Sample records for a508 gr 4n

  1. Master curve characterization of the fracture toughness behavior in SA508 Gr.4N low alloy steels

    NASA Astrophysics Data System (ADS)

    Lee, Ki-Hyoung; Kim, Min-Chul; Lee, Bong-Sang; Wee, Dang-Moon

    2010-08-01

    The fracture toughness properties of the tempered martensitic SA508 Gr.4N Ni-Mo-Cr low alloy steel for reactor pressure vessels were investigated by using the master curve concept. These results were compared to those of the bainitic SA508 Gr.3 Mn-Mo-Ni low alloy steel, which is a commercial RPV material. The fracture toughness tests were conducted by 3-point bending with pre-cracked charpy (PCVN) specimens according to the ASTM E1921-09c standard method. The temperature dependency of the fracture toughness was steeper than those predicted by the standard master curve, while the bainitic SA508 Gr.3 steel fitted well with the standard prediction. In order to properly evaluate the fracture toughness of the Gr.4N steels, the exponential coefficient of the master curve equation was changed and the modified curve was applied to the fracture toughness test results of model alloys that have various chemical compositions. It was found that the modified curve provided a better description for the overall fracture toughness behavior and adequate T0 determination for the tempered martensitic SA508 Gr.4N steels.

  2. Influence of the thermodynamic parameters on the temper embrittlement of SA508 Gr.4N Ni-Cr-Mo low alloy steel with variation of Ni, Cr and Mn contents

    NASA Astrophysics Data System (ADS)

    Park, Sang-Gyu; Lee, Ki-Hyoung; Min, Ki-Deuk; Kim, Min-Chul; Lee, Bong-Sang

    2012-07-01

    It is well known that SA508 Gr.4N low alloy steel offers improved fracture toughness and strength compared to commercial low alloy steels such as SA508 Gr.3 Mn-Mo-Ni low alloy steel. In this study, the effects of Cