). Palmitoylation serves as a key regulator of maturational processing in other integral membrane proteins, but has not been tested previously for functional effects on CFTR. In the present study, we used metabolic labelling to confirm that wild-type and F508del CFTR are palmitoylated, and show that blocking palmitoylation with the pharmacologic inhibitor 2-BP (2-bromopalmitate) decreases steady-state levels of both wild-type and low temperature-corrected F508del CFTR, disrupts post-ER (endoplasmic reticulum) maturation and reduces ion channel function at the cell surface. PATs (protein acyl transferases) comprise a family of 23 gene products that contain a DHHC motif and mediate palmitoylation. Recombinant expression of specific PATs led to increased levels of CFTR protein and enhanced palmitoylation as judged by Western blot and metabolic labelling. Specifically, we show that DHHC-7 (i) increases steady-state levels of wild-type and F508del CFTR band B, (ii) interacts preferentially with the band B glycoform, and (iii) augments radiolabelling by [3H]palmitic acid. Interestingly, immunofluorescence revealed that DHHC-7 also sequesters the F508del protein to a post-ER (Golgi) compartment. Our findings point to the importance of palmitoylation during wild-type and F508del CFTR trafficking.

  7. Hepatic iodothyronine deiodinase type 1 activity is decreased in two DeltaF508 cystic fibrosis mouse models.

    NARCIS (Netherlands)

    Klaren, P.H.M.; Looijmans, P.H.

    2004-01-01

    BACKGROUND: Abnormal thyroid status has been reported in cystic fibrosis (CF) patients, and this can possibly be correlated to neuromuscular symptoms. Iodothyronine deiodinase type 1 (D1) activity is an important determinant of thyroid status, and we chose to investigate D1 activity in CF liver. MET

  8. HEK293T Cells Are Heterozygous for CCR5 Delta 32 Mutation.

    Science.gov (United States)

    Qi, Chunxia; Jia, Xiaopeng; Lu, Lingling; Ma, Ping; Wei, Min

    2016-01-01

    C-C chemokine receptor 5 (CCR5) is a receptor for chemokines and a co-receptor for HIV-1 entry into the target CD4+ cells. CCR5 delta 32 deletion is a loss-of-function mutation, resistant to HIV-1 infection. We tried to induce the CCR5 delta 32 mutation harnessing the genome editing technique, CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR and CRISPR associated protein 9, Cas9) in the commonly used cell line human embryonic kidney HEK 293T cells. Surprisingly, we found that HEK293T cells are heterozygous for CCR5 delta 32 mutation, in contrast to the wild type CCR5 cells, human acute T cell leukemia cell line Jurkat and human breast adenocarcinoma cell line MDA-MB-231 cells. This finding indicates that at least one human cell line is heterozygous for the CCR5 delta 32 mutation. We also found that in PCR amplification, wild type CCR5 DNA and mutant delta 32 DNA can form mismatched heteroduplex and move slowly in gel electrophoresis.

  9. HEK293T Cells Are Heterozygous for CCR5 Delta 32 Mutation.

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    Chunxia Qi

    Full Text Available C-C chemokine receptor 5 (CCR5 is a receptor for chemokines and a co-receptor for HIV-1 entry into the target CD4+ cells. CCR5 delta 32 deletion is a loss-of-function mutation, resistant to HIV-1 infection. We tried to induce the CCR5 delta 32 mutation harnessing the genome editing technique, CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR and CRISPR associated protein 9, Cas9 in the commonly used cell line human embryonic kidney HEK 293T cells. Surprisingly, we found that HEK293T cells are heterozygous for CCR5 delta 32 mutation, in contrast to the wild type CCR5 cells, human acute T cell leukemia cell line Jurkat and human breast adenocarcinoma cell line MDA-MB-231 cells. This finding indicates that at least one human cell line is heterozygous for the CCR5 delta 32 mutation. We also found that in PCR amplification, wild type CCR5 DNA and mutant delta 32 DNA can form mismatched heteroduplex and move slowly in gel electrophoresis.

  10. HEK293T Cells Are Heterozygous for CCR5 Delta 32 Mutation

    OpenAIRE

    2016-01-01

    C-C chemokine receptor 5 (CCR5) is a receptor for chemokines and a co-receptor for HIV-1 entry into the target CD4+ cells. CCR5 delta 32 deletion is a loss-of-function mutation, resistant to HIV-1 infection. We tried to induce the CCR5 delta 32 mutation harnessing the genome editing technique, CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR and CRISPR associated protein 9, Cas9) in the commonly used cell line human embryonic kidney HEK 293T cells. Surprisingly, ...

  11. Mechanistic Approaches to Improve Correction of the Most Common Disease-Causing Mutation in Cystic Fibrosis.

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    Vedrana Bali

    Full Text Available The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR gene leads to deletion of the phenylalanine at position 508 (ΔF508 in the CFTR protein and causes multiple folding and functional defects. Contrary to large-scale efforts by industry and academia, no significant therapeutic benefit has been achieved with a single "corrector". Therefore, investigations concentrate on drug combinations. Orkambi (Vertex Pharmaceuticals, the first FDA-approved drug for treatment of cystic fibrosis (CF caused by this mutation, is a combination of a corrector (VX-809 that facilitates ΔF508 CFTR biogenesis and a potentiator (VX-770, which improves its function. Yet, clinical trials utilizing this combination showed only modest therapeutic benefit. The low efficacy Orkambi has been attributed to VX-770-mediated destabilization of VX-809-rescued ΔF508 CFTR. Here we report that the negative effects of VX-770 can be reversed by increasing the half-life of the endoplasmic reticulum (ER form (band B of ΔF508 CFTR with another corrector (Corr-4a. Although Corr-4a alone has only minimal effects on ΔF508 CFTR rescue, it increases the half-life of ΔF508 CFTR band B when it is present during half-life measurements. Our data shows that stabilization of band B ΔF508 CFTR with Corr-4a and simultaneous rescue with VX-809, leads to a >2-fold increase in cAMP-activated, CFTRinh-172-inhibited currents compared to VX-809 alone, or VX-809+VX-770. The negative effects of VX-770 and the Corr-4a protection are specific to the native I507-ATT ΔF508 CFTR without affecting the inherently more stable, synonymous variant I507-ATC ΔF508 CFTR. Our studies emphasize that stabilization of ΔF508 CFTR band B in the ER might improve its functional rescue by Orkambi.

  12. Two Small Molecules Restore Stability to a Subpopulation of the Cystic Fibrosis Transmembrane Conductance Regulator with the Predominant Disease-causing Mutation*

    Science.gov (United States)

    Meng, Xin; Wang, Yiting; Wang, Xiaomeng; Wrennall, Joe A.; Rimington, Tracy L.; Li, Hongyu; Cai, Zhiwei; Ford, Robert C.; Sheppard, David N.

    2017-01-01

    Cystic fibrosis (CF) is caused by mutations that disrupt the plasma membrane expression, stability, and function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel. Two small molecules, the CFTR corrector lumacaftor and the potentiator ivacaftor, are now used clinically to treat CF, although some studies suggest that they have counteracting effects on CFTR stability. Here, we investigated the impact of these compounds on the instability of F508del-CFTR, the most common CF mutation. To study individual CFTR Cl− channels, we performed single-channel recording, whereas to assess entire CFTR populations, we used purified CFTR proteins and macroscopic CFTR Cl− currents. At 37 °C, low temperature-rescued F508del-CFTR more rapidly lost function in cell-free membrane patches and showed altered channel gating and current flow through open channels. Compared with purified wild-type CFTR, the full-length F508del-CFTR was about 10 °C less thermostable. Lumacaftor partially stabilized purified full-length F508del-CFTR and slightly delayed deactivation of individual F508del-CFTR Cl− channels. By contrast, ivacaftor further destabilized full-length F508del-CFTR and accelerated channel deactivation. Chronic (prolonged) co-incubation of F508del-CFTR-expressing cells with lumacaftor and ivacaftor deactivated macroscopic F508del-CFTR Cl− currents. However, at the single-channel level, chronic co-incubation greatly increased F508del-CFTR channel activity and temporal stability in most, but not all, cell-free membrane patches. We conclude that chronic lumacaftor and ivacaftor co-treatment restores stability in a small subpopulation of F508del-CFTR Cl− channels but that the majority remain destabilized. A fuller understanding of these effects and the characterization of the small F508del-CFTR subpopulation might be crucial for CF therapy development. PMID:28087700

  13. Frecuencia de la mutación F508del en estudiantes de la Facultad de Medicina de la Universidad del Rosario, Bogotá, Colombia

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    Heidi Eliana Mateus

    2007-12-01

    Full Text Available Introducción: La fibrosis quística es la enfermedad letal autosómica recesiva más frecuente en caucásicos, donde su incidencia es de 1 en 2000 nacidos vivos. Se debe a mutaciones en el gen CFTR, de las cuales la más frecuente es la F508del presente en 66% de los enfermos y en 1 de cada 25 personas sanas de origen caucásico.Objetivo: Identificar la tasa de portadores de la mutación F508del en una muestra de estudiantes de la Facultad de Medicina de la Universidad del Rosario.Materiales y métodos: Se determinó la presencia de la mutación F508del mediante PCR y análisis de heterodúplex en 110 estudiantes de IV y VII semestre de la Facultad de Medicina.Resultados: Se obtuvieron 4 heterocigotos para la mutación F508del, es decir, una frecuencia de portadores de 1 en 27 estudiantes.Conclusiones: La frecuencia de portadores de esta mutación en la población analizada es considerable, e indica que hay un alto número de personas en riesgo de heredar la enfermedad y que deben recibir asesoramiento genético. Es necesario aumentar el tamaño de la muestra para obtener datos representativos de la población colombiana.

  14. Prevalência da mutação ΔF508 no gene cystic fibrosis transmembrane conductance regulator em pacientes com fibrose cística em um centro de referência no Brasil

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    Andréia Marisa Bieger

    2012-12-01

    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 < 0,001. A população analisada está fora do equilíbrio. Os valores esperados são, para os respectivos genótipos -/-, ΔF508/- e ΔF508F508: 32,22% (60,48 pacientes, 47,93% (80,04 pacientes e 15,86% (26,48 pacientes. CONCLUSÕES: Na população analisada, a mutação ΔF508 se mostrou menos prevalente em relação ao alelo sem a mutação. A frequência encontrada neste estudo foi semelhante à de outras regiões do Brasil e do mundo, principalmente devido à origem predominantemente caucasoide da população incluída no estudo.

  15. 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

    2011-08-01

    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.

  16. Evolution of the CCR5 Delta32 mutation based on haplotype variation in Jewish and Northern European population samples.

    Science.gov (United States)

    Klitz, W; Brautbar, C; Schito, A M; Barcellos, L F; Oksenberg, J R

    2001-05-01

    The chemokine receptor 5 (CCR5) serves as a fusion cofactor for macrophage-tropic strains of HIV-1. In addition, CCR5 has been shown to mediate the entry of poxviruses into target cells. Individuals homozygous for the Delta32 deletion-mutation have no surface expression of CCR5 and are highly protected against HIV-1 infection. To gain insights into the evolution of the mutation in modern populations, the relatively high frequency of the Delta32-ccr5 allele in some European and Jewish populations is explored here by examining haplotypes of 3p21.3 constructed of five polymorphic marker loci surrounding CCR5. By sampling Ashkenazi, non-Ashkenazi and non-Jewish populations, we utilize the natural experiment that occurred as a consequence of the Jewish Diaspora, and demonstrate that a single mutation was responsible for all copies of Delta32. This mutation must have moved from Northern European populations to the Ashkenazi Jews where evidence suggests that Delta32 carriers of both groups were favored by repeated occurrence of epidemic small pox beginning in the 8th century AD.

  17. Correlation of the level of full-length CFTR transcript with pulmonary phenotype in patients carrying R117H and 1342-1,-2delAG mutations

    Energy Technology Data Exchange (ETDEWEB)

    Hamosh, A.; Cutting, G.R. [Johns Hopkins Univ. School of Medicine, Balitmore, MD (United States); Oates, R.; Amos, J. [Boston Univ. School of Medicine, Boston, MA (United States)

    1994-09-01

    The R117H mutation occurs on two chromosome backgrounds, one associated with a 7 thymidine tract (7T-R11H) in the splice-acceptor site of intron 8, the other with a 5 thymidine tract (5T-R117H). We examined exon 9 splicing efficiency in 5 patients of genotype R117H/{delta}F508 and one carrying 1342-1,-2delAG{delta}F508, an obligate exon 9 slice site mutation. Four patients carried R117H on a 7T background -- three adult men with congenital bilateral absence of the vas deferens and one adolescent female with pancreatitis and borderline sweat chloride concentration. The patient with R117H on a 5T background had pancreatic sufficient CF (PS-CF). The 1342-1,-2delAG patient has classic pancreatic insufficient CF (PI-CF). cDNA was synthesized from total RNA extracted from nasal epithlial cells and analyzed for CFTR splicing by 35 cycle PCR using primers in exon 7 and 11. The quantity of full length transcript derived from the R117H or {delta}F508 alleles was assessed by allele-specific oligonucleotide hybridization. While 91.4% of transcript from the 5T-R117H allele was full-length, only 42.2% of CFTR transcript from the 5T-R117H allele was full length. Since CBAVD patients have no lung disease and PS-CF patients do, this indicates that the threshold of developing CF lung disease is crossed when the amount of CFTR transcript bearing R117H is reduced by half. Interestingly, 17.1% of transcript derived from the 1342-1,-2delAG allele (or 8.6% of total CFTR transcript) was normal and full length. This suggests that up to 9% of full length wild-type CFTR transcript may be inadequate to escape the lung disease of CF and that a 9 thymidine tract followed by AAC (the result of the AG deletion) can be used as a splice donor with 2-9% efficiency.

  18. Effects of the CCR5-Delta32 mutation on hepatitis C virus-specific immune responses in patients with haemophilia.

    Science.gov (United States)

    Ahlenstiel, Golo; Woitas, Rainer P; Iwan, Agathe; Nattermann, Jacob; Feldmann, Georg; Rockstroh, Jürgen K; Oldenburg, Johannes; Kupfer, Bernd; Sauerbruch, Tilman; Spengler, Ulrich

    2009-01-01

    In hepatitis C virus (HCV) infection antiviral T cells express the CC chemokine receptor 5 (CCR5). Their recruitment to the liver is an important step in the immune response. A 32 base pair deletion in the CCR5 gene leads to reduced expression and total loss of CCR5 in CCR5-Delta32 heterozygous and homozygous subjects, respectively. However, the role of this mutation for antiviral immunity remains unclear. Here, we analysed proliferation, IFN-gamma and IL-4 secretion (ELISpot) induced by the HCV antigens core, NS3, NS4, and NS5a in 21 anti-HCV-positive haemophiliac patients in relationship to their CCR5 genotypes (CCR5 wildtype n = 10, CCR5-Delta32 heterozygous n = 5 and CCR5-Delta32 homozygous n = 6). Furthermore, T cell migration in response to the CCR5 ligands CCL3, -4 and -5 was studied. Overall IFN-gamma responses to HCV proteins were only slightly greater in CCR5 wild-type patients than in CCR5-Delta32 carriers (0.6 versus 0.24 SFC/10(4) PBMC; p = 0.043). This difference was consistently seen with all tested HCV antigens. In contrast, neither T cell migration, nor PBMC proliferation, nor IL-4 production differed between CCR5 genotypes. Interruption of the CCR5 signalling pathway due to CCR5-Delta32 may potentially result in subtle reduction of HCV specific IFN-gamma responses in anti-HCV-positive haemophiliac patients.

  19. Distribution of CFTR mutations in Saguenay- Lac-Saint-Jean: proposal of a panel of mutations for population screening.

    Science.gov (United States)

    Madore, Anne-Marie; Prévost, Claude; Dorfman, Ruslan; Taylor, Chelsea; Durie, Peter; Zielenski, Julian; Laprise, Catherine

    2008-03-01

    Saguenay-Lac-Saint-Jean is a region located in the northeastern part of the Province of Quebec, Canada, and is characterized by a founder effect. In this region, it has been documented that the incidence of cystic fibrosis reached 1/902 live births between 1975 and 1988, three times higher than the average incidence of 1/2500 live births reported in other Caucasian populations. This corresponds to a carrier rate of 1/15. Using genotyping data from the Canadian Consortium for Cystic Fibrosis Genetic Studies, this article describes the cystic fibrosis transmembrane conductance regulator profile of the cystic fibrosis population living in the Saguenay-Lac-Saint-Jean region and compares it with cystic fibrosis populations living in three other regions of the Province of Quebec. Significant differences in allelic frequencies of common mutations (as DeltaF508, 621 + 1G>T and A455E), and in percentage of covered allele with three or six mutations, were found in Saguenay-Lac-Saint-Jean compared to other regions. Based on this result, two mutation panels exceeding 90% sensitivity threshold are now proposed for cystic fibrosis carrier screening in this region. The implementation of the proposed carrier screening program could diminish the incidence of this disease in this region and allow future parents to make informed decisions about family planning.

  20. No effect of high fat diet-induced obesity on spontaneous reporter gene mutations in gpt delta mice.

    Science.gov (United States)

    Takasu, Shinji; Ishii, Yuji; Matsushita, Kohei; Kuroda, Ken; Kijima, Aki; Kodama, Yukio; Ogawa, Kumiko; Umemura, Takashi

    2014-01-01

    A large number of epidemiological studies have demonstrated that obesity is a risk factor for several human cancers. Several animal studies using rodents with diet-induced or genetic obesity have also demonstrated that obesity can promote tumor development. However, the effects of obesity on the early stages of carcinogenesis, and especially on the spontaneous occurrence of somatic gene mutations, remain unclear. To investigate the effects of obesity on the rate of spontaneous gene mutations, we performed reporter gene mutation assays in liver, kidney, and colon, organs in which obesity appears to be associated with cancer development on the basis of epidemiological or animal studies, in mice with high fat diet (HFD)-induced obesity. Six-week-old male and female C57BL/6 gpt delta mice were fed HFD or standard diet (STD) for 13 or 26 weeks. At the end of the experiments, reporter gene mutation assays of liver, kidney, and colon were performed. Final body weights and serum leptin levels of male and female mice fed HFD for 13 or 26 weeks were significantly increased compared with corresponding STD-fed groups. Reporter gene mutation assays of liver, kidney, and colon revealed that there were no significant differences in gpt or Spi- mutant frequencies between STD- and HFD-fed mice in either the 13-week or 26-week groups. These results indicate that HFD treatment and consequent obesity does not appear to influence the spontaneous occurrence of somatic gene mutations.

  1. The pch2Delta mutation in baker's yeast alters meiotic crossover levels and confers a defect in crossover interference.

    Directory of Open Access Journals (Sweden)

    Sarah Zanders

    2009-07-01

    Full Text Available Pch2 is a widely conserved protein that is required in baker's yeast for the organization of meiotic chromosome axes into specific domains. We provide four lines of evidence suggesting that it regulates the formation and distribution of crossover events required to promote chromosome segregation at Meiosis I. First, pch2Delta mutants display wild-type crossover levels on a small (III chromosome, but increased levels on larger (VII, VIII, XV chromosomes. Second, pch2Delta mutants show defects in crossover interference. Third, crossovers observed in pch2Delta require both Msh4-Msh5 and Mms4-Mus81 functions. Lastly, the pch2Delta mutation decreases spore viability and disrupts crossover interference in spo11 hypomorph strains that have reduced levels of meiosis-induced double-strand breaks. Based on these and previous observations, we propose a model in which Pch2 functions at an early step in crossover control to ensure that every homolog pair receives an obligate crossover.

  2. Frequency of CCR5 Delta-32 Mutation in Human Immunodeficiency Virus (HIV-seropositive and HIV-exposed Seronegative Individuals and in General Population of Medellin, Colombia

    Directory of Open Access Journals (Sweden)

    Francisco J Díaz

    2000-04-01

    Full Text Available Repeated exposure to human immunodeficiency virus (HIV does not always result in seroconversion. Modifications in coreceptors for HIV entrance to target cells are one of the factors that block the infection. We studied the frequency of Delta-32 mutation in ccr5 gene in Medellin, Colombia. Two hundred and eighteen individuals distributed in three different groups were analyzed for Delta-32 mutation in ccr5 gene by polymerase chain reaction (PCR: 29 HIV seropositive (SP, 39 exposed seronegative (ESN and 150 individuals as a general population sample (GPS. The frequency of the Delta-32 mutant allele was 3.8% for ESN, 2.7% for GPS and 1.7% for SP. Only one homozygous mutant genotype (Delta-32/Delta-32 was found among the ESN (2.6%. The heterozygous genotype (ccr5/Delta-32 was found in eight GPS (5.3%, in one SP (3.4% and in one ESN (2.6%. The differences in the allelic and genotypic frequencies among the three groups were not statistically significant. A comparison between the expected and the observed genotypic frequencies showed that these frequencies were significantly different for the ESN group, which indirectly suggests a protective effect of the mutant genotype (Delta-32/Delta-32. Since this mutant genotype explained the resistance of infection in only one of our ESN persons, different mechanisms of protection must be playing a more important role in this population.

  3. More about the Viking hypothesis of origin of the delta32 mutation in the CCR5 gene conferring resistance to HIV-1 infection.

    Science.gov (United States)

    Lucotte, Gérard; Dieterlen, Florent

    2003-11-01

    The chemokine receptor CCR5 constitutes the major coreceptor for the HIV-1, because a mutant allele of the CCR5 gene named delta32 was shown to provide to homozygotes a strong resistance against infection. In the present study the frequency of the delta32 allele was collected in 36 European populations and in Cyprus, and the highest allele frequencies were found in Nordic countries. We constructed an allele map of delta32 frequencies in Europe; the map is in accordance to the Vikings hypothesis of the origin of the mutation and his dissemination during the eighth to the tenth centuries.

  4. Stimulation of Wild-Type, F508del- and G551D-CFTR Chloride Channels by Non-Toxic Modified pyrrolo[2,3-b]pyrazine Derivatives.

    Science.gov (United States)

    Dannhoffer, Luc; Billet, Arnaud; Jollivet, Mathilde; Melin-Heschel, Patricia; Faveau, Christelle; Becq, Frédéric

    2011-01-01

    Cystic fibrosis (CF) 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 (HBEC). 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 GP(inh)5a). Moreover, RP193 stimulates CFTR in temperature-rescued CuFi-1 (F508del/F508del) HBEC 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.

  5. Novel methods to enhance single strand conformation polymorphism (SSCP) senstivity and efficiency: Application to mutation detection in cystic fibrosis (CF)

    Energy Technology Data Exchange (ETDEWEB)

    Hagstrom, D.J.; Snow, K.; Yuan, Z.; Thibodeau, S.N. [Mayo Clinic, Rochester, MN (United States)

    1994-09-01

    For single gene defects in which there are a variety of mutations with significant frequencies, it is a challenge to find an efficient and sensitive method for mutation detection. For example, although 70% to 75% of CF chromosomes in a North American Caucasian population have the mutation {delta}F508, more than 400 mutations (mostly single base pair substitutions) are represented on the remaining chromosomes. SSCP analysis is a relatively straightforward procedure and therefore suitable for routine use in a clinical laboratory. However, previous reports have demonstrated suboptimal sensitivity rates in screening for mutations. We have developed a novel set of conditions which greatly enhances sensitivity and efficiency of SSCP. Our protocol incorporates multiplex PCR, stepping of wattages during electrophoresis and increased salt concentration at the anode relative to the gel. To screen for mutations in the CFTR gene, three multiplex PCR reactions are performed using identical thermocycler parameters. Sizes of PCR products range from 441 bp to 196 bp: size differences of > 30 bp are necessary to ensure separation during electrophoresis. All PCR products are separated by electrophoresis at room temperature on a single gel containing 8% (37.5:1) polyacrylamide, 5% glycerol and 1x TBE. Using an anode buffer with increased salt (2x TBE) sharpens smaller sized bands, and stepping watts from 5W to 20W during electrophoresis enhances sensitivity. Positive controls were used to demonstrate that mutations could be detected. Other mutations or polymorphisms were verified by cycle sequencing of PCR products or by alternative PCR-based assays for the more common mutations. Thus, using 3 PCR reactions per patient and one gel condition, we are able to achieve a CF mutation detection rate of approximately 90% in a North American Caucasian population.

  6. Mating-type suppression of the DNA-repair defect of the yeast rad6 delta mutation requires the activity of genes in the RAD52 epistasis group.

    Science.gov (United States)

    Yan, Y X; Schiestl, R H; Prakash, L

    1995-06-01

    The RAD6 gene of Saccharomyces cerevisiae is required for post-replication repair of UV-damaged DNA, UV mutagenesis, and sporulation. Here, we show that the radiation sensitivity of a MATa rad6 delta strain can be suppressed by the MAT alpha 2 gene carried on a multicopy plasmid. The a1-alpha 2 suppression is specific to the RAD6 pathway, as mutations in genes required for nucleotide excision repair or for recombinational repair do not show such mating-type suppression. The a1-alpha 2 suppression of the rad6 delta mutation requires the activity of the RAD52 group of genes, suggesting that suppression occurs by channelling of post-replication gaps present in the rad6 delta mutant into the RAD52 recombinational repair pathway. The a1-alpha 2 repressor could mediate this suppression via an enhancement in the expression, or the activity, of recombination genes.

  7. Novel BRCA1 deleterious mutation (c.1949_1950delTA) in a woman of Senegalese descent with triple-negative early-onset breast cancer.

    Science.gov (United States)

    Diez, Orland; Pelegrí, Amadeu; Gadea, Neus; Gutiérrez-Enríquez, Sara; Masas, Miriam; Tenés, Anna; Bosch, Nina; Balmaña, Judith; Graña, Begoña

    2011-11-01

    Limited information exists regarding BRCA1 and BRCA2 genetic testing and genetic diversity in BRCA1 and BRCA2 in sub-Saharan African populations. We report a novel mutation that consists of a deletion of 2 bp (c.1949_1950delTA) in the exon 11 of the BRCA1 gene. This is a frameshift mutation that causes the disruption of the translational reading frame resulting in a premature stop codon downstream in the BRCA1 protein. The mutation was present in a Senegalese woman with a triple-negative breast tumor and a family history of breast cancer.

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

    Energy Technology Data Exchange (ETDEWEB)

    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)

    2012-04-30

    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

  9. Structure and dynamics of NBD1 from CFTR characterized using crystallography and hydrogen/deuterium exchange mass spectrometry.

    Science.gov (United States)

    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

    2010-02-19

    The DeltaF508 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 DeltaF508 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 DeltaF508 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 DeltaF508 constructs, and the DeltaF508 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 (1)H/(2)H exchange rates in matched F508 and DeltaF508 constructs reveal that DeltaF508 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 DeltaF508 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-DeltaF508 structures but completely solvent exposed in all DeltaF508 structures. These results reinforce the importance of the perturbation DeltaF508 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 exposure of the 509-511 loop

  10. Lack of MEF2A Delta7aa mutation in Irish families with early onset ischaemic heart disease, a family based study.

    LENUS (Irish Health Repository)

    Horan, Paul G

    2006-01-01

    BACKGROUND: Ischaemic heart disease (IHD) is a complex disease due to the combination of environmental and genetic factors. Mutations in the MEF2A gene have recently been reported in patients with IHD. In particular, a 21 base pair deletion (Delta7aa) in the MEF2A gene was identified in a family with an autosomal dominant pattern of inheritance of IHD. We investigated this region of the MEF2A gene using an Irish family-based study, where affected individuals had early-onset IHD. METHODS: A total of 1494 individuals from 580 families were included (800 discordant sib-pairs and 64 parent-child trios). The Delta7aa region of the MEF2A gene was investigated based on amplicon size. RESULTS: The Delta7aa mutation was not detected in any individual. Variation in the number of CAG (glutamate) and CCG (proline) residues was detected in a nearby region. However, this was not found to be associated with IHD. CONCLUSION: The Delta7aa mutation was not detected in any individual within the study population and is unlikely to play a significant role in the development of IHD in Ireland. Using family-based tests of association the number of tri-nucleotide repeats in a nearby region of the MEF2A gene was not associated with IHD in our study group.

  11. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.

    Science.gov (United States)

    Veit, Gudio; Avramescu, Radu G; Chiang, Annette N; Houck, Scott A; Cai, Zhiwei; Peters, Kathryn W; Hong, Jeong S; Pollard, Harvey B; Guggino, William B; Balch, William E; Skach, William R; Cutting, Garry R; Frizzell, Raymond A; Sheppard, David N; Cyr, Douglas M; Sorscher, Eric J; Brodsky, Jeffrey L; Lukacs, Gergely L

    2016-02-01

    More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients.

  12. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations

    Science.gov (United States)

    Veit, Gudio; Avramescu, Radu G.; Chiang, Annette N.; Houck, Scott A.; Cai, Zhiwei; Peters, Kathryn W.; Hong, Jeong S.; Pollard, Harvey B.; Guggino, William B.; Balch, William E.; Skach, William R.; Cutting, Garry R.; Frizzell, Raymond A.; Sheppard, David N.; Cyr, Douglas M.; Sorscher, Eric J.; Brodsky, Jeffrey L.; Lukacs, Gergely L.

    2016-01-01

    More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients. PMID:26823392

  13. A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome.

    Science.gov (United States)

    Bicknell, Louise S; Pitt, James; Aftimos, Salim; Ramadas, Ram; Maw, Marion A; Robertson, Stephen P

    2008-10-01

    There are several rare syndromes combining wrinkled, redundant skin and neurological abnormalities. Although phenotypic overlap between conditions has suggested that some might be allelic to one another, the aetiology for many of them remains unknown. A consanguineous New Zealand Maori family has been characterised that segregates an autosomal recessive connective tissue disorder (joint dislocations, lax skin) associated with neurological abnormalities (severe global developmental delay, choreoathetosis) without metabolic abnormalities in four affected children. A genome-screen performed under a hypothesis of homozygosity by descent for an ancestral mutation, identified a locus at 10q23 (Z = 3.63). One gene within the candidate interval, ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), was considered a plausible disease gene since a missense mutation had previously been shown to cause progressive neurodegeneration, cataracts, skin laxity, joint dislocations and metabolic derangement in a consanguineous Algerian family. A missense mutation, 2350C>T, was identified in ALDH18A1, which predicts the substitution H784Y. H784 is invariant across all phyla and lies within a previously unrecognised, conserved C-terminal motif in P5CS. In an in vivo assay of flux through this metabolic pathway using dermal fibroblasts obtained from an affected individual, proline and ornithine biosynthetic activity of P5CS was not affected by the H784Y substitution. These data suggest that P5CS may possess additional uncharacterised functions that affect connective tissue and central nervous system function.

  14. Molecular characterization of HIV-1 CRF01_AE in Mekong Delta, Vietnam, and impact of T-cell epitope mutations on HLA recognition (ANRS 12159.

    Directory of Open Access Journals (Sweden)

    Estibaliz Lazaro

    Full Text Available BACKGROUND: To date, 11 HIV-1 subtypes and 48 circulating recombinant forms have been described worldwide. The underlying reason why their distribution is so heterogeneous is not clear. Host genetic factors could partly explain this distribution. The aim of this study was to describe HIV-1 strains circulating in an unexplored area of Mekong Delta, Vietnam, and to assess the impact of optimal epitope mutations on HLA binding. METHODS: We recruited 125 chronically antiretroviral-naive HIV-1-infected subjects from five cities in the Mekong Delta. We performed high-resolution DNA typing of HLA class I alleles, sequencing of Gag and RT-Prot genes and phylogenetic analysis of the strains. Epitope mutations were analyzed in patients bearing the HLA allele restricting the studied epitope. Optimal wild-type epitopes from the Los Alamos database were used as reference. T-cell epitope recognition was predicted using the immune epitope database tool according to three different scores involved in antigen processing (TAP and proteasome scores and HLA binding (MHC score. RESULTS: All sequences clustered with CRF01_AE. HLA class I genotyping showed the predominance of Asian alleles as A*11:01 and B*46:01 with a Vietnamese specificity held by two different haplotypes. The percentage of homology between Mekong and B consensus HIV-1 sequences was above 85%. Divergent epitopes had TAP and proteasome scores comparable with wild-type epitopes. MHC scores were significantly lower in divergent epitopes with a mean of 2.4 (±0.9 versus 2 (±0.7 in non-divergent ones (p<0.0001. CONCLUSIONS: Our study confirms the wide predominance of CRF01_AE in the Mekong Delta where patients harbor a specific HLA pattern. Moreover, it demonstrates the lower MHC binding affinity among divergent epitopes. This weak immune pressure combined with a narrow genetic diversity favors immune escape and could explain why CRF01_AE is still predominant in Vietnam, particularly in the Mekong area.

  15. Frequency of the CCR5-delta32 mutation in the Atlantic island populations of Madeira, the Azores, Cabo Verde, and São Tomé e Príncipe.

    Science.gov (United States)

    Freitas, Tamira; Brehm, António; Fernandes, Ana Teresa

    2006-12-01

    There is evidence that the CCR5-delta32 mutation confers protection against HIV-1 infection to homozygous individuals. It is believed that this mutation spread through Europe with the Vikings and that it has been subjected to positive selection, leading to a high frequency in Europe (approximately 10%). We carried out the present study to determine the 32-bp deletion allele and genotype frequencies of the CCR5 gene (CCR5-delta32) in the Atlantic island populations of Madeira, the Azores, Cabo Verde, and São Tomé e Principe. These Atlantic archipelagos were all colonized by the Portuguese in the 15th and 16th centuries, but the latter two received most of their settlers from the West African coast. The frequency of the CCR5-delta32 mutation varies between 0% in São Tomé e Príncipe and 16.5% in the Azores. The Azores Islands have one of the highest frequencies of homozygotes found in Europe (4.8%). There are significant differences (P < 0.05) between some of these populations, for example, between São Tomé e Príncipe and Cabo Verde, and even within populations (e.g., Portugal, Madeira, and the Azores).

  16. First report of c. 1499G>C mutation in a 6-month-child with cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Abbas Sahami

    2014-01-01

    Full Text Available So far, more than 1800 mutations identified in the cystic fibrosis transmembrane conductance regulator (CFTR gene. In this case report, we presented first report of c. 1499G>C mutation in a 6-month-old girl with cystic fibrosis (CF diagnosis. A 6-month-old girl with weakness and meconium Ileus referred to the pediatric clinic in Ilam, in the west of Iran. Patient′s skin was dark and suffered from bronchiectasis. The sweat test was performed, and the concentration of chloride and sodium in patient′s sweat was 130-135 mmol/L and 125-128 mmol/L, respectively. The exon 10 mutation analysis of a CF patient was performed. CFTR mutation analysis revealed the identification of 2 mutations in patient, the mutations were p.F508del (ΔF508 and c. 1499G>C (cd500, respectively. The mutation c. 1499G>C (cd500 were found for the first time in the world. Assessing this mutation in future study and genetic investigation is recommended.

  17. 荷叶碱对野生型和突变型囊性纤维化跨膜电导调节因子氯离子通道的激活作用%Natural compound nuciferine activates chloride channel of wild type and △F508 mutant cystic fibrosis transmembrane conductance regulator

    Institute of Scientific and Technical Information of China (English)

    林森; 侯曙光; 金伶伶; 于波; 杨红

    2008-01-01

    目的:从天然单体化合物中筛选能够激活囊性纤维化跨膜电导调节因子(CFTR)Cl-通道转运活性的激活剂.方法:利用稳定表达人CFTR和对卤族元素碘离子高度敏感的荧光绿蛋白突变体EYFP-H148Q的Fischer大鼠甲状腺上皮细胞为筛选模型,测定386种中药单体化合物对CFTR 介导的I-内流速度的影响.结果:发现生物碱类化合物荷叶碱对野生型和△F508突变型CFTR Cl-通道具有激活作用,而对G551D突变型CFTR Cl-通道无激活作用.荷叶碱对野生型和△F508突变型CFTR Cl-通道的激活作用具有作用迅速、可逆的特点,并且依赖于细胞内cAMP水平.荷叶碱不提高细胞内cAMP水平,当CFTR磷酸化程度达到最大时仍能进一步激活CFTR Cl-通道激活作用,表明它可能是通过与CFTR直接结合而发挥作用的.结论:首次发现荷叶碱对野生型和△F508突变型CFTR Cl-通道的激活作用,该天然化合物将在阐明CFR活性机制及作为先导化合物开发与CFTR有关的疾病治疗药物等方面具有重要用途.

  18. Evaluation of CFTR gene mutations in Adana

    Directory of Open Access Journals (Sweden)

    Ozlem Goruroglu Ozturk

    2013-04-01

    Full Text Available ABSTRACT Objective: Cystic fibrosis is the most common autosomal recessive inherited disorder seen in the white populations. It develops in result of mutations of cystic fibrosis transmembrane regulator (CFTR gene. Rate of these mutations vary in different geographical regions. In this study, we aimed to determine the frequency of CFTR gene mutations in Adana. Methods: DNA samples of 63 subjects (21 women, 42 men who were diagnosed as cystic fibrosis at Balcali Hospital of Cukurova University, were studied for 19 different CFTR mutations by the strip assay method which is based on reverse hybridization. Results: In cystic fibrosis diagnosed patients, 19 mutations were observed of which 9 were homozygous and 10 were heterozygous. ∆F508 frequency was found as 11.9%, and rate of homozygous was found as 66.7%. Mutation frequencies of W1282X and N1303K were found as 2.40% and 4.80% respectively and rate of homozygous mutations were 50% for both. I148T mutation frequency was found as 3.20% and all were heterozygous. For the whole 19 mutations, frequency of mutation in 63 subjects was 22.3%. Conclusion: Detection of CFTR gene mutations by the strip assay method by reverse hybridization is an easy, fast and informative method. However, due to improvability of the common mutations in probable cystic fibrosis patients because of heterogenity in this region, it is still a major problem and does not exclude cystic fibrosis diagnosis. But this problematic issue can be overcome by evaluating the whole exons of CFTR mutations by advanced molecular tecniques. Key words: CFTR, cystic fibrosis, molecular diagnosis, reverse hibridisation [Cukurova Med J 2013; 38(2.000: 202-208

  19. Observational $\\Delta\

    CERN Document Server

    Hernández, Antonio García; Monteiro, Mário J P F G; Suárez, Juan Carlos; Reese, Daniel R; Pascual-Granado, Javier; Garrido, Rafael

    2015-01-01

    Delta Scuti ($\\delta$ Sct) stars are intermediate-mass pulsators, whose intrinsic oscillations have been studied for decades. However, modelling their pulsations remains a real theoretical challenge, thereby even hampering the precise determination of global stellar parameters. In this work, we used space photometry observations of eclipsing binaries with a $\\delta$ Sct component to obtain reliable physical parameters and oscillation frequencies. Using that information, we derived an observational scaling relation between the stellar mean density and a frequency pattern in the oscillation spectrum. This pattern is analogous to the solar-like large separation but in the low order regime. We also show that this relation is independent of the rotation rate. These findings open the possibility of accurately characterizing this type of pulsator and validate the frequency pattern as a new observable for $\\delta$ Sct stars.

  20. The beta-globin gene in Sardinian delta beta 0-thalassemia carries a C----T nonsense mutation at codon 39.

    OpenAIRE

    Guida, S; Giglioni, B; Comi, P; Ottolenghi, S; Camaschella, C.; Saglio, G

    1984-01-01

    Sardinian delta beta 0-thalassemia is an inherited syndrome characterized by the inactivity of the beta-globin gene and the persistent activity of the fetal gamma-globin genes, particularly the A gamma-globin gene. Previous mapping studies with restriction enzymes failed to show any abnormality in the non-alpha globin gene cluster. We have now examined the possibility that this syndrome might result from a single rather than two different defects. Restriction enzyme polymorphisms linked to th...

  1. The CFTR frameshift mutation 3905insT and its effect at transcript and protein level.

    Science.gov (United States)

    Sanz, Javier; von Känel, Thomas; Schneider, Mircea; Steiner, Bernhard; Schaller, André; Gallati, Sabina

    2010-02-01

    Cystic fibrosis (CF) is one of the most common genetic diseases in the Caucasian population and is characterized by chronic obstructive pulmonary disease, exocrine pancreatic insufficiency, and elevation of sodium and chloride concentrations in the sweat and infertility in men. The disease is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a protein that functions as chloride channel at the apical membrane of different epithelia. Owing to the high genotypic and phenotypic disease heterogeneity, effects and consequences of the majority of the CFTR mutations have not yet been studied. Recently, the frameshift mutation 3905insT was identified as the second most frequent mutation in the Swiss population and found to be associated with a severe phenotype. The frameshift mutation produces a premature termination codon (PTC) in exon 20, and transcripts bearing this PTC are potential targets for degradation through nonsense-mediated mRNA decay (NMD) and/or for exon skipping through nonsense-associated alternative splicing (NAS). Using RT-PCR analysis in lymphocytes and different tissue types from patients carrying the mutation, we showed that the PTC introduced by the mutation does neither elicit a degradation of the mRNA through NMD nor an alternative splicing through NAS. Moreover, immunocytochemical analysis in nasal epithelial cells revealed a significantly reduced amount of CFTR at the apical membrane providing a possible molecular explanation for the more severe phenotype observed in F508del/3905insT compound heterozygotes compared with F508del homozygotes. However, further experiments are needed to elucidate the fate of the 3905insT CFTR in the cell after its biosynthesis.

  2. Delta robot

    NARCIS (Netherlands)

    Herder, J.L.; Van der Wijk, V.

    2010-01-01

    The invention relates to a delta robot comprising a stationary base (2) and a movable platform (3) that is connected to the base with three chains of links (4,5,6), and comprising a balancing system incorporating at least one pantograph (7) for balancing the robot's center of mass, wherein the at le

  3. Delta robot

    NARCIS (Netherlands)

    Herder, J.L.; Van der Wijk, V.

    2010-01-01

    The invention relates to a delta robot comprising a stationary base (2) and a movable platform (3) that is connected to the base with three chains of links (4,5,6), and comprising a balancing system incorporating at least one pantograph (7) for balancing the robot's center of mass, wherein the at le

  4. The effect of a DeltaK280 mutation on the unfolded state of a microtubule-binding repeat in Tau.

    Directory of Open Access Journals (Sweden)

    Austin Huang

    Full Text Available Tau is a natively unfolded protein that forms intracellular aggregates in the brains of patients with Alzheimer's disease. To decipher the mechanism underlying the formation of tau aggregates, we developed a novel approach for constructing models of natively unfolded proteins. The method, energy-minima mapping and weighting (EMW, samples local energy minima of subsequences within a natively unfolded protein and then constructs ensembles from these energetically favorable conformations that are consistent with a given set of experimental data. A unique feature of the method is that it does not strive to generate a single ensemble that represents the unfolded state. Instead we construct a number of candidate ensembles, each of which agrees with a given set of experimental constraints, and focus our analysis on local structural features that are present in all of the independently generated ensembles. Using EMW we generated ensembles that are consistent with chemical shift measurements obtained on tau constructs. Thirty models were constructed for the second microtubule binding repeat (MTBR2 in wild-type (WT tau and a DeltaK280 mutant, which is found in some forms of frontotemporal dementia. By focusing on structural features that are preserved across all ensembles, we find that the aggregation-initiating sequence, PHF6*, prefers an extended conformation in both the WT and DeltaK280 sequences. In addition, we find that residue K280 can adopt a loop/turn conformation in WT MTBR2 and that deletion of this residue, which can adopt nonextended states, leads to an increase in locally extended conformations near the C-terminus of PHF6*. As an increased preference for extended states near the C-terminus of PHF6* may facilitate the propagation of beta-structure downstream from PHF6*, these results explain how a deletion at position 280 can promote the formation of tau aggregates.

  5. The effect of a DeltaK280 mutation on the unfolded state of a microtubule-binding repeat in Tau.

    Directory of Open Access Journals (Sweden)

    Austin Huang

    Full Text Available Tau is a natively unfolded protein that forms intracellular aggregates in the brains of patients with Alzheimer's disease. To decipher the mechanism underlying the formation of tau aggregates, we developed a novel approach for constructing models of natively unfolded proteins. The method, energy-minima mapping and weighting (EMW, samples local energy minima of subsequences within a natively unfolded protein and then constructs ensembles from these energetically favorable conformations that are consistent with a given set of experimental data. A unique feature of the method is that it does not strive to generate a single ensemble that represents the unfolded state. Instead we construct a number of candidate ensembles, each of which agrees with a given set of experimental constraints, and focus our analysis on local structural features that are present in all of the independently generated ensembles. Using EMW we generated ensembles that are consistent with chemical shift measurements obtained on tau constructs. Thirty models were constructed for the second microtubule binding repeat (MTBR2 in wild-type (WT tau and a DeltaK280 mutant, which is found in some forms of frontotemporal dementia. By focusing on structural features that are preserved across all ensembles, we find that the aggregation-initiating sequence, PHF6*, prefers an extended conformation in both the WT and DeltaK280 sequences. In addition, we find that residue K280 can adopt a loop/turn conformation in WT MTBR2 and that deletion of this residue, which can adopt nonextended states, leads to an increase in locally extended conformations near the C-terminus of PHF6*. As an increased preference for extended states near the C-terminus of PHF6* may facilitate the propagation of beta-structure downstream from PHF6*, these results explain how a deletion at position 280 can promote the formation of tau aggregates.

  6. A novel donor splice site in intron 11 of the CFTR gene, created by mutation 1811 + 1.6kbA {yields} G, produces a new exon: High frequency in spanish cystic fibrosis chromosomes and association with severe phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Chillon, M.; Casals, T.; Gimenez, J.; Ramos, D.; Nunes, V.; Estivill, X. [Cancer Research Institute, Barcelona (Spain); Doerk, T.; Will, K. [Medizinische Hochschule Hannover (Germany); Fonknechten, N. [Institut Cochin de Genetique Moleculaire, Paris (France)

    1995-03-01

    mRNA analysis of the cystic fibrosis transmembrane regulator (CFTR) gene in tissues of cystic fibrosis (CF) patients has allowed us to detect a cryptic exon. The new exon involves 49 base pairs between exons 11 and 12 and is due to a point mutation (1811+1.6bA{yields}G) that creates a new donor splice site in intron 11. Semiquantitative mRNA analysis showed that 1811+1.6kbA{r_arrow}G-mRNA was 5-10-fold less abundant than {triangle}F508 mRNA. Mutations 1811+1.6kbA{yields}G was found in 21 Spanish and 1 German CF chromosome(s), making it the fourth-most-frequent mutation (2%) in the Spanish population. Individuals with genotype {triangle}F508/1811+1.6kbA{yields}G have only 1%-3% of normal CFTR mRNA. This loss of 97% of normal CFTR mRNA must be responsible for the pancreatic insufficiency and for the severe CF phenotype in these patients. 30 refs., 3 figs., 2 tabs.

  7. Delta III—an evolutionary delta growth

    Science.gov (United States)

    Arvesen, R. J.; Simpson, J. S.

    1996-03-01

    In order to remain competitive in the future and expand the McDonnell Douglas Aerospace market share, MDA has developed an expendable launch system strategy that devices cost-effective launch systems from the Delta II with a growth vehicle configuration called Delta III. The Delta III evolves from the Delta II launch system through development of a larger payload fairing (4-meter diameter), new cryogenically propelled upper stage, new first stage fuel tank, and larger strap-on solid rocket motors. We are developing the Delta III using Integrated Product Development Teams that capitalize on the experience base that has led us to a world record breaking mission success of 49 consecutive Delta II missions. The Delta III first-launch capability is currently planned for the spring of 1998 in support of our first spacecraft customer, Hughes Space and Communications International.

  8. Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment.

    LENUS (Irish Health Repository)

    Rogan, Mark P

    2012-02-01

    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?

  9. The Delta 2 launcher

    Science.gov (United States)

    Ousley, Gilbert W., Sr.

    1991-12-01

    The utilization of the Delta 2 as the vehicle for launching Aristoteles into its near Sun synchronous orbit is addressed. Delta is NASA's most reliable launch vehicle and is well suited for placing the present Aristoteles spacecraft into a 400 m circular orbit. A summary of some of the Delta 2 flight parameters is presented. Diagrams of a typical Delta 2 two stage separation are included along with statistics on delta reliability and launch plans.

  10. Delta Plaza kohvik = Delta Plaza cafe

    Index Scriptorium Estoniae

    2010-01-01

    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)

  11. Delta Plaza kohvik = Delta Plaza cafe

    Index Scriptorium Estoniae

    2010-01-01

    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)

  12. Cascade testing for carrier status in cystic fibrosis in a large family.

    Science.gov (United States)

    Turner, G; Meagher, W; Willis, C; Colley, P

    1993-08-02

    The offer to determine carrier status for cystic fibrosis (CF) was made to the 230 descendants of a couple who were presumed to carry the delta F508 mutation. "Cascade testing" was employed, in which the mutation is followed from the oldest generation down. Compliance was over 75% and family members were relieved of the anxiety engendered by uncertainty. In one couple considering having a family, both partners were found to be carriers.

  13. A novel CFTR mutation found in a Chinese patient with cystic fibrosis

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Background Cystic fibrosis (CF) is rare in Chinese. We investigated the mutations in the gene of cystic fibrosis transmembrane conductance regulator (CFTR) in a Chinese CF patient and reviewed the clinical features, gene mutations in Chinese CF cases. Methods Blood samples were collected from a previously reported CF girl and her parents. The 24 coding exons of CFTR of the proband were amplified and sequenced. Results A Chinese girl of 16 years old was diagnosed as CF at the age of 14. She had recurrent productive cough with bronchiectasis in bilateral upper lobes, parasinusitis and otitis media, but without pancreatic involvement. Her sweat chloride was (108.9 ±3.3) mmol/L. A heterozygous novel missense mutation of 699 C→A which results in the amino acid change of N189K was identified in exon 5. In addition, a heterozygous 3821-3823 delT mutation in exon 19 was found in CFTR. The mutation 699C→A was inherited from her father, and the 3821-3823delT mutation was from her mother. Twenty patients with CF in Chinese reported from 1974 to 2004 were also reviewed. DelF508 mutation was not found in the nine cases whose CFTR mutations were analyzed. Conclusions The CF proband carries two heterozygous mutations (699C→A and 3821-3823delT) in CFTR. 699C→A mutation is a novel mutation which is not reported previously. Review of reported Chinese cases suggests that the genotype of Chinese CF may be different from those of white cases. More studies are needed to understand the spectra of CFTR and clinical CF features in Chinese.

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

    Directory of Open Access Journals (Sweden)

    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

  15. Functional analysis of a promoter variant identified in the CFTR gene in cis of a frameshift mutation.

    Science.gov (United States)

    Viart, Victoria; Des Georges, Marie; Claustres, Mireille; Taulan, Magali

    2012-02-01

    In monogenic diseases, the presence of several sequence variations in the same allele may complicate our understanding of genotype-phenotype relationships. We described new alterations identified in a cystic fibrosis (CF) patient harboring a 48C>G promoter sequence variation associated in cis of a 3532AC>GTA mutation and in trans with the F508del mutation. Functional analyses including in vitro experiments confirmed the deleterious effect of the 3532GTA frameshift mutation through the creation of a premature termination codon. The analyses also revealed that the 48G promoter variant has a negative effect on both transcription and mRNA level, thus demonstrating the importance of analyzing all mutations or sequence variations with potential impact on CF transmembrane conductance regulator processing, even when the two known disease-causing mutations have already been detected. Our results emphasize the need to perform, wherever possible, functional studies that may greatly assist the interpretation of the disease-causing potential of rare mutation-associated sequence variations.

  16. Delta hedging strategies comparison

    DEFF Research Database (Denmark)

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

    2008-01-01

    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 ...

  17. Horizontal Symmetries $\\Delta(150)$ and $\\Delta(600)$

    CERN Document Server

    Lam, C S

    2013-01-01

    Using group theory of mixing to examine all finite subgroups of SU(3) with an order less than 512, we found recently that only the group $\\Delta(150)$ can give rise to a correct reactor angle $\\th_{13}$ of neutrino mixing without any free parameter. It predicts $\\sin^22\\th_{13}=0.11$ and a sub-maximal atmospheric angle with $\\sin^22\\th_{23}=0.94$, in good agreement with experiment. The solar angle $\\th_{12}$, the CP phase $\\d$, and the neutrino masses $m_i$ are left as free parameters. In this article we provide more details of this case, discuss possible gain and loss by introducing right-handed symmetries, and/or valons to construct dynamical models. A simple model is discussed where the solar angle agrees with experiment, and all its mixing parameters can be obtained from the group $\\Delta(600)$ by symmetry alone. The promotion of $\\Delta(150)$ to $\\Delta(600)$ is on the one hand analogous to the promotion of $S_3$ to $S_4$ in the presence of tribimaximal mixing, and on the other hand similar to the extens...

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

    Directory of Open Access Journals (Sweden)

    Dinić Jelena

    2007-01-01

    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

  19. On the width of N-Delta and Delta-Delta states

    CERN Document Server

    Niskanen, J A

    2016-01-01

    It is seen by a coupled-channel calculation that in the two-baryon N-Delta or Delta-Delta system the width of the state is greatly diminished due to the relative kinetic energy of the two baryons, since the internal energy of the particles, available for pionic decay, is smaller. A similar state dependent effect arises from the centrifugal barrier in N-Delta or Delta-Delta systems with non-zero orbital angular momentum. The double-Delta width can become even smaller than the free width of a single Delta. This has some bearing to the interpretation of the d'(2380) resonance recently discovered at COSY.

  20. Identification of CFTR Gene Mutations in Chinese Patients with Congenital Obstructive Azoospermia

    Institute of Scientific and Technical Information of China (English)

    曾国华; 吴开俊; 梅骅; 庄广伦

    2001-01-01

    Objective To analyze the frequency and hot spot of CFTR gene mutations in Chinese patients with congenital obstructive azoospermia Materials & Methods Mutations in CFTR exon 2,3,4,5,6a,8,10,11,12,13,15A 17b, 19A,20,21and 23 were detected. PCR-single strand conformation poly-morphism (SSCP) and direct sequencing were performed on 32 patients with congenital bilateral absence of the vas deferens (CBAVD), 17 patients with congenital unilateral absence of the vas deferens (CUAVD) and 50 normal Chinese.Results No CFTR gene mutations were detected in 50 normal Chinese. One CBAVD patient exhibited an abnormal band on SSCP for exon 10 of the CFTR gene and subsequent DNA sequencing showed a 3 bp deletion at position 1 653~ 1 655, which caused the deletion of a single amino acid, phenyalanine, in codon 508, i. e. , △F 508. A shift mutation was detected in another CBAVD patient in exon 2, a 1 bp deletion at position 225, 225 delC. One CUAVD patient exhibited an abnormal band on SSCP for exon 17 b of CFTR gene. Subsequent DNA sequencing showed a C-to-A transversion at position 3 295, which led to a predicted change of Leusine (codon 1 055,CUU) to Isoleucine (codon AUU), L1055I.Conclusion CFTR mutation could be detected in Chinese patients with congenital obstructive azoospermia. But no hot spots of mutations are discovered. 225 delC and L1055I are identified as two novel mutations, which are found only in Chinese.

  1. geomorphology_delta

    Data.gov (United States)

    California Department of Resources — Surficial geology of the Delta area of California by Brian Atwater of the U.S. Geological Survey. Source maps are from the USGS publication MF-1401. This digital...

  2. Delta-Reliability

    OpenAIRE

    Eugster, P.; Guerraoui, R.; Kouznetsov, P.

    2001-01-01

    This paper presents a new, non-binary measure of the reliability of broadcast algorithms, called Delta-Reliability. This measure quantifies the reliability of practical broadcast algorithms that, on the one hand, were devised with some form of reliability in mind, but, on the other hand, are not considered reliable according to the ``traditional'' notion of broadcast reliability [HT94]. Our specification of Delta-Reliability suggests a further step towards bridging the gap between theory and...

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

    Science.gov (United States)

    Ziętkiewicz, Ewa; Rutkiewicz, Ewa; Pogorzelski, Andrzej; Klimek, Barbara; Voelkel, Katarzyna; Witt, Michał

    2014-01-01

    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 efficiency of

  4. Impact of Cystic Fibrosis Transmembrane Regulator (CFTR gene mutations on male infertility

    Directory of Open Access Journals (Sweden)

    Jlenia Elia

    2014-09-01

    Full Text Available Objective. The aim of this study was to evaluate the prevalence of most common mutations and intron 8 5T (IVS8-5T polymorphism of CFTR gene in Italian: a azoospermic males; b non azoospermic subjects, male partners of infertile couples enrolled in assisted reproductive technology (ART programs. Material and methods. We studied 242 subjects attending our Andrology Unit (44 azoospermic subjects and 198 non azoospermic subjects, male partners of infertile couples enrolled in ART programs. Semen analysis, molecular analysis for CFTR gene mutations and genomic variant of IVS8-5T polymorphic tract, karyotype and chromosome Y microdeletions, hormonal profile (LH, FSH, Testosterone and seminal biochemical markers (fructose, citric acid and L-carnitine were carried out. Results. The prevalence of the common CFTR mutations and/or the IVS8-5T polymorphism was 12.9% (4/31 cases in secretory azoospermia, while in obstructive azoospermia was 84.6% (11/13 cases; in these, the most frequent mutations were the F508del, R117H and W1282X. Regarding the non azoospermic subjects, the prevalence of the CFTR and/or the IVS8-5T polymorphism was 11.1% (11/99 cases in severe dyspermia, 8.1% (6/74 cases in moderate dyspermia and finally 4.0% (1/25 cases in normospermic subjects. Conclusions. This study confirms the highly significant prevalence of CFTR mutations in males with bilateral absence of the vas deferens or ejaculatory ducts obstruction compared with subjects with secretory azoospermia. Moreover, the significant prevalence of mutations in severely dyspermic subjects may suggest the possible involvement of CFTR even in the spermatogenic process. This could explain the unsatisfactory recovery of sperm from testicular fine needle aspiration in patients affected by genital tract blockage.

  5. Hemoglobinopathies in the Dogon Country: presence of beta S, beta C, and delta A' genes.

    Science.gov (United States)

    Ducrocq, R; Bennani, M; Bellis, G; Baby, M; Traore, K; Nagel, R L; Krishnamoorthy, R; Chaventre, A

    1994-07-01

    The population of the Dogon, located in Mali, is divided in an endogamic Noble class and two endogamic servant castes (Tanners and Blacksmiths). We find that the polymorphic frequencies of beta c, beta S, and, unexpectedly, a mutation of the delta-chain (delta A'), are geographically (valley vs. plateau) as well as social status dependent.

  6. {\\delta}M Formalism

    CERN Document Server

    Talebian-Ashkezari, Alireza; Abolhasani, Ali Akbar

    2016-01-01

    We study the evolution of the "non-perturbative" metric perturbations in a Bianchi background in the long-wavelength limit. By applying the gradient expansion to the equations of motion we exhibit a generalized "Separate Universe" approach to the cosmological perturbation theory. Having found this consistent separate universe picture, we introduce the "{\\delta}M formalism" for calculating the evolution of the tensor perturbations in anisotropic inflation models in almost similar way as the so-called {\\delta}N formula for the super-horizon dynamics of the curvature perturbations. Likewise its ancestor, {\\delta}N formalism, this new method can substantially reduce the amount of calculations related to the evolution of the tensor modes.

  7. The Niger Delta Crisis

    African Journals Online (AJOL)

    chifaou.amzat

    2013-09-28

    Sep 28, 2013 ... lions de barils par jour à environ 1 million au plus fort de la crise du Delta ... (JTF) between 13 May 2009 and 4 October 2009 (the deadline for embrac- ..... He had just ended his welcome address as the occasion's chairman.

  8. DELTAS: A new Global Delta Sustainability Initiative (Invited)

    Science.gov (United States)

    Foufoula-Georgiou, E.

    2013-12-01

    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

  9. 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;

    2001-01-01

    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....

  10. Estimating the age of alleles by use of intraallelic variability

    Energy Technology Data Exchange (ETDEWEB)

    Slatkin, M.; Rannala, B. [Univ of California, Berkeley, CA (United States)

    1997-02-01

    A method is presented for estimating the age of an allele by use of its frequency and the extent of variation among different copies. The method uses the joint distribution of the number of copies in a population sample and the coalescence times of the intraallelic gene genealogy conditioned on the number of copies. The linear birth-death process is used to approximate the dynamics of a rare allele in a finite population. A maximum-likelihood estimate of the age of the allele is obtained by Monte Carlo integration over the coalescence times. The method is applied to two alleles at the cystic fibrosis (CFTR) locus, {Delta}F508 and G542X, for which intraallelic variability at three intronic microsatellite loci has been examined. Our results indicate that G542X is somewhat older than {Delta}F508. Although absolute estimates depend on the mutation rates at the microsatellite loci, our results support the hypothesis that {Delta}F508 arose <500 generations ({approx}10,000 years) ago. 32 refs., 4 figs.

  11. Timelike gamma* N -> Delta form factors and Delta Dalitz decay

    CERN Document Server

    Ramalho, G

    2012-01-01

    We extend a covariant model, tested before in the spacelike region for the physical and lattice QCD regimes, to a calculation of the gamma* N -> Delta reaction in the timelike region, where the square of the transfered momentum, q^2, is positive (q^2>0). We estimate the Dalitz decay Delta -> Ne+e- and the Delta distribution mass distribution function. The results presented here can be used to simulate the NN -> NNe+e- reactions at moderate beam kinetic energies.

  12. Delta II commercial space transportation

    Science.gov (United States)

    Meyers, J. F.

    1988-07-01

    Delta II is an upgraded variant of the Delta family of launch vehicles that has been in use by NASA since 1960. Among the design improvements incorporated by Delta II is a cryogenic-propellant second stage, a 2.89-m diameter satellite-protecting nose fairing, graphite/epoxy solid rocket motor cases, and 12:1 main engine expansion nozzle. The manufacturer/operator offers Delta II customers a dedicated, single satellite launch capability fully tailored to the given spacecraft's unique mission requirements.

  13. Mutations in antiquitin in individuals with pyridoxine-dependent seizures.

    NARCIS (Netherlands)

    Mills, P.B.; Struys, E.A.; Jakobs, C.; Plecko, B.; Baxter, P.; Baumgartner, M.; Willemsen, M.A.A.P.; Omran, H.; Tacke, U.; Uhlenberg, B.; Weschke, B.; Clayton, P.T.

    2006-01-01

    We show here that children with pyridoxine-dependent seizures (PDS) have mutations in the ALDH7A1 gene, which encodes antiquitin; these mutations abolish the activity of antiquitin as a delta1-piperideine-6-carboxylate (P6C)-alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase. The accumulating

  14. 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

    1999-01-01

    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

  15. 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

    1999-01-01

    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 wh

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

    NARCIS (Netherlands)

    van Asselen, S.|info:eu-repo/dai/nl/304838101

    2010-01-01

    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

  17. 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

    1999-01-01

    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 wh

  18. $\\Delta$-N Electromagnetic Transition

    CERN Document Server

    Loan, M

    1999-01-01

    The EM ratio for a free Delta electromagnetic transition is discussed within the frame work of nonrelativistic approach. Such an approach gives a good account of data for a free Delta but is less important for an intrinsically relativistic nuclear many body problem.

  19. Mida pakub Delta? / Teele Kurm

    Index Scriptorium Estoniae

    Kurm, Teele

    2011-01-01

    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

  20. Delta Electroproduction in 12-C

    Energy Technology Data Exchange (ETDEWEB)

    Steven McLauchlan

    2003-01-31

    The Delta-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 delta mass indicating that this potential is dependent on the momentum of the delta. 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 delta resonance in 12C, performed using the high energy electron beam at the Thomas Jefferson National Accelerator Facility, and the near 4(pie) 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 delta mass was only observed in the exclusive measurements indicating that the delta-nucleus potential is affected by the momentum of the delta.

  1. Mida pakub Delta? / Teele Kurm

    Index Scriptorium Estoniae

    Kurm, Teele

    2011-01-01

    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

  2. Azithromycin reduces spontaneous and induced inflammation in ΔF508 cystic fibrosis mice

    NARCIS (Netherlands)

    R. Legssyer (Rachida); F. Huaux (François); J. Lebacq (Jean); M. Delos (Monique); E. Marbaix (Etienne); P. Lebecque (Patrick); D. Lison (Dominique); B.J. Scholte (Bob); P. Wallemacq (Pierre); T. Leal (Teresinha)

    2006-01-01

    textabstractBackground: Inflammation plays a critical role in lung disease development and progression in cystic fibrosis. Azithromycin is used for the treatment of cystic fibrosis lung disease, although its mechanisms of action are poorly understood. We tested the hypothesis that azithromycin

  3. Mackenzie River Delta, Canada

    Science.gov (United States)

    2007-01-01

    The Mackenzie River in the Northwest Territories, Canada, with its headstreams the Peace and Finley, is the longest river in North America at 4241 km, and drains an area of 1,805,000 square km. The large marshy delta provides habitat for migrating Snow Geese, Tundra Swans, Brant, and other waterfowl. The estuary is a calving area for Beluga whales. The Mackenzie (previously the Disappointment River) was named after Alexander Mackenzie who travelled the river while trying to reach the Pacific in 1789. The image was acquired on August 4, 2005, covers an area of 55.8 x 55.8 km, and is located at 68.6 degrees north latitude, 134.7 degrees west longitude. The U.S. science team is located at NASA's Jet Propulsion Laboratory, Pasadena, Calif. The Terra mission is part of NASA's Science Mission Directorate.

  4. DELTA 3D PRINTER

    Directory of Open Access Journals (Sweden)

    ȘOVĂILĂ Florin

    2016-07-01

    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.

  5. Birth of healthy female twins after preimplantation genetic diagnosis of cystic fibrosis combined with gender determination.

    Science.gov (United States)

    Ray, Pierre F; Frydman, Nelly; Attié, Tania; Hamamah, Samir; Kerbrat, Violaine; Tachdjian, Gérard; Romana, Serge; Vekemans, Michel; Frydman, René; Munnich, Arnold

    2002-07-01

    Two healthy sisters with a familial history of mental retardation were referred to our centre for preimplantation genetic diagnosis (PGD). Their two brothers showed severe mental retardation. The molecular basis for their disorder could not be identified, but one of the sisters and the mother presented a highly skewed pattern of X-inactivation reinforcing the likelihood of an X-linked mode of inheritance. Both sisters requested PGD to avoid the abortion of potentially affected male fetuses. PGD for sex by fluorescent in-situ hybridization was carried out for the first sister and resulted in the birth of a female child. The second sister and her partner, whose niece had cystic fibrosis (CF), were tested for CF mutations, and were both found to be deltaF508 heterozygous. We developed an efficient single cell PCR protocol for the simultaneous amplification of the CF (deltadeltaF508) locus as well as the X-linked amelogenin gene and its highly homologous pseudogene on the Y chromosome. Two PGD cycles were carried out to screen against male and deltaF508 homozygous deleted embryos. In each case several embryos could be selected for transfer and the second cycle resulted in a twin pregnancy followed by the birth of two healthy female infants.

  6. Alopecia in a viable phospholipase C delta 1 and phospholipase C delta 3 double mutant.

    Directory of Open Access Journals (Sweden)

    Fabian Runkel

    Full Text Available BACKGROUND: Inositol 1,4,5trisphosphate (IP(3 and diacylglycerol (DAG are important intracellular signalling molecules in various tissues. They are generated by the phospholipase C family of enzymes, of which phospholipase C delta (PLCD forms one class. Studies with functional inactivation of Plcd isozyme encoding genes in mice have revealed that loss of both Plcd1 and Plcd3 causes early embryonic death. Inactivation of Plcd1 alone causes loss of hair (alopecia, whereas inactivation of Plcd3 alone has no apparent phenotypic effect. To investigate a possible synergy of Plcd1 and Plcd3 in postnatal mice, novel mutations of these genes compatible with life after birth need to be found. METHODOLOGY/PRINCIPAL FINDINGS: We characterise a novel mouse mutant with a spontaneously arisen mutation in Plcd3 (Plcd3(mNab that resulted from the insertion of an intracisternal A particle (IAP into intron 2 of the Plcd3 gene. This mutation leads to the predominant expression of a truncated PLCD3 protein lacking the N-terminal PH domain. C3H mice that carry one or two mutant Plcd3(mNab alleles are phenotypically normal. However, the presence of one Plcd3(mNab allele exacerbates the alopecia caused by the loss of functional Plcd1 in Del(9olt1Pas mutant mice with respect to the number of hair follicles affected and the body region involved. Mice double homozygous for both the Del(9olt1Pas and the Plcd3(mNab mutations survive for several weeks and exhibit total alopecia associated with fragile hair shafts showing altered expression of some structural genes and shortened phases of proliferation in hair follicle matrix cells. CONCLUSIONS/SIGNIFICANCE: The Plcd3(mNab mutation is a novel hypomorphic mutation of Plcd3. Our investigations suggest that Plcd1 and Plcd3 have synergistic effects on the murine hair follicle in specific regions of the body surface.

  7. Impact of gene patents and licensing practices on access to genetic testing for cystic fibrosis.

    Science.gov (United States)

    Chandrasekharan, Subhashini; Heaney, Christopher; James, Tamara; Conover, Chris; Cook-Deegan, Robert

    2010-04-01

    Cystic fibrosis is one of the most commonly tested autosomal recessive disorders in the United States. Clinical cystic fibrosis is associated with mutations in the CFTR gene, of which the most common mutation among Caucasians, DeltaF508, was identified in 1989. The University of Michigan, Johns Hopkins University, and the Hospital for Sick Children, where much of the initial research occurred, hold key patents on cystic fibrosis genetic sequences, mutations, and methods for detecting them. Several patents, including the one that covers detection of the DeltaF508 mutation, are jointly held by the University of Michigan and the Hospital for Sick Children in Toronto, with Michigan administering patent licensing in the United States. The University of Michigan broadly licenses the DeltaF508 patent for genetic testing with >60 providers of genetic testing to date. Genetic testing is now used in newborn screening, diagnosis, and for carrier screening. Interviews with key researchers and intellectual property managers, a survey of laboratories' prices for cystic fibrosis genetic testing, a review of literature on cystic fibrosis tests' cost-effectiveness, and a review of the developing market for cystic fibrosis testing provide no evidence that patents have significantly hindered access to genetic tests for cystic fibrosis or prevented financially cost-effective screening. Current licensing practices for cystic fibrosis genetic testing seem to facilitate both academic research and commercial testing. More than 1000 different CFTR mutations have been identified, and research continues to determine their clinical significance. Patents have been nonexclusively licensed for diagnostic use and have been variably licensed for gene transfer and other therapeutic applications. The Cystic Fibrosis Foundation has been engaged in licensing decisions, making cystic fibrosis a model of collaborative and cooperative patenting and licensing practice.

  8. WORLD DELTAS AND THEIR EVOLUTION

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    In August 1998, an international symposium on the world deltas was held in New Orleans, Louisiana, USA. This symposium attracted discussion about more than 25 deltas from around the world with emphasis placed on those that are most densely populated and impacted by humans. Keynote papers printed details about the physical, biological, engineering and socioeconomic aspects of six deltas including the Mississippi, Nile, Ganges-Brahmaputra, Rhine-Meuse, Changjiang and Po. The main purpose of this symposium was to inform scientists, engineers and decision-makers about information that is currently available and to provide them a basis for working in such environments.

  9. Dynamical Casimir effect with $\\delta-\\delta^{\\prime}$ mirrors

    CERN Document Server

    Silva, Jeferson Danilo L; Alves, Danilo T

    2016-01-01

    We calculate the spectrum and the total rate of created particles for a real massless scalar field in $1+1$ dimensions, in the presence of a partially transparent moving mirror simulated by a Dirac $\\delta-\\delta^{\\prime}$ point interaction. We show that, strikingly, a partially reflecting mirror can produce a larger number of particles in comparison with a perfectly reflecting one. In the limit of a perfect mirror, our formulas recover those found in the literature for the Robin boundary condition.

  10. PARAMETRIC DESIGN OF DELTA ROBOT

    Directory of Open Access Journals (Sweden)

    Mert Gürgen

    2016-09-01

    Full Text Available This article describes a sophisticated determination and presentation of a workspace volume for a delta robot, with consideration of its kinematic behavior. With the help of theoretical equations, optimization is performed with the aid of the stiffness and dexterity analysis. Theoretical substructure is coded in Matlab and three-dimensional (3D data for delta robot are developed in computer-aided design (CAD environment. In later stages of the project, both 3D and theoretical data are linked together and thus, with the changing design parameter of the robot itself, the Solidworks CAD output adapts and regenerates output with a new set of parameters. To achieve an optimum workspace volume with predefined parameters, a different set of robot parameters are iterated through design optimization in Matlab, and the delta robot design is finalized and illustrated in the 3D CAD environment, Solidworks. This study provides a technical solution to accomplish a generic delta robot with optimized workspace volume.

  11. Limited premature termination codon suppression by read-through agents in cystic fibrosis intestinal organoids.

    Science.gov (United States)

    Zomer-van Ommen, D D; Vijftigschild, L A W; Kruisselbrink, E; Vonk, A M; Dekkers, J F; Janssens, H M; de Winter-de Groot, K M; van der Ent, C K; Beekman, J M

    2016-03-01

    Premature termination codon read-through drugs offer opportunities for treatment of multiple rare genetic diseases including cystic fibrosis. We here analyzed the read-through efficacy of PTC124 and G418 using human cystic fibrosis intestinal organoids (E60X/4015delATTT, E60X/F508del, G542X/F508del, R1162X/F508del, W1282X/F508del and F508del/F508del). G418-mediated read-through induced only limited CFTR function, but functional restoration of CFTR by PTC124 could not be confirmed. These studies suggest that better read-through agents are needed for robust treatment of nonsense mutations in cystic fibrosis.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Student Difficulties with the Dirac Delta Function

    CERN Document Server

    Wilcox, Bethany R

    2014-01-01

    The Dirac delta function is a standard mathematical tool used in multiple topical areas in the undergraduate physics curriculum. While Dirac delta functions are usually introduced in order to simplify a problem mathematically, students often struggle to manipulate and interpret them. To better understand student difficulties with the delta function at the upper-division level, we examined responses to traditional exam questions 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 physics. Here, we focus on student difficulties using the delta function to express charge distributions in the context of junior-level electrostatics. Challenges included: invoking the delta function spontaneously, constructing two- and three-dimensional delta functions, integrating novel delta function expressions, and recognizing that the delta function can have units.

  14. Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome).

    Science.gov (United States)

    Herman, Gail E; Kelley, Richard I; Pureza, V; Smith, D; Kopacz, Kevin; Pitt, James; Sutphen, Rebecca; Sheffield, Leslie J; Metzenberg, Aida B

    2002-01-01

    Human X-linked dominant chondrodysplasia punctata (CDPX2) or Happle syndrome is associated with mutations in the human emopamil binding protein (EBP), a delta8-delta7-sterol isomerase involved in cholesterol biosynthesis. The purpose of the current study was to determine the spectrum of EBP mutations in females with CDPX2 and the utility of biochemical screening for the disorder by analysis of plasma sterols. Genomic sequencing of the coding exons of the human delta8-delta7-sterol isomerase gene was performed on DNA from 26 females with suspected X-linked dominant chondrodysplasia punctata. Clinical data and sterol analyses were obtained for 24 and 23 of the patients, respectively. Mutations in the human EBP delta8-delta7-sterol isomerase gene were found in 22 (85%) of 26 females studied, including 20 (91%) of 22 patients who demonstrated an abnormal sterol profile. Thirteen of the mutations have not been reported previously. All of the females in whom mutations were found demonstrated typical skin manifestations of CDPX2, and all but one had a skeletal dysplasia. Plasma sterol analysis was a highly specific and sensitive indicator of the presence of an EBP mutation in females with suspected CDPX2, including a clinically unaffected mother of a sporadic case. No clear genotype/phenotype correlations were ascertained, probably because phenotypic expression is influenced substantially by the pattern of X-inactivation in an affected female.

  15. Prevalence of Lithuanian mutation among St. Petersburg Jews with familial hypercholesterolemia.

    Science.gov (United States)

    Mandelshtam, M; Chakir, K; Shevtsov, S; Golubkov, V; Skobeleva, N; Lipovetsky, B; Konstantinov, V; Denisenko, A; Gaitskhoki, V; Schwartz, E

    1998-01-01

    We used polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis to detect LDL receptor gene defects in the St. Petersburg population. We have found a deltaG197 mutation in several patients of Jewish origin. The mutation named is shown to be responsible for one-third (7/23) of familial hypercholesterolemia (FH) cases in St. Petersburg Jews and absent in patients of Russian descent. The prevalence of a deltaG197 mutation in St. Petersburg Jews is consistent with its origin in Lithuania or Poland. The deltaG197 mutation can be easily detected in polyacrylamide minigels because of formation of specific heteroduplexes during PCR with DNA of heterozygous patients. Taken together with high prevalence of the mutation in St. Petersburg Jews, this observation provides an opportunity for DNA diagnostics of FH in this ethnic group.

  16. {Delta}I = 3/2 and {Delta}S = 2 Hyperon decays in chiral perturbation theory

    Energy Technology Data Exchange (ETDEWEB)

    He, X.G. [University of Melbourne, Parkville, VIC (Australia). School of Physics; Valencia, G. [Iowa State University, Ames, Iowa (United States). Department of Physics and Astronomy

    1997-05-01

    We study the| {Delta}I| = 3/2 and |{Delta}S| = 2 amplitudes for hyperon decays of the form B {yields} B`{pi} at lowest order in chiral perturbation theory. At this order, the {Delta}I = 3/2 amplitudes depend on only one constant. We extract the value of this constant from experiment and find a reasonable description of these processes within experimental errors. The same constant determines the {Delta}S = 2 transitions which, in the standard model, are too small to be observed. We find that new physics with parity odd {Delta}S = 2 interactions can produce observable rates in hyperon decays while evading the bounds from K{sup 0} - K-bar{sup 0} mixing. (authors) 10 refs., 3 tabs.

  17. Reactive versus anticipative adaptive management of Deltas: The Sacramento-San Joaquin Delta and the Rhine-Meuse Delta compared

    NARCIS (Netherlands)

    Vlieg, T.J.; Zandvoort, M.

    2013-01-01

    In this paper Californian Adaptive Management (AM) and Dutch Adaptive Delta Management (ADM) are compared. The concepts are introduced in a policy context to deal with prevailing types of uncertainty in water management in the Californian Sacramento-San Joaquin Delta and the Dutch Rhine-Meuse Delta

  18. Facts About Delta Pi Epsilon

    Science.gov (United States)

    Delta Pi Epsilon Journal, 1976

    1976-01-01

    The article discusses the purpose and structure of Delta Pi Epsilon and the general qualifications for membership. Service projects and publications, research awards, timely facts, the year of each chapter's origination, national presidents, and executive secretaries for the last 40 years are listed. (BP)

  19. Hydrological and Climatic Significance of Martian Deltas

    Science.gov (United States)

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

    2017-10-01

    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.

  20. Yellow River Delta Faces a Historic Opportunity

    Institute of Scientific and Technical Information of China (English)

    Li Zhen

    2010-01-01

    @@ China's State Council has endorsed the Development Plan of an Efficient Eco-Economic Zone at Yellow River Delta. The plan is meant to create a more ecologically sustainable economic zone along the river delta.

  1. Yellow River Delta Faces a Historic Opportunity

    Institute of Scientific and Technical Information of China (English)

    Li Zhen

    2011-01-01

    @@ China's State Council has endorsed the Development Plan of an Efficient Eco-Economic Zone at Yellow River Delta.The plan is meant to create a more ecologically sustainable economic zone along the river delta.

  2. On the modelling of river delta formation

    NARCIS (Netherlands)

    Geleynse, N.

    2013-01-01

    This thesis presents approaches to the modelling of river delta formation. In particular, it provides results of numerical stratigraphic-morphodynamic modelling of river delta formation under various environmental forcings.

  3. 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.

    2015-01-01

    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, metropoli

  4. Delta Vegetation and Land Use [ds292

    Data.gov (United States)

    California Department of Resources — 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....

  5. Limited junctional diversity of V delta 5-J delta 1 rearrangement in multiple sclerosis patients.

    Science.gov (United States)

    Nowak, J S; Michałowska-Wender, G; Januszkiewicz, D; Wender, M

    1997-01-01

    T-cell receptor (TCR) delta gene repertoire, as assessed by V delta-J delta rearrangements, has been analyzed in nine multiple sclerosis (MS) cases and in 30 healthy individuals by seminested PCR technique. Among the V delta-J delta junctional diversities studied, the most striking result has been observed in V delta 5-J delta 1 rearrangement. The detection of repeated V delta 5-J delta 1 nucleotide sequences in all analyzed clones from seven out of nine patients studied proved the monoclonal nature of gamma delta T-cells with V delta 5-J delta 1 rearrangement. The clonal nature of this rearrangement proved by PAGE and sequencing analysis may suggest an antigen-driven expansion of gamma delta T cells and argues for a significant role of gamma delta T-cells with V delta 5-J delta 1 rearrangement in MS pathogenesis. However, it cannot be excluded that clonal expansion of these lymphocytes may represent secondary change to central nervous system damage.

  6. Reflections on Development Strategy of Pearl River Delta: In Comparison with Yangtze River Delta

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    <正>1. A comparison between Pearl River Delta and Yangtze River Delta 1.1 Basic conditions 1.1.1 Location, area and scope Located in the southeast of Guangdong Province, the Pearl River Delta (PRD) as an economic zone is a compound delta

  7. Assessment of the mutagenic potential of arecoline in gpt delta transgenic mice.

    Science.gov (United States)

    Wu, Mengjun; Xing, Guozhen; Qi, Xinming; Feng, Chenchen; Liu, Mingxia; Gong, Likun; Luan, Yang; Ren, Jin

    2012-10-09

    Chewing the areca nut is carcinogenic to humans. Arecoline, a major alkaloid in areca nut, is suspected to be a carcinogenic component. It has been shown to have genotoxic potential in various in vitro systems; but information on its in vivo genotoxicity is limited. To investigate the organ-specific mutagenic potential of arecoline, we employed gpt delta transgenic mice to analyze the mutagenicity of arecoline in the oral tissues and liver. Male gpt delta mice were given arecoline hydrobromide in drinking water at 300 and 700μg/mL for 6 weeks. 4-Nitroquinoline-1 (4-NQO) was used as a positive control. Two weeks after the last treatment, mutation frequencies in the oral tissues (a mixture of gingival, buccal, pharyngeal and sublingual tissue) and liver were detected and mutation spectra were analyzed. There were no statistically significant differences in the average mutation frequencies between arecoline-treated and untreated groups in both the oral tissues and liver. However, in the oral tissues, one mouse in arecoline-300μg/mL group and two mice in arecoline-700μg/mL group showed more than 2.5-fold higher mutation frequencies than the untreated group; they also exhibited unique mutation spectra compared to spontaneous mutation types. In these three mice, all mutations occurred at G:C sites, where G:C→T:A transversions were most frequent, followed by G:C→A:T transitions and G:C→C:G transversions. The main type of spontaneous mutation in both the oral tissues and liver was G:C→A:T transition. These results suggest that arecoline poses a mutagenic hazard in the oral tissues of gpt delta transgenic mice. © 2012 Elsevier B.V. All rights reserved.

  8. What is $\\Delta m^2_{ee}$ ?

    CERN Document Server

    Parke, Stephen

    2016-01-01

    The current short baseline reactor experiments, Daya Bay and RENO (Double Chooz) have measured (or are capable of measuring) an effective $\\Delta m^2$ associated with the atmospheric oscillation scale of 0.5 km/MeV in electron anti-neutrino disappearance. In this paper, I compare and contrast the different definitions of such an effective $\\Delta m^2$ and argue that the simple, L/E independent, definition given by $\\Delta m^2_{ee} \\equiv \\cos^2 \\theta_{12} \\Delta m^2_{31}+ \\sin^2 \\theta_{12} \\Delta m^2_{32}$, i.e. "the $\

  9. [delta-Aminolevulinate dehydratase deficiency].

    Science.gov (United States)

    Fujita, H; Ishida, N; Akagi, R

    1995-06-01

    delta-Aminolevulinate dehydratase (ALAD: E. C. 4.2.1.24), the second enzyme in the heme biosynthetic pathway, condenses two moles of delta-aminolevulinic acid to form porphobilinogen. ALAD deficiency is well known to develop signs and symptoms of typical hepatic porphyria, and classified into three categories as follows: (i) ALAD porphyria, a genetic defect of the enzyme, (ii) tyrosinemia type I, a genetic defect of fumarylacetoacetase in the tyrosine catabolic pathway, producing succinylacetone (a potent inhibitor of ALAD), and (iii) ALAD inhibition by environmental hazards, such as lead, trichloroethylene, and styrene. In the present article, we will describe molecular and biochemical mechanisms to cause the enzyme defect to discuss the significance of ALAD defect on human health.

  10. Periodicity in Delta-modulated feedback control

    Institute of Scientific and Technical Information of China (English)

    Xiaohua XIA; Guanrong CHEN; Rudong GAI; Alan S. I. ZINOBER

    2008-01-01

    The Delta-modulated feedback control of a linear system introduces nonlinearity into the system through switchings between two input values. It has been found that Delta-modulation gives rise to periodic orbits. The existence of periodic points of all orders of Sigma-Delta modulation with "leaky" integration is completely characterized by some interesting groups of polynomials with "sign" coefficients. The results are naturally generalized to Sigma-Delta modulations with multiple delays, Delta-modulations in the "downlink", unbalanced Delta-modulations and systems with two-level quantized feedback. Further extensions relate to the existence of periodic points arising from Delta-modulated feedback control of a stable linear system in an arbitrary direction, for which some necessary and sufficient conditions are given.

  11. Entendiendo Delta desde las Humanidades

    OpenAIRE

    José Calvo Tello

    2016-01-01

    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...

  12. 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.

    2013-01-01

    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 ch

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

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, H.Y., E-mail: haiyanzhang@imr.ac.cn [Institute of Metal Research, Chinese Academy of Sciences, Shenyang 110016 (China); Zhang, S.H., E-mail: shzhang@imr.ac.cn [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)

    2010-01-15

    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.

  14. Migration in Deltas: An Integrated Analysis

    Science.gov (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

    2017-04-01

    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

  15. Casimir force between $\\delta-\\delta^{\\prime}$ mirrors transparent at high frequencies

    CERN Document Server

    Braga, Alessandra N; Alves, Danilo T

    2016-01-01

    We investigate, in the context of a real massless scalar field in $1+1$ dimensions, models of partially reflecting mirrors simulated by Dirac $\\delta-\\delta^{\\prime}$ point interactions. In the literature, these models do not exhibit full transparency at high frequencies. In order to provide a more realistic feature for these models, we propose a modified $\\delta-\\delta^{\\prime}$ point interaction that enables to achieve full transparency in the limit of high frequencies. Taking this modified $\\delta-\\delta^{\\prime}$ model into account, we investigate the Casimir force, comparing our results with those found in the literature.

  16. Delta 并联机器人抓放轨迹优化%Delta Parallel Robot Pick and Place Trajectory Optimization

    Institute of Scientific and Technical Information of China (English)

    李云辉

    2016-01-01

    On the basis of Delta parallel robot trajectory of gate-shaped picking and placing,we described the method of trajectory planning and gate-shaped path synthesis by using the sinusoidal correcting keystone acceleration curve.From the perspective of mechanical vibration and shock reduction mechanism,taking the initiative to reduce Delta robot arm maximum angular shaft as the goal,the relevant operating parameters of trajectory were optimized.For the presence of jerk mutations on the acceleration curve approach to planning the start and end-side movement,resulting in a flexible shock problem,it is proposed that modified sinusoidal correcting keystone acceleration curve,making the entire operating cycle jerk curve become continuous,eliminating the system flexible impact.%在 Delta 并联机器人门形抓放轨迹的基础上,阐述了采用正弦修正梯形加速度曲线进行轨迹规划和门形路径合成的方法。从减小机构震动和冲击的角度出发,以降低 Delta 机器人主动臂驱动轴端的最大角加速度为目标,对门形轨迹的相关运行参数进行了优化。针对正弦修正梯形加速度曲线规划方式中运动始末端存在跃度突变,导致柔性冲击的问题,提出了改进型的正弦修正梯形加速度曲线,使得整个运行周期内跃度曲线变得连续,消除了系统的柔性冲击。

  17. Delta-Notch signaling and lateral inhibition in zebrafish spinal cord development

    Directory of Open Access Journals (Sweden)

    Givan Lee Anne

    2001-07-01

    Full Text Available Abstract Background Vertebrate neural development requires precise coordination of cell proliferation and cell specification to guide orderly transition of mitotically active precursor cells into different types of post-mitotic neurons and glia. Lateral inhibition, mediated by the Delta-Notch signaling pathway, may provide a mechanism to regulate proliferation and specification in the vertebrate nervous system. We examined delta and notch gene expression in zebrafish embryos and tested the role of lateral inhibition in spinal cord patterning by ablating cells and genetically disrupting Delta-Notch signaling. Results Zebrafish embryos express multiple delta and notch genes throughout the developing nervous system. All or most proliferative precursors appeared to express notch genes whereas subsets of precursors and post-mitotic neurons expressed delta genes. When we ablated identified primary motor neurons soon after they were born, they were replaced, indicating that specified neurons laterally inhibit neighboring precursors. Mutation of a delta gene caused precursor cells of the trunk neural tube to cease dividing prematurely and develop as neurons. Additionally, mutant embryos had excess early specified neurons, with fates appropriate for their normal positions within the neural tube, and a concomitant deficit of late specified cells. Conclusions Our results are consistent with the idea that zebrafish Delta proteins, expressed by newly specified neurons, promote Notch activity in neighboring precursors. This signaling is required to maintain a proliferative precursor population and generate late-born neurons and glia. Thus, Delta-Notch signaling may diversify vertebrate neural cell fates by coordinating cell cycle control and cell specification.

  18. Evolving deltas: Conceptualising coevolution with engineered interventions

    Science.gov (United States)

    Welch, Amy; Nicholls, Robert; Lazar, Attila

    2017-04-01

    Mid to low latitude deltas have been populated for thousands of years due to their fertile soil and coastal location. This has led to an alteration in the land cover of deltas to primary agriculture and dense rural settlements and more recently, major cities and megacities have developed on or adjacent to many deltas. Deltas may be prosperous in terms of their outputs and services; however, they are also susceptible to many hazards due to their location and low-lying nature. Hazards include storm surges, fluvial flooding and erosion of both coastal and riverine areas, as well as subsidence, relative sea-level rise and pollution. This can have severe impacts on the delta, its population and its services. Therefore engineered interventions have been used for some time to protect the population and the valuable land from the consequences of hazards. Coevolution can be described as a feedback loop between nature and humans: each has an effect on how the other behaves and hence this inter-dependence interaction continues. Therefore the natural evolution of the delta interacts with engineered interventions, such as promoting accelerated subsidence over time, necessitating further adaptation. The deltaic landscape and associated livelihoods are thus the result of this co-evolution process between natural delta processes and engineered interventions. This presentation will identify and discuss various drivers and consequences of large scale engineered interventions, comparing and contrasting the management approaches taken in five populated deltas (Ganges-Brahmaputra-Meghna, Yangtze, Rhine-Meuse-Scheldt, Mekong and Nile). The type of engineered intervention and management approaches had a direct effect on the coevolution of deltas, with each of the deltas being at different stages in terms of extent of coevolution. A qualitative timeline of the typical steps of coevolution between the human system and the delta system of the studied deltas was produced. The major

  19. Delta hepatitis agent: structural and antigenic properties of the delta-associated particle.

    Science.gov (United States)

    Bonino, F; Hoyer, B; Shih, J W; Rizzetto, M; Purcell, R H; Gerin, J L

    1984-01-01

    Delta agent (delta) was serially passaged to a second and third hepatitis B surface antigen (HBsAg) carrier chimpanzee, using as inoculum the peak delta antigen (delta Ag) serum of an animal previously infected with human serum. The characteristics of serially transmitted delta Ag were similar to those described in first-passage animals. It was consistently detected before the development of anti-delta, in association with a 35- to 37-nm subpopulation of HBsAg particles and a unique low-molecular-weight (5.5 X 10(5)) RNA. RNase susceptibility of the delta-associated RNA and release of delta Ag activity upon treatment of delta-associated particles with detergent revealed that this particle is organized into a virion-like form with the RNA and delta Ag as internal components within a coat of HBsAg. Surface determinants of the delta-associated particle other than HBsAg were not detected by radioimmunoprecipitation experiments, using sera of humans and chimpanzees convalescent from delta hepatitis. The HBsAg-associated particle is the "candidate agent" of delta hepatitis. Images PMID:6698598

  20. The Niger Delta Amnesty Program

    Directory of Open Access Journals (Sweden)

    Benjamin A. Okonofua

    2016-06-01

    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. Analysis and Synthesis of Delta Operator Systems

    CERN Document Server

    Yang, Hongjiu; Shi, Peng; Zhao, Ling

    2012-01-01

    This book is devoted to analysis and design on delta operator systems. When sampling is fast, a dynamical system will become difficult to control, which can be seen in wide real world applications. Delta operator approach is very effective to deal with fast sampling systems. Moreover, it is easy to observe and analyze the control effect with different sampling periods in delta operator systems. The framework of this book has been carefully constructed for delta operator systems to handle sliding mode control, time delays, filter design, finite frequency and networked control. These problems indeed are especially important and significant in automation and control systems design. Through the clear framework of the book, readers can easily go through the learning process on delta operator systems via a precise and comfortable learning sequence. Following this enjoyable trail, readers will come out knowing how to use delta operator approach to deal with control problems under fast sampling case. This book should...

  2. Delta Clipper - Design for supportability

    Science.gov (United States)

    Smiljanic, Ray R.; Conrad, Charles; Spaulding, Ed; Gisburne, Don

    1993-07-01

    The 'Delta Clipper' Single Stage Rocket Technology (SSRT) currently under development in the DC-X program will implement reliability-centered maintenance and support, involving on-equipment/off-equipment two-level maintenance, a logistics and spares pipeline, and a minimization of 'blue suit' skill-level personnel. Attention is given to the range of SSRT features that are to be validated via the DC-X test program; these prominently involve LRUs replaceability and accessibility, standardization and interchangeability, and 'aircraft-like' automated data collection.

  3. Climate change and the Delta

    Science.gov (United States)

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

    2016-01-01

    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

  4. Histo-blood group gene polymorphisms as potential genetic modifiers of infection and cystic fibrosis lung disease severity.

    Directory of Open Access Journals (Sweden)

    Jennifer L Taylor-Cousar

    Full Text Available BACKGROUND: The pulmonary phenotype in cystic fibrosis (CF is variable; thus, environmental and genetic factors likely contribute to clinical heterogeneity. We hypothesized that genetically determined ABO histo-blood group antigen (ABH differences in glycosylation may lead to differences in microbial binding by airway mucus, and thus predispose to early lung infection and more severe lung disease in a subset of patients with CF. METHODS AND PRINCIPAL FINDINGS: Clinical information and DNA was collected on >800 patients with the DeltaF508/DeltaF508 genotype. Patients in the most severe and mildest quartiles for lung phenotype were enrolled. Blood samples underwent lymphocyte transformation and DNA extraction using standard methods. PCR and sequencing were performed using standard techniques to identify the 9 SNPs required to determine ABO blood type, and to identify the four SNPs that account for 90-95% of Lewis status in Caucasians. Allele identification of the one nonsynonymous SNP in FUT2 that accounts for >95% of the incidence of nonsecretor phenotype in Caucasians was completed using an ABI Taqman assay. The overall prevalence of ABO types, and of FUT2 (secretor and FUT 3 (Lewis alleles was consistent with that found in the Caucasian population. There was no difference in distribution of ABH type in the severe versus mild patients, or the age of onset of Pseudomonas aeruginosa infection in the severe or mild groups. Multivariate analyses of other clinical phenotypes, including gender, asthma, and meconium ileus demonstrated no differences between groups based on ABH type. CONCLUSIONS AND SIGNIFICANCE: Polymorphisms in the genes encoding ABO blood type, secretor or Lewis genotypes were not shown to associate with severity of CF lung disease, or age of onset of P. aeruginosa infection, nor was there any association with other clinical phenotypes in a group of 808 patients homozygous for the DeltaF508 mutation.

  5. CF Mutation Panel

    Science.gov (United States)

    ... Testing; Cystic Fibrosis Transmembrane Conductance Regulator Mutation Analysis; CFTR Mutation Analysis Formal name: Cystic Fibrosis Gene Mutation ... an elevated immunoreactive trypsinogen (IRT) or positive sweat chloride test , to confirm the diagnosis of cystic fibrosis. ...

  6. Biosynthesis of Tcr-alpha, beta and Tcr-gamma, delta/CD3 complexes

    DEFF Research Database (Denmark)

    Bauguil-Caspar, S; Arnaud, J; Kuhlmann, J;

    1993-01-01

    Jurkat J76 clone, LYON L12.37 clone and L12.37 cells transfected with J76-alpha cDNA or J76 Tcr-alpha mutated cDNA (J79) were analysed for membrane expression of Tcr/CD3 complex using WT31 mAb (Tcr-alpha, beta) or Tcr-delta 1 mAb (Tcr-gamma, delta): LYON cells express V beta 9 bearing Tcr-beta...... chains. J76 Tcr-alpha cDNA transfected LYON cells have intracellular Tcr-gamma, delta chains and J79 Tcr-alpha cDNA transfected LYON cells have intracellular Tcr-alpha (M), beta chains....

  7. From Natural to Design River Deltas

    Science.gov (United States)

    Giosan, Liviu

    2016-04-01

    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.

  8. Charged current weak electroproduction of $\\Delta$ resonance

    CERN Document Server

    Alvarez-Ruso, L; Vacas, M J V

    1998-01-01

    We study the weak production of $\\Delta$ (i.e. $e^{-} + p \\to \\Delta^{0}+ energy range corresponding to the Mainz and TJNAF electron accelerators. The differential cross sections $\\sigma(\\theta)$ are found to be of the order of $ 10^{-39}$ cm$^2$/sr, over a range of angles which increases with energy. The possibility of observing these reactions with the high luminosities available at these accelerators, and studying the weak N-$\\Delta$ transition form factors through these reactions is discussed. The production cross section of N$^*(1440)$ in the kinematic region of $\\Delta$ production is also estimated and found to be small.

  9. Delta Semantics Defined By Petri Nets

    DEFF Research Database (Denmark)

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

    This report is identical to an earlier version of May 1978 except that Chapter 5 has been revised. A new paper: "A Petri Net Definition of a System Description Language", DAIMI, April 1979, 20 pages, extends the Petri net model to include a data state representing the program variables. Delta...... 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...

  10. SNC 80 and related delta opioid agonists.

    Science.gov (United States)

    Calderon, S N; Coop, A

    2004-01-01

    The discovery of the selective delta (delta) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, was a major advance in the field of delta-opioid ligands. Much research has been performed to uncover the structure-activity relationships (SAR) of this class of ligands and also to compare the diarylmethylpiperazines with the traditional morphinan-based delta opioids. This review focuses on the development of the SAR of this unique series of ligands, and discusses questions which remain unanswered.

  11. Activating mutations of STAT5B and STAT3 in lymphomas derived from ??-T or NK cells.

    OpenAIRE

    2015-01-01

    Lymphomas arising from NK or gamma delta-T cells are very aggressive diseases and little is known regarding their pathogenesis. Here we report frequent activating mutations of STAT3 and STAT5B in NK/T-cell lymphomas (n - 51), gamma delta-T-cell lymphomas (n - 43) and their cell lines (n = 9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of gamma delta-T-cell lymphomas. STAT3 and STAT5B mutations are associated with increased phosphorylate...

  12. $\\Delta$ decay in nuclear medium

    CERN Document Server

    Jain, B K; Kundu, Bijoy

    1996-01-01

    Proton-nucleus collisions, where the beam proton gets excited to the delta resonance and then decays to p\\pi ^+, either inside or outside the nuclear medium, are studied. Cross-sections for various kinematics for the (p,p' \\pi ^+) reaction between 500 MeV and 1 GeV beam energy are calculated to see the effects of the nuclear medium on the propagation and decay of the resonance. The cross-sections studied include proton energy spectra in coincidence with the pion, four momentum transfer distributions, and the invariant p\\pi^+ mass distributions. We find that the effect of the nuclear medium on these cross-sections mainly reduces their magnitudes. Comparing these cross-sections with those considering the decay of the delta outside the nucleus only, we further find that at 500 MeV the two sets of cross-sections have large differences, while by 1 GeV the differences between them become much smaller.

  13. beta (+)-Thalassaemia in the Po river delta region (northern Italy): genotype and beta globin synthesis.

    Science.gov (United States)

    Del Senno, L; Pirastu, M; Barbieri, R; Bernardi, F; Buzzoni, D; Marchetti, G; Perrotta, C; Vullo, C; Kan, Y W; Conconi, F

    1985-01-01

    Six beta(+)-thalassaemic patients from the Po river delta region have been studied. Using synthetic oligonucleotides as specific hybridisation probes, the beta(+) IVS I mutation (G----A at position 108) was demonstrated. This lesion and the enzyme polymorphism pattern in the subjects examined are the same as have been described for other Mediterranean beta(+)-thalassaemias. Antenatal diagnosis through DNA analysis of beta(+)-thalassaemia is therefore possible. The production of beta globin in a beta(+), homozygote and in a beta (+), beta(0) 39 (nonsense mutation at codon 39) double heterozygote is approximately 20% and 10% respectively of total non-alpha globin synthesis. Despite some overlapping of the results, similar beta globin synthesis levels have been obtained in 43 beta(+)-thalassaemia patients. This suggests that in the Po river delta region the most common thalassaemic genes are beta(0) 39 and beta(+) IVS I. Images PMID:2580095

  14. Comparative assessment of the vulnerability and resilience of deltas : extended version with 14 deltas : synthesis report

    NARCIS (Netherlands)

    Bucx, T.; Driel, van W.F.; Boer, de H.; Graas, S.; Langenberg, V.; Marchand, M.; Guchte, van de C.

    2014-01-01

    Worldwide, deltas host dense populations and are important centres of agricultural and industrial production, and economic activity. Many deltas are areas of great ecological importance as well, featuring wetlands of high and unique biodiversity. Deltas are vulnerable to changes by natural forces an

  15. $\\Delta I=4$ and $\\Delta I=8$ bifurcations in rotational bands of diatomic molecules

    CERN Document Server

    Bonatsos, Dennis; Lalazissis, G A; Drenska, S B; Minkov, N; Raychev, P P; Roussev, R P; Bonatsos, Dennis

    1996-01-01

    It is shown that the recently observed $\\Delta I=4$ bifurcation seen in superdeformed nuclear bands is also occurring in rotational bands of diatomic molecules. In addition, signs of a $\\Delta I=8$ bifurcation, of the same order of magnitude as the $\\Delta I=4$ one, are observed both in superdeformed nuclear bands and rotational bands of diatomic molecules.

  16. INFLUENCE OF THE DELTA-DELTA-MESON COUPLING ON NUCLEON AND DELTA PROPERTIES IN NUCLEAR-MATTER

    NARCIS (Netherlands)

    DEJONG, F; MALFLIET, R

    1994-01-01

    We introduce a scalar and a vector DELTADELTA-meson vertex in the relativistic Dirac-Brueckner model for nuclear matter and investigate the consequences. We find small effects on the effective nucleon properties. The effects in the DELTA sector are more profound, although the DELTA is still effectiv

  17. Spectrum of mutations in sarcoglycan genes in the Mumbai region of western India: High prevalence of 525del T

    Directory of Open Access Journals (Sweden)

    Khadilkar Satish

    2009-01-01

    Full Text Available Background : While the clinical and immunocytochemical features of sarcoglycanopathies have been reported from India, genetic aspects have not been studied. There is large variation in the sarcoglycan mutations among the studied populations. Aim : To study the spectrum of mutations in sarcoglycan genes (SG. Materials and Methods : Patients fulfilling Bushby′s criteria for limb girdle muscular dystrophy were prospectively analyzed. Patients gave their medical history and underwent a clinical examination, serum creatine kinase estimation, electrophysiology, muscle biopsy with immunostaining for alpha, beta, gamma, and delta subunits and mutational analysis using denaturing high pressure liquid chromatography and direct sequencing. Results : Mutations in SG accounted for 26.4% of the cohort of limb girdle muscular dystrophy. The mean age of these 18 patients was 22.5 years. Generally, proximal weakness affected the flexor and adductor compartments of the lower and upper limbs. The clinical profile of various mutations was indistinguishable from each other. Gamma SG mutations were most common, seen in 8 patients, followed by delta SG mutation in 5 patients and alpha mutation in 4 patients, while only 1 patient had mutation in the beta sarcoglycan gene. The most prevalent mutation in the gamma SG gene was 525del T. This is of interest as the mutation has been known to exist only in specific populations. Conclusion : This study, the first mutational analysis of Indian patients with sarcoglycanopathies suggests gamma SG mutations were the most common and the most prevalent mutation in the gamma SG gene was 525del T.

  18. beta (+)-Thalassaemia in the Po river delta region (northern Italy): genotype and beta globin synthesis.

    OpenAIRE

    del Senno, L; Pirastu, M; Barbieri, R.; De Bernardi, F.; Buzzoni, D; Marchetti, G.; Perrotta, C; Vullo, C; Kan, Y W; Conconi, F

    1985-01-01

    Six beta(+)-thalassaemic patients from the Po river delta region have been studied. Using synthetic oligonucleotides as specific hybridisation probes, the beta(+) IVS I mutation (G----A at position 108) was demonstrated. This lesion and the enzyme polymorphism pattern in the subjects examined are the same as have been described for other Mediterranean beta(+)-thalassaemias. Antenatal diagnosis through DNA analysis of beta(+)-thalassaemia is therefore possible. The production of beta globin in...

  19. 表现为婴儿胆汁淤积的CFTR基因缺陷致囊性纤维化病一例并文献复习%Infantile cholestasis caused by CFTR mutation: case report and literature review

    Institute of Scientific and Technical Information of China (English)

    李丽; 王能里; 龚敬宇; 王建设

    2016-01-01

    Objective To study the clinical presentation,biochemical features and genetic analysis of an infant with cholestasis related to the CFTR mutations.Method The clinical presentation,laboratory investigations and management of a case with infantile cholestasis caused by CFTR mutations were summarized and the relevant literature was reviewed.Result (1) The patient was a 5 months old boy with cholestasis which developed in neonatal period with delayed meconium exclusion.The laparoscopic exploration was performed to exclude biliary atresia because of acholic stool when he was two months old.Ursodeoxycholic acid (UDCA),cholestyramine and phenobarbital treatment was applied.The genetic analysis showed compound heterozygous mutations in CFTR.The liver function normalized when he was 11 months old.When he was 21 months old,he had normal appearance except mild splenomegaly.(2) Literatures review identified 25 infantile cholestatic cases related to cystic fibrosis (CF) diagnosed by sweat test or gene analysis.Delayed meconium passage was found in five,meconium ileus in six cases.The liver function tests characterized by the direct hyperbilirubinemia with elevated transaminase,glutamyltranspeptidase and alkaline phosphatase levels.Genetic analysis revealed eight homozygotes of delF508,four heterozygotes of delF508 and one compound heterozygotes of c.263T > G/ c.2089-2090ins in CFTR.Jaundice resolved in 20 patients,ten of them were prescribed oral ursodesoxycholic acid (15-20 mg/(kg· d)).Five patients died,none of them received oral UDCA.Two of them had persisted cholestatic until death.Among the other three dead,two died from respiratory failure and one from cardiopulmonary failure.Conclusion Cystic fibrosis should be considered in cholestatic infants with meconium ileus or delayed meconium passage.Genetic analysis could confirm the diagnosis.UDCA may be beneficial to improve the liver function.%目的 总结表现为婴儿胆汁淤积的CFTR基因缺陷致囊性纤维化

  20. Electromagnetic excitation of the Delta(1232) resonance

    Energy Technology Data Exchange (ETDEWEB)

    V. Pascalutsa; M. Vanderhaeghen; Shin Nan Yang

    2006-09-05

    We review the description of the lowest-energy nucleon excitation--the Delta(1232)-resonance. Much of the recent effort has been focused on the precision measurements of the nucleon to Delta transition by means of electromagnetic probes. We review the results of those measurements and confront them with the state-of-the-art calculations based on chiral effective-field theories (EFT), lattice QCD, and QCD-inspired models. Some of the theoretical approaches are reviewed in detail. In particular, we describe the chiral EFT of QCD in the energy domain of the Delta-resonance, and its applications to the electromagnetic nucleon-to-Delta transition (gamma N Delta). We also describe the recent dynamical and unitary-isobar models of pion electroproduction which are extensively used in the extraction of the gamma* N Delta form factors from experiment. Furthermore, we discuss the link of the gamma* N Delta form factors to generalized parton distributions (GPDs), as well as the predictions of perturbative QCD for these transition form factors. The present status of understanding the Delta-resonance properties and the nature of its excitation is summarized.

  1. Structure and replication of hepatitis delta virus

    African Journals Online (AJOL)

    STORAGESEVER

    2008-12-29

    Dec 29, 2008 ... Unidade de Biologia Molecular, Centro de Malária e outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, ... molecules of both delta antigens (Ryu et al., 1993). This ..... Glenn JS, Watson JA, Havel CM, White JO (1992). ... HDV RNA encoding the large delta antigen cannot replicate. J. Gen.

  2. Generalised CP and $\\Delta (96)$ Family Symmetry

    CERN Document Server

    Ding, Gui-Jun

    2014-01-01

    We perform a comprehensive study of the $\\Delta (96)$ family symmetry combined with the generalised CP symmetry $H_{\\rm{CP}}$. We investigate the lepton mixing parameters which can be obtained from the original symmetry $\\Delta (96)\\rtimes H_{\\rm{CP}}$ breaking to different remnant symmetries in the neutrino and charged lepton sectors, namely $G_{\

  3. Delta Blues Scholarship and Imperialist Nostalgia.

    Science.gov (United States)

    Nye, William P.

    When Delta blues are considered to be "folk music," the genre is inextricably tied to the neocolonial, sharecropping system of cotton production characteristic of the Mississippi Delta region between the Civil War and World War II. "Imperialist nostalgia," then, arises in accounts which pay primary and positive tribute to blues…

  4. The delta opioid receptor tool box.

    Science.gov (United States)

    Vicente-Sanchez, Ana; Segura, Laura; Pradhan, Amynah A

    2016-12-03

    In recent years, the delta opioid receptor has attracted increasing interest as a target for the treatment of chronic pain and emotional disorders. Due to their therapeutic potential, numerous tools have been developed to study the delta opioid receptor from both a molecular and a functional perspective. This review summarizes the most commonly available tools, with an emphasis on their use and limitations. Here, we describe (1) the cell-based assays used to study the delta opioid receptor. (2) The features of several delta opioid receptor ligands, including peptide and non-peptide drugs. (3) The existing approaches to detect delta opioid receptors in fixed tissue, and debates that surround these techniques. (4) Behavioral assays used to study the in vivo effects of delta opioid receptor agonists; including locomotor stimulation and convulsions that are induced by some ligands, but not others. (5) The characterization of genetically modified mice used specifically to study the delta opioid receptor. Overall, this review aims to provide a guideline for the use of these tools with the final goal of increasing our understanding of delta opioid receptor physiology.

  5. Entendiendo Delta desde las Humanidades

    Directory of Open Access Journals (Sweden)

    José Calvo Tello

    2016-05-01

    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.

  6. Jiaxing: Delicacy of the Yangtze River Delta

    Institute of Scientific and Technical Information of China (English)

    WUXINYI; WANGNAN

    2004-01-01

    THE yangtze River Delta,where the Yangtzc River crosses China's east coast,has one of the country's most dynamic economies.In 1976Jcan Gottmann.a french geographer,called shanghai and its neighboring Yangtze River Delta the world's "sixth largest megalopolis." The Yangtze River Delta has 15 cities. Its territory accounts for one percent of China's total, 5.8 percent of hthe population, and 19.5 percent of the national GDP.In terms of both aggregate economy and growth speed, the Delta currently leads China and could likely be the "enginc" of the world's future economic growth. Located at the juncition of Shanghai Jiangsu and Zhejiang, Jiaxing City holds a central economic belt. It is within 100 kilometers of Shanghai, Hangzhou and Suzhou. In 200 and 2003, Jiaxing's GDP growth rate was first in Zhejiang Province and second among the 1.5 Delta cities.

  7. Studies on mu and delta opioid receptor selectivity utilizing chimeric and site-mutagenized receptors.

    Science.gov (United States)

    Wang, W W; Shahrestanifar, M; Jin, J; Howells, R D

    1995-01-01

    Opioid receptors are members of the guanine nucleotide binding protein (G protein)-coupled receptor family. Three types of opioid receptors have been cloned and characterized and are referred to as the delta, kappa and mu types. Analysis of receptor chimeras and site-directed mutant receptors has provided a great deal of information about functionally important amino acid side chains that constitute the ligand-binding domains and G-protein-coupling domains of G-protein-coupled receptors. We have constructed delta/mu opioid receptor chimeras that were express in human embryonic kidney 293 cells in order to define receptor domains that are responsible for receptor type selectivity. All chimeric receptors and wild-type delta and mu opioid receptors displayed high-affinity binding of etorphine (an agonist), naloxone (an antagonist), and bremazocine (a mixed agonist/antagonist). In contrast, chimeras that lacked the putative first extracellular loop of the mu receptor did not bind the mu-selective peptide [D-Ala2,MePhe4,Gly5-ol]enkephalin (DAMGO). Chimeras that lacked the putative third extracellular loop of the delta receptor did not bind the delta-selective peptide, [D-Ser2,D-Leu5]enkephalin-Thr (DSLET). Point mutations in the putative third extracellular loop of the wild-type delta receptor that converted vicinal arginine residues to glutamine abolished DSLET binding while not affecting bremazocine, etorphine, and naltrindole binding. We conclude that amino acids in the putative first extracellular loop of the mu receptor are critical for high-affinity DAMGO binding and that arginine residues in the putative third extracellular loop of the delta receptor are important for high-affinity DSLET binding. Images Fig. 3 PMID:8618916

  8. Common mutations in the phosphofructokinase-M gene in Ashkenazi Jewish patients with glycogenesis VII - and their population frequency

    Energy Technology Data Exchange (ETDEWEB)

    Sherman, J.B.; Raben, N.; Nicastri, C.; Adams, E.M.; Plotz, P.H. (National Institutes of Health, Bethesda, MD (United States)); Argov, Z. (Hebrew Univ., Jerusalem (Israel)); Nakajima, Hiromu (Osaka Univ. (Japan)); Eng, C.M.; Cowan, T.M. (Univ. of Maryland School of Medicine, Baltimore, MD (United States))

    1994-08-01

    Phosphofructokinase (PFK) catalyzes the rate-limiting step of glycolysis. Deficiency of the muscle enzyme is manifested by exercise intolerance and a compensated hemolytic anemia. Case reports of this autosomal recessive disease suggest a predominance in Ashkenazi Jews in the United States. The authors have explored the genetic basis for this illness in nine affected families and surveyed the normal Ashkenazi population for the mutations found. Genomic DNA was amplified using PCR, and denaturing gradient-gel electrophoresis. The polymorphic exons were sequenced or digested with restriction enzymes. A previously described splicing mutation, [Delta]5, accounted for 11 (61%) of 18 abnormal alleles in the nine families. A single base deletion leading to a frameshift mutation in exon 22 ([Delta]C-22) was found in six of seven alleles. A third mutation, resulting in a nonconservative amino acid substitution in exon 4, accounted for the remaining allele. Thus, three mutations could account for an illness in this group, and two mutations could account for 17 of 18 alleles. In screening 250 normal Ashkenazi individuals for all three mutations, they found only one [Delta]5 allele. Clinical data revealed no correlation between the particular mutations and symptoms, but male patients were more symptomatic than females, and only males had frank hemolysis and hyperuricemia. Because PFK deficiency in Ashkenazi Jews is caused by a limited number of mutations, screening genomic DNA from peripheral blood for the described mutations in this population should enable rapid diagnosis without muscle biopsy. 41 refs., 4 figs., 2 tabs.

  9. Differentiation of Boc-protected alpha,delta-/delta,alpha- and beta,delta-/delta,beta-hybrid peptide positional isomers by electrospray ionization tandem mass spectrometry.

    Science.gov (United States)

    Raju, G; Ramesh, V; Srinivas, R; Sharma, G V M; Shoban Babu, B

    2010-06-01

    Two new series of Boc-N-alpha,delta-/delta,alpha- and beta,delta-/delta,beta-hybrid peptides containing repeats of L-Ala-delta(5)-Caa/delta(5)-Caa-L-Ala and beta(3)-Caa-delta(5)-Caa/delta(5)-Caa-beta(3)-Caa (L-Ala = L-alanine, Caa = C-linked carbo amino acid derived from D-xylose) have been differentiated by both positive and negative ion electrospray ionization (ESI) ion trap tandem mass spectrometry (MS/MS). MS(n) spectra of protonated isomeric peptides produce characteristic fragmentation involving the peptide backbone, the Boc-group, and the side chain. The dipeptide positional isomers are differentiated by the collision-induced dissociation (CID) of the protonated peptides. The loss of 2-methylprop-1-ene is more pronounced for Boc-NH-L-Ala-delta-Caa-OCH(3) (1), whereas it is totally absent for its positional isomer Boc-NH-delta-Caa-L-Ala-OCH(3) (7), instead it shows significant loss of t-butanol. On the other hand, second isomeric pair shows significant loss of t-butanol and loss of acetone for Boc-NH-delta-Caa-beta-Caa-OCH(3) (18), whereas these are insignificant for its positional isomer Boc-NH-beta-Caa-delta-Caa-OCH(3) (13). The tetra- and hexapeptide positional isomers also show significant differences in MS(2) and MS(3) CID spectra. It is observed that 'b' ions are abundant when oxazolone structures are formed through five-membered cyclic transition state and cyclization process for larger 'b' ions led to its insignificant abundance. However, b(1)(+) ion is formed in case of delta,alpha-dipeptide that may have a six-membered substituted piperidone ion structure. Furthermore, ESI negative ion MS/MS has also been found to be useful for differentiating these isomeric peptide acids. Thus, the results of MS/MS of pairs of di-, tetra-, and hexapeptide positional isomers provide peptide sequencing information and distinguish the positional isomers.

  10. 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).

    Science.gov (United States)

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

    2010-03-24

    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.

  11. Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770.

    Science.gov (United States)

    Gentzsch, Martina; Ren, Hong Y; Houck, Scott A; Quinney, Nancy L; Cholon, Deborah M; Sopha, Pattarawut; Chaudhry, Imron G; Das, Jhuma; Dokholyan, Nikolay V; Randell, Scott H; Cyr, Douglas M

    2016-09-01

    Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients.

  12. Identifying hazards associated with lava deltas

    Science.gov (United States)

    Poland, Michael P.; Orr, Tim R.

    2014-01-01

    Lava deltas, formed where lava enters the ocean and builds a shelf of new land extending from the coastline, represent a significant local hazard, especially on populated ocean island volcanoes. Such structures are unstable and prone to collapse—events that are often accompanied by small explosions that can deposit boulders and cobbles hundreds of meters inland. Explosions that coincide with collapses of the East Lae ‘Apuki lava delta at Kīlauea Volcano, Hawai‘i, during 2005–2007 followed an evolutionary progression mirroring that of the delta itself. A collapse that occurred when the lava–ocean entry was active was associated with a blast of lithic blocks and dispersal of spatter and fine, glassy tephra. Shortly after delta growth ceased, a collapse exposed hot rock to cold ocean water, resulting in an explosion composed entirely of lithic blocks and lapilli. Further collapse of the delta after several months of inactivity, by which time it had cooled significantly, resulted in no recognizable explosion deposit. Seaward displacement and subsidence of the coastline immediately inland of the delta was measured by both satellite and ground-based sensors and occurred at rates of several centimeters per month even after the lava–ocean entry had ceased. The anomalous deformation ended only after complete collapse of the delta. Monitoring of ground deformation may therefore provide an indication of the potential for delta collapse, while the hazard associated with collapse can be inferred from the level of activity, or the time since the last activity, on the delta.

  13. Bounding The Rate of Adaptation In A Large Asexually Reproducing Population With Fast Mutation Rates

    CERN Document Server

    Kelly, Michael

    2011-01-01

    We consider a model of asexually reproducing individuals. The birth and death rates of the individuals are affected by a fitness parameter. The rate of mutations that cause the fitnesses to change is proportional to the population size, $N$. The mutations may be either beneficial or deleterious. In a paper by Yu, Etheridge and Cuthbertson (2009) it was shown that the average rate at which the mean fitness increases in this model is bounded below by $\\log^{1-\\delta} N$ for any $\\delta > 0$. We achieve an upper bound on the average rate at which the mean fitness increases of $O(\\log N/\\log \\log N)$.

  14. Delta Electroproduction in 12-C

    Energy Technology Data Exchange (ETDEWEB)

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

    2003-01-01

    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.

  15. Novel diazabicycloalkane delta opioid agonists.

    Science.gov (United States)

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80. Published by Elsevier Ltd.

  16. Theoretical prediction of familial amyotrophic lateral sclerosis missense mutation effects on Cu/Zn superoxide dismutase structural stability

    Energy Technology Data Exchange (ETDEWEB)

    Potier, M.; Tu, Y. [Universite de Montreal, Quebec (Canada)

    1994-09-01

    Cu/Zn superoxide dismutase (SOD) deficiency is associated with the progressive paralytic disorder familial amyotrophic lateral sclerosis (FALS). Fifteen missense mutations in the SOD gene were identified in several patients. These mutations may prevent correct promoter folding or hamper homodimer formation necessary for SOD activity. To understand the effect of the missense mutations on SOD structure and function, we used a theoretical analysis of structural effects based on two predictive methods using the modeled tertiary structure of human SOD. The first method uses the TORSO program which optimizes amino acid side-chains repacking in both wild-type and mutant SODs and calculates protein internal packing energy. The second method uses a hydrophobicity scale of the amino acid residues and considers both solvent accessibility and hydrophobic nature of residue substitutions to compute a stabilization energy change ({delta}E). These predictive methods have been tested in 187 single and multiple missense mutants of 8 proteins (T4 lysozyme, human carbonic anhydrase II, chymotrypsin inhibitor 2, f1 gene V protein, barnase, {lambda}-repressor, chicken and human lysozymes) with experimentally determined thermostability. The overall prediction accuracy with these proteins was 88%. Analysis of FALS missense mutations {delta}E predicts that 14 of 15 mutations destabilize the SOD structure. The other missense mutation is located at the homodimer interface and may hinder dimer formation. This approach is applicable to any protein with known tertiary structure to predict missense mutation effects on protein stability.

  17. Damped Oscillator with Delta-Kicked Frequency

    Science.gov (United States)

    Manko, O. V.

    1996-01-01

    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.

  18. Delta-nucleus dynamics: proceedings of symposium

    Energy Technology Data Exchange (ETDEWEB)

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

    1983-10-01

    The appreciation of the role in nuclear physics of the first excited state of the nucleon, the delta ..delta..(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 ..delta..-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. (WHK)

  19. in the Niger Delta of Nigeria

    African Journals Online (AJOL)

    suggestions as policy options for the resolution of the armed conflict in the. Niger Delta ... indiscriminate use of lethal weapons by local militias, the cumulative effect of which is the ... of many 'child' soldiers in local conflicts or wars nowadays.

  20. Contemporary depositional environments of the Omo delta.

    Science.gov (United States)

    Butzer, K W

    1970-05-02

    Geomorphological and sedimentological studies of depositional environments of the modern Omo River delta and floodplain are essential to an understanding of the Pliocene to Pleistocene Mursi, Nkalabong and Kibish Formations of the Lower Omo Basin (southwestern Ethiopia).

  1. Legal Delta Boundary, 2001, DWR [ds586

    Data.gov (United States)

    California Department of Resources — 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...

  2. Cackling Canada goose nesting populations, Yukon Delta

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Number of potential territories, number of cackling Canada Goose nests, and percent occupancy of available territories from CCG plots on the Yukon Delta National...

  3. Water quality in the Okavango Delta

    African Journals Online (AJOL)

    2010-03-12

    Mar 12, 2010 ... water and sediments in the Okavango Delta published between 2000 and 2010. Despite the shortage ... Their interactions with light, water, dissolved nutrients and suspended solids ...... temporal remote sensing. Int. J. Remote ...

  4. California Black Rail - Central Delta [ds17

    Data.gov (United States)

    California Department of Resources — Results of taped-call black rail surveys of in-stream habitat within certain waterways in the central Sacramento / San Joaquin Delta during 1992 and 1993. TIME...

  5. Propagator for the double delta potential

    Energy Technology Data Exchange (ETDEWEB)

    Cacciari, Ilaria [Istituto di Fisica Applicata ' Nello Carrara' , CNR, via Madonna del Piano 10, 50019 Sesto Fiorentino, Florence (Italy); Moretti, Paolo [Istituto dei Sistemi Complessi, CNR, Sezione di Firenze, via Madonna del Piano 10, 50019 Sesto Fiorentino, Florence (Italy)]. E-mail: paolo.moretti@isc.cnr.it

    2006-12-04

    The propagator for the double delta potential is calculated starting from the integral form of the Schroedinger equation. A compact expression of its Laplace transform is found, that can be explicitly inverted in some limiting cases.

  6. The Atchafalaya River Delta. Report 4. Generic Analysis of Delta Development.

    Science.gov (United States)

    1984-01-01

    contemporaneously with delta growth (Donaldson, Martin , and Kanes 1970). The average rate of contour advancement has been ap- proximately 12 m/yr. Assuming the...Donaldson, Martin , ’, and Kanes 1970) shows that the delta has transgressed over 60 m. Average rates of deterioration are reported to be 2.75 m/yr...after 1965 ( Keown , Dardeau, and Causey 1980). Coarse sediment not reaching the delta is precisely the material needed for subaerial land. Third, the

  7. Optimized $\\delta$ expansion for relativistic nuclear models

    CERN Document Server

    Krein, G I; Peres-Menezes, D; Nielsen, M; Pinto, M B

    1998-01-01

    The optimized $\\delta$-expansion is a nonperturbative approach for field theoretic models which combines the techniques of perturbation theory and the variational principle. This technique is discussed in the $\\lambda \\phi^4$ model and then implemented in the Walecka model for the equation of state of nuclear matter. The results obtained with the $\\delta$ expansion are compared with those obtained with the traditional mean field, relativistic Hartree and Hartree-Fock approximations.

  8. Migration in Vulnerable Deltas: A Research Strategy

    Science.gov (United States)

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

    2015-12-01

    C. Hutton1, & R. J. Nicholls1, , 1 University of Southampton, University Road, Southampton, Hampshire, United Kingdom, SO17 1BJ. cwh@geodata. soton.ac.ukAbstractGlobally, 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.

  9. Transgenic Animal Mutation Assays

    Institute of Scientific and Technical Information of China (English)

    Tao Chen; Ph.D.D.A.B.T.

    2005-01-01

    @@ The novel transgenic mouse and rat mutation assays have provided a tool for analyzing in vivo mutation in any tissue, thus permitting the direct comparison of cancer incidence with mutant frequency.

  10. Stellar delta matter with delta-meson coupling constants constrained by QCD sum rule

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Antonio Ferreira da [Secretaria de Educacao, Cultura e Desportos do Estado de Roraima (SECD/RR), Boa Vista, RR (Brazil); Oliveira, Jose Carlos Teixeira de [Universidade Federal de Roraima (UFRR), Boa Vista, RR (Brazil); Rodrigues, Hilario [Centro Federal de Educacao Tecnologica (CEFET-RJ), Rio de Janeiro, RJ (Brazil); Duarte, Sergio Barbosa [Centro Brasileiro de Pesquisas Fisicas (CBPF), Rio de Janeiro, RJ (Brazil); Chiapparini, Marcelo [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil)

    2010-07-01

    The considerable presence of delta-resonances (30% of baryonic population) in the dense phase of relativistic heavy ion collisions leads to a great interest in the study of the delta matter formation in the deep interior of compact stars. In the present work we determine the equation of state and the population of baryons and leptons and discuss the effects of the baryon-meson coupling constants to the formation of delta matter in the stellar medium. We use the non-linear Walecka model consisting of the octet of baryons of spin 1=2 (n, p, {Lambda}{sup 0}, {Sigma}{sup -}, {Sigma}{sup 0}, {Sigma}{sup +}, {Xi}{sup -}, {Xi}{sup 0}) and baryonic resonances of spin 3=2, represented by the delta resonances ({Delta}{sup -}, ({Delta}{sup 0}, ({Delta}{sup +}, ({Delta}{sup ++}) and {Omega}{sup -}, in the baryonic sector. In the leptonic sector we consider the electrons and muons. The coupling constants between the hyperons {Lambda}, {Sigma}, and {Xi} and the mesons {omega} and {rho} are fixed by using SU(6) symmetry, while the hyperons-{sigma} coupling constants are constrained by the consistence of the hypernuclear potential in the nuclear matter with hypernuclear data. In addition, we use the finite density QCD sum rule to determine the possible values of delta-meson coupling constants. (author)

  11. delta(13)C and delta(2)H isotope ratios in amphetamine synthesized from benzaldehyde and nitroethane.

    Science.gov (United States)

    Collins, Michael; Salouros, Helen; Cawley, Adam T; Robertson, James; Heagney, Aaron C; Arenas-Queralt, Andrea

    2010-06-15

    Previous work in these laboratories and by Butzenlechner et al. and Culp et al. has demonstrated that the delta(2)H isotope value of industrial benzaldehyde produced by the catalytic oxidation of toluene is profoundly positive, usually in the range +300 per thousand to +500 per thousand. Synthetic routes leading to amphetamine, methylamphetamine or their precursors and commencing with such benzaldehyde may be expected to exhibit unusually positive delta(2)H values. Results are presented for delta(13)C and delta(2)H isotope values of 1-phenyl-2-nitropropene synthesized from an industrial source of benzaldehyde, having a positive delta(2)H isotope value, by a Knoevenagel condensation with nitroethane. Results are also presented for delta(13)C and delta(2)H isotope values for amphetamine prepared from the resulting 1-phenyl-2-nitropropene. The values obtained were compared with delta(13)C and delta(2)H isotope values obtained for an amphetamine sample prepared using a synthetic route that did not involve benzaldehyde. Finally, results are presented for samples of benzaldehyde, 1-phenyl-2-nitropropene and amphetamine that had been seized at a clandestine amphetamine laboratory.

  12. Identification of pathways controlling DNA damage induced mutation in Saccharomyces cerevisiae.

    Science.gov (United States)

    Lis, Ewa T; O'Neill, Bryan M; Gil-Lamaignere, Cristina; Chin, Jodie K; Romesberg, Floyd E

    2008-05-01

    Mutation in response to most types of DNA damage is thought to be mediated by the error-prone sub-branch of post-replication repair and the associated translesion synthesis polymerases. To further understand the mutagenic response to DNA damage, we screened a collection of 4848 haploid gene deletion strains of Saccharomyces cerevisiae for decreased damage-induced mutation of the CAN1 gene. Through extensive quantitative validation of the strains identified by the screen, we identified ten genes, which included error-prone post-replication repair genes known to be involved in induced mutation, as well as two additional genes, FYV6 and RNR4. We demonstrate that FYV6 and RNR4 are epistatic with respect to induced mutation, and that they function, at least partially, independently of post-replication repair. This pathway of induced mutation appears to be mediated by an increase in dNTP levels that facilitates lesion bypass by the replicative polymerase Pol delta, and it is as important as error-prone post-replication repair in the case of UV- and MMS-induced mutation, but solely responsible for EMS-induced mutation. We show that Rnr4/Pol delta-induced mutation is efficiently inhibited by hydroxyurea, a small molecule inhibitor of ribonucleotide reductase, suggesting that if similar pathways exist in human cells, intervention in some forms of mutation may be possible.

  13. [TUB9 polymorphism in the CFTR gene of cystic fibrosis patients, carriers, and healthy donors from the Moscow region. SSCP and restriction analyses].

    Science.gov (United States)

    Amosenko, F A; Trubnikova, I S; Zakhar'ev, V M; Bannikov, V M; Sazonova, M A; Petrova, N V; Kapranov, N I; Kaplinin, V N

    1997-02-01

    Data on the screening of 266 non-delta F508 chromosomes (42 cystic fibrosis patients, 43 carriers, and 48 healthy donors from the Moscow region) for the presence of structural abnormalities within the tenth exon of the CFTR gene conducted by means of the single-stranded conformation polymorphism (SSCP) technique in nonisotope modification are presented. The method used made it possible to detect three SSCP variants, one of which was present in cystic fibrosis patients (23.8%) and carriers (9.3%), but not in healthy donors. Sequencing of the 5 amplified DNA fragments carrying this SSCP variant revealed an A-->G substitution in the 1525-61 position, which indicated the presence of TUB9 polymorphism with allele 1 in the homozygous state in all cases tested. The three SSCP variants described corresponded to the three allelic variants of TUB9 polymorphism as judged by MnlI restriction analysis of the amplified tenth exon sequence. The modified SSCP technique is also suitable for routine screening for the G542X, G55ID, and W1282X point mutations within the CFTR gene. The frequency distribution of polymorphic TUB9 marker alleles across the non-delta F508 chromosomes in the three studied groups were estimated. Homozygotes for the TUB9 allele 1 were shown to have identical GATT-TUB9-M470V haplotypes.

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

    Energy Technology Data Exchange (ETDEWEB)

    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)

    2010-04-26

    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.

  15. 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

    2011-12-31

    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.

  16. The Okavango: Whose Delta is it?

    Science.gov (United States)

    Magole, Lapologang; Magole, Lefatshe Innocent

    The Okavango Delta is amongst the largest Ramsar sites ( http://www.ramsar.org/sitelist.pdf) in the world and an important wetland for community livelihoods, conservation and tourism in Botswana. Over the years, the utilization of the delta has shifted from communal use to state control, with an increased use for conservation and tourism. This increased use for conservation and tourism has manifested in the physical expansion of the conservation area - Moremi Game Reserve and the formation of Wildlife Management Areas (WMAs) around the reserve, whose primary land use is wildlife utilization. The expansion of the conservation area has translated into several practical matters, including expansion of the area for non-hunting activities or photographic areas. The livelihoods of local communities of the Okavango delta who depended on fishing, hunter-gathering, livestock rearing, rain-fed agriculture and flood recession farming have been negatively affected by the expansion of conservation and tourism in the delta. The livelihoods alternatives in the form of Community Based Natural Resource Management (CBNRM) and tourism have not provided substitutes for the people as the communities are still reliant on the same old livelihood sources as in the past, albeit within smaller and restricted areas. This paper explores the ownership of the natural resources within the Okavango Delta. It asks and attempts to answer the following questions: Who owns and controls the use of the land? Who has access to other resources there in? Who makes the decisions on how the delta resources should be managed and used? Who benefits from the delta resources? We argue firstly that ownership of the delta as defined by legal parameters and demonstrated in natural resource management practice is vested on government. Secondly, government, after assuming ownership of the delta continues to sell its stake to the international community, at the expense of local ownership and access to resources. We

  17. Maize Mutator transposon

    Institute of Scientific and Technical Information of China (English)

    Yijun WANG; Mingliang XU; Dexiang DENG; Yunlong BIAN

    2008-01-01

    Transposable elements are widely distributed in eukaryotes. Due to its high copy numbers, high forward mutation rate and preferential insertion into low-copy DNA sequences, among others, the Mutator system has been widely used as a mutagen in genomic research. The discovery, classification, transposition specificity and epige-netic regulation of Mutator transposons were described. The application of Mutator tagging in plant genomic research was also presented. The role of Mu-like elements in genome evolution was briefly depicted. Moreover, the direction of Mutator transposon research in the future was discussed.

  18. 先天性双侧输精管缺如患者囊性纤维化跨膜传导调节因子基因的检测%CFTR gene mutation in patients with congenital bilateral absence of vas deferens

    Institute of Scientific and Technical Information of China (English)

    卢少明; 王来诚; 张浩波; 李晓; 刘蛟龙; 崔延义; 陈子江

    2013-01-01

    Objective To study the frequency of cystic fibrosis transmembrane conductance regulator(CFTR)mutations in patients with congenital bilateral absence of vas deferens(CBAVD).Methods Eighty-five CBAVD patients were collected from May 2007 to May 2009.The diagnosis of CBAVD included azoospermia,normal of 4 sex hormone items,absence of seminal vesicle,normal volume of testicular and epididymis dilated siltation.And 85 normal fertile men served as controls.Genomic DNA was isolated from peripheral blood.The mutations of CFTR exons 10,11 were detected by PCR-single strand conformation polymorphism,and direct sequencing was performed on 85 cases of CBAVD and the control males.Results Of the 85 CBAVD,10 cases(11.8%)exhibited an abnormal CFTR gene mutation,with 4 cases I556V,2 cases M469V,and 1 case of E527N,A F508,L558S,S485C.No mutations were detected in 85 controls.There was a significant difference between the 2 groups(x2 =8.606,P =0.003).Conclusions CBAVD might be caused by the CFTR mutations.The frequencies and the spectrum of CFTR mutations might be different from those Caucasian population in the west country.%目的 探讨先天性双侧输精管缺如(CBAVD)患者与囊性纤维化跨膜传导调节因子(CFTR)基因突变的关系. 方法 收集2007年5月至2009年5月85例CBAVD患者.CBAVD诊断依据:无精子;性激素4项正常;双侧输精管未触及;双睾丸体积正常,附睾饱满淤积.另设健康已生育男性85例作为对照.抽取外周血,应用聚合酶链反应-单链构象多态及PCR产物直接序列测定法检测患者及对照组CFTR基因第10,11外显子,比较两组的突变情况. 结果 CBAVD组85例,CFTR基因突变10例,占11.8%,分别是I556V突变4例,M469V突变2例,E527N、△F508、L558S、S485C各1例.对照组85例均未见突变.两组间比较差异有统计学意义(x2=8.606,P=0.003).结论 CBAVD主要由CFTR基因突变引起,CFTR基因突变的位点与频率与西方白种人有所不同.

  19. Impact of sea-level rise in a Mediteranean delta: The Ebro delta cast

    NARCIS (Netherlands)

    Sánchez-Arcilla, A.; Stive, M.D.F.; Jiménez, J.A.; García, M.A.

    1993-01-01

    In anticipation of a comprehensive, multidisciplinary study on the impact of climatic change on the Ebro Delta preliminary results are here presented of the response of the outer delta coast to present and future relative sea-level rise. Due to the absence of observations and predictions of regional

  20. Final State Interactions and Delta S=-1, Delta C=\\pm 1 B--decays

    CERN Document Server

    Fayyazuddin, A

    2002-01-01

    The final state interactions (FSI) in Delta S=-1, Delta C=\\pm 1, decays of B-meson are discussed. The rescattering corrections are found to be of order of 15-20%. The strong interaction phase shifts are estimated and their effects on CP-asymmetry are discussed.

  1. A model for the Delta(1600) resonance and gamma N -> Delta(1600) transition

    CERN Document Server

    Ramalho, G

    2010-01-01

    A covariant spectator constituent quark model is applied to study the gamma N -> Delta(1600) transition. Two processes are important in the transition: a photon couples to the individual quarks of the Delta(1600) core (quark core), and a photon couples to the intermediate pion-baryon states (pion cloud). While the quark core contributions are estimated assuming Delta(1600) as the first radial excitation of Delta(1232), the pion cloud contributions are estimated based on an analogy with the gamma N -> Delta(1232) transition. To estimate the pion cloud contributions in the gamma N -> Delta(1600) transition, we include the relevant intermediate states, pi-N, pi-Delta, pi-N(1440) and pi-Delta(1600). Dependence on the four-momentum transfer squared, Q2, is predicted for the magnetic dipole transition form factor, GM*(Q2), as well as the helicity amplitudes, A_1/2(Q2) and A_3/2(Q2). The results at Q2=0 are compared with the existing data.

  2. A model for the Delta(1600) resonance and gamma N -> Delta(1600) transition

    Energy Technology Data Exchange (ETDEWEB)

    G. Ramalho, K. Tsushima

    2010-10-01

    A covariant spectator constituent quark model is applied to study the gamma N -> Delta(1600) transition. Two processes are important in the transition: a photon couples to the individual quarks of the Delta(1600) core (quark core), and a photon couples to the intermediate pion-baryon states (pion cloud). While the quark core contributions are estimated assuming Delta(1600) as the first radial excitation of Delta(1232), the pion cloud contributions are estimated based on an analogy with the gamma N -> Delta(1232) transition. To estimate the pion cloud contributions in the gamma N -> Delta(1600) transition, we include the relevant intermediate states, pi-N, pi-Delta, pi-N(1440) and pi-Delta(1600). Dependence on the four-momentum transfer squared, Q2, is predicted for the magnetic dipole transition form factor, GM*(Q2), as well as the helicity amplitudes, A_1/2(Q2) and A_3/2(Q2). The results at Q2=0 are compared with the existing data.

  3. Impact of sea-level rise in a Mediteranean delta: The Ebro delta cast

    NARCIS (Netherlands)

    Sánchez-Arcilla, A.; Stive, M.D.F.; Jiménez, J.A.; García, M.A.

    1993-01-01

    In anticipation of a comprehensive, multidisciplinary study on the impact of climatic change on the Ebro Delta preliminary results are here presented of the response of the outer delta coast to present and future relative sea-level rise. Due to the absence of observations and predictions of regional

  4. 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.

    2014-01-01

    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 arou

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

    Data.gov (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....

  6. \\Delta Y/ \\Delta Z from the analysis of local K dwarfs

    CERN Document Server

    Gennaro, Mario; Degl'Innocenti, Scilla

    2010-01-01

    The stellar helium-to-metal enrichment ratio, \\Delta Y/\\Delta Z, is a widely studied astrophysical quantity. However, its value is still not precisely constrained. This paper is focused on the study of the main sources of uncertainty which affect the \\Delta Y/\\Delta Z derived from the analysis of the low-main sequence (MS) stars in the solar neighborhood. The possibility to infer the value of \\Delta Y/\\Delta Z from the study of low-MS stars relies on the dependence of the stellar luminosity and effective temperature on the initial Y and Z. The \\Delta Y/\\Delta Z ratio is obtained by comparing the magnitude difference between the observed stars and a reference theoretical zero age main sequence (ZAMS) with the related theoretical magnitude differences computed from a new set of stellar models with up-to-date input physics and a fine grid of chemical compositions. A Monte Carlo approach has been used to evaluate the impact on the result of different sources of uncertainty, i.e. observational errors, evolutionary...

  7. Holocene delta plain development in the Song Hong (Red River) delta, Vietnam

    Science.gov (United States)

    Funabiki, Ayako; Haruyama, Shigeko; Quy, Nguyen Van; Hai, Pham Van; Thai, Dinh Hung

    2007-05-01

    Holocene delta plain development was investigated based on three sediment cores analyzed in detail from the Song Hong (Red River) delta plain in Vietnam. Two cores (DA and PD) from the western delta plain showed both the landward limit of the transgressive estuarine system in the valley incised during the last glacial maximum and floodplain evolution since the middle Holocene. On the other hand, a core (TL) from the eastern delta plain revealed a Pleistocene terrace buried under the deltaic sediments and a slow accumulation rate compared with that in the west. At 8 cal ky BP, the shoreline migrated very close to the present Hanoi city area, and the sedimentary environment changed to tidal flat or salt marsh. Hanoi city marks the northern limit of shoreline transgression. The mangrove swamp expanded from 8 to 5 cal ky BP to the landward limit of the delta plain. Subsequently, the shoreline migrated seaward as a result of delta progradation and sea-level lowering. From 5 cal ky BP, the emerged area evolved into a floodplain and natural levees formed along the abandoned river channels on the western delta plain, but at 2 cal ky, archeological sites indicate that the Holocene terrace in the eastern delta plain was still inundated.

  8. Improvement of bioinsecticides production through mutagenesis of Bacillus thuringiensis by u.v. and nitrous acid affecting metabolic pathways and/or delta-endotoxin synthesis.

    Science.gov (United States)

    Ghribi, D; Zouari, N; Jaoua, S

    2004-01-01

    The present work aimed to obtain bioinsecticide over-producing mutants through classical mutagenesis of vegetative cells of Bacillus thuringiensis (Bt) by using u.v. and nitrous acid, and to evidence the involvement of cell metabolism in delta-endotoxin synthesis. Vegetative cells of Bt were treated by nitrous acid (0.17 mg ml(-1)) or exposed to u.v. rays (emitted at a wave length of 240 nm). The isolated survivors were screened on the basis of the production of delta-endotoxins and biomass in glucose and/or in gruel-based media at two aeration conditions. Bioinsecticide over-producing mutants were obtained with high frequencies because random mutations were shown to affect cell metabolism at different pathways related to the regulation of delta-endotoxin synthesis. Classical mutagenesis of Bt cells lead to the isolation of a large variety of delta-endotoxin over-producing mutants that could be classified into six groups based on the location of the mutations, particularly in metabolism pathways and delta-endotoxin synthesis. High frequencies of delta-endotoxin over-producing mutants of Bt could be obtained through classical mutagenesis of vegetative cells. This should contribute to a significant reduction of production and utilization costs of Bt bioinsecticides.

  9. MODIFICATION OF DELTA FOR CHOOSER OPTIONS

    Directory of Open Access Journals (Sweden)

    Marek Ďurica

    2015-09-01

    Full Text Available Correctly used financial derivatives can help investors increase their expected returns and minimize their exposure to risk. To ensure the specific needs of investors, a large number of different types of non-standard exotic options is used. Chooser option is one of them. It is an option that gives its holder the right to choose at some predetermined future time whether the option will be a standard call or put with predetermined strike price and maturity time. Although the chooser options are more expensive than standard European-style options, in many cases they are a more suitable instrument for investors in hedging their portfolio value. For an effective use of the chooser option as a hedging instrument, it is necessary to check the values of the Greek parameters delta and gamma for the options. Especially, if the value of the parameter gamma is too large, hedging of the portfolio value using only parameter delta is insufficient and brings high transaction costs because the portfolio has to be reviewed relatively often. Therefore, in this article, a modification of delta-hedging as well as using the value of parameter gamma is suggested. Error of the delta modification is analyzed and compared with the error of widely used parameter delta. Typical patterns for the modified hedging parameter variation with various time to choose time for chooser options are also presented in this article.

  10. Notched delta, phenotype, and Angelman syndrome.

    Science.gov (United States)

    Korff, Christian M; Kelley, Kent R; Nordli, Douglas R

    2005-08-01

    The notched delta pattern is one of the characteristic EEG features found in Angelman syndrome patients. The purpose of this study was to evaluate the possibility of using the notched delta pattern as a detection tool for Angelman syndrome patients by analyzing its frequency in a tertiary care pediatric center, its specificity for Angelman syndrome, and the age at which it was observed. The authors performed a retrospective review of the video-EEG recordings of all the patients who had either the notched delta pattern or a phenotype consistent with Angelman syndrome. The notched delta was observed in 1.1% of all the EEGs performed. Its specificity for Angelman syndrome was evaluated at 38%. The youngest age at which it was noted was 14 months. The results indicate that the notched delta pattern is relatively rare, but more frequent than expected, and is easily recognizable. The pattern was observed not only in Angelman syndrome patients, but also in children with a spectrum of conditions wider than reported. It is a powerful detection tool for Angelman syndrome when correlated to a suggestive phenotype, and the association of these features should raise suspicion for Angelman syndrome in both infants and adults.

  11. Tracking Nile Delta vulnerability to Holocene change.

    Directory of Open Access Journals (Sweden)

    Nick Marriner

    Full Text Available Understanding deltaic resilience in the face of Holocene climate change and human impacts is an important challenge for the earth sciences in characterizing the full range of present and future wetland responses to global warming. Here, we report an 8000-year mass balance record from the Nile Delta to reconstruct when and how this sedimentary basin has responded to past hydrological shifts. In a global Holocene context, the long-term decrease in Nile Delta accretion rates is consistent with insolation-driven changes in the 'monsoon pacemaker', attested throughout the mid-latitude tropics. Following the early to mid-Holocene growth of the Nile's deltaic plain, sediment losses and pronounced erosion are first recorded after ~4000 years ago, the corollaries of falling sediment supply and an intensification of anthropogenic impacts from the Pharaonic period onwards. Against the backcloth of the Saharan 'depeopling', reduced river flow underpinned by a weakening of monsoonal precipitation appears to have been particularly conducive to the expansion of human activities on the delta by exposing productive floodplain lands for occupation and irrigation agriculture. The reconstruction suggests that the Nile Delta has a particularly long history of vulnerability to extreme events (e.g. floods and storms and sea-level rise, although the present sediment-starved system does not have a direct Holocene analogue. This study highlights the importance of the world's deltas as sensitive archives to investigate Holocene geosystem responses to climate change, risks and hazards, and societal interaction.

  12. 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)

    2011-03-15

    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.)

  13. The subunit delta-subunit b domain of the Escherichia coli F1F0 ATPase. The B subunits interact with F1 as a dimer and through the delta subunit.

    Science.gov (United States)

    Rodgers, A J; Wilkens, S; Aggeler, R; Morris, M B; Howitt, S M; Capaldi, R A

    1997-12-05

    The delta and b subunits are both involved in binding the F1 to the F0 part in the Escherichia coli ATP synthase (ECF1F0). The interaction of the purified delta subunit and the isolated hydrophilic domain of the b subunit (bsol) has been studied here. Purified delta binds to bsol weakly in solution, as indicated by NMR studies and protease protection experiments. On F1, i.e. in the presence of ECF1-delta, delta, and bsol interact strongly, and a complex of ECF1.bsol can be isolated by native gel electrophoresis. Both delta subunit and bsol are protected from trypsin cleavage in this complex. In contrast, the delta subunit is rapidly degraded by the protease when bound to ECF1 when bsol is absent. The interaction of bsol with ECF1 involves the C-terminal domain of delta as delta(1-134) cannot replace intact delta in the binding experiments. As purified, bsol is a stable dimer with 80% alpha helix. A monomeric form of bsol can be obtained by introducing the mutation A128D (Howitt, S. M., Rodgers, A. J.,W., Jeffrey, P. D., and Cox, G. B. (1996) J. Biol. Chem. 271, 7038-7042). Monomeric bsol has less alpha helix, i.e. only 58%, is much more sensitive to trypsin cleavage than dimer, and unfolds at much lower temperatures than the dimer in circular dichroism melting studies, indicating a less stable structure. The bsol dimer, but not monomer, binds to delta in ECF1. To examine whether subunit b is a monomor or dimer in intact ECF1F0, CuCl2 was used to induce cross-link formation in the mutants bS60C, bQ104C, bA128C, bG131C, and bS146C. With the exception of bS60C, CuCl2 treatment resulted in formation of b subunit dimers in all mutants. Cross-linking yield was independent of nucleotide conditions and did not affect ATPase activity. These results show the b subunit to be dimeric for a large portion of the C terminus, with residues 124-131 likely forming a pair of parallel alpha helices.

  14. Interactions among mu- and delta-opioid receptors, especially putative delta1- and delta2-opioid receptors, promote dopamine release in the nucleus accumbens.

    NARCIS (Netherlands)

    Hirose, N.; Murakawa, K.; Takada, K.; Oi, Y.; Suzuki, T.; Nagase, H.; Cools, A.R.; Koshikawa, N.

    2005-01-01

    The effect of interactions among mu- and delta-opioid receptors, especially the putative delta(1)- and delta(2)-opioid receptors, in the nucleus accumbens on accumbal dopamine release was investigated in awake rats by in vivo brain microdialysis. In agreement with previous studies, perfusion of the

  15. Hydraulic engineering in the social-ecological delta: understanding the interplay between social, ecological, and technological systems in the Dutch delta by means of “delta trajectories”

    NARCIS (Netherlands)

    Staveren, van M.F.; Tatenhove, van J.P.M.

    2016-01-01

    Several of the world's largest deltas have recently been conceptualized as social-ecological delta systems. Although such conceptualizations are valuable in emphasizing complex interaction between social actors and ecological processes in deltas, they do not go into specific dynamics that surround t

  16. Interactions among mu- and delta-opioid receptors, especially putative delta1- and delta2-opioid receptors, promote dopamine release in the nucleus accumbens.

    NARCIS (Netherlands)

    Hirose, N.; Murakawa, K.; Takada, K.; Oi, Y.; Suzuki, T.; Nagase, H.; Cools, A.R.; Koshikawa, N.

    2005-01-01

    The effect of interactions among mu- and delta-opioid receptors, especially the putative delta(1)- and delta(2)-opioid receptors, in the nucleus accumbens on accumbal dopamine release was investigated in awake rats by in vivo brain microdialysis. In agreement with previous studies, perfusion of the

  17. El plan del delta - Holanda

    Directory of Open Access Journals (Sweden)

    Editorial, Equipo

    1963-09-01

    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

  18. NATO-3C/Delta launch

    Science.gov (United States)

    1978-01-01

    NATO-3C, the third in a series of NATO defense-related communication satellites, is scheduled to be launched on a delta vehicle from the Eastern Test Range no earlier than November 15, 1978. NATO-3A and -3B were successfully launched by Delta vehicles in April 1976 and January 1977, respectively. The NATO-3C spacecraft will be capable of transmitting voice, data, facsimile, and telex messages among military ground stations. The launch vehicle for the NATO-3C mission will be the Delta 2914 configuration. The launch vehicle is to place the spacecraft in a synchronous transfer orbit. The spacecraft Apogee Kick motor is to be fired at fifth transfer orbit apogee to circularize its orbit at geosynchronous altitude of 35,900 km(22,260 miles) above the equator over the Atlantic Ocean somewhere between 45 and 50 degrees W longitude.

  19. Liquefaction potential of Nile delta, Egypt

    Science.gov (United States)

    Fergany, Elsayed; Omar, Khaled

    2017-06-01

    Understanding how sedimentary basins respond to seismic-wave energy generated by earthquake events is a significant concern for seismic-hazard estimation and risk analysis. The main goal of this study is assessing the vulnerability index, Kg, as an indicator for liquefaction potential sites in the Nile delta basin based on the microtremor measurements. Horizontal to Vertical spectral ratio analyses (HVSR) of ambient noise data, which was conducted in 2006 at 120 sites covering the Nile delta from south to north were reprocessed using Geopsy software. HVSR factors of amplification, A, and fundamental frequency, F, were calculated and Kg was estimated for each measurement. The Kg value varies widely from south toward north delta and the potential liquefaction places were estimated. The higher vulnerability indices are associated with sites located in southern part of the Nile delta and close to the branches of Nile River. The HVSR factors were correlated with geologic setting of the Nile delta and show good correlations with the sediment thickness and subsurface stratigraphic boundaries. However, we note that sites located in areas that have greatest percentage of sand also yielded relatively high Kg values with respect to sites in areas where clay is abundant. We concluded that any earthquake with ground acceleration more than 50 gal at hard rock can cause a perceived deformation of sandy sediments and liquefaction can take place in the weak zones of Kg ≥ 20. The worst potential liquefaction zones (Kg > 30) are frequently joined to the Damietta and Rosetta Nile River branches and south Delta where relatively coarser sand exists. The HVSR technique is a very sensitive tool for lithological stratigraphy variations in two dimensions and varying liquefaction susceptibility.

  20. All optical binary delta-sigma modulator

    Science.gov (United States)

    Sayeh, Mohammad R.; Siahmakoun, Azad

    2005-09-01

    This paper describes a novel A/D converter called "Binary Delta-Sigma Modulator" (BDSM) which operates only with nonnegative signal with positive feedback and binary threshold. This important modification to the conventional delta-sigma modulator makes the high-speed (>100GHz) all-optical implementation possible. It has also the capability to modify its own sampling frequency as well as its input dynamic range. This adaptive feature helps designers to optimize the system performance under highly noisy environment and also manage the power consumption of the A/D converters.

  1. Measurement of the Muon Decay Parameter delta

    CERN Document Server

    Gaponenko, A N; Davydov, Yu I; Depommier, P; Doornbos, J; Faszer, W; Fujiwara, M C; Gagliardi, C A; Gill, D R; Green, P; Gumplinger, P; Hasinoff, M D; Henderson, R S; Hu, J; Jamieson, B; Kitching, P; Koetke, D D; Krushinsky, A A; Lachin, Yu Yu; MacDonald, J A; MacDonald, R P; Marshall, G M; Mathie, E L; Miasoedov, L V; Mischke, R E; Musser, J R; Nord, P M; Nozar, M; Olchanski, K; Olin, A; Openshaw, R; Porcelli, T A; Poutissou, J M; Poutissou, R; Quraan, M A; Rodning, N L; Selivanov, V; Sheffer, G; Shin, B; Sobratee, F; Stanislaus, T D S; Tacik, R; Torokhov, V D; Tribble, R E; Vasilev, M A; Wright, D H

    2004-01-01

    The muon decay parameter delta has been measured by the TWIST collaboration. We find delta = 0.74964 +- 0.00066(stat.) +- 0.00112(syst.), consistent with the Standard Model value of 3/4. This result implies that the product Pmuxi of the muon polarization in pion decay, Pmu, and the muon decay parameter xi falls within the 90% confidence interval 0.9960 < Pmuxi < xi < 1.0040. It also has implications for left-right-symmetric and other extensions of the Standard Model.

  2. Flood Inundation Modelling in Data Sparse Deltas

    Science.gov (United States)

    Hawker, Laurence; Bates, Paul; Neal, Jeffrey

    2017-04-01

    An estimated 7% of global population currently live in deltas, and this number is increasing over time. This has resulted in numerous human induced impacts on deltas ranging from subsidence, upstream sediment trapping and coastal erosion amongst others. These threats have already impacted on flood dynamics in deltas and could intensify in line with human activities. However, the myriad of threats creates a large number of potential scenarios that need to be evaluated. Therefore, to assess the impacts of these scenarios, a pre-requisite is a flood inundation model that is both computationally efficient and flexible in its setup so it can be applied in data-sparse settings. An intermediate scale, which compromises between the computational speed of a global model and the detail of a case specific bespoke model, was chosen to achieve this. To this end, we have developed an intermediate scale flood inundation model at a resolution of 540m of the Mekong Delta, built with freely available data, using the LISFLOOD-FP hydrodynamic model. The purpose of this is to answer the following questions: 1) How much detail is required to accurately simulate flooding in the Mekong Delta? , 2) What characteristics of deltas are most important to include in flood inundation models? Models were run using a vegetation removed SRTM DEM and a hind-casting of tidal heights as a downstream boundary. Results indicate the importance of vegetation removal in the DEM for inundation extent and the sensitivity of water level to roughness coefficients. The propagation of the tidal signal was found to be sensitive to bathymetry, both within the river channel and offshore, yet data availability for this is poor, meaning the modeller has to be careful in his or her choice of bathymetry interpolation Supplementing global river channel data with more localised data demonstrated minor improvements in results suggesting detailed channel information is not always needed to produce good results. It is

  3. DNA polymerase III accessory proteins. I. holA and holB encoding delta and delta'.

    Science.gov (United States)

    Dong, Z; Onrust, R; Skangalis, M; O'Donnell, M

    1993-06-05

    The genes encoding the delta and delta' subunits of the 10-subunit Escherichia coli replicase, DNA polymerase III holoenzyme, have been identified and sequenced. The holA gene encoding delta is located downstream of rlpB at 15.2 min and predicts a 38.7 kda protein. The holB gene encoding delta' is located at 24.3 min and predicts a 36.9-kDa protein. Hence the delta and delta' subunits are unrelated proteins encoded by separate genes. The genes have been used to express and purify delta and delta' in quantity. The predicted amino acid sequence of delta' is homologous to the sequences of the tau and gamma subunits revealing a large amount of structural redundancy within the holoenzyme.

  4. Heat Kernel Estimate for $\\Delta+\\Delta^{\\alpha/2}$ in $C^{1,1}$ open sets

    CERN Document Server

    Chen, Zhen-Qing; Song, Renming

    2010-01-01

    We consider a family of pseudo differential operators $\\{\\Delta+ a^\\alpha \\Delta^{\\alpha/2}; a\\in (0, 1]\\}$ on $\\bR^d$ for every $d\\geq 1$ that evolves continuously from $\\Delta$ to $\\Delta + \\Delta^{\\alpha/2}$, where $\\alpha \\in (0, 2)$. It gives rise to a family of L\\'evy processes $\\{X^a, a\\in (0, 1]\\}$ in $\\bR^d$, where $X^a$ is the sum of a Brownian motion and an independent symmetric $\\alpha$-stable process with weight $a$. We establish sharp two-sided estimates for the heat kernel of $\\Delta + a^{\\alpha} \\Delta^{\\alpha/2}$ with zero exterior condition in a family of open subsets, including bounded $C^{1, 1}$ (possibly disconnected) open sets. This heat kernel is also the transition density of the sum of a Brownian motion and an independent symmetric $\\alpha$-stable process with weight $a$ in such open sets. Our result is the first sharp two-sided estimates for the transition density of a Markov process with both diffusion and jump components in open sets. Moreover, our result is uniform in $a$ in the s...

  5. Three kinds of mutation

    CERN Document Server

    Buan, Aslak Bakke; Thomas, Hugh

    2010-01-01

    For a finite dimensional hereditary algebra, we consider: exceptional sequences in the category of finite dimensional modules, silting objects in the bounded derived category, and m-cluster tilting objects in the m-cluster category. There are mutation operations on both the set of m-cluster tilting objects and the set of exceptional sequences. It is also possible to define a mutation operation for silting objects. We compare these three different notions of mutation.

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

    Data.gov (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...

  7. Redundant role of protein kinase C delta and epsilon during mouse embryonic development.

    Directory of Open Access Journals (Sweden)

    Sergio Carracedo

    Full Text Available Protein Kinase C delta and epsilon are mediators of important cellular events, such as cell proliferation, migration or apoptosis. The formation of blood vessels, i.e., vasculo- and angiogenesis, is a process where these isoforms have also been shown to participate. However, mice deficient in either Protein Kinase C delta or epsilon are viable and therefore their individual contribution to the formation of the vasculature appeared so far dispensable. In this study, we show that double null mutation of Protein Kinase C delta and epsilon causes embryonic lethality at approximately E9.5. At this stage, whole mount staining of the endothelial marker CD31 in double null embryos revealed defective blood vessel formation. Moreover, culture of double deficient mouse allantois showed impaired endothelial cell organization, and analyses of double deficient embryo sections showed dilated vessels, decreased endothelial-specific adherent junctions, and decreased contact of endothelial cells with mural cells. Protein kinase C delta and epsilon also appeared essential for vascular smooth muscle cell differentiation, since α-smooth muscle actin, a classical marker for vascular smooth muscle cells, was almost undetectable in double deficient embryonic aorta at E9.5. Subsequent qPCR analyses showed decreased VE-cadherin, Vegfr2, Cd31, Cdh2, Ets1, and Fli-1, among other angiogenesis related transcripts in double deficient embryos. Taken together, these data suggest for the first time an in vivo redundant role between members of the novel Protein Kinase C subfamily that allows for mutual compensation during mouse embryonic development, with vasculogenesis/angiogenesis as an obvious common function of these two Protein Kinase Cs. Protein Kinase C delta and epsilon might therefore be useful targets for inhibiting vasculo- and/or angiogenesis.

  8. Redundant role of protein kinase C delta and epsilon during mouse embryonic development.

    Science.gov (United States)

    Carracedo, Sergio; Sacher, Frank; Brandes, Gudrun; Braun, Ursula; Leitges, Michael

    2014-01-01

    Protein Kinase C delta and epsilon are mediators of important cellular events, such as cell proliferation, migration or apoptosis. The formation of blood vessels, i.e., vasculo- and angiogenesis, is a process where these isoforms have also been shown to participate. However, mice deficient in either Protein Kinase C delta or epsilon are viable and therefore their individual contribution to the formation of the vasculature appeared so far dispensable. In this study, we show that double null mutation of Protein Kinase C delta and epsilon causes embryonic lethality at approximately E9.5. At this stage, whole mount staining of the endothelial marker CD31 in double null embryos revealed defective blood vessel formation. Moreover, culture of double deficient mouse allantois showed impaired endothelial cell organization, and analyses of double deficient embryo sections showed dilated vessels, decreased endothelial-specific adherent junctions, and decreased contact of endothelial cells with mural cells. Protein kinase C delta and epsilon also appeared essential for vascular smooth muscle cell differentiation, since α-smooth muscle actin, a classical marker for vascular smooth muscle cells, was almost undetectable in double deficient embryonic aorta at E9.5. Subsequent qPCR analyses showed decreased VE-cadherin, Vegfr2, Cd31, Cdh2, Ets1, and Fli-1, among other angiogenesis related transcripts in double deficient embryos. Taken together, these data suggest for the first time an in vivo redundant role between members of the novel Protein Kinase C subfamily that allows for mutual compensation during mouse embryonic development, with vasculogenesis/angiogenesis as an obvious common function of these two Protein Kinase Cs. Protein Kinase C delta and epsilon might therefore be useful targets for inhibiting vasculo- and/or angiogenesis.

  9. The microscopic structure of $\\pi NN$, $\\pi N\\Delta$ and $\\pi\\Delta\\Delta$ vertices in a hybrid constituent quark model

    CERN Document Server

    Jung, Ju-Hyun

    2016-01-01

    We present a microscopic description of the strong $\\pi NN$, $\\pi N\\Delta$ and $\\pi\\Delta\\Delta$ vertices. Our starting point is a constituent-quark model supplemented by an additional $3q\\pi$ non-valence component. In the spirit of chiral constituent-quark models, quarks are allowed to emit and reabsorb a pion. This multichannel system is treated in a relativistically invariant way within the framework of point-form quantum mechanics. Starting with a common $SU(6)$ spin-flavor-symmetric wave function for $N$ and $\\Delta$, we calculate the strength of the $\\pi NN$, $\\pi N\\Delta$ and $\\pi\\Delta\\Delta$ couplings and the corresponding vertex form factors. Our results are in accordance with phenomenological fits of these quantities that have been obtained within purely hadronic multichannel models for baryon resonances.

  10. Gestational mutations in radiation carcinogenesis

    Science.gov (United States)

    Meza, R.; Luebeck, G.; Moolgavkar, S.

    Mutations in critical genes during gestation could increase substantially the risk of cancer. We examine the consequences of such mutations using the Luebeck-Moolgavkar model for colorectal cancer and the Lea-Coulson modification of the Luria-Delbruck model for the accumulation of mutations during gestation. When gestational mutation rates are high, such mutations make a significant contribution to cancer risk even for adult tumors. Furthermore, gestational mutations ocurring at distinct times during emryonic developmemt lead to substantially different numbers of mutated cells at birth, with early mutations leading to a large number (jackpots) of mutated cells at birth and mutation occurring late leading to only a few mutated cells. Thus gestational mutations could confer considerable heterogeneity of the risk of cancer. If the fetus is exposed to an environmental mutagen, such as ionizing radiation, the gestational mutation rate would be expected to increase. We examine the consequences of such exposures during gestation on the subsequent development of cancer.

  11. Reduced complexity MASH delta-sigma modulator

    OpenAIRE

    Ye, Zhipeng; Kennedy, Michael Peter

    2007-01-01

    A reduced complexity digital multi-stage noise shaping (MASH) delta-sigma modulator for fractional-N frequency synthesizer applications is proposed. A long word is used for the first modulator in a MASH structure; the sequence length is maximized by setting the least significant bit of the input to 1; shorter words are used in subsequent stages. Experimental results confirm simulations

  12. Strong decays of nucleon and $\\Delta$ resonances

    CERN Document Server

    Bijker, R

    1996-01-01

    We study the strong couplings of the nucleon and delta resonances in a collective model. In the ensuing algebraic treatment we derive closed expressions for decay widths which are used to analyze the experimental data for strong decays into the pion and eta channels.

  13. How stable is the Mississippi Delta?

    NARCIS (Netherlands)

    Törnqvist, T.E.; Bick, S.J.; van der Borg, K.; de Jong, A.F.M.

    2006-01-01

    Large deltas are commonly believed to exhibit rapid rates of tectonic subsidence, largely due to sediment loading of the lithosphere. As a result, deltaic plains are prone to accelerated relative sea-level rise, coastal erosion, and wetland loss. Hurricane Katrina's devastation testifies to the seve

  14. Design of Low Power Sigma Delta ADC

    Directory of Open Access Journals (Sweden)

    Mohammed Arifuddin Sohel

    2012-08-01

    Full Text Available A Low power discrete time sigma delta ADC consisting of a second order sigma delta modulator and third order Cascaded Integrated Comb (CIC filter is proposed. The second order modulator is designed to work at a signal band of 20 K Hz at an oversampling ratio of 64 with a sampling frequency of 2.56 MHz. It achieves a signal to noise ratio of 85.2dB and a resolution of 14 bits. The CIC digital filter is designed to implement a decimation factor of 64, operating at a maximum sampling frequency of 2.56 MHz. A second order sigma delta modulator is implemented in 0.18 micron CMOS technology using full custom design and the third order digital CIC decimation filter is implemented in verilog HDL. The complete Sigma Delta ADC, consisting of analog block of second order modulator and digital block of decimator consumes a total power 1.96mW.

  15. Design of Low Power Sigma Delta ADC

    Directory of Open Access Journals (Sweden)

    Mohammed Arifuddin Sohel

    2012-09-01

    Full Text Available A Low power discrete time sigma delta ADC consisting of a second order sigma delta modulator and third order Cascaded Integrated Comb (CIC filter is proposed. The second order modulator is designed to work at a signal band of 20K Hz at an oversampling ratio of 64 with a sampling frequency of 2.56 MHz. It achieves a signal to noise ratio of 85.2dB and a resolution of 14 bits. The CIC digital filter is designed to implement a decimation factor of 64, operating at a maximum sampling frequency of 2.56 MHz. A second order sigma delta modulator is implemented in 0.18micron CMOS technology using full custom design and the third order digital CIC decimation filter is implemented in verilog HDL. The complete Sigma Delta ADC, consisting of analog block of second order modulator and digital block of decimator consumes a total power 1.96mW.

  16. The Niger Delta Avengers, Autonomous Ethnic Clans and Common ...

    African Journals Online (AJOL)

    Nneka Umera-Okeke

    The situation in Niger Delta region has remained an unanswered research question. When oil was discovered .... From the foregone analysis, the greed factor is sufficient to explain the crisis in Niger. Delta given the ..... homeless. The sizeable ...

  17. Habitat Management Plan for Delta and Breton National Wildlife Refuges

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — The Delta and Breton NWRs Habitat Management Plan provides a long-term vision and specific guidance on managing habitats for the resources of concern at Delta and...

  18. $\\delta-\\delta^\\prime$ generalized Robin boundary conditions and quantum vacuum fluctuations

    CERN Document Server

    Munoz-Castaneda, J M

    2014-01-01

    The effects induced by the quantum vacuum fluctuations of one massless real scalar field on a configuration of two partially transparent plates are investigated. The physical properties of the infinitely thin plates are simulated by means of Dirac-$\\delta-\\delta^\\prime$ point interactions. It is shown that the distortion caused on the fluctuations by this external background gives rise to a generalization of Robin boundary conditions. The $T$-operator for potentials concentrated on points with non defined parity is computed with total generality. The quantum vacuum interaction energy between the two plates is computed using the $TGTG$ formula to find positive, negative, and zero Casimir energies. The parity properties of the $\\delta-\\delta^\\prime$ potential allow repulsive quantum vacuum force between identical plates.

  19. Delta-Bar-Delta and directed random search algorithms to study capacitor banks switching overvoltages

    Directory of Open Access Journals (Sweden)

    Sadeghkhani Iman

    2012-01-01

    Full Text Available This paper introduces an approach to analyse transient overvoltages during capacitor banks switching based on artificial neural networks (ANN. Three learning algorithms, delta-bar-delta (DBD, extended delta-bar-delta (EDBD and directed random search (DRS were used to train the ANNs. The ANN training is based on equivalent parameters of the network and therefore, a trained ANN is applicable to every studied system. The developed ANN is trained with extensive simulated results and tested for typical cases. The new algorithms are presented and demonstrated for a partial 39-bus New England test system. The simulated results show the proposed technique can accurately estimate the peak values of switching overvoltages.

  20. Delta Delta Excitation in Proton-Proton Induced pi0pi0 Production

    CERN Document Server

    Skorodko, T; Bogoslawsky, D; Calen, H; Clement, H; Doroshkevich, E; Demiroers, L; Ekstroem, C; Fransson, K; Gustafsson, L; Hoistad, B; Ivanov, G; Jacewicz, M; Jiganov, E; Johansson, T; Khakimova, O; Keleta, S; Koch, I; Kren, F; Kullander, S; Kupsc, A; Marciniewski, P; Meier, R; Morosov, B; Pauly, C; Petren, H; Petukhov, Y; Povtorejko, A; Ruber, R J M Y; Schoenning, K; Scobel, W; Shwartz, B; Stepaniak, J; Thoerngren-Engblom, P; Tikhomirov, V; Wagner, G J; Wolke, M; Yamamoto, A; Zabierowski, J; Zlomanczuk, J

    2010-01-01

    Exclusive measurements of the $pp \\to pp\\pi^0\\pi^0$ reaction have been performed at CELSIUS/WASA at energies from threshold up to $T_p$ = 1.3 GeV. Total and differential cross sections have been obtained. Here we concentrate on energies $T_p \\ge$ 1 GeV, where the $\\Delta\\Delta$ excitation becomes the leading process. No evidence is found for a significant ABC effect beyond that given by the conventional $t$-channel $\\Delta\\Delta$ excitation. This holds also for the double-pionic fusion to the quasibound $^2$He. The data are compared to model predictions, which are based on both pion and $\\rho$ exchange. Total and differential cross sections are at variance with these predictions and call for a profound modification of the $\\rho$-exchange. A phenomenological modification allowing only a small $\\rho$ exchange contribution leads to a quantitative description of the data.

  1. {Delta}{Delta} excitation in proton-proton induced {pi}{sup 0{pi}0} production

    Energy Technology Data Exchange (ETDEWEB)

    Skorodko, T.; Bashkanov, M. [Physikalisches Institut der Universitaet Tuebingen, D-72076 Tuebingen (Germany); Bogoslawsky, D. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Calen, H. [The Svedberg Laboratory, Uppsala (Sweden); Clement, H., E-mail: Clement@pit.physik.uni-tuebingen.d [Physikalisches Institut der Universitaet Tuebingen, D-72076 Tuebingen (Germany); Doroshkevich, E. [Physikalisches Institut der Universitaet Tuebingen, D-72076 Tuebingen (Germany); Demiroers, L. [Hamburg University, Hamburg (Germany); Ekstroem, C.; Fransson, K. [The Svedberg Laboratory, Uppsala (Sweden); Gustafsson, L.; Hoeistad, B. [Uppsala University, Uppsala (Sweden); Ivanov, G. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Jacewicz, M. [Uppsala University, Uppsala (Sweden); Jiganov, E. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Johansson, T. [Uppsala University, Uppsala (Sweden); Khakimova, O. [Physikalisches Institut der Universitaet Tuebingen, D-72076 Tuebingen (Germany); Keleta, S.; Koch, I. [Uppsala University, Uppsala (Sweden); Kren, F. [Physikalisches Institut der Universitaet Tuebingen, D-72076 Tuebingen (Germany); Kullander, S. [Uppsala University, Uppsala (Sweden)

    2011-01-10

    Exclusive measurements of the pp{yields}pp{pi}{sup 0{pi}0} reaction have been performed at CELSIUS/WASA at energies from threshold up to T{sub p}=1.3 GeV. Total and differential cross sections have been obtained. Here we concentrate on energies T{sub p{>=}}1 GeV, where the {Delta}{Delta} excitation becomes the leading process. No evidence is found for a significant ABC effect beyond that given by the conventional t-channel {Delta}{Delta} excitation. This holds also for the double-pionic fusion to the quasibound {sup 2}He. The data are compared to model predictions, which are based on both {pi}- and {rho}-exchange. Total and differential cross sections are at variance with these predictions and call for a profound modification of the {rho}-exchange. A phenomenological modification allowing only a small {rho}-exchange contribution leads to a quantitative description of the data.

  2. Mutation and premating isolation.

    Science.gov (United States)

    Woodruff, R C; Thompson, J N

    2002-11-01

    While premating isolation might be traceable to different genetic mechanisms in different species, evidence supports the idea that as few as one or two genes may often be sufficient to initiate isolation. Thus, new mutation can theoretically play a key role in the process. But it has long been thought that a new isolation mutation would fail, because there would be no other individuals for the isolation-mutation-carrier to mate with. We now realize that premeiotic mutations are very common and will yield a cluster of progeny carrying the same new mutant allele. In this paper, we discuss the evidence for genetically simple premating isolation barriers and the role that clusters of an isolation mutation may play in initiating allopatric, and even sympatric, species divisions.

  3. A delta-catenin signaling pathway leading to dendritic protrusions.

    Science.gov (United States)

    Abu-Elneel, Kawther; Ochiishi, Tomoyo; Medina, Miguel; Remedi, Monica; Gastaldi, Laura; Caceres, Alfredo; Kosik, Kenneth S

    2008-11-21

    Delta-catenin is a synaptic adherens junction protein pivotally positioned to serve as a signaling sensor and integrator. Expression of delta-catenin induces filopodia-like protrusions in neurons. Here we show that the small GTPases of the Rho family act coordinately as downstream effectors of delta-catenin. A dominant negative Rac prevented delta-catenin-induced protrusions, and Cdc42 activity was dramatically increased by delta-catenin expression. A kinase dead LIMK (LIM kinase) and a mutant Cofilin also prevented delta-catenin-induced protrusions. To link the effects of delta-catenin to a physiological pathway, we noted that (S)-3,5-dihydroxyphenylglycine (DHPG) activation of metabotropic glutamate receptors induced dendritic protrusions that are very similar to those induced by delta-catenin. Furthermore, delta-catenin RNA-mediated interference can block the induction of dendritic protrusions by DHPG. Interestingly, DHPG dissociated PSD-95 and N-cadherin from the delta-catenin complex, increased the association of delta-catenin with Cortactin, and induced the phosphorylation of delta-catenin within the sites that bind to these protein partners.

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

    NARCIS (Netherlands)

    Maren, D.S. van

    2004-01-01

    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 oi

  5. 78 FR 45592 - DeltaPoint Capital IV, LP;

    Science.gov (United States)

    2013-07-29

    ... ADMINISTRATION DeltaPoint Capital IV, LP; 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., 45 East Avenue... Business Administration (``SBA'') Rules and Regulations (13 CFR 107.730). DeltaPoint Capital IV,...

  6. Comparative assessment of the vulnerability and resilience of 10 deltas : work document

    NARCIS (Netherlands)

    Bucx, T.; Marchand, M.; Makaske, B.; Guchte, van de C.

    2010-01-01

    Background information about: Nile delta (Egypt), Incomati delta (Mozambique), Ganges-Brahmaputra-Meghna (Bangladesh), Yangtze (China), Ciliwung (Indonesia), Mekong (Vietnam), Rhine-Meuse (The Netherlands), Danube (Romania), California Bay-Delta, Mississippi River Delta (USA)

  7. Evidence for a parity doublet Delta(1920)P33 and Delta(1940)D33 from gammap-->ppi;{0}eta.

    Science.gov (United States)

    Horn, I; Anisovich, A V; Anton, G; Bantes, R; Bartholomy, O; Beck, R; Beloglazov, Yu; Bogendörfer, R; Castelijns, R; Crede, V; Ehmanns, A; Ernst, J; Fabry, I; Flemming, H; Fösel, A; Fuchs, M; Funke, Chr; Gothe, R; Gridnev, A; Gutz, E; Höffgen, St; Hössl, J; Junkersfeld, J; Kalinowsky, H; Klein, F; Klempt, E; Koch, H; Konrad, M; Kopf, B; Krusche, B; Langheinrich, J; Löhner, H; Lopatin, I; Lotz, J; Matthäy, H; Menze, D; Messchendorp, J; Metag, V; Nikonov, V A; Novinski, D; Ostrick, M; van Pee, H; Sarantsev, A V; Schmidt, C; Schmieden, H; Schoch, B; Suft, G; Sumachev, V; Szczepanek, T; Thoma, U; Walther, D; Weinheimer, Chr

    2008-11-14

    Evidence is reported for the existence of a parity doublet of Delta resonances with total angular momentum J=3/2 from photoproduction of the ppi;{0}eta final state. The two parity partners Delta(1920)P33 and Delta(1940)D33 make significant contributions to the reaction. Cascades of resonances into Delta(1232)eta, N(1535)pi, and Na0(980) are clearly observed.

  8. Mutation rates among RNA viruses

    OpenAIRE

    Drake, John W.; Holland, John J.

    1999-01-01

    The rate of spontaneous mutation is a key parameter in modeling the genetic structure and evolution of populations. The impact of the accumulated load of mutations and the consequences of increasing the mutation rate are important in assessing the genetic health of populations. Mutation frequencies are among the more directly measurable population parameters, although the information needed to convert them into mutation rates is often lacking. A previous analysis of mutation rates in RNA viru...

  9. 78 FR 22911 - Delta Air Lines, Inc., Reservation Sales and Customer Care Call Center, Seatac, WA; Delta Air...

    Science.gov (United States)

    2013-04-17

    ... Employment and Training Administration Delta Air Lines, Inc., Reservation Sales and Customer Care Call Center, Seatac, WA; Delta Air Lines, Inc., Reservation Sales and Customer Care Call Center, Sioux City, IA... workers and former workers of Delta Air Lines, Inc., Reservation Sales and Customer Care Call...

  10. Partial protective effect of CCR5-Delta 32 heterozygosity in a cohort of heterosexual Italian HIV-1 exposed uninfected individuals

    Directory of Open Access Journals (Sweden)

    Cauda Roberto

    2006-09-01

    Full Text Available Abstract Despite multiple sexual exposure to HIV-1 virus, some individuals remain HIV-1 seronegative (exposed seronegative, ESN. The mechanisms underlying this resistance remain still unclear, although a multifactorial pathogenesis can be hypothesised. Although several genetic factors have been related to HIV-1 resistance, the homozigosity for a mutation in CCR5 gene (the 32 bp deletion, i.e. CCR5-Delta32 allele is presently considered the most relevant one. In the present study we analysed the genotype at CCR5 locus of 30 Italian ESN individuals (case group who referred multiple unprotected heterosexual intercourse with HIV-1 seropositive partner(s, for at least two years. One hundred and twenty HIV-1 infected patients and 120 individuals representative of the general population were included as control groups. Twenty percent of ESN individuals had heterozygous CCR5-Delta 32 genotype, compared to 7.5% of HIV-1 seropositive and 10% of individuals from the general population, respectively. None of the analysed individuals had CCR5-Delta 32 homozygous genotype. Sequence analysis of the entire open reading frame of CCR5 was performed in all ESN subjects and no polymorphisms or mutations were identified. Moreover, we determined the distribution of C77G variant in CD45 gene, which has been previously related to HIV-1 infection susceptibility. The frequency of the C77G variant showed no significant difference between ESN subjects and the two control groups. In conclusion, our data show a significantly higher frequency of CCR5-Delta 32 heterozygous genotype (p = 0.04 among the Italian heterosexual ESN individuals compared to HIV-1 seropositive patients, suggesting a partial protective role of CCR5-Delta 32 heterozygosity in this cohort.

  11. Modeling of the Ebola Virus Delta Peptide Reveals a Potential Lytic Sequence Motif

    Directory of Open Access Journals (Sweden)

    William R. Gallaher

    2015-01-01

    Full Text Available Filoviruses, such as Ebola and Marburg viruses, cause severe outbreaks of human infection, including the extensive epidemic of Ebola virus disease (EVD in West Africa in 2014. In the course of examining mutations in the glycoprotein gene associated with 2014 Ebola virus (EBOV sequences, a differential level of conservation was noted between the soluble form of glycoprotein (sGP and the full length glycoprotein (GP, which are both encoded by the GP gene via RNA editing. In the region of the proteins encoded after the RNA editing site sGP was more conserved than the overlapping region of GP when compared to a distant outlier species, Tai Forest ebolavirus. Half of the amino acids comprising the “delta peptide”, a 40 amino acid carboxy-terminal fragment of sGP, were identical between otherwise widely divergent species. A lysine-rich amphipathic peptide motif was noted at the carboxyl terminus of delta peptide with high structural relatedness to the cytolytic peptide of the non-structural protein 4 (NSP4 of rotavirus. EBOV delta peptide is a candidate viroporin, a cationic pore-forming peptide, and may contribute to EBOV pathogenesis.

  12. Molecular analysis of the most prevalent mutations of the FANCA and FANCC genes in Brazilian patients with Fanconi anaemia

    Directory of Open Access Journals (Sweden)

    David Enrique Aguilar Rodriguez

    2005-01-01

    Full Text Available Fanconi anaemia (FA is a recessive autosomal disease determined by mutations in genes of at least eleven complementation groups, with distinct distributions in different populations. As far as we know, there are no reports regarding the molecular characterisation of the disease in unselected FA patients in Brazil. OBECTIVE: This study aimed to investigate the most prevalent mutations of FANCA and FANCC genes in Brazilian patients with FA. METHODS: Genomic DNA obtained from 22 racially and ethnically diverse unrelated FA patients (mean age ± SD: 14.0 ± 7.8 years; 10 male, 12 female; 14 white, 8 black was analysed by polymerase chain reaction and restriction site assays for identification of FANCA (delta3788-3790 and FANCC (delta322G, IVS4+4A -> T, W22X, L496R, R548X, Q13X, R185X, and L554P gene mutations. RESULTS: Mutations in FANCA and FANCC genes were identified in 6 (27.3% and 14 (63.6% out of 22 patients, respectively. The disease could not be attributed to the tested mutations in the two remaining patients enrolled in the study (9.1%. The registry of the two most prevalent gene abnormalities (delta3788-3790 and IVS4 + 4 -> T revealed that they were present in 18.2% and 15.9% of the FA alleles, respectively. Additional FANCC gene mutations were found in the study, with the following prevalence: delta322G (11.4%, W22X (9.1%, Q13X (2.3%, L554P (2.3%, and R548X (2.3% of total FA alleles. CONCLUSION: These results suggest that mutations of FANCA and FANCC genes are the most prevalent mutations among FA patients in Brazil.

  13. Spectral factorization using the delta operator

    DEFF Research Database (Denmark)

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

    1994-01-01

    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 i......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 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...

  14. Nucleon and Delta structure in continuum QCD

    Science.gov (United States)

    Cloet, Ian

    2014-03-01

    Quantum Chromodynamics (QCD) is the only known example in nature of a fundamental quantum field theory that is innately non-perturbative. Solving QCD will have profound implications for our understanding of the natural world, for example, it will explain how light quarks and massless gluons bind together to form the observed mesons and baryons; hence explaining the origin of more than 98% of the mass in the visible universe. Given the challenges posed by QCD, it is insufficient to study hadron ground-states alone if one seeks a solution; in this regard the delta plays a special role as the lightest baryon resonance. I will discuss recent progress using continuum QCD approaches to the study of nucleon and delta properties, with a focus on insights gained by the calculation (and measurement) of their electromagnetic form factors.

  15. Pluviometric anomaly in the Llobregat Delta

    Directory of Open Access Journals (Sweden)

    J. Mazón

    2009-01-01

    Full Text Available The data from surface automatic weather stations show that in the area of the Llobregat delta (northeast of the Iberian Peninsula we can observe greater precipitation than in nearby inland areas (Ordal, Collserola, Garraf, than on the other side of a massif located on the coast (Garraf and than on the northern coast. This distribution of the precipitation could be explained by the formation of a nocturnal surface cold front in the Llobregat delta. In order to analyze in-depth the physical mechanisms that can influence the formation of this front (topography, sea and drainage winds, two rain episodes in the area were simulated with the MM5 mesoscale model, reproducing satisfactorily the physical mechanisms that favor the appearance of the front.

  16. On regularizations of the Dirac delta distribution

    Science.gov (United States)

    Hosseini, Bamdad; Nigam, Nilima; Stockie, John M.

    2016-01-01

    In this article we consider regularizations of the Dirac delta distribution with applications to prototypical elliptic and hyperbolic partial differential equations (PDEs). We study the convergence of a sequence of distributions SH to a singular term S as a parameter H (associated with the support size of SH) shrinks to zero. We characterize this convergence in both the weak-* topology of distributions and a weighted Sobolev norm. These notions motivate a framework for constructing regularizations of the delta distribution that includes a large class of existing methods in the literature. This framework allows different regularizations to be compared. The convergence of solutions of PDEs with these regularized source terms is then studied in various topologies such as pointwise convergence on a deleted neighborhood and weighted Sobolev norms. We also examine the lack of symmetry in tensor product regularizations and effects of dissipative error in hyperbolic problems.

  17. Matrix multiplication on the Intel Touchstone Delta

    Energy Technology Data Exchange (ETDEWEB)

    Huss-Lederman, S.; Jacobson, E.M.; Tsao, A. [Supercomputing Research Center, Bowie, MD (United States); Zhang, G. [CONVEX Computer Corp., Richardson, TX (United States)

    1993-12-31

    Matrix multiplication is a key primitive in block matrix algorithms such as those found in LAPACK. We present results from our study of matrix multiplication algorithms on the Intel Touchstone Delta, a distributed memory message-passing architecture with a two-dimensional mesh topology. We obtain an implementation that uses communication primitives highly suited to the Delta and exploits the single node assembly-coded matrix multiplication. Our algorithm is completely general, able to deal with arbitrary mesh aspect ratios and matrix dimensions, and has achieved parallel efficiency of 86% with overall peak performance in excess of 8 Gflops on 256 nodes for an 8800 {times} 8800 matrix. We describe our algorithm design and implementation, and present performance results that demonstrate scalability and robust behavior over varying mesh topologies.

  18. Clostridium perfringens Delta-Toxin Induces Rapid Cell Necrosis.

    Directory of Open Access Journals (Sweden)

    Soshi Seike

    Full Text Available Clostridium perfringens delta-toxin is a β-pore-forming toxin and a putative pathogenic agent of C. perfringens types B and C. However, the mechanism of cytotoxicity of delta-toxin remains unclear. Here, we investigated the mechanisms of cell death induced by delta-toxin in five cell lines (A549, A431, MDCK, Vero, and Caco-2. All cell lines were susceptible to delta-toxin. The toxin caused rapid ATP depletion and swelling of the cells. Delta-toxin bound and formed oligomers predominantly in plasma membrane lipid rafts. Destruction of the lipid rafts with methyl β-cyclodextrin inhibited delta-toxin-induced cytotoxicity and ATP depletion. Delta-toxin caused the release of carboxyfluorescein from sphingomyelin-cholesterol liposomes and formed oligomers; toxin binding to the liposomes declined with decreasing cholesterol content in the liposomes. Flow cytometric assays with annexin V and propidium iodide revealed that delta-toxin treatment induced an elevation in the population of annexin V-negative and propidium iodide-positive cells. Delta-toxin did not cause the fragmentation of DNA or caspase-3 activation. Furthermore, delta-toxin caused damage to mitochondrial membrane permeability and cytochrome c release. In the present study, we demonstrate that delta-toxin produces cytotoxic activity through necrosis.

  19. Elastic and transition form factors of the \\Delta(1232)

    CERN Document Server

    Segovia, Jorge; Cloët, Ian C; Roberts, Craig D; Schmidt, Sebastian M; Wan, Shaolong

    2013-01-01

    Predictions obtained with a confining, symmetry-preserving treatment of a vector-vector contact interaction at leading-order in a widely used truncation of QCD's Dyson-Schwinger equations are presented for \\Delta and \\Omega baryon elastic form factors and the \\gamma N -> \\Delta transition form factors. This simple framework produces results that are practically indistinguishable from the best otherwise available, an outcome which highlights that the key to describing many features of baryons and unifying them with the properties of mesons is a veracious expression of dynamical chiral symmetry breaking in the hadron bound-state problem. The following specific results are of particular interest. The \\Delta elastic form factors are very sensitive to m_\\Delta. Hence, given that the parameters which define extant simulations of lattice-regularised QCD produce \\Delta-resonance masses that are very large, the form factors obtained therewith are a poor guide to properties of the \\Delta(1232). Considering the \\Delta-b...

  20. [Quantitative relationship between molecular structure of polychlorinated biphenyls (PCBs) and enthalpy change (deltaH), entropy change (deltaS') in chromatographic process].

    Science.gov (United States)

    Zhang, Qing; Dai, Chaozheng

    2005-09-01

    The relationship between the rule of chromatographic retention value and molecular structure is an important part in the research of chromatographic thermodynamics. The topological index structural parameter JG and the topological index adjoining parameter LJ are put forward. Parameter J(G) describes the correlation of quantity and position of chlorine atoms in polychlorinated biphenyl (PCB) molecules. Parameter L(J) describes the ortho-position correlation of chlorine atoms in PCB molecules. The relational expression between the PCB molecular structures and their enthalpy change (deltaH), entropy change (deltaS') in chromatographic process was discovered. The values of enthalpy change and entropy change for about 140 kinds of polychlorinated biphenyls in chromatographic process on three stationary phases, DB-1, DB-5 and DB-1701, were determined. In comparison with deltaH and deltaS' of the experimental data those calculated from the relational expression had the average relative deviations for deltaH and deltaS' are 0.56% -0.97% and 0.55% - 1.06%, respectively.

  1. Performance evaluation of photonic Sigma Delta ADCS

    OpenAIRE

    Tan, Yean Wee

    2010-01-01

    Approved for public release; distribution is unlimited The integration of photonic and electronic components to realize a photonic sigma delta ADC is considered in this thesis. The integration process was broken up into steps. First, the performance of a pair of dual-port Mach-Zehnder interferometers (MZI) modulating a train of narrow high-speed laser pulses from a mode-locked laser was investigated. Various parameters like the half-wave voltage (V) and insertion loss were verified. Nex...

  2. Delta Greenbriar - Atlanta – (EE. UU.

    Directory of Open Access Journals (Sweden)

    Heery, George

    1975-05-01

    Full Text Available «Delta Greenbriar» is a corporate centre for the Delta air line company. The complex comprises four buildings containing: 1 the installations for flight simulation; 2 the air training base; 3 the control centre for flights and communications; 4 the department for tickets and reservations. They consist of one of two storeys. The lower ones can be extended both horizontally as well as vertically, whereas the other ones can only be enlarged in horizontal direction. The unit has been designed like a university campus, with patios, inner gardens and exterior corridors which apart from connecting the various buildings with each other also provide a close contact between the office premises and the park.El «Delta Greenbriar» es un centro corporativo para la compañía de líneas aéreas Delta. El complejo está constituido por cuatro edificios, que alojan: 1 las instalaciones para la simulación de vuelo; 2 la base de entrenamiento aéreo; 3 el centro de control de vuelo y comunicaciones; 4 el departamento de reservas y venta de billetes. Constan de una o dos plantas, pudiéndose ampliar los más bajos tanto horizontal como verticalmente, mientras que los otros sólo pueden aumentarse en sentido horizontal. El conjunto se ha diseñado como un campus universitario, con patios, ajardinamiento interior y corredores exteriores que, además de enlazar los distintos edificios entre sí, ponen en estrecha relación los espacios de oficinas con el parque.

  3. Mutations in GABRB3

    DEFF Research Database (Denmark)

    Møller, Rikke S; Wuttke, Thomas V; Helbig, Ingo

    2017-01-01

    OBJECTIVE: To examine the role of mutations in GABRB3 encoding the β3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. METHODS: We performed massive parallel sequencing...... of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. RESULTS: We identified 22 patients with heterozygous mutations in GABRB3, including 3...... probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies...

  4. AIP mutations and gigantism.

    Science.gov (United States)

    Rostomyan, Liliya; Potorac, Iulia; Beckers, Pablo; Daly, Adrian F; Beckers, Albert

    2017-06-01

    AIP mutations are rare in sporadic acromegaly but they are seen at a higher frequency among certain specific populations of pituitary adenoma patients (pituitary gigantism cases, familial isolated pituitary adenoma (FIPA) kindreds, and patients with macroadenomas who are diagnosed ≤30 years). AIP mutations are most prevalent in patients with pituitary gigantism (29% of this group were found to have mutations in AIP gene). These data support targeted genetic screening for AIP mutations/deletions in these groups of pituitary adenoma patients. Earlier diagnosis of AIP-related acromegaly-gigantism cases enables timely clinical evaluation and treatment, thereby improving outcomes in terms of excessive linear growth and acromegaly comorbidities. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Mapping Mutations on Phylogenies

    DEFF Research Database (Denmark)

    Nielsen, Rasmus

    2005-01-01

    This chapter provides a short review of recent methodologies developed for mapping mutations on phylogenies. Mapping of mutations, or character changes in general, using the maximum parsimony principle has been one of the most powerful tools in phylogenetics, and it has been used in a variety...... of different applications, for example, in the detection of correlated evolution and to identify selection acting on DNA sequences. However, many uses of parsimony mappings have been criticized because they focus on only one of many possible mappings and/or because they do not incorporate statistical...... uncertainty in the mapping. Recently developed probabilistic methods can incorporate statistical uncertainty in the character mappings. In these methods, focus is on a probability distribution of mutational mappings instead of a single estimate of the mutational mapping....

  6. Probing Delta structure with pion electromagnetic production

    CERN Document Server

    Yang, S N; Yang, Shin Nan

    2003-01-01

    The Dubna-Mainz-Taipei dynamical model for pion electromagnetic production, which can describe well the existing data from threshold up to 1 GeV photon lab energy, is presented and used to analyze the recent precision data in the $\\Delta$ region. We find that, within our model, the bare Delta is almost spherical while the physical Delta is oblate. The deformation is almost saturated by the pion cloud effects. We further find that up to Q^2 = 4.0 (GeV/c)^2, the extracted helicity amplitude A_{3/2} and A_{1/2} remain comparable with each other, implying that hadronic helicity is not conserved at this range of Q^2. The ratio E_{1+}/M_{1+} obtained show, starting from a small and negative value at the real photon point, a clear tendency to cross zero, and to become positive with increasing Q^2. This is a possible indication of a very slow approach toward the pQCD region. Finally, we find that the bare helicity amplitude A_{1/2} and S_{1/2}, but not A_{3/2}, starts exhibiting the scaling behavior at about Q^2 \\ge ...

  7. Evolution of Modern Yellow River Delta Coast

    Institute of Scientific and Technical Information of China (English)

    尹延鸿; 周永青; 丁东

    2004-01-01

    This paper deals with the development and evolution of modem Yellow River delta and the erosion or deposition rates of its different sections. In June, 1996,Yellow Rivers terminal course was artificially turned eastwards to empty into the sea and then the 11th lobe of the modern Yellow River delta began to form. This course change may mark the beginning of the 3rd subdelta formation. As a result of that, the Yellow River delta advances towards east by north with the 1st, 2nd and 3rd subdeltas arranged in succession. Coast zone in the deltaic area is divided into 7 different sections according to their different erosion or deposition rates: the relatively stable section from Dakou River to Shunjiang Stream, the weakly retreating section from Shun jiang Stream to the Tiaohe River mouth, the strongly retreating section from the Tiaohe River mouth to the station 106, the artificially stable section due to stone dam protection from the station 106 to Gudong Oilfield, the strong deposition section from Gudong Oilfield to Dawenliu Haipu, the weakly deposition section from Dawenliu Haipu to the Zimai Stream mouth, and the stable section from the Zimai Stream mouth to the Jiaolai River mouth. It is predicted that the erosion and deposition situations of the sections will nearly remain the same in 10 years, but the retreating and silting-up rates will tend to become slower gradually. Human activities have an evident influence on the changes of the coastline.

  8. GLOBAL CHARM OF THE CHANGJIANG RIVER DELTA

    Institute of Scientific and Technical Information of China (English)

    CHEN Shu-peng; ZHOU Cheng-hu; CHEN Qiu-xiao

    2003-01-01

    Based on the theory of geo-economy, under the new situation of global economy, information network and China's entry into WTO, also with the holding of APEC (in 2001) and the International Exposition in the near future, the Changjiang (Yangtze) River Delta is striding toward the spectacular international multi-polar situation and becomes one of core regions with high-speed development. Facing the ocean and world all along, leading the progressive tides of the age and scintillating the splendor of the nation, she does advance with time. Through a long period of irrigation projects construction and intensive operation of lands in previous agricultural society, the artificial wetland ecosystem with a positive cycle had ever been formed in this region. At present, environmental pollution and urban expansion resulted from post-industrialization are being rectified. The delta will be the paradigm of industrial and agricultural modernization along the sustainable development road. With the rapid development of urbanization,she has been one of the regions with the highest density population and high urbanization level. Taking the Changjiang River estuary and the Hangzhou Bay as two parts, she is continuously strengthening and adjusting her interiorstructure, expanding mothball space and constructing the oriental modern "logistics center" to link the whole world. The butterfly-style urban system of the Changjiang River Delta is flying, probably engendering earthshaking "butterfly effect".

  9. Delta: Data Reduction for Integrated Application Workflows.

    Energy Technology Data Exchange (ETDEWEB)

    Lofstead, Gerald Fredrick [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Jean-Baptiste, Gregory [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Oldfield, Ron A. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-06-01

    Integrated Application Workflows (IAWs) run multiple simulation workflow components con- currently on an HPC resource connecting these components using compute area resources and compensating for any performance or data processing rate mismatches. These IAWs require high frequency and high volume data transfers between compute nodes and staging area nodes during the lifetime of a large parallel computation. The available network band- width between the two areas may not be enough to efficiently support the data movement. As the processing power available to compute resources increases, the requirements for this data transfer will become more difficult to satisfy and perhaps will not be satisfiable at all since network capabilities are not expanding at a comparable rate. Furthermore, energy consumption in HPC environments is expected to grow by an order of magnitude as exas- cale systems become a reality. The energy cost of moving large amounts of data frequently will contribute to this issue. It is necessary to reduce the volume of data without reducing the quality of data when it is being processed and analyzed. Delta resolves the issue by addressing the lifetime data transfer operations. Delta removes subsequent identical copies of already transmitted data during transfers and restores those copies once the data has reached the destination. Delta is able to identify duplicated information and determine the most space efficient way to represent it. Initial tests show about 50% reduction in data movement while maintaining the same data quality and transmission frequency.

  10. Modelling repeatedly flaring delta-sunspots

    CERN Document Server

    Chatterjee, Piyali; Carlsson, Mats

    2016-01-01

    Active regions (AR) appearing on the surface of the Sun are classified into $\\alpha$, $\\beta$, $\\gamma$, and $\\delta$ by the rules of the Mount Wilson Observatory, California on the basis of their topological complexity. Amongst these, the $\\delta$-sunspots are known to be super-active and produce the most X-ray flares. Here, we present results from a simulation of the Sun by mimicking the upper layers and the corona, but starting at a more primitive stage than any earlier treatment. We find that this initial state consisting of only a thin sub-photospheric magnetic sheet breaks into multiple flux-tubes which evolve into a colliding-merging system of spots of opposite polarity upon surface emergence, similar to those often seen on the Sun. The simulation goes on to produce many exotic $\\delta$-sunspot associated phenomena: repeated flaring in the range of typical solar flare energy release and ejective helical flux ropes with embedded cool-dense plasma filaments resembling solar coronal mass ejections.

  11. Understanding delta-sigma data converters

    CERN Document Server

    Pavan, Shanti; Temes, Gabor C

    2017-01-01

    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...

  12. Non-native Conformers of Cystic Fibrosis Transmembrane Conductance Regulator NBD1 Are Recognized by Hsp27 and Conjugated to SUMO-2 for Degradation.

    Science.gov (United States)

    Gong, Xiaoyan; Ahner, Annette; Roldan, Ariel; Lukacs, Gergely L; Thibodeau, Patrick H; Frizzell, Raymond A

    2016-01-22

    A newly identified pathway for selective degradation of the common mutant of the cystic fibrosis transmembrane conductance regulator (CFTR), F508del, is initiated by binding of the small heat shock protein, Hsp27. Hsp27 collaborates with Ubc9, the E2 enzyme for protein SUMOylation, to selectively degrade F508del CFTR via the SUMO-targeted ubiquitin E3 ligase, RNF4 (RING finger protein 4) (1). Here, we ask what properties of CFTR are sensed by the Hsp27-Ubc9 pathway by examining the ability of NBD1 (locus of the F508del mutation) to mimic the disposal of full-length (FL) CFTR. Similar to FL CFTR, F508del NBD1 expression was reduced 50-60% by Hsp27; it interacted preferentially with the mutant and was modified primarily by SUMO-2. Mutation of the consensus SUMOylation site, Lys(447), obviated Hsp27-mediated F508del NBD1 SUMOylation and degradation. As for FL CFTR and NBD1 in vivo, SUMO modification using purified components in vitro was greater for F508del NBD1 versus WT and for the SUMO-2 paralog. Several findings indicated that Hsp27-Ubc9 targets the SUMOylation of a transitional, non-native conformation of F508del NBD1: (a) its modification decreased as [ATP] increased, reflecting stabilization of the nucleotide-binding domain by ligand binding; (b) a temperature-induced increase in intrinsic fluorescence, which reflects formation of a transitional NBD1 conformation, was followed by its SUMO modification; and (c) introduction of solubilizing or revertant mutations to stabilize F508del NBD1 reduced its SUMO modification. These findings indicate that the Hsp27-Ubc9 pathway recognizes a non-native conformation of mutant NBD1, which leads to its SUMO-2 conjugation and degradation by the ubiquitin-proteasome system.

  13. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1.

    Science.gov (United States)

    Ren, Hong Yu; Grove, Diane E; De La Rosa, Oxana; Houck, Scott A; Sopha, Pattarawut; Van Goor, Fredrick; Hoffman, Beth J; Cyr, Douglas M

    2013-10-01

    Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.

  14. Adaptive Delta Management: cultural aspects of dealing with uncertainty

    Science.gov (United States)

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

    2016-04-01

    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

  15. PRRT2 gene mutations

    Science.gov (United States)

    Gardiner, Alice R.; Bhatia, Kailash P.; Stamelou, Maria; Dale, Russell C.; Kurian, Manju A.; Schneider, Susanne A.; Wali, G.M.; Counihan, Tim; Schapira, Anthony H.; Spacey, Sian D.; Valente, Enza-Maria; Silveira-Moriyama, Laura; Teive, Hélio A.G.; Raskin, Salmo; Sander, Josemir W.; Lees, Andrew; Warner, Tom; Kullmann, Dimitri M.; Wood, Nicholas W.; Hanna, Michael

    2012-01-01

    ABSTRACT Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders. PMID:23077024

  16. On the determination of low-energy constants for {delta}S=1 transitions

    Energy Technology Data Exchange (ETDEWEB)

    Giusti, L.; Pena, C. [European Organization for Nuclear Research, Geneva (Switzerland); Hernandez, P. [Dpto. Fisica Teorica and IFIC, Edificio Institutos Investigacion, Valencia (Spain); Laine, M. [Bielefeld Univ. (Germany). Fakultaet fuer Physik; Wennekers, J.; Wittig, H. [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)

    2005-10-01

    We present our preliminary results for three-point correlation functions involving the operators entering the {delta}S=1 effective Hamiltonian with an active charm quark, obtained using overlap fermions in the quenched approximation. This is the first computation carried out for valence quark masses small enough so as to permit a matching to Quenched Chiral Perturbation Theory in the {epsilon}-regime. The commonly observed large statistical fluctuations are tamed by means of low-mode averaging techniques, combined with restrictions to individual topological sectors. We also discuss the matching of the resulting hadronic matrix elements to the effective low-energy constants for {delta}S=1 transitions. This involves (a) finite-volume corrections which can be evaluated at NLO in Quenched Chiral Perturbation Theory, and (b) the short-distance renormalization of the relevant four-quark operators in discretizations based on the overlap operator. We discuss perturbative estimates for the renormalization factors and possible strategies for their non-perturbative evaluation. Our results can be used to isolate the long-distance contributions to the {delta}I=1/2 rule, coming from physics effects around the intrinsic QCD scale. (orig.)

  17. Subquivers of mutation-acyclic quivers are mutation-acyclic

    CERN Document Server

    Warkentin, Matthias

    2011-01-01

    Quiver mutation plays a crucial role in the definition of cluster algebras by Fomin and Zelevinsky. It induces an equivalence relation on the set of all quivers without loops and two-cycles. A quiver is called mutation-acyclic if it is mutation-equivalent to an acyclic quiver. The aim of this note is to show that full subquivers of mutation-acyclic quivers are mutation-acyclic.

  18. The effect of the CCR5-delta32 deletion on global gene expression considering immune response and inflammation

    Directory of Open Access Journals (Sweden)

    Hütter Gero

    2011-10-01

    Full Text Available Abstract Background The natural function of the C-C chemokine receptor type 5 (CCR5 is poorly understood. A 32 base pair deletion in the CCR5 gene (CCR5-delta32 located on chromosome 3 results in a non-functional protein. It is supposed that this deletion causes an alteration in T-cell response to inflammation. For example, the presence of the CCR5-delta32 allele in recipients of allografts constitutes as an independent and protective factor associated with a decreased risk of graft-versus-host disease (GVHD and graft rejection. However, the mechanism of this beneficial effect of the deletion regarding GVHD is unknown. In this survey we searched for a CCR5-delta32 associated regulation of critical genes involved in the immune response and the development of GVHD. Methods We examined CD34+ hematopoietic progenitor cells derived from bone marrow samples from 19 healthy volunteers for the CCR5-delta32 deletion with a genomic PCR using primers flanking the site of the deletion. Results 12 individuals were found to be homozygous for CCR5 WT and 7 carried the CCR5-delta32 deletion heterozygously. Global gene expression analysis led to the identification of 11 differentially regulated genes. Six of them are connected with mechanisms of immune response and control: LRG1, CXCR2, CCRL2, CD6, CD7, WD repeat domain, and CD30L. Conclusions Our data indicate that the CCR5-delta32 mutation may be associated with differential gene expression. Some of these genes are critical for immune response, in the case of CD30L probably protective in terms of GVHD.

  19. Molecular basis of hereditary fructose intolerance in Italy: identification of two novel mutations in the aldolase B gene.

    Science.gov (United States)

    Santamaria, R; Tamasi, S; Del Piano, G; Sebastio, G; Andria, G; Borrone, C; Faldella, G; Izzo, P; Salvatore, F

    1996-09-01

    We screened the aldolase B gene in 14 unrelated Italian patients with hereditary fructose intolerance (HFI), and found two novel disease related mutations: a single nucleotide deletion in exon 2 (delta A20) that leads to an early stop codon, and a C-->T transition in exon 8 that substitutes an Arg with a Trp residue at codon 303 (R303W).

  20. Analysis, testing, and evaluation of faulted and unfaulted Wye, Delta, and open Delta connected electromechanical actuators

    Science.gov (United States)

    Nehl, T. W.; Demerdash, N. A.

    1983-07-01

    Mathematical models capable of simulating the transient, steady state, and faulted performance characteristics of various brushless dc machine-PSA (power switching assembly) configurations were developed. These systems are intended for possible future use as primemovers in EMAs (electromechanical actuators) for flight control applications. These machine-PSA configurations include wye, delta, and open-delta connected systems. The research performed under this contract was initially broken down into the following six tasks: development of mathematical models for various machine-PSA configurations; experimental validation of the model for failure modes; experimental validation of the mathematical model for shorted turn-failure modes; tradeoff study; and documentation of results and methodology.

  1. Positive influence of the Delta32CCR5 allele on response to highly active antiretroviral therapy (HAART) in HIV-1 infected patients.

    Science.gov (United States)

    Kasten, S; Goldwich, A; Schmitt, M; Rascu, A; Grunke, M; Dechant, C; Kalden, J R; Harrer, T

    2000-08-18

    The heterozygous 32 base pair deletion of the chemokine receptor 5 (Delta32CCR5) has been associated with a more benign course of HIV-1-infection. To study the influence of Delta32CCR5 on the response to antiviral therapy we analyzed the presence of Delta32CCR5 by PCR in PBMC from 107 randomly selected HIV-1-infected patients treated with HAART for at least three months. 24 of 107 patients were heterozygous for Delta32CCR5 (22.4%). Before initiation of HAART Delta32CCR5 heterozygous patients (d/w) did not differ from homozygous CCR5 wild-type patients (w/w) regarding viral load and CD4 counts. After a median treatment time on HAART of 17.5 months (d/w, range 6-31 months, p = n.s.) or 19 months (w/w, range 3-33 months) all 24 patients (100%) with the Delta32CCR5 mutation, but only 58/83 patients (69.9%) with wild-type CCR5 showed a suppression of HIV-1-viremia below 500 copies/ml (p = 0.0020). Furthermore, 20/24 (83.3%) of the Delta32CCR5 heterozygous patients achieved CD4 counts above 200/microliter, but only 57/83 (68.7%) of the patients homozygous for CCR5 wild-type (p = 0.011). Our data indicate that the presence of heterozygous Delta32CCR5 is associated with a better response to HAART suggesting that therapeutic strategies targeting CCR5 could be of value for a sustained suppression of HIV-1 by HAART.

  2. Mutational spectrum drives the rise of mutator bacteria.

    Directory of Open Access Journals (Sweden)

    Alejandro Couce

    Full Text Available Understanding how mutator strains emerge in bacterial populations is relevant both to evolutionary theory and to reduce the threat they pose in clinical settings. The rise of mutator alleles is understood as a result of their hitchhiking with linked beneficial mutations, although the factors that govern this process remain unclear. A prominent but underappreciated fact is that each mutator allele increases only a specific spectrum of mutational changes. This spectrum has been speculated to alter the distribution of fitness effects of beneficial mutations, potentially affecting hitchhiking. To study this possibility, we analyzed the fitness distribution of beneficial mutations generated from different mutator and wild-type Escherichia coli strains. Using antibiotic resistance as a model system, we show that mutational spectra can alter these distributions substantially, ultimately determining the competitive ability of each strain across environments. Computer simulation showed that the effect of mutational spectrum on hitchhiking dynamics follows a non-linear function, implying that even slight spectrum-dependent fitness differences are sufficient to alter mutator success frequency by several orders of magnitude. These results indicate an unanticipated central role for the mutational spectrum in the evolution of bacterial mutation rates. At a practical level, this study indicates that knowledge of the molecular details of resistance determinants is crucial for minimizing mutator evolution during antibiotic therapy.

  3. Tidal river dynamics: Implications for deltas

    Science.gov (United States)

    Hoitink, A. J. F.; Jay, D. A.

    2016-03-01

    Tidal rivers are a vital and little studied nexus between physical oceanography and hydrology. It is only in the last few decades that substantial research efforts have been focused on the interactions of river discharge with tidal waves and storm surges into regions beyond the limit of salinity intrusion, a realm that can extend inland hundreds of kilometers. One key phenomenon resulting from this interaction is the emergence of large fortnightly tides, which are forced long waves with amplitudes that may increase beyond the point where astronomical tides have become extinct. These can be larger than the linear tide itself at more landward locations, and they greatly influence tidal river water levels and wetland inundation. Exploration of the spectral redistribution and attenuation of tidal energy in rivers has led to new appreciation of a wide range of consequences for fluvial and coastal sedimentology, delta evolution, wetland conservation, and salinity intrusion under the influence of sea level rise and delta subsidence. Modern research aims at unifying traditional harmonic tidal analysis, nonparametric regression techniques, and the existing understanding of tidal hydrodynamics to better predict and model tidal river dynamics both in single-thread channels and in branching channel networks. In this context, this review summarizes results from field observations and modeling studies set in tidal river environments as diverse as the Amazon in Brazil, the Columbia, Fraser and Saint Lawrence in North America, the Yangtze and Pearl in China, and the Berau and Mahakam in Indonesia. A description of state-of-the-art methods for a comprehensive analysis of water levels, wave propagation, discharges, and inundation extent in tidal rivers is provided. Implications for lowland river deltas are also discussed in terms of sedimentary deposits, channel bifurcation, avulsion, and salinity intrusion, addressing contemporary research challenges.

  4. THE RURAL TOURISM IN DANUBE DELTA

    Directory of Open Access Journals (Sweden)

    Ionica SOARE

    2014-06-01

    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.

  5. Delta Shell: Integrated Modeling by Example

    Science.gov (United States)

    Donchyts, G.; Jagers, B.; Baart, F.; Geer, P. V.

    2011-12-01

    We present the integrated modeling environment Delta Shell. It supports the full workflow of integrated environmental modeling: setup, configuration, simulation, analysis and reporting of results. Many components of the environment can be reused independently, allowing development of scientific, geospatial and other applications focused on data analysis, editing, visualization and storage. One of the unique features is that the Delta Shell environment integrates models from many different fields, such as hydrodynamics, hydrology, morphology, ecology, water quality, geospatial and decision support systems. This integration is possible due to flexible general data types, lightweight model coupling framework, the plugin system and the inclusion of a number of high quality open source components. Here we will use the open source morphological model XBeach as an example showing how to integrate models into the Delta Shell environment. Integration of XBeach adds a graphical interface which can be used to make testing coastal safety for complicated coastal areas easier. By using this example, we give an overview of the modeling framework and its possibilities. To increase the usability, the model is integrated with a coastal profile data set covering the whole coast of the Netherlands. This gives the end user a system to easily use the model for scanning the safety of the Dutch coast. The reuse of the components of the environment individually or combined is encouraged. They are available as separate components and have minimal or no dependencies on other components. This includes libraries to work with scientific multidimensional data, geospatial data (in particular geospatial coverages: values of some quantities defined on a spatial domain), editors, visualisation of time-dependent data and the modeling framework (projects, data linking, workflow management, model integration). Most components and the XBeach example are available as open source.

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

    CERN Document Server

    Wilcox, Bethany R

    2015-01-01

    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 c...

  7. Compositeness of the Delta(1232) resonance in pi N scattering

    CERN Document Server

    Sekihara, Takayasu; Yamagata-Sekihara, Junko; Yasui, Shigehiro

    2015-01-01

    We evaluate the $\\pi N$ compositeness of the $\\Delta (1232)$ resonance so as to clarify the internal structure of $\\Delta (1232)$ in terms of the $\\pi N$ component. Here the compositeness is defined as contributions from two-body wave functions to the normalization of the total wave function and is extracted from the $\\pi N$ scattering amplitude. In this study we employ the chiral unitary approach with the interaction up to the next-to-leading order plus a bare $\\Delta$ term in chiral perturbation theory and describe $\\Delta (1232)$ in an elastic $\\pi N$ scattering. Fitting the $\\pi N$ scattering amplitude to the solution of the partial wave analysis, we obtain a large real part of the $\\pi N$ compositeness for $\\Delta (1232)$ comparable to unity and non-negligible imaginary part as well, with which we reconfirm the result in the previous study on the $\\pi N$ compositeness for $\\Delta (1232)$.

  8. Monitoring the Polarimetric Variability of \\delta\\ Scorpii

    CERN Document Server

    Bednarski, Daniel

    2012-01-01

    The Be star \\delta\\ Scorpii is an interesting binary system, whose primary companion created a circumstellar disk after the periastron passage of the secondary in 2000, being since then classified as Be. This work presents the results of a long-term monitoring of this star in broad-band imaging polarimetry. The observational data collected since 2006 in the Pico dos Dias Observatory (Brazil) show a variable polarization that seems to correlate with the photometric light curve. From this data we see that the disk density varied since 2006; furthermore, the data suggests that there was some disturbance of the disk during the last periastron passage in July, 2011.

  9. Error Minimization of Polynomial Approximation of Delta

    Indian Academy of Sciences (India)

    Islam Sana; Sadiq Muhammad; Qureshi Muhammad Shahid

    2008-09-01

    The difference between Universal time (UT) and Dynamical time (TD), known as Delta ( ) is tabulated for the first day of each year in the Astronomical Almanac. During the last four centuries it is found that there are large differences between its values for two consecutive years. Polynomial approximations have been developed to obtain the values of for any time of a year for the period AD 1620 to AD 2000 (Meeu 2000) as no dynamical theories describe the variations in . In this work, a new set of polynomials for is obtained for the period AD 1620 to AD 2007 that is found to produce better results compared to previous attempts.

  10. International Financial Centers Delta in China

    Institute of Scientific and Technical Information of China (English)

    Emily Yu

    2009-01-01

    @@ It has called a lot of attention tnat China should build a pattern of International Financial Centers Delta:Make Beijing the centre of International Finance Management and Cooperation,working as the management and cooperation base and headquarter for China's participation in the iriternational Financial competition;Make Shanghai the centre of International Finance Market.working as the main battlefield of China's participation in international financial competition;Make Hong Kong the centre of Intemational Finance Open and Innovation,working as the frontier of China's participation in international financial competition.

  11. Hepatitis Delta Virus: A Peculiar Virus

    OpenAIRE

    Carolina Alves; Cristina Branco; Celso Cunha

    2013-01-01

    The hepatitis delta virus (HDV) is distributed worldwide and related to the most severe form of viral hepatitis. HDV is a satellite RNA virus dependent on hepatitis B surface antigens to assemble its envelope and thus form new virions and propagate infection. HDV has a small 1.7 Kb genome making it the smallest known human virus. This deceivingly simple virus has unique biological features and many aspects of its life cycle remain elusive. The present review endeavors to gather the available ...

  12. Stratigraphy and Evolution of Delta Channel Deposits, Jezero Crater, Mars

    Science.gov (United States)

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

    2017-01-01

    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.

  13. Delta Doping High Purity CCDs and CMOS for LSST

    Science.gov (United States)

    Blacksberg, Jordana; Nikzad, Shouleh; Hoenk, Michael; Elliott, S. Tom; Bebek, Chris; Holland, Steve; Kolbe, Bill

    2006-01-01

    A viewgraph presentation describing delta doping high purity CCD's and CMOS for LSST is shown. The topics include: 1) Overview of JPL s versatile back-surface process for CCDs and CMOS; 2) Application to SNAP and ORION missions; 3) Delta doping as a back-surface electrode for fully depleted LBNL CCDs; 4) Delta doping high purity CCDs for SNAP and ORION; 5) JPL CMP thinning process development; and 6) Antireflection coating process development.

  14. Silting mutation in triangulated categories

    CERN Document Server

    Aihara, Takuma

    2010-01-01

    In representation theory of algebras the notion of `mutation' often plays important roles, and two cases are well known, i.e. `cluster tilting mutation' and `exceptional mutation'. In this paper we focus on `tilting mutation', which has a disadvantage that it is often impossible, i.e. some of summands of a tilting object can not be replaced to get a new tilting object. The aim of this paper is to take away this disadvantage by introducing `silting mutation' for silting objects as a generalization of `tilting mutation'. We shall develope a basic theory of silting mutation. In particular, we introduce a partial order on the set of silting objects and establish the relationship with `silting mutation' by generalizing the theory of Riedmann-Schofield and Happel-Unger. We show that iterated silting mutation act transitively on the set of silting objects for local, hereditary or canonical algebras. Finally we give a bijection between silting subcategories and certain t-structures.

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

    Index Scriptorium Estoniae

    Mutso, Margit, 1966-

    2010-01-01

    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

  16. Global Heat Kernel Estimates for $\\Delta+\\Delta^{\\alpha/2}$ in Half-space-like domains

    CERN Document Server

    Chen, Zhen-Qing; Song, Renming

    2011-01-01

    Suppose that $d\\ge 1$ and $\\alpha\\in (0, 2)$. In this paper, by using probabilistic methods, we establish sharp two-sided pointwise estimates for the Dirichlet heat kernels of $\\{\\Delta+ a^\\alpha \\Delta^{\\alpha/2}; \\ a\\in (0, 1]\\}$ on half-space-like $C^{1, 1}$ domains in ${\\mathbb R}^d$ for all time $t>0$. The large time estimates for half-space-like domains are very different from those for bounded domains. Our estimates are uniform in $a \\in (0, 1]$ in the sense that the constants in the estimates are independent of $a\\in (0, 1]$. Thus it yields the Dirichlet heat kernel estimates for Brownian motion in half-space-like domains by taking $a\\to 0$. Integrating the heat kernel estimates in time $t$, we obtain uniform sharp two-sided estimates for the Green functions of $\\{\\Delta+ a^\\alpha \\Delta^{\\alpha/2}; \\ a\\in (0, 1]\\}$ in half-space-like $C^{1, 1}$ domains in ${\\mathbb R}^d$.

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

    Index Scriptorium Estoniae

    Mutso, Margit, 1966-

    2010-01-01

    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

  18. MUTATIONS IN CALMODULIN GENES

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to an isolated polynucleotide encoding at least a part of calmodulin and an isolated polypeptide comprising at least a part of a calmodulin protein, wherein the polynucleotide and the polypeptide comprise at least one mutation associated with a cardiac disorder. The ...... the binding of calmodulin to ryanodine receptor 2 and use of such compound in a treatment of an individual having a cardiac disorder. The invention further provides a kit that can be used to detect specific mutations in calmodulin encoding genes....

  19. MUTATIONS IN CALMODULIN GENES

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to an isolated polynucleotide encoding at least a part of calmodulin and an isolated polypeptide comprising at least a part of a calmodulin protein, wherein the polynucleotide and the polypeptide comprise at least one mutation associated with a cardiac disorder...... the binding of calmodulin to ryanodine receptor 2 and use of such compound in a treatment of an individual having a cardiac disorder. The invention further provides a kit that can be used to detect specific mutations in calmodulin encoding genes....

  20. Are There Mutator Polymerases?

    Directory of Open Access Journals (Sweden)

    Miguel Garcia-Diaz

    2003-01-01

    Full Text Available DNA polymerases are involved in different cellular events, including genome replication and DNA repair. In the last few years, a large number of novel DNA polymerases have been discovered, and the biochemical analysis of their properties has revealed a long list of intriguing features. Some of these polymerases have a very low fidelity and have been suggested to play mutator roles in different processes, like translesion synthesis or somatic hypermutation. The current view of these processes is reviewed, and the current understanding of DNA polymerases and their role as mutator enzymes is discussed.

  1. Hydraulic Geometry of a tidally influenced delta channel network: the Mahakam Delta, East Kalimantan, Indonesia

    Science.gov (United States)

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

    2011-12-01

    Hydraulic Geometry (HG) refers to relations between the characteristics of channels in a network, including mean depth, width, and bed slope, and the discharge conveyed by the channel during bank-full conditions. HG relations are of fundamental importance to water management in channel networks, and they bear an interesting relation with geomorphology. River delta channel networks typically scale according to HG relations such as log(A) ~ p*log(Q), where A is channel cross sectional area, Q water discharge, and the exponent p is in between 0.8 and 1.2. In tidal networks, the tidal prism or tidal discharge can be used, instead of a discharge with a constant frequency of occurrence. In the tidal case, the exponent often shows the same range of variation. Tidal rivers are intrinsically complex, as tidal propagation is influenced by river discharge and vice-versa. Consequently, channel geometry in tidally influenced river deltas may show a mixed scaling behavior of river and tidal channel networks, as the channel forming discharges may both be of river and tidal origin. In tidal regions, the tidal dynamics may lead to a cyclic variation in water discharge distribution at bifurcations, readily affecting HG relations. We present results from the Mahakam delta channel network in Indonesia, a tide-river dominated delta which has been prograding for 60 km over the last 5000 years. Bathymetric surveys were conducted over the distributary network and connected tidal channels. Based on a geomorphic analysis of the present distributary network, we show that channel geometry of the fluvial distributary network scales with bifurcation order. The bifurcation order does not feature a clear relation with bifurcate branch length or bifurcate width ratio, as in the case of river deltas. HG relations of the area of selected cross-sections are well represented by the tidal prism or by the river discharge, when scaled with the bifurcation order. Numerical simulations show that river

  2. QCD corrections to inclusive $\\Delta S=1,2$ transitions

    OpenAIRE

    Jamin, Matthias

    1994-01-01

    The talk summarises a calculation of the two-point functions for $\\Delta S=1$ current-current and QCD-penguin operators, as well as for the $\\Delta S=2$ operator, at the next-to-leading order. The size of the gluonic corrections to current-current operators is large, providing a qualitative understanding of the observed enhancement in $\\Delta I=1/2$ transitions. In the $\\Delta S=2$ sector the QCD corrections are quite moderate ($\\approx -20\\%$). This work has been done in collaboration with A...

  3. [A study of 158 cases of acute delta hepatitis].

    Science.gov (United States)

    Castro, A; Buti, M; Esteban, R; Jardí, R; Allende, H; Roget, M; Rodríguez-Frías, F; Guardia, J

    1990-09-22

    We have prospectively studied 158 cases of acute hepatitis delta observed during the last 7 years in a general hospital. Among them 136 were male and 22 female. The mean age was 22.7 years with a range between 16 and 61 years. The epidemiologic factors were drug addiction by parenteral route in 145 cases (92%), sexual transmission in 5 (3%), post transfusional in 2 (1%) and unknown in 6 (4%). With respect to the delta type infection, 105 cases (66%) were coinfections with type B and delta, and 53 patients had a type delta superinfection (34%). The clinical course was a fulminant hepatitis in three cases (two cases of coinfection B and delta an one case of delta superinfection), and an acute benign hepatitis in 155 patients. The follow-up of 118 patients revealed that 96% of coinfections by type B and delta evolved to the chronicity showing findings of active chronic hepatitis or hepatic cirrhosis. It should be noted that in 4 cases of superinfection delta type (11%) the HBsAg was negative after several months of positivity. In these patients the level of transaminases normalized and the hepatic histology evidenced alterations of chronic active hepatitis (2 cases) and hepatic cirrhosis (2 cases) without identification of tissular delta antigen.

  4. A global analysis of human habitation on river deltas

    Science.gov (United States)

    Edmonds, Douglas; Caldwell, Rebecca; Baumgardner, Sarah; Paola, Chris; Roy, Samapriya; Nelson, Amelia; Nienhuis, Jaap

    2017-04-01

    River deltas are ideal sites for human habitation because of their fertile floodplains, easy access to the ocean, and abundant land. But anthropogenic and natural processes are causing deltas to sink, which increases the probability of coastal flooding and human exposure to risk. The full extent of the risk posed to humans is unclear because the number of people living on river deltas is unknown. Towards this end we mapped the locations and areas of all deltas in the world (n= 1813). Using Google Earth we identified all river mouths (≥ 50 m wide) on marine coastlines that are also connected to an upstream catchment. Rivers that split into two or more active or relict distributary channels, end in a depositional protrusion from the shoreline, or do both, are defined as deltas. The depositional protrusion and distributary channel network define the geomorphic area of each delta. We mark the position of the delta apex at the first bifurcation, or for a single channel delta at the intersection of the regional shoreline and the main channel. We mark three lateral extents, one on either side of the main channel at the maximum displacement of the depositional protrusion or the distributary network, and one on the most basinward position of the delta. We define delta area as the convex hull around these extent points and the delta apex. For each delta area polygon we extract elevation from the Shuttle Radar Topography Mission dataset and population count in years 2000, 2005, 2010, 2015, and 2020 from Gridded Population of the World, version 4. In total, deltas cover 0.56% of the total area of the world yet contain 4.1% of the world's population. The population on deltas has grown from 237 million in 2000 to projected values of 322 million in 2020. Deltaic population is growing at 1.59% per year, which outpaces the world growth rate of 1.11%. Additionally, population density is increasing with time from 322 people per km2 in year 2000 to projected values of 422 people per

  5. Superconducting bandpass delta-sigma modulator

    Science.gov (United States)

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

    1999-11-01

    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.

  6. Superconducting bandpass delta-sigma modulator

    Energy Technology Data Exchange (ETDEWEB)

    Bulzacchelli, J.F.; Lee, H.-S. [Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Misewich, J.A.; Ketchen, M.B. [IBM Research Division, T. J. Watson Research Center, Yorktown Heights, NY 10598 (United States)

    1999-11-01

    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)

  7. Characteristics of the somatic hypermutation in the Camelus dromedarius T cell receptor gamma (TRG) and delta (TRD) variable domains.

    Science.gov (United States)

    Ciccarese, Salvatrice; Vaccarelli, Giovanna; Lefranc, Marie-Paule; Tasco, Gianluca; Consiglio, Arianna; Casadio, Rita; Linguiti, Giovanna; Antonacci, Rachele

    2014-10-01

    In previous reports, we had shown in Camelus dromedarius that diversity in T cell receptor gamma (TRG) and delta (TRD) variable domains can be generated by somatic hypermutation (SHM). In the present paper, we further the previous finding by analyzing 85 unique spleen cDNA sequences encoding a total of 331 mutations from a single animal, and comparing the properties of the mutation profiles of dromedary TRG and TRD variable domains. The transition preference and the significant mutation frequency in the AID motifs (dgyw/wrch and wa/tw) demonstrate a strong dependence of the enzymes mediating SHM in TRG and TRD genes of dromedary similar to that of immunoglobulin genes in mammals. Overall, results reveal no asymmetry in the motifs targeting, i.e. mutations are equally distributed among g:c and a:t base pairs and replacement mutations are favored at the AID motifs, whereas neutral mutations appear to be more prone to accumulate in bases outside of the motifs. A detailed analysis of clonal lineages in TRG and TRD cDNA sequences also suggests that clonal expansion of mutated productive rearrangements may be crucial in shaping the somatic diversification in the dromedary. This is confirmed by the fact that our structural models, computed by adopting a comparative procedure, are consistent with the possibility that, irrespective of where (in the CDR-IMGT or in FR-IMGT) the diversity was generated by mutations, both clonal expansion and selection seem to be strictly related to an enhanced structural stability of the γδ subunits.

  8. Catalyzing action towards the sustainability of deltas: deltas as integrated socio-ecological systems and sentinels of regional and global change

    Science.gov (United States)

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

    2016-12-01

    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.

  9. Semi-automated, reverse-hybridization detection of multiple mutations causing hereditary fructose intolerance.

    Science.gov (United States)

    Kriegshäuser, Gernot; Halsall, David; Rauscher, Bettina; Oberkanins, Christian

    2007-06-01

    Hereditary fructose intolerance (HFI) is a potentially fatal nutritional disease that is caused by mutations in the liver isoenzyme of fructoaldolase (aldolase B). Our aim was to evaluate a diagnostic assay capable of simultaneously analyzing three-point mutations and a small deletion in the aldolase B (ALDOB) gene. The test under investigation is based on multiplex DNA amplification and hybridization to membrane strips presenting a parallel array of allele-specific oligonucleotide probes. We used the novel reverse-hybridization (RH) protocol to analyze 54 individuals previously genotyped by direct sequencing. RH genotyping for ALDOB mutations Delta4E4, A149P, A174D, and N334K was in complete concordance with results obtained by DNA sequencing. The procedure is rapid (<6h) and may be automated to a large extent. The RH assay tested in this study represents an accurate and robust screening tool to identify common ALDOB mutations.

  10. Msx1 Mutations

    Science.gov (United States)

    Wang, Y.; Kong, H.; Mues, G.; D’Souza, R.

    2011-01-01

    Mutations in the transcription factors PAX9 and MSX1 cause selective tooth agenesis in humans. In tooth bud mesenchyme of mice, both proteins are required for the expression of Bmp4, which is the key signaling factor for progression to the next step of tooth development. We have previously shown that Pax9 can transactivate a 2.4-kb Bmp4 promoter construct, and that most tooth-agenesis-causing PAX9 mutations impair DNA binding and Bmp4 promoter activation. We also found that Msx1 by itself represses transcription from this proximal Bmp4 promoter, and that, in combination with Pax9, it acts as a potentiator of Pax9-induced Bmp4 transactivation. This synergism of Msx1 with Pax9 is significant, because it is currently the only documented mechanism for Msx1-mediated activation of Bmp4. In this study, we investigated whether the 5 known tooth-agenesis-causing MSX1 missense mutations disrupt this Pax9-potentiation effect, or if they lead to deficiencies in protein stability, protein-protein interactions, nuclear translocation, and DNA-binding. We found that none of the studied molecular mechanisms yielded a satisfactory explanation for the pathogenic effects of the Msx1 mutations, calling for an entirely different approach to the investigation of this step of odontogenesis on the molecular level. PMID:21297014

  11. delta13C and delta18O trends across overstory environments in whole foliage and cellulose of three Pinus species.

    Science.gov (United States)

    Powers, Matthew D; Pregitzer, Kurt S; Palik, Brian J

    2008-09-01

    Stable isotope ratios of carbon (delta(13)C) and oxygen (delta(18)O) are increasingly used to investigate environmental influences on plant physiology. Cellulose is often isolated for isotopic studies, but some authors have questioned the value of this process. We studied trends in delta(13)C and delta(18)O of whole foliage and holocellulose from seedlings of three Pinus species across three overstory environments to evaluate the benefits of holocellulose extraction in the context of a traditional ecological experiment. Both tissue types showed increasing delta(13)C from closed-canopy controls to thinned plots to 0.3 ha canopy gaps, and no change in delta(18)O between overstory environments. delta(13)C of P. resinosa and P. strobus was greater than delta(13)C of P. banksiana in whole foliage and holocellulose samples, and there were no differences in delta(18)O associated with species in either tissue type. Our results suggest whole foliage and holocellulose provide similar information about isotopic trends across broad environmental gradients and between species, but holocellulose may be better suited for studying differences in stable isotope composition between multiple species across several treatments.

  12. Multidecadal Fluvial Sediment Fluxes to Deltas under Environmental Change Scenarios

    Science.gov (United States)

    Dunn, Frances; Darby, Stephen; Nicholls, Robert

    2016-04-01

    Sediment delivery is vital to sustain delta environments on which over half a billion people live worldwide. Due to factors such as subsidence and sea level rise, deltas sink relative to sea level if sediment is not delivered to and retained on their surfaces. Deltas which sink relative to sea level experience flooding, land degradation and loss, which endangers anthropogenic activities and populations. The future of fluvial sediment fluxes, a key mechanism for sediment delivery to deltas, is uncertain due to complex environmental changes which are predicted to occur over the coming decades. This research investigates fluvial sediment fluxes under environmental changes in order to assess the sustainability of delta environments under potential future scenarios up to 2100. Global datasets of climate change, reservoir construction, and population and GDP as proxies for anthropogenic influence through land use changes are used to drive the catchment numerical model WBMsed, which is being used to investigate the effects of these environmental changes on fluvial sediment delivery. This process produces fluvial sediment fluxes under multiple future scenarios which will be used to assess the future sustainability of a selection of 8 vulnerable deltas, although the approach can be applied to deltas worldwide. By modelling potential future scenarios of fluvial sediment flux, this research contributes to the prognosis for delta environments. The future scenarios will inform management at multiple temporal scales, and indicate the potential consequences for deltas of various anthropogenic activities. This research will both forewarn managers of potentially unsustainable deltas and indicate those anthropogenic activities which encourage or hinder the creation of sustainable delta environments.

  13. No muscle involvement in myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations1

    DEFF Research Database (Denmark)

    Hjermind, L.E.; Vissing, J.; Asmus, F.;

    2008-01-01

    Mutations in the epsilon-sarcoglycan gene (SGCE) can cause autosomal dominant inherited myoclonus-dystonia (M-D). Defects in other sarcoglycans; alpha-, beta-, gamma-, and delta can cause autosomal recessive inherited limb girdle muscular dystrophies. epsilon- and alpha-sarcoglycans are very...... homologous and may substitute for one-another in different tissues. We therefore investigated whether mutations in SGCE also cause abnormalities of skeletal and myocardial muscle. Six patients with clinically and genetically verified M-D and no signs of limb-girdle muscular dystrophy were included. Skeletal...

  14. Mutations in galactosemia

    Energy Technology Data Exchange (ETDEWEB)

    Reichardt, J.K.V. [Univ. of Southern California School of Medicine, Los Angeles, CA (United States)

    1995-10-01

    This Letter raises four issues concerning two papers on galactosemia published in the March 1995 of the Journal. First, table 2 in the paper by Elsas et al. incorrectly attributes seven galactose-l-phosphate uridyl transferase (GALT) mutations (S135L, L195P, K285N, N314D, R333W, R333G, and K334R). The table also fails to mention that others have reported the same two findings attributed to {open_quotes}Leslie et al.; Elsas et al. and in press{close_quotes} and {open_quotes}Leslie et al.; Elsas et al.{close_quotes} The first finding on the prevalence of the Q188R galactosemia mutation in the G/G Caucasian population has also been described by Ng et al., and the second finding on the correlation of the N314D GALT mutation with the Duarte variant was reported by Lin et al. Second, Elsas et al. suggest that the E203K and N314D mutations may {open_quotes}produce intra-allelic complementation when in cis{close_quotes}. This speculation is supported by the activity data of individual III-2 but is inconsistent with the activities of three other individuals I-1, II-1, and III-1 of the same pedigree. The GALT activity measured in these three individuals suggests a dominant negative effect of E203K in E203K-N314D chromosomes, since they all have less than normal activity. Thus, the preponderance of the data in this paper is at odds with the authors speculation. It is worth recalling that Lin et al. also identified four N314D GALT mutations on 95 galactosemic chromosomes examined. A similar situation also appears to be the case in proband III-1 (with genotype E203K-N314D/IVSC) in the Elsas et al. paper. 9 refs.

  15. Identification of CANT1 Mutations in Desbuquois Dysplasia

    Science.gov (United States)

    Huber, Céline; Oulès, Bénédicte; Bertoli, Marta; Chami, Mounia; Fradin, Mélanie; Alanay, Yasemin; Al-Gazali, Lihadh I.; Ausems, Margreet G.E.M.; Bitoun, Pierre; Cavalcanti, Denise P.; Krebs, Alexander; Le Merrer, Martine; Mortier, Geert; Shafeghati, Yousef; Superti-Furga, Andrea; Robertson, Stephen P.; Le Goff, Carine; Muda, Andrea Onetti; Paterlini-Bréchot, Patrizia; Munnich, Arnold; Cormier-Daire, Valérie

    2009-01-01

    Desbuquois dysplasia is a severe condition characterized by short stature, joint laxity, scoliosis, and advanced carpal ossification with a delta phalanx. Studying nine Desbuquois families, we identified seven distinct mutations in the Calcium-Activated Nucleotidase 1 gene (CANT1), which encodes a soluble UDP-preferring nucleotidase belonging to the apyrase family. Among the seven mutations, four were nonsense mutations (Del 5′ UTR and exon 1, p.P245RfsX3, p.S303AfsX20, and p.W125X), and three were missense mutations (p.R300C, p.R300H, and p.P299L) responsible for the change of conserved amino acids located in the seventh nucleotidase conserved region (NRC). The arginine substitution at position 300 was identified in five out of nine families. The specific function of CANT1 is as yet unknown, but its substrates are involved in several major signaling functions, including Ca2+ release, through activation of pyrimidinergic signaling. Importantly, using RT-PCR analysis, we observed a specific expression in chondrocytes. We also found electron-dense material within distended rough endoplasmic reticulum in the fibroblasts of Desbuquois patients. Our findings demonstrate the specific involvement of a nucleotidase in the endochondral ossification process. PMID:19853239

  16. Evolutionary Stability Against Multiple Mutations

    CERN Document Server

    Ghatak, Anirban; Shaiju, A J

    2012-01-01

    It is known (see e.g. Weibull (1995)) that ESS is not robust against multiple mutations. In this article, we introduce robustness against multiple mutations and study some equivalent formulations and consequences.

  17. BRAF mutations in conjunctival melanoma

    DEFF Research Database (Denmark)

    Larsen, Ann-Cathrine; Dahl, Christina; Dahmcke, Christina M.

    2016-01-01

    Purpose: To investigate incidence, clinicopathological features and prognosis of BRAF-mutated conjunctival melanoma in Denmark. Furthermore, to determine BRAF mutations in paired premalignant lesions and evaluate immunohistochemical BRAF V600E oncoprotein detection. Methods: Data from 139 patients...

  18. Delta-doping in diffusion studies

    Science.gov (United States)

    Bénière, François; Chaplain, René; Gauneau, Marcel; Reddy, Viswanatha; Régrény, André

    1993-12-01

    The δ-doping where the dopant is confined on the length-scale of the lattice constant provides perfectly ideal conditions to study the atomic transport processes. We have studied MBE-grown GaAs samples δ-doped with Si and Al layers. Long time diffusion anneals have been performed in the temperature range 550 800 °C. The distribution profiles are examined by SIMS-profiling. We obtain Si diffusion coefficients in good agreement with the other recent studies using different techniques (rapid thermal annealing, capacitance-voltage profiling, sandwiched diffusion source). This contrasts with the earlier measurements based on diffusion of implanted dopants which were much more widely spread. We conclude that the more accurate data allowed with the δ-doping show that the diffusion coefficient is an intrinsic parameter provided that the amount of dopant and the dislocation density are kept sufficiently small. Le dopage-delta, où le dopant est confiné à l'échelle du paramètre du réseau, fournit les conditions parfaitement idéales pour étudier les processus de transport atomique. Nous avons étudié des échantillons de GaAs obtenus par épitaxie par jet moléculaire dopés par des couches-delta de Si et Al. Des traitements de diffusion de longue durée ont été réalisés dans l'intervalle de température 550 à 800°C. Les profils de distribution sont examinés par spectrométrie d'émission d'ions secondaires. Nous obtenons des coefficients de diffusion de Si en bon accord avec les autres études récentes utilisant des techniques différentes (traitement thermique ultrarapide, profil de distribution par la méthode capacité-voltage, diffusion d'une couche “ sandwich ”). Ceci diffère des mesures antérieures qui, basées sur la diffusion de dopants implantés, étaient beaucoup plus dispersées. Nous concluons que les données plus précises rendues possibles par le dopage-delta montrent que le coefficient de diffusion est un paramètre intrinsèque

  19. A NOTE ON DELTA-PERTURBATION EXPANSION METHOD

    Institute of Scientific and Technical Information of China (English)

    何吉欢

    2002-01-01

    The Delta-perturbation expansion method, a kind of new perturbation technique depending upon an artificial parameter Delta was studied. The study reveals that the method exits some advantages, but also exits some limitations. To overcome the limitations, the socalled linearized perturbation method proposed by HE Ji-huan can be powerfully applied.

  20. Automatisierte VHDL-Code-Generierung eines Delta-Sigma Modulators

    Science.gov (United States)

    Spilka, R.; Ostermann, T.

    2006-09-01

    Im vorliegenden Beitrag wird eine automatische Generierung des VHDL-Codes eines Delta-Sigma Modulators präsentiert. Die Koeffizientenmultiplikation wird hierbei durch Bit-Serielle-Addition durchgeführt. Mit Hilfe zweier neuer Matlab Funktionen wird der Systementwurf durch die bekannte Delta-Sigma Toolbox von R. Schreier erweitert und direkt synthesefähiger VHDL Code erzeugt.

  1. A BRITE view on delta Scuti and gamma Doradus stars

    CERN Document Server

    Zwintz, Konstanze

    2016-01-01

    BRITE-Constellation has obtained data for a few delta Scuti and gamma Doradus type stars. A short overview of the pulsational content found in five stars - beta Cassiopeiae, epsilon Cephei, M Velorum, beta Pictoris and QW Puppis - is given and the potential of BRITE-Constellation observations of delta Scuti and gamma Doradus pulsators is discussed.

  2. Terahertz radiation from delta-doped GaAs

    DEFF Research Database (Denmark)

    Birkedal, Dan; Hansen, Ole; Sørensen, Claus Birger;

    1994-01-01

    Terahertz pulse emission from four different delta-doped molecular beam epitaxially grown GaAs samples is studied. We observe a decrease of the emitted THz pulse amplitude as the distance of the delta-doped layer from the surface is increased, and a change in polarity of the THz pulses as compared...

  3. Women in Leadership Roles in Phi Delta Kappa.

    Science.gov (United States)

    Harder, Martha B.; And Others

    The professional and personal characteristics of the men and women in Phi Delta Kappa who hold the top elected positions in local chapters were compared, and the perceptions of these leaders of the impact of allowing women to be members of Phi Delta Kappa were assessed. A 43-item questionnaire was developed and mailed to 1,340 chapter presidents…

  4. Downstream hydraulic geometry of a tidally influenced river delta

    NARCIS (Netherlands)

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

    2012-01-01

    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 extendin

  5. Towards a Comprehensive Framework for Adaptive Delta Management

    NARCIS (Netherlands)

    Marchand, M.; Ludwig, F.

    2014-01-01

    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

  6. Delta's paradise: a challenge for lan[d]scape architects

    NARCIS (Netherlands)

    Boekhorst, te J.K.M.; Toorn, van den M.W.M.

    1996-01-01

    Paradise as a metaphor has always played an important role in art. This is definitely true for the art of garden design, but paradise is also a metaphor that can be used for the landscape. Some of the most interesting landscapes are found in deltas. Deltas are rich in natural and economic potential.

  7. Towards a Comprehensive Framework for Adaptive Delta Management

    NARCIS (Netherlands)

    Marchand, M.; Ludwig, F.

    2014-01-01

    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 econom

  8. An annotated list of Fishes from the Niger Delta

    NARCIS (Netherlands)

    Boeseman, M.

    1963-01-01

    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

  9. Delta's paradise: a challenge for lan[d]scape architects

    NARCIS (Netherlands)

    te Boekhorst, J.K.M.; Toorn, van den M.W.M.

    1996-01-01

    Paradise as a metaphor has always played an important role in art. This is definitely true for the art of garden design, but paradise is also a metaphor that can be used for the landscape. Some of the most interesting landscapes are found in deltas. Deltas are rich in natural and economic potential.

  10. Emerging leadership from communities in the Lower Mississippi Delta (LMD)

    Science.gov (United States)

    The Delta NIRI (Nutrition Intervention Research Initiative) team has conducted several research studies in the Lower Mississippi Delta (LMD) region employing the community-based participatory research (CBPR) model. Our collaborative work in the LMD focuses on interventions conducted in each of our c...

  11. 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.

    of these parameters. From the distributions of delta18O and salinity (S), and the relationships between delta18OdeltaD and delta18O–S, the following inferences have been drawn: (1) there is a broad correspondence between...

  12. 78 FR 21491 - DeltaPoint Capital IV, L.P., DeltaPoint Capital IV (New York), L.P.; Notice Seeking Exemption...

    Science.gov (United States)

    2013-04-10

    ... ADMINISTRATION 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 Capital IV (New York), L.P., 45 East Avenue, 6th...

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

    Science.gov (United States)

    Gary, Ronald K.

    2004-01-01

    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…

  14. Molecular identification of Sicilian (deltaß)º-thalassemia associated with ß-thalassemia and hemoglobin S in Brazil

    OpenAIRE

    2002-01-01

    We describe the clinical and molecular characteristics of two unrelated Brazilian families with an association of the Sicilian form of (deltaß)º-thalassemia with hemoglobin S and ß-thalassemia. Direct sequencing of the ß-globin gene showed only the hemoglobin S mutation in patient 1 and the ß-thalassemia IVS1-110 in patient 2. The other allele was deleted in both patients and PCR of DNA samples of the breakpoint region of both patients showed a band of approximately 1,150 bp, expected to be o...

  15. A DNA polymerase mutation that suppresses the segregation bias of an ARS plasmid in Saccharomyces cerevisiae.

    Science.gov (United States)

    Houtteman, S W; Elder, R T

    1993-03-01

    Yeast autonomously replicating sequence (ARS) plasmids exhibit an unusual segregation pattern during mitosis. While the nucleus divides equally into mother and daughter cells, all copies of the ARS plasmid will often remain in the mother cell. A screen was designed to isolate mutations that suppress this segregation bias. A plasmid with a weak ARS (wARS) that displayed an extremely high segregation bias was constructed. When cells were grown under selection for the wARS plasmid, the resulting colonies grew slowly and had abnormal morphology. A spontaneous recessive mutation that restored normal colony morphology was identified. This mutation suppressed plasmid segregation bias, as indicated by the increased stability of the wARS plasmid in the mutant cells even though the plasmid was present at a lower copy number. An ARS1 plasmid was also more stable in mutant cells than in wild-type cells. The wild-type allele for this mutant gene was cloned and identified as POL delta (CDC2). This gene encodes DNA polymerase delta, which is essential for DNA replication. These results indicate that DNA polymerase delta plays some role in causing the segregation bias of ARS plasmids.

  16. Drosophila Lyra mutations are gain-of-function mutations of senseless

    Science.gov (United States)

    Nolo, R.; Abbott, L. A.; Bellen, H. J.

    2001-01-01

    The Lyra mutation was first described by Jerry Coyne in 1935. Lyra causes recessive pupal lethality and adult heterozygous Lyra mutants exhibit a dominant loss of the anterior and posterior wing margins. Unlike many mutations that cause loss of wing tissue (e.g., scalloped, Beadex, cut, and apterous-Xasta), Lyra wing discs do not exhibit increased necrotic or apoptotic cell death, nor do they show altered BrdU incorporation. However, during wing disc eversion, loss of the anterior and posterior wing margins is apparent. We have previously shown that senseless, a gene that is necessary and sufficient for peripheral nervous system (PNS) development, is allelic to Lyra. Here we show by several genetic criteria that Lyra alleles are neomorphic alleles of senseless that cause ectopic expression of SENSELESS in the wing pouch. Similarly, overexpression of SENSELESS in the wing disc causes loss of wing margin tissue, thereby mimicking the Lyra phenotype. Lyra mutants display aberrant expression of DELTA, VESTIGIAL, WINGLESS, and CUT. As in Lyra mutants, overexpression of SENSELESS in some areas of the wing pouch also leads to loss of WINGLESS and CUT. In summary, our data indicate that overexpression of SENSELESS causes a severe reduction in NOTCH signaling that in turn may lead to decreased transcription of several key genes required for wing development, leading to a failure in cell proliferation and loss of wing margin tissue.

  17. Surface Delta Interaction and g factors

    CERN Document Server

    Yu, Xiaofei

    2015-01-01

    Using an attractive surface delta interaction we obtain wave functions for 2 neutrons (or neutron holes) in the model space of 2 orbits (l=4, j=7/2) and (l=2, j=5/2). If we take the single particle energies to be degenerate we find that the g factors for I=2, 4 and 6 are all the same -namely the orbital g factor of the single nucleon. For a free neutron this quantity zero all 2particle or 2 hole g factors are equal to zero as well.. Only the orbital part of the g -factors contribute - the spin part cancels out. We then consider the effects of introducing a single energy splititng between the 2 orbits.

  18. Historical floods in the Dutch Rhine Delta

    Directory of Open Access Journals (Sweden)

    R. Glaser

    2003-01-01

    Full Text Available Historical records provide direct information about the climatic impact on society. Especially great natural disasters such as river floods have been for long attracting the attention of humankind. Time series for flood development on the Rhine branches Waal, Nederrijn/Lek and IJssel in the Dutch Rhine Delta are presented in this paper. In the case of the Waal it is even possible to compare historical flood frequencies based on documentary data with the recent development reconstructed from standardized instrumental measurements. In brief, we will also discuss various parameters concerning the structure of the flood series and the "human dimension" of natural disaster, i.e. the vulnerability of society when facing natural disasters.

  19. Head orientation prediction: delta quaternions versus quaternions.

    Science.gov (United States)

    Himberg, Henry; Motai, Yuichi

    2009-12-01

    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.

  20. Spectral factorization using the delta operator

    DEFF Research Database (Denmark)

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

    1994-01-01

    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 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...... solution to the spectral factorization problem. The key idea is to use the gamma-operator resembled by its behavior to the differential operator....

  1. Delta-excitations and the three-nucleon force

    CERN Document Server

    Epelbaum, E; Meißner, Ulf-G

    2007-01-01

    We study the three-nucleon force in chiral effective field theory with explicit Delta-resonance degrees of freedom. We show that up to next-to-next-to-leading order, the only contribution to the isospin symmetric three-nucleon force involving the spin-3/2 degrees of freedom is given by the two-pion-exchange diagram with an intermediate delta, frequently called the Fujita-Miyazawa force. We also analyze the leading isospin-breaking corrections due to the delta. For that, we give the first analysis of the delta quartet mass splittings in chiral effective field theory. The charge-symmetry breaking three-nucleon force due to an intermediate delta excitation is small, of the order of a few keV.

  2. Automatic Detection of Magnetic delta in Sunspot Groups

    CERN Document Server

    Padinhatteeri, Sreejith; Bloomfield, D Shaun; Gallagher, Peter T

    2015-01-01

    Large and magnetically complex sunspot groups are known to be associated with flares. To date, the Mount Wilson scheme has been used to classify sunspot groups based on their morphological and magnetic properties. The most flare prolific class, the delta sunspot-group, is characterised by opposite polarity umbrae within a common penumbra, separated by less than 2 degrees. In this article, we present a new system, called the Solar Monitor Active Region Tracker - Delta Finder (SMART-DF), that can be used to automatically detect and classify magnetic deltas in near-realtime. Using continuum images and magnetograms from the Helioseismic and Magnetic Imager (HMI) onboard NASA's Solar Dynamics Observatory (SDO), we first estimate distances between opposite polarity umbrae. Opposite polarity pairs having distances of less that 2 degrees are then identified, and if these pairs are found to share a common penumbra, they are identified as a magnetic delta configuration. The algorithm was compared to manual delta detect...

  3. Effects of isovector scalar $\\delta$-meson on hypernuclei

    CERN Document Server

    Ikram, M; Biswal, S K; Patra, S K

    2014-01-01

    We analyze the effects of $\\delta-$ meson on hypernuclei within the frame-work of relativistic mean field theory. The $\\delta-$ meson is included into the Lagrangian for hypernuclei. The extra nucleon-meson coupling ($g_\\delta$) affects the every piece of physical observables, like binding energy, radii and single particle energy of hypernuclei. The lambda mean field potential is investigated which is consistent with other predictions. Flipping of single particle energy levels are observed with the strength of $g_\\delta$ in the considered hypernuclei as well as normal nuclei. The spin-orbit potentials are observed for considered hypernuclei and the effect of $g_\\delta$ on spin-orbit potentials is also analyzed. The calculated single-$\\Lambda$ binding energies ($B_\\Lambda$) are quite agreeable with the experimental data.

  4. Isolation of Delta9-THCA-A from hemp and analytical aspects concerning the determination of Delta9-THC in cannabis products.

    Science.gov (United States)

    Dussy, Franz E; Hamberg, Cornelia; Luginbühl, Marco; Schwerzmann, Thomas; Briellmann, Thomas A

    2005-04-20

    A simple procedure based on a common silica gel column chromatography for the isolation of Delta9-tetrahydrocannabinolic acid A (Delta9-THCA-A) from hemp in a multi-milligram scale is presented. Further, the decarboxylation reaction of Delta9-THCA-A to the toxicologically active Delta9-tetrahydrocannabinol (Delta9-THC) at different analytical and under-smoking conditions is investigated. Maximal conversion in an optimised analytical equipment yields about 70% Delta9-THC. In the simulation of the smoking process, only about 30 % of the spiked substance could be recovered as Delta9-THC.

  5. 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: ff@tf.uni-kiel.de [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)

    2016-05-30

    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}.

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

    Science.gov (United States)

    Zabel, Sebastian; Reermann, Jens; Fichtner, Simon; Kirchhof, Christine; Quandt, Eckhard; Wagner, Bernhard; Schmidt, Gerhard; Faupel, Franz

    2016-05-01

    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-0.5.

  7. 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: josemanuel.chicharro@uclm.es; 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)

    2006-02-15

    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.

  8. Studies on the metabolism of the Delta9-tetrahydrocannabinol precursor Delta9-tetrahydrocannabinolic acid A (Delta9-THCA-A) in rat using LC-MS/MS, LC-QTOF MS and GC-MS techniques.

    Science.gov (United States)

    Jung, Julia; Meyer, Markus R; Maurer, Hans H; Neusüss, Christian; Weinmann, Wolfgang; Auwärter, Volker

    2009-10-01

    In Cannabis sativa, Delta9-Tetrahydrocannabinolic acid-A (Delta9-THCA-A) is the non-psychoactive precursor of Delta9-tetrahydrocannabinol (Delta9-THC). In fresh plant material, about 90% of the total Delta9-THC is available as Delta9-THCA-A. When heated (smoked or baked), Delta9-THCA-A is only partially converted to Delta9-THC and therefore, Delta9-THCA-A can be detected in serum and urine of cannabis consumers. The aim of the presented study was to identify the metabolites of Delta9-THCA-A and to examine particularly whether oral intake of Delta9-THCA-A leads to in vivo formation of Delta9-THC in a rat model. After oral application of pure Delta9-THCA-A to rats (15 mg/kg body mass), urine samples were collected and metabolites were isolated and identified by liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high resolution LC-MS using time of flight-mass spectrometry (TOF-MS) for accurate mass measurement. For detection of Delta9-THC and its metabolites, urine extracts were analyzed by gas chromatography-mass spectrometry (GC-MS). The identified metabolites show that Delta9-THCA-A undergoes a hydroxylation in position 11 to 11-hydroxy-Delta9-tetrahydrocannabinolic acid-A (11-OH-Delta9-THCA-A), which is further oxidized via the intermediate aldehyde 11-oxo-Delta9-THCA-A to 11-nor-9-carboxy-Delta9-tetrahydrocannabinolic acid-A (Delta9-THCA-A-COOH). Glucuronides of the parent compound and both main metabolites were identified in the rat urine as well. Furthermore, Delta9-THCA-A undergoes hydroxylation in position 8 to 8-alpha- and 8-beta-hydroxy-Delta9-tetrahydrocannabinolic acid-A, respectively, (8alpha-Hydroxy-Delta9-THCA-A and 8beta-Hydroxy-Delta9-THCA-A, respectively) followed by dehydration. Both monohydroxylated metabolites were further oxidized to their bishydroxylated forms. Several glucuronidation conjugates of these metabolites were identified. In vivo conversion of Delta9-THCA-A to Delta9-THC was

  9. Extensive junctional diversity of rearranged human T cell receptor delta genes.

    Science.gov (United States)

    Hata, S; Satyanarayana, K; Devlin, P; Band, H; McLean, J; Strominger, J L; Brenner, M B; Krangel, M S

    1988-06-10

    The human T cell receptor delta (TCR delta) gene encodes one component of the TCR gamma delta-CD3 complex found on subsets of peripheral blood and thymic T cells. Human TCR delta diversity was estimated by characterizing rearrangements in TCR gamma delta cell lines and determining the structures of complementary DNA clones representing functional and nonfunctional transcripts in these cell lines. One V delta segment and one J delta segment were identified in all functional transcripts, although a distinct J delta segment was identified in a truncated transcript. Further, one D delta element was identified, and evidence for the use of an additional D delta element was obtained. Thus human TCR delta genes appear to use a limited number of germline elements. However, the apparent use of two D delta elements in tandem coupled with imprecise joining and extensive incorporation of N nucleotides generates unprecedented variability in the junctional region.

  10. Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A

    Energy Technology Data Exchange (ETDEWEB)

    McGinniss, M.J.; Kazazian, H.H. Jr.; Bi, L.; Antonarakis, S.E. (John Hopkins Univ., Baltimore, MD (United States)); Hoyer, L.W. (American Red Cross Blood Services, Rockville, MD (United States)); Inaba, H. (Tokyo Medical College (Japan))

    1993-02-01

    Hemophilia A is due to the functional deficiency of factor VIII (FVIII, gene locus F8C). Although half the patients have no detectable FVIII protein in their plasma, the more rare patients ([approximately]5%) have normal levels of a dysfunctional FVIII and are termed cross-reacting material (CRM)-positive. More commonly ([approximately]45%), patients have plasma FVIII protein reduced to an extent roughly comparable to the level of FVIII activity and are designated CRM-reduced. We used denaturing gradient gel electrophoresis to screen for mutations within the F8C gene of 11 patients (6CRM-positive, 5 CRM-reduced) and identified 9 different mutations in 9 patients after analyses of all 26 exons, the promoter region, and the polyadenylation site. Six mutations have not been described previously. Five weree missense (Ser289Leu, Ser558Phe, Val634Ala, Val634Met, Asn1441Lys), and the sixth was a 3-bp deletion ([Delta]Phe652). A review of the literature and the assay of FVIII antigen in 5 hemophilia A patients with previously identified missense mutations from this laboratory yielded a total of 20 other unique CRM-reduced and CRM-positive mutations. Almost all CRM-positive/reduced mutations (24/26) were missense, and many (12/26) occurred at CpG dinucleotides. We examined 19 missense mutation for evolutionary conservation using the portions of the porcine and murine F8C sequences that are known, and 18/19 amino acid residue altered by mutation in these patients wer conserved. Almost 50% of mutations (11/26) clustered in the A2 domain, suggesting that this region is critical for the function of FVIII. The results indicate a nonrandom distribution of mutations and suggest that mutations in a limited number of FVIII regions may cause CRM-positive and CRM-reduced heomphilia A. 48 refs., 1 fig., 1 tab.

  11. Potency of Mahakam Delta in East Kalimantan, Indonesia

    Directory of Open Access Journals (Sweden)

    Zairin Zain

    2014-04-01

    Full Text Available Normal 0 false false false IN X-NONE X-NONE Mahakam Delta is not only utilized for fishery activities but also for several industrial purposes such as coal and oil mining, shipping and timber. The objective of this paper is to provide information in term of the potency of Mahakam Delta located in East Kalimantan province, Indonesia. The study was conducted in Mahakam Delta, East Kalimantan Province, Indonesia. Participatory rural appraisal is a group of methods to collect information in a participatory fashion from rural communities. The method employed in this research was descriptive analysis describing the environmental potency found in Mahakam Delta. Massive conversion of mangrove forest particularly Nypa (Nypa fruticans area into pond has driven conflict among related stakeholders on the utilization of natural resource and land which subsequently impacts on the fish and shrimp source regeneration, loss of ecological functions of mangrove forest for feeding, nursery and spawning ground of fish and other organisms. Besides of fisheries, oil and gas activity also exists in Mahakam Delta. Mahakam Delta is regarded as important area due to the largest producer of oil and gas mining. Thus, oil and gas industry is the most reliable sector that contributes to the economic development of Kutai Kartanegara district. As a resource provider, Mahakam Delta ecosystem provides various resources for livelihoods. As a life-support service provider, Mahakam Delta ecosystem provides habitat and ideal environment to support variety of living kinds. As a convenience provider, Mahakam Delta ecosystem provides unique and interesting recreation site. As a protector from natural disaster, Mahakam Delta ecosystem is able to protect human kinds from natural disaster threatening coastal area.

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

    Directory of Open Access Journals (Sweden)

    Morteza Jabarpoor-Bonyadi

    2017-03-01

    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.

  13. Kin Selection - Mutation Balance

    DEFF Research Database (Denmark)

    Dyken, J. David Van; Linksvayer, Timothy Arnold; Wade, Michael J.

    2011-01-01

    Abstract Social conflict, in the form of intraspecific selfish "cheating" has been observed in a number of natural systems. However, a formal, evolutionary genetic theory of social cheating that provides an explanatory, predictive framework for these observations is lacking. Here we derive the kin...... selection-mutation balance, which provides an evolutionary null hypothesis for the statics and dynamics of cheating. When social interactions have linear fitness effects and Hamilton´s rule is satisfied, selection is never strong enough to eliminate recurrent cheater mutants from a population, but cheater...... lineages are transient and do not invade. Instead, cheating lineages are eliminated by kin selection but are constantly reintroduced by mutation, maintaining a stable equilibrium frequency of cheaters. The presence of cheaters at equilibrium creates a "cheater load" that selects for mechanisms of cheater...

  14. Sustainable Growth in Urbanised Delta Areas: the Opportunities of a Geographical Approach to the Pearl River Delta

    NARCIS (Netherlands)

    Van Rens, G.; Nillisen, A.L.; Schamhart, C.; Lugt, N.

    2006-01-01

    The attractions of delta areas have boomed economies and founded major cities, but the threats of the adjacent water have persisted and natural resources have declined. The objective to facilitate sustainable urban growth in delta areas can only be met by a simultaneous approach of all the stakehold

  15. Preservation potential of the Last Interglacial lower Rhine delta relative to the Holocene Rhine-Meuse delta

    NARCIS (Netherlands)

    Peeters, J.; Martinius, A.W.; Cohen, K.M.; Middelkoop, H.; Stouthamer, E.

    2013-01-01

    In order to improve our insights in the sequence stratigraphic and architectural development of lower deltaic hydrocarbon reservoirs we study the Last Interglacial Rhine delta (MIS-5), and compare it to its well investigated counterpart, the Holocene (MIS-1) Rhine- Meuse delta (Berendsen & Stouthame

  16. Mutation of Auslander generators

    CERN Document Server

    Lada, Magdalini

    2009-01-01

    Let $\\Lambda$ be an artin algebra with representation dimension equal to three and $M$ an Auslander generator of $\\Lambda$. We show how, under certain assumptions, we can mutate $M$ to get a new Auslander generator whose endomorphism ring is derived equivalent to the endomorphism ring of $M$. We apply our results to selfinjective algebras with radical cube zero of infinite representation type, where we construct an infinite set of Auslander generators.

  17. Sex and deleterious mutations.

    Science.gov (United States)

    Gordo, Isabel; Campos, Paulo R A

    2008-05-01

    The evolutionary advantage of sexual reproduction has been considered as one of the most pressing questions in evolutionary biology. While a pluralistic view of the evolution of sex and recombination has been suggested by some, here we take a simpler view and try to quantify the conditions under which sex can evolve given a set of minimal assumptions. Since real populations are finite and also subject to recurrent deleterious mutations, this minimal model should apply generally to all populations. We show that the maximum advantage of recombination occurs for an intermediate value of the deleterious effect of mutations. Furthermore we show that the conditions under which the biggest advantage of sex is achieved are those that produce the fastest fitness decline in the corresponding asexual population and are therefore the conditions for which Muller's ratchet has the strongest effect. We also show that the selective advantage of a modifier of the recombination rate depends on its strength. The quantification of the range of selective effects that favors recombination then leads us to suggest that, if in stressful environments the effect of deleterious mutations is enhanced, a connection between sex and stress could be expected, as it is found in several species.

  18. Distribution of the CCR5-delta32 deletion in Southwest Germany.

    Science.gov (United States)

    Hütter, Gero; Blüthgen, Christian; Elvers-Hornung, Susanne; Klüter, Harald; Bugert, Peter

    2015-01-01

    A 32 base pair deletion in the c-c chemokine receptor gene 5 (CCR5) leads to an inactive protein. Carriers of this deletion must have had a selective advantage because the allelic frequency of the CCR5-delat32 mutation is much higher than expected. Furthermore, there is a decline from North to South Europe. For Germany there are just very few cross-sectional surveys available. Here we investigated a large number of healthy blood donors from Northern Baden-Wuerttemberg. We observed an allelic frequency of 9.21 % of the CCR5-delta32 deletion. The distribution did not follow the Hardy-Weinberg equilibrium suggesting that homozygous carriers of the deletion were overrepresented in this random sample.

  19. Septin mutations in human cancers

    Directory of Open Access Journals (Sweden)

    Elias T Spiliotis

    2016-11-01

    Full Text Available Septins are GTP-binding proteins that are evolutionarily and structurally related to the RAS oncogenes. Septin expression levels are altered in many cancers and new advances point to how abnormal septin expression may contribute to the progression of cancer. In contrast to the RAS GTPases, which are frequently mutated and actively promote tumorigenesis, little is known about the occurrence and role of septin mutations in human cancers. Here, we review septin missense mutations that are currently in the Catalog of Somatic Mutations in Cancer (COSMIC database. The majority of septin mutations occur in tumors of the large intestine, skin, endometrium and stomach. Over 25% of the annotated mutations in SEPT2, SEPT4 and SEPT9 belong to large intestine tumors. From all septins, SEPT9 and SEPT14 exhibit the highest mutation frequencies in skin, stomach and large intestine cancers. While septin mutations occur with frequencies lower than 3%, recurring mutations in several invariant and highly conserved amino acids are found across different septin paralogs and tumor types. Interestingly, a significant number of these mutations occur in the GTP-binding pocket and septin dimerization interfaces. Future studies may determine how these somatic mutations affect septin structure and function, whether they contribute to the progression of specific cancers and if they could serve as tumor-specific biomarkers.

  20. Mucopolysaccharidosis IVA mutations in Chinese patients: 16 novel mutations.

    Science.gov (United States)

    Wang, Zheng; Zhang, Weimin; Wang, Yun; Meng, Yan; Su, Liang; Shi, Huiping; Huang, Shangzhi

    2010-08-01

    Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disease caused by deficiency of N-acetylgalactosamine-6-sulfatase (GALNS) and transmitted as an autosomal recessive trait. This is the first systematic mutation screen in Chinese MPS IVA patients. Mutation detections in 24 unrelated Chinese MPS IVA patients were performed by PCR and direct sequencing of exons or the mRNA of GALNS. A total of 42 mutant alleles were identified, belonging to 27 different mutations. Out of the 27 mutations, 16 were novel, including 2 splicing mutations (c.567-1G>T and c.634-1G>A), 2 nonsense mutations (p.W325X and p.Q422X) and 12 missense mutations (p.T88I, p.H142R, p.P163H, p.G168L, p.H236D, p.N289S, p.T312A, p.G316V, p.A324E, p.L366P, p.Q422K and p.F452L). p.G340D was found to be a common mutation in the Chinese MPS IVA patients, accounting for 16.7% of the total number of mutant alleles. The results show that the mutations in Chinese MPS IVA patients are also family specific but have a different mutation spectrum as compared to those of other populations.

  1. Calreticulin Mutations in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Noa Lavi

    2014-10-01

    Full Text Available With the discovery of the JAK2V617F mutation in patients with Philadelphia chromosome-negative (Ph− myeloproliferative neoplasms (MPNs in 2005, major advances have been made in the diagnosis of MPNs, in understanding of their pathogenesis involving the JAK/STAT pathway, and finally in the development of novel therapies targeting this pathway. Nevertheless, it remains unknown which mutations exist in approximately one-third of patients with non-mutated JAK2 or MPL essential thrombocythemia (ET and primary myelofibrosis (PMF. At the end of 2013, two studies identified recurrent mutations in the gene encoding calreticulin (CALR using whole-exome sequencing. These mutations were revealed in the majority of ET and PMF patients with non-mutated JAK2 or MPL but not in polycythemia vera patients. Somatic 52-bp deletions (type 1 mutations and recurrent 5-bp insertions (type 2 mutations in exon 9 of the CALR gene (the last exon encoding the C-terminal amino acids of the protein calreticulin were detected and found always to generate frameshift mutations. All detected mutant calreticulin proteins shared a novel amino acid sequence at the C-terminal. Mutations in CALR are acquired early in the clonal history of the disease, and they cause activation of JAK/STAT signaling. The CALR mutations are the second most frequent mutations in Ph− MPN patients after the JAK2V617F mutation, and their detection has significantly improved the diagnostic approach for ET and PMF. The characteristics of the CALR mutations as well as their diagnostic, clinical, and pathogenesis implications are discussed in this review.

  2. Presenilin-1 mutations alter K+ currents in the human neuroblastoma cell line, SH-SY5Y

    DEFF Research Database (Denmark)

    Plant, Leigh D; Boyle, John P; Thomas, Natasha M

    2002-01-01

    Mutations in presenilin 1 (PS1) are the major cause of autosomal dominant Alzheimer's disease. We have measured the voltage-gated K+ current in the human neuroblastoma cell line SH-SY5Y using whole-cell patch-clamp. When cells were stably transfected to over-express PS1, no change in K+ current...... membrane distribution when the deltaE9 over-expressing cells were compared to control cells. Intracellular retention of Kv3.1 is consistent with the notion that PS1 can modulate the activity and trafficking of ion channels in central neurones and implicates a compromise in electrical signalling...

  3. The humanδ2 glutamate receptor gene is not mutated in patients with spinocerebellar ataxia

    Institute of Scientific and Technical Information of China (English)

    Jinxiang Huang; Aiyu Lin; Haiyan Dong; Chaodong Wang

    2014-01-01

    The human glutamate receptor delta 2 gene (GRID2) shares 90%homology with the orthologous mouse gene. The mouse Grid2 gene is involved with functions of the cerebellum and sponta-neous mutation of Grid2 leads to a spinocerebellar ataxia-like phenotype. To investigate whether such mutations occur in humans, we screened for mutations in the coding sequence of GRID2 in 24 patients with familial or sporadic spinocerebellar ataxia and in 52 normal controls. We de-tected no point mutations or insertion/deletion mutations in the 16 exons of GRID2. However, a polymorphic 4 nucleotide deletion (IVS5-121_-118 GAGT) and two single nucleotide polymor-phisms (c.1251G>T and IVS14-63C>G) were identiifed. The frequency of these polymorphisms was similar between spinocerebellar ataxia patients and normal controls. These data indicate that spontaneous mutations do not occur in GRID2 and that the incidence of spinocerebellar ataxia in humans is not associated with GRID2 mutation or polymorphisms.

  4. The fluvial evolution of the Holocene Nile Delta

    Science.gov (United States)

    Pennington, B. T.; Sturt, F.; Wilson, P.; Rowland, J.; Brown, A. G.

    2017-08-01

    The evolution of the Nile Delta, the largest delta system in the Mediterranean Sea, has both high palaeoenvironmental and archaeological significance. A dynamic model of the landscape evolution of this delta system is presented for the period c.8000-4500 cal BP. Analysis of sedimentary data and chronostratigraphic information contained within 1640 borehole records has allowed for a redefinition of the internal stratigraphy of the Holocene delta, and the construction of a four-dimensional landscape model for the delta's evolution through time. The mid-Holocene environmental evolution is characterised by a transition from an earlier set of spatially varied landscapes dominated by swampy marshland, to better-drained, more uniform floodplain environments. Archaeologically important Pleistocene inliers in the form of sandy hills protruding above the delta plain surface (known as ;turtlebacks;), also became smaller as the delta plain continued to aggrade, while the shoreline and coastal zone prograded north. These changes were forced by a decrease in the rate of relative sea-level rise under high rates of sediment-supply. This dynamic environmental evolution needs to be integrated within any discussion of the contemporary developments in the social sphere, which culminated in the emergence of the Ancient Egyptian State c.5050 cal BP.

  5. Hot deformation behavior of delta-processed superalloy 718

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Y., E-mail: wangyanhit@yahoo.cn [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)

    2011-03-25

    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.

  6. Primary production in the Delta: Then and now

    Science.gov (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.

    2016-01-01

    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.

  7. Holocene evolution of the western Orinoco Delta, Venezuela

    Science.gov (United States)

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

    2003-01-01

    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

  8. Regional pole assignment for uncertain delta-operator systems

    Institute of Scientific and Technical Information of China (English)

    Man LIU; Yuanwei JING; Siying ZHANG

    2004-01-01

    The pole assignment in a specified disk by state feedback for uncertain delta-operator systems is studied.By making use of algebra Riccati equations,a sufficient and necessary condition of pole assignment for a kind of parameter uncertain delta-operator system in a specified disk by state feedback is presented.And the design method of state feedback controller is also developed.The proposed method can unify some previous related results of continuous and discrete time systems into the delta framework.The efficiency of the design method is illustrated by a numerical example.

  9. Electromagnetic form factors of the Delta with D-waves

    CERN Document Server

    Ramalho, G; Gross, Franz

    2010-01-01

    The electromagnetic form factors of the Delta baryon are evaluated within the framework of a covariant spectator quark model, where S and D-states are included in the $\\Delta$ wave function. We predict all the four Delta multipole form factors: the electric charge GE0, the magnetic dipole GM1, the electric quadrupole GE2 and the magnetic octupole GM3. We compare our predictions with other theoretical calculations. Our results are compatible with the available experimental data and recent lattice QCD data.

  10. Late quaternary evolution of the Orinoco Delta, Venezuela

    Science.gov (United States)

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

    2002-01-01

    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

  11. On generalized {delta}-semiclosed sets in topological spaces

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jin Han [Division of Mathematical Sciences, Pukyong National University, Pusan 608-737 (Korea, Republic of)]. E-mail: jihpark@pknu.ac.kr; Song, Dae Seob [Division of Mathematical Sciences, Pukyong National University, Pusan 608-737 (Korea, Republic of); Saadati, Reza [Department of Mathematics, and Computer Science, Amirkabir University of Technology, 424 Hafez Avenue, Tehran 15914 (Iran, Islamic Republic of) and Department of Mathematics, Amol Islamic Azad University, Amol 46176-54553 (Iran, Islamic Republic of)]. E-mail: rsaadati@eml.cc

    2007-08-15

    The aim of this paper is to introduce the class of g{delta}s-closed sets and obtain the characterizations of T {sub 3/4} space due to Dontchev and Ganster [Dontchev J, Ganster M. On {delta}-generalized closed set and T {sub 3/4}-spaces. Mem Fac Sci Kochi Univ Ser A (Math) 1996;17:15-31]. We also introduce the notion of g{delta}s-continuity and investigate the relationships between it and other types of continuity.

  12. Is there a self-organization principle of river deltas?

    Science.gov (United States)

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

    2017-04-01

    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

  13. Monte Carlo simulations of the stability of delta-Pu

    CERN Document Server

    Landa, A; Ruban, A

    2003-01-01

    The transition temperature (T sub 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. It is found that at T sub c approx 548 K, delta-Pu undergoes transformation from a disordered magnetic state to a structure with an antiferromagnetic spin alignment that is mechanically unstable with respect to tetragonal distortion. The calculated transition temperature is in good agreement with the temperature measured at the gamma -> delta transition (593 K). (letter to the editor)

  14. Genomic organization of the human T-cell antigen-receptor alpha/delta locus.

    Science.gov (United States)

    Satyanarayana, K; Hata, S; Devlin, P; Roncarolo, M G; De Vries, J E; Spits, H; Strominger, J L; Krangel, M S

    1988-11-01

    Two clusters of overlapping cosmid clones comprising about 100 kilobases (kb) at the human T-cell antigen-receptor alpha/delta locus were isolated from a genomic library. The structure of the germ-line V delta 1 variable gene segment was determined. V delta 1 is located 8.5 kb downstream of the V alpha 13.1 gene segment, and both V segments are arranged in the same transcriptional orientation. The V alpha 17.1 segment is located between V delta 1 and the D delta, J delta, C delta region (containing the diversity, joining, and constant gene segments). Thus, V delta and V alpha segments are interspersed along the chromosome. The germ-line organization of the D delta 2, J delta 1, and J delta 2 segments was determined. Linkage of C delta to the J alpha region was established by identification of J alpha segments within 20 kb downstream of C delta. The organization of the locus was also analyzed by field-inversion gel electrophoresis. The unrearranged V delta 1 and D delta, J delta, C delta regions are quite distant from each other, apparently separated by a minimum of 175-180 kb.

  15. Expression profiling of peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues using tissue microarray.

    Science.gov (United States)

    Higashiyama, Hiroyuki; Billin, Andrew N; Okamoto, Yuji; Kinoshita, Mine; Asano, Satoshi

    2007-05-01

    Peroxisome proliferator-activated receptor-delta (PPAR-delta) is known as a transcription factor involved in the regulation of fatty acid oxidation and mitochondrial biogenesis in several tissues, such as skeletal muscle, liver and adipose tissues. In this study, to elucidate systemic physiological functions of PPAR-delta, we examined the tissue distribution and localization of PPAR-delta in adult mouse tissues using tissue microarray (TMA)-based immunohistochemistry. PPAR-delta positive signals were observed on variety of tissues/cells in multiple systems including cardiovascular, urinary, respiratory, digestive, endocrine, nervous, hematopoietic, immune, musculoskeletal, sensory and reproductive organ systems. In these organs, PPAR-delta immunoreactivity was generally localized on the nucleus, although cytoplasmic localization was observed on several cell types including neurons in the nervous system and cells of the islet of Langerhans. These expression profiling data implicate various physiological roles of PPAR-delta in multiple organ systems. TMA-based immunohistochemistry enables to profile comprehensive protein localization and distribution in a high-throughput manner.

  16. miR-155 Over-expression Promotes Genomic Instability by Reducing High-fidelity Polymerase Delta Expression and Activating Error-prone DSB Repair

    Science.gov (United States)

    Czochor, Jennifer R.; Sulkowski, Parker; Glazer, Peter M.

    2016-01-01

    miR-155 is an oncogenic microRNA (miR) that is often over-expressed in cancer and is associated with poor prognosis. miR-155 can target several DNA repair factors including RAD51, MLH1, and MSH6, and its over-expression results in an increased mutation frequency in vitro, although the mechanism has yet to be fully understood. Here, we demonstrate that over-expression of miR-155 drives an increased mutation frequency both in vitro and in vivo, promoting genomic instability by affecting multiple DNA repair pathways. miR-155 over-expression causes a decrease in homologous recombination, but yields a concurrent increase in the error-prone non-homologous end-joining (NHEJ) pathway. Despite repressing established targets MLH1 and MSH6, the identified mutation pattern upon miR-155 over-expression does not resemble that of a mismatch repair-deficient background. Further investigation revealed that all four subunits of polymerase delta, a high-fidelity DNA replication and repair polymerase, are down-regulated at the mRNA level in the context of miR-155 over-expression. FOXO3a, a transcription factor and known target of miR-155, has one or more putative binding site(s) in the promoter of all four polymerase delta subunits. Finally, suppression of FOXO3a by miR-155 or by siRNA knockdown is sufficient to repress the expression of the catalytic subunit of polymerase delta, POLD1, at the protein level, indicating that FOXO3a contributes to the regulation of polymerase delta levels. PMID:26850462

  17. Sharecropping Contract Experience in Delta State, Nigeria

    Institute of Scientific and Technical Information of China (English)

    Albert Ukaro Ofuoku

    2015-01-01

    Sharecropping has been an age long practice from ancient times. Some scholars saw the practice as being exploitative of the tenants, yet it is still being practiced. The reasons behind it continual practice need to be unveiled. This study was therefore conducted to examine the sharecropping contract experience in Delta State, Nigeria. The landlords decided to practice sharecropping as a result of emigration of their household members, farm size and cost of labours, some of them gave age and their primary occupation as factors for their decisions to opt for sharecropping arrangement. The yields were shared on the basis of 60% for the landlord to 40% for the tenant. The landlords provided all the equipment and inputs, while the tenant's carried out all the farm operations. They faced the constraints of stress, but were able to cope with them, because of hospitals and health centres nearby. The result of the test of hypothesis confirmed the reasons given for deciding on sharecropping arrangement. It was concluded that sharecropping was not exploitative. It was recommended that the practice of sharecropping should be encouraged and not diversified into other sources of livelihood should do so.

  18. The DELTA 181 lithium thionyl chloride battery

    Science.gov (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.

  19. Delta Haptic Device as a nanomanipulator

    Science.gov (United States)

    Grange, Sebastien; Conti, Francois; Helmer, Patrick; Rouiller, Patrice; Baur, Charles

    2001-10-01

    At the EPFL, we have developed a force-feedback device and control architecture for high-end research and industrial applications. The Delta Haptic Device (DHD) consists of a 6 degrees-of-freedom (DOF) mecatronic device driven by a PC. Several experiments have been carried out in the fields of manipulation and simulation to assess the dramatic improvement haptic information brings to manipulation. This system is particularly well suited for scaled manipulation such as micro-, nano- and biomanipulation. Not only can it perform geometric and force scaling, but it can also include fairly complex physical models into the control loop to assist manipulation and enhance human understanding of the environment. To demonstrate this ability, we are currently interfacing our DHD with an atomic force microscope (AFM). In a first stage, we will be able to feel in real-time the topology of a given sample while visualizing it in 3D. The aim of the project is to make manipulation of carbon nanotubes possible by including physical models of such nanotubes behavior into the control loop, thus allowing humans to control complex structures. In this paper, we give a brief description of our device and present preliminary results of its interfacing with the AFM.

  20. Filaggrin mutations and the skin

    Directory of Open Access Journals (Sweden)

    Dipankar De

    2012-01-01

    Full Text Available Filaggrin is very important in the terminal differentiation of the skin and the formation of cornified envelope in the stratum corneum. Several mutations in the filaggrin gene have been identified in the last decade, mostly from the European countries. Loss of function mutations in the filaggrin gene results in reduced production of filaggrin, depending on the type and site of mutation. Such mutations in the filaggrin gene have been shown to be the most significant genetic risk factor for development of atopic dermatitis and undoubtedly has a role in the pathogenesis of ichthyosis vulgaris. Though there is theoretical possibility of association with hand eczema and allergic contact dermatitis; in clinical studies, the strength of these associations was not significantly strong. In this review, we have discussed the structure and function of filaggrin, basic genetics, type of mutations in filaggrin gene, and association of such mutations with different dermatoses.

  1. Muller's ratchet with compensatory mutations

    CERN Document Server

    Pfaffelhuber, Peter; Wakolbinger, Anton

    2011-01-01

    We consider an infinite dimensional system of stochastic differential equations which describes the evolution of type frequencies in a large population. Random reproduction is modeled by a Wright-Fisher noise whose inverse diffusion coefficient $N$ corresponds to the total population size. The type of an individual is the number $k$ of deleterious mutations it carries. We assume that fitness of individuals carrying $k$ mutations is decreased by $\\alpha k$ for some $\\alpha >0$. Along the individual lines of descent, (new) mutations accumulate at rate $\\lambda$ per generation, and each of these mutations has a small probability $\\gamma$ per generation to disappear. While the case $\\gamma =0 $ is known as (the Fleming-Viot version of) {\\em Muller's ratchet}, the case $\\gamma > 0$ is referred to as that of {\\em compensatory mutations} in the biological literature. In the former case ($\\gamma=0$), an ever increasing number of mutations is accumulated over time, while in the latter ($\\gamma > 0$) this is prevented ...

  2. Filaggrin mutations and the skin.

    Science.gov (United States)

    De, Dipankar; Handa, Sanjeev

    2012-01-01

    Filaggrin is very important in the terminal differentiation of the skin and the formation of cornified envelope in the stratum corneum. Several mutations in the filaggrin gene have been identified in the last decade, mostly from the European countries. Loss of function mutations in the filaggrin gene results in reduced production of filaggrin, depending on the type and site of mutation. Such mutations in the filaggrin gene have been shown to be the most significant genetic risk factor for development of atopic dermatitis and undoubtedly has a role in the pathogenesis of ichthyosis vulgaris. Though there is theoretical possibility of association with hand eczema and allergic contact dermatitis; in clinical studies, the strength of these associations was not significantly strong. In this review, we have discussed the structure and function of filaggrin, basic genetics, type of mutations in filaggrin gene, and association of such mutations with different dermatoses.

  3. Development of a Medium-term Animal Model Using gpt Delta Rats to Evaluate Chemical Carcinogenicity and Genotoxicity

    Science.gov (United States)

    Matsushita, Kohei; Kijima, Aki; Ishii, Yuji; Takasu, Shinji; Jin, Meilan; Kuroda, Ken; Kawaguchi, Hiroaki; Miyoshi, Noriaki; Nohmi, Takehiko; Ogawa, Kumiko; Umemura, Takashi

    2013-01-01

    In this study, the potential for development of an animal model (GPG46) capable of rapidly detecting chemical carcinogenicity and the underlying mechanisms of action were examined in gpt delta rats using a reporter gene assay to detect mutations and a medium-term rat liver bioassay to detect tumor promotion. The tentative protocol for the GPG46 model was developed based on the results of dose-response exposure to diethylnitrosamine (DEN) and treatment with phenobarbital over time following DEN administration. Briefly, gpt delta rats were exposed to various chemicals for 4 weeks, followed by a partial hepatectomy (PH) to collect samples for an in vivo mutation assay. The mutant frequencies (MFs) of the reporter genes were examined as an indication of tumor initiation. A single intraperitoneal (ip) injection of 10 mg/kg DEN was administered to rats 18 h after the PH to initiate hepatocytes. Tumor-promoting activity was evaluated based on the development of glutathione S-transferase placental form (GST-P)-positive foci at week 10. The genotoxic carcinogens 2-acetylaminofluorene (2-AAF), 2-amino-3-methylimidazo [4,5-f] quinolone (IQ) and safrole (SF), the non-genotoxic carcinogens piperonyl butoxide (PBO) and phenytoin (PHE), the non-carcinogen acetaminophen (APAP) and the genotoxic non-hepatocarcinogen aristolochic acid (AA) were tested to validate the GPG46 model. The validation results indicate that the GPG46 model could be a powerful tool in understanding chemical carcinogenesis and provide valuable information regarding human risk hazards. PMID:23723564

  4. Delta Morphodynamics Matters! Ecosystem Services, Poverty and Morphodynamic Change in the Ganges-Brahmaputra Mega-Delta

    Science.gov (United States)

    Nicholls, R. J.; Adger, N.; Allan, A.; Darby, S. E.; Hutton, C.; Matthews, Z.; Rahman, M.; Whitehead, P. G.; Wolf, J.

    2013-12-01

    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

  5. Mutations induced in plant breeding

    Energy Technology Data Exchange (ETDEWEB)

    Barriga B, P. (Universidad Austral de Chile, Valdivia. Inst. de Produccion y Sanidad Vegetal)

    1984-10-01

    The most significant aspects of the use of ionizing radiations in plant breeding are reviewed. Aspects such as basic principles of mutation, expression and selection in obtention of mutants, methods for using induced mutations and sucess achieved with this methodology in plant breeding are reviewed. Results obtained in a program of induced mutation on wheat for high content of protein and lysine at the Universidad Austral de Chile are presented.

  6. EAARL Coastal Topography--Pearl River Delta 2008: First Surface

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — A first surface elevation map (also known as a Digital Elevation Model, or DEM) of the Pearl River Delta in Louisiana and Mississippi was produced from remotely...

  7. EAARL Coastal Topography--Pearl River Delta 2008: Bare Earth

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — A bare earth elevation map (also known as a Digital Elevation Model, or DEM) of the Pearl River Delta in Louisiana and Mississippi was produced from remotely sensed,...

  8. GPC Using a Delta-Domain Emulator-Based Approach

    DEFF Research Database (Denmark)

    Lauritsen, Morten Bach; Jensen, Morten Rostgaard; Poulsen, Niels Kjølstad

    1997-01-01

    This paper describes new approaches to generalized predictive control formulated in the delta (delta) domain. A new delta-domain version of the continuous-time emulator-based predictor is presented. It is shown to contain the optimal discrete-time predictor based on incomplete information...... as a special case. Usually, a good estimate is obtained in a much longer range of samples than obtained by the optimal predictor of the same complexity. This is particularly advantageous at fast sampling rates where a `conventional' predictor is bound to become very computationally demanding. Two controllers...... are considered: one having a well-defined limit as the sampling period tends to zero, the other being a close approximation to the conventional discrete-time GPC. Both algorithms are discrete in nature and well-suited for adaptive control. The fact that delta-domain models are used does not introduce...

  9. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1990

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1990 calendar year. The report begins with a summary...

  10. Delta- Sigma Modulator with Signal Dependant Feedback Gain

    National Research Council Canada - National Science Library

    K.Diwakar; V.Vinoth Kumar

    2015-01-01

    Higher order Delta-Sigma Modulator (DSM) is basically an unstable system. The approximate conditions for stability cannot be used for the design of a DSM for industrial applications where risk is involved...

  11. A High Performance Delta-Sigma Modulator for Neurosensing

    National Research Council Canada - National Science Library

    Xu, Jian; Zhao, Menglian; Wu, Xiaobo; Islam, Md Kafiul; Yang, Zhi

    2015-01-01

    ... to achieve and would require excessive circuit area and power for implementation. In this paper, we present a high performance Delta-Sigma modulator along with several design techniques and enabling blocks to reduce circuit area and power...

  12. An integrated delta-sigma based IIR filter

    Science.gov (United States)

    Au, Dennis Kin-Wah

    Delta-sigma based infinite impulse response (IIR) filters are a recently developed circuit technique for efficiently realizing IIR filters operating directly on oversampled delta-sigma modulated signals. The design and single-chip implementation of a fifth-order delta-sigma based IIR filter are described. The filter coefficients are fully programmable and with the use of a structure that is inherently scaled for dynamic range, good filter performance is maintained over a wide variety of transfer functions. To eliminate multi-bit multiplications, five second-order digital delta-sigma modulators were used and dynamic range improvement was obtained through the use of multi-bit quantizers in these modulators. The filter was implemented as a very large scale integration chip using 1.2 micron complementary metal oxide semiconductor technology, occupying an area of 4,355 by 5,962 square microns. Simulations indicate that the clock range should operate up to 45 MHz.

  13. Yukon Delta National Wildlife Refuge coastal survey, final report

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Aerial surveys were conducted along the coastline of the Yukon Delta National Wildlife Refuge to determine the distribution and abundance of waterfowl and...

  14. Alternative Interpretation for the Eberswalde Delta, Holden NE Crater, Mars

    Science.gov (United States)

    Fedo, C. M.; Finkelstein, D. B.; Moersch, J. E.

    2008-03-01

    Examination of HiRISE images from the Eberswalde Delta reveal that it is hard to identify sedimentologic and stratigraphic components of a fluvio-deltaic system, leaving open alternative interpretations for the origin of the strata and geomorphpology.

  15. Linear delta expansion technique for the solution of anharmonic oscillations

    Indian Academy of Sciences (India)

    P K Bera; J Datta

    2007-01-01

    The linear delta expansion technique has been developed for solving the differential equation of motion for symmetric and asymmetric anharmonic oscillators. We have also demonstrated the sophistication and simplicity of this new perturbation technique.

  16. Lead analysis of waterfowl from Yukon Delta NWR

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — In 1995, WAES received funds from the Yukon Delta Ecosystem Team to analyze livers of waterfowl, other than spectacled eiders, for lead concentrations. Nineteen...

  17. LiDAR data for the Delta Area of California

    Data.gov (United States)

    California Department of Resources — 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...

  18. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1992

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1992 calendar year. The report begins with a summary...

  19. Migratory Bird Avian Influenza Sampling; Yukon Kuskokwim Delta, Alaska, 2015

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — Data set containing avian influenza sampling information for spring and summer waterbirds on the Yukon Kuskokwim Delta, 2015. Data contains sample ID, species common...

  20. Delta and Breton National Wildlife Refuges: Comprehensive Conservation Plan

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This Comprehensive Conservation Plan (CCP) was written to guide management on Delta and Breton NWRs for the next 15 years. This plan outlines the refuges' vision and...

  1. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1995

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1995 calendar year. The report begins with a summary...

  2. EAARL Coastal Topography--Pearl River Delta 2008: Bare Earth

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — A bare earth elevation map (also known as a Digital Elevation Model, or DEM) of the Pearl River Delta in Louisiana and Mississippi was produced from remotely sensed,...

  3. Topography data from the Elwha River delta, Washington, September 2014

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — This part of the data release presents topography data from the Elwha River delta collected in September 2014. Topography data were collected on foot with global...

  4. Calculating Lake Morphology in the Colville River Delta, Alaska

    Science.gov (United States)

    McGraw, M.; Walker, H. J.

    2013-12-01

    The morphology and surface area of a lake can be determined using simple mathematical formulas. These formulas can be plugged into a Geographic Information System (GIS) and used to calculate the circularity, smoothness, compactness and orientation of a lake or pond in remotely sensed imagery. The calculated output can then be used to differentiate circular lakes from elongated lakes, lakes with smooth shorelines from those with complex shorelines, and lake orientation; such information can then be used to classify and quantify different types of lakes in complex environments such as river deltas. The Colville River delta is located on the North Slope of Arctic Alaska. Previous studies have classified the delta's 230,000+ lakes into five types: 1. thermokarst (thaw) lakes, 2. oriented lakes, 3. perched lakes, 4 channel lakes and 5. ice-wedge polygon ponds. This study uses 2004 aerial photography and 2011 satellite imagery to quantify the different types of lake in the delta.

  5. Water Quality Assessment of River Areba, Niger Delta, Nigeria ...

    African Journals Online (AJOL)

    Water Quality Assessment of River Areba, Niger Delta, Nigeria Using Physical ... phosphate (0.78mg/l) were above World Health Organization limits for drinking water. Seasonally, water temperatures, total dissolved solids, biological oxygen ...

  6. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1983

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1983 calendar year. The report begins with a summary...

  7. Hypertension in a Rural Community in Rivers State, Niger Delta ...

    African Journals Online (AJOL)

    Hypertension in a Rural Community in Rivers State, Niger Delta Region of Nigeria: ... (SSA), is now a serious endemic threat and an important public health issue. ... Medical history such as prior knowledge of blood pressure status and family ...

  8. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1994

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1994 calendar year. The report begins with a summary...

  9. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1987

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1987 calendar year. The report begins with a summary...

  10. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 2001

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 2001 calendar year. The report begins with a summary...

  11. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1986

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1986 calendar year. The report begins with a summary...

  12. Birds and mammals of the Copper River Delta

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — The objectives of this report are: (1) to describe the habitats available for birds and mammals on the Copper River Delta (2) to present an annotated list of birds...

  13. Inventory Management in Delta Allied Wire Industries Limited Asaba ...

    African Journals Online (AJOL)

    Inventory Management in Delta Allied Wire Industries Limited Asaba. ... review and customers' handling processes equally studied for improvement. The data collated were collated were analyzed using the Economic Order Quantity (EOQ) ...

  14. Profiling risk and sustainability in coastal deltas of the world

    Science.gov (United States)

    Tessler, Z. D.; Vörösmarty, C. J.; Grossberg, M.; Gladkova, I.; Aizenman, H.; Syvitski, J. P. M.; Foufoula-Georgiou, E.

    2015-08-01

    Deltas are highly sensitive to increasing risks arising from local human activities, land subsidence, regional water management, global sea-level rise, and climate extremes. We quantified changing flood risk due to extreme events using an integrated set of global environmental, geophysical, and social indicators. Although risks are distributed across all levels of economic development, wealthy countries effectively limit their present-day threat by gross domestic product-enabled infrastructure and coastal defense investments. In an energy-constrained future, such protections will probably prove to be unsustainable, raising relative risks by four to eight times in the Mississippi and Rhine deltas and by one-and-a-half to four times in the Chao Phraya and Yangtze deltas. The current emphasis on short-term solutions for the world’s deltas will greatly constrain options for designing sustainable solutions in the long term.

  15. EAARL Coastal Topography--Pearl River Delta 2008: First Surface

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — A first surface elevation map (also known as a Digital Elevation Model, or DEM) of the Pearl River Delta in Louisiana and Mississippi was produced from remotely...

  16. LiDAR data for the Delta Area of California

    Data.gov (United States)

    California Department of Resources — 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...

  17. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1998

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1998 calendar year. The report begins with a summary...

  18. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 2002

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 2002 calendar year. The report begins with a summary...

  19. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1996

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1996 calendar year. The report begins with a summary...

  20. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1997

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1997 calendar year. The report begins with a summary...

  1. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1982

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta, Nunivak National Wildlife Refuge outlines Refuge accomplishments during the 1982 calendar year. The report begins with...

  2. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1989

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1989 calendar year. The report begins with a summary...

  3. The Byron Syring DELTA Center--Leadership in Action.

    Science.gov (United States)

    Snyder, Timothy

    1997-01-01

    Byron Spring DELTA Center serves a small farming community in Colorado offers high school diploma programs, English-as-a-Second-Language courses, lifelong learning, and a variety of other programs for teens and adults. (JOW)

  4. Rarotonga Radiocarbon (delta 14C) for 1950 to 1997

    Data.gov (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...

  5. precise delta extraction scheme for reprogramming of wireless ...

    African Journals Online (AJOL)

    eobe

    Keywords- reprogramming; operating system, wireless sensor network, Delta. 1. ... implemented via the use of embedded operating systems. Jun-Zhao in [6] as well as Dunkiels et al. in [7] ..... Pister, “System architecture directions for.

  6. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 1999

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 1999 calendar year. The report begins with a summary...

  7. Yukon Delta National Wildlife Refuge : Narrative Report : Calendar Year 2000

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This annual narrative report for Yukon Delta National Wildlife Refuge outlines Refuge accomplishments during the 2000 calendar year. The report begins with a summary...

  8. Morphologic and stratigraphic evolution of muddy ebb-tidal deltas along a subsiding coast: Barataria Bay, Mississippi River delta

    Science.gov (United States)

    FitzGerald, D.M.; Kulp, M.; Penland, S.; Flocks, J.; Kindinger, J.

    2004-01-01

    The Barataria barrier coast formed between two major distributaries of the Mississippi River delta: the Plaquemines deltaic headland to the east and the Lafourche deltaic headland to the west. Rapid relative sea-level rise (1??03 cm year-1) and other erosional processes within Barataria Bay have led to substantial increases in the area of open water (> 775 km2 since 1956) and the attendant bay tidal prism. Historically, the increase in tidal discharge at inlets has produced larger channel cross-sections and prograding ebb-tidal deltas. For example, the ebb delta at Barataria Pass has built seaward > 2??2 km since the 1880s. Shoreline erosion and an increasing bay tidal prism also facilitated the formation of new inlets. Four major lithofacies characterize the Barataria coast ebb-tidal deltas and associated sedimentary environments. These include a proximal delta facies composed of massive to laminated, fine grey-brown to pale yellow sand and a distal delta facies consisting of thinly laminated, grey to pale yellow sand and silty sand with mud layers. The higher energy proximal delta deposits contain a greater percentage of sand (75-100%) compared with the distal delta sediments (60-80%). Associated sedimentary units include a nearshore facies consisting of horizontally laminated, fine to very fine grey sand with mud layers and an offshore facies that is composed of grey to dark grey, laminated sandy silt to silty clay. All facies coarsen upwards except the offshore facies, which fines upwards. An evolutionary model is presented for the stratigraphic development of the ebb-tidal deltas in a regime of increasing tidal energy resulting from coastal land loss and tidal prism growth. Ebb-tidal delta facies prograde over nearshore sediments, which interfinger with offshore facies. The seaward decrease in tidal current velocity of the ebb discharge produces a gradational contact between proximal and distal tidal delta facies. As the tidal discharge increases and the inlet

  9. The late-Holocene progradation of the Mahakam Delta, Indonesia - A case study of tidal, tropical deltas

    Science.gov (United States)

    Dalman, R.; Ranawijaya, D.; Missiaen, T.; Kroonenberg, S.; Storms, J.

    2011-12-01

    The Mahakam Delta is an oft-cited example of a mixed fluvial-tidally influenced delta. Yet the distinct separation of the tide-dominated delta plain and the fluvial distributaries make the delta unique amongst tidally influenced deltas. The delta prograded an average of 60 km over the last 5000 years. Most sediment transport is induced by tidal currents and fluvial discharge, which resulted in a distinct, dense network of distributary and tidal channels. In order to characterize the Holocene sedimentary architecture we describe a dataset of 10 new cores and a large survey of very high-resolution, shallow seismics. The seismics are recorded using an echosounder with a novel parametric source, allowing subsurface penetration in excess of 15 m while achieving a vertical resolution of 0.2 m. Distinct sedimentary facies are described in detail for delta plain, delta front, distributary and mouthbar deposits. A notable difference in stratal pattern has been observed between the inner and outer tide-dominated delta plain facies. The inner tidal channels cut deeply into the underlying deltafront deposits and form a distinct heterogenic laterally accreting and intercutting facies. Whereas the outer tide-dominated delta plain deposits accrete conformably on the marine deltafront facies and show a much more homogenous sedimentary architecture. The continual reworking of the inner tide-dominated delta plain results in a patchwork of deposits greatly varying in thickness and age albeit with a similar silty clay lithology. The area of the present-day delta was largely flooded after the early to mid-Holocene transgression, our data indicate that a small branch of fluvial distributaries was active on the current delta plain around 5 ka. Subsequently, the northernmost fluvial distributary built out rapidly over a period of 3 kyrs. The southern distributaries built out later, from 2 ka to the present. The mouthbar deposits in the south are significantly thicker than in the northern

  10. Longitudinal spin asymmetries and $\\Delta G$ at COMPASS

    CERN Document Server

    Le Goff, Jean-Marc

    2008-01-01

    The spin structure $g_{1}$ of the deuteron has been measured by COMPASS with unprecedented accuracy at low $x$, providing much more reliable values for the first moment $\\Gamma_{1}$ and for the quark spin contribution $\\Delta\\Sigma$. Difference-charge semi-inclusive asymmetries have been measured and seem to favor a flavor asymmetric polarized sea. The gluon polarization has been measured in the open-charm and high-$p_{t}$ channels. Large values of $\\Delta G$ are now unlikely.

  11. delta. t tuneup procedure for the LAMPF 805-MHz linac

    Energy Technology Data Exchange (ETDEWEB)

    Crandall, K.R.

    1976-05-01

    An important part of tuning the LAMPF accelerator is the adjustment of the phases and amplitudes in the 805-MHz linac. The technique used is called the ..delta..t procedure because of the time-of-flight measurements that are required. The theory behind the ..delta..t procedure, a brief description of the hardware, and a description of the many computer programs that have been written to implement the procedure are presented.

  12. Properties of the $\\delta$ Scorpii Circumstellar Disk from Continuum Modeling

    OpenAIRE

    Carciofi, A. C.; Miroshnichenko, A. S.; Kusakin, A. V.; Bjorkman, J. E.; Bjorkman, K. S.; Marang, F.; Kuratov, K.S.; a-Lario, P. Garcí; Calderón, J. V. Perea; Fabregat, J.; Magalhães, A.M.

    2006-01-01

    We present optical $WBVR$ and infrared $JHKL$ photometric observations of the Be binary system $\\delta$ Sco, obtained in 2000--2005, mid-infrared (10 and $18 \\mu$m) photometry and optical ($\\lambda\\lambda$ 3200--10500 \\AA) spectropolarimetry obtained in 2001. Our optical photometry confirms the results of much more frequent visual monitoring of $\\delta$ Sco. In 2005, we detected a significant decrease in the object's brightness, both in optical and near-infrared brightness, which is associate...

  13. Multimegawatt DAE$\\delta$ALUS Cyclotrons for Neutrino Physics

    CERN Document Server

    Abs, M; Alonso, J R; Barletta, W A; Barlow, R; Calabretta, L; Calanna, A; Campo, D; Celona, L; Conrad, J M; Gammino, S; Kleeven, W; Koeth, T; Maggiore, M; Okuno, H; Piazza, L A C; Seidel, M; Shaevitz, M H; Stingelin, L; Yang, J J; Yeck, J

    2012-01-01

    DAE$\\delta$ALUS (Decay-At-rest Experiment for $\\delta_{CP}$ studies At the Laboratory for Underground Science) provides a new approach to the search for CP violation in the neutrino sector. High-power continuous-wave proton cyclotrons efficiently provide the necessary proton beams with an energy of up to 800 MeV to create neutrinos from pion and muon decay-at-rest. The experiment searches for $\\bar{\

  14. Automatisierte VHDL-Code-Generierung eines Delta-Sigma Modulators

    Directory of Open Access Journals (Sweden)

    R. Spilka

    2006-01-01

    Full Text Available Im vorliegenden Beitrag wird eine automatische Generierung des VHDL-Codes eines Delta-Sigma Modulators präsentiert. Die Koeffizientenmultiplikation wird hierbei durch Bit-Serielle-Addition durchgeführt. Mit Hilfe zweier neuer Matlab Funktionen wird der Systementwurf durch die bekannte Delta-Sigma Toolbox von R. Schreier erweitert und direkt synthesefähiger VHDL Code erzeugt.

  15. Sedimentation patterns in floodplains of the Mekong Delta - Vietnam

    Science.gov (United States)

    Van Manh, Nguyen; Merz, Bruno; Viet Dung, Nguyen; Apel, Heiko

    2013-04-01

    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.

  16. Origin of Hb A2' (Hb B2) [delta16(A13)Gly --> Arg (GGC --> CGC)].

    Science.gov (United States)

    Bennani, Mohcine; Mombo, Landry-Erik; Chaventre, André; Barakat, Amina; Ducrocq, Rolande; Nagel, Ronald L; Krishnamoorthy, Rajagopal

    2003-05-01

    On a field trip to the Dogon country (le Pays Dogon) in central Mali, we detected a high frequency of the Hb A2 abnormality, reaching higher numbers among blacksmiths (up to 12.4%) living in the same villages. In this report, by direct nucleotide sequencing and employing a polymerase chain reaction-restriction fragment length polymorphism approach, we show that the Hb A2 variant observed in the Dogon population is indeed Hb A2', also called Hb B2, and that in all of the cases the abnormal delta-globin gene is linked to a unique haplotype. The same haplotype was found linked to Hb A2' in the Herero population belonging to the South African Bantu-speaking Blacks from Namibia. Although the unique origin of this mutation in Africa is a possibility, a recurrent mutational event cannot be excluded because the linked beta cluster haplotype is one of the two major haplotypes found in all African populations. A study of populations from other regions of Africa is required to clarify this issue.

  17. An integrated assessment framework for land subsidence in delta cities

    Directory of Open Access Journals (Sweden)

    T. H. M. Bucx

    2015-11-01

    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.

  18. Near-infrared spectropolarimetry of a delta-spot

    CERN Document Server

    Balthasar, H; Louis, R E; Verma, M; Denker, C

    2014-01-01

    Sunspots harboring umbrae of both magnetic polarities within a common penumbra (delta-spots) are often but not always related to flares. We present first near-infrared (NIR) observations (Fe I 1078.3 nm and Si I 1078.6 nm spectra) obtained with the Tenerife Infrared Polarimeter (TIP) at the Vacuum Tower Telescope (VTT) in Tenerife on 2012 June 17, which afford accurate and sensitive diagnostics to scrutinize the complex fields along the magnetic neutral line of a delta-spot within active region NOAA 11504. We examine the vector magnetic field, line-of-sight (LOS) velocities, and horizontal proper motions of this rather inactive delta-spot. We find a smooth transition of the magnetic vector field from the main umbra to that of opposite polarity (delta-umbra), but a discontinuity of the horizontal magnetic field at some distance from the delta-umbra on the polarity inversion line. The magnetic field decreases faster with height by a factor of two above the delta-umbra. The latter is surrounded by its own Eversh...

  19. An integrated assessment framework for land subsidence in delta cities

    Science.gov (United States)

    Bucx, T. H. M.; van Ruiten, C. J. M.; Erkens, G.; de Lange, G.

    2015-11-01

    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.

  20. Governance of ‘long term delta planning’ in Bangladesh, Vietnam and the Netherlands

    NARCIS (Netherlands)

    Staveren, van M.F.

    2014-01-01

    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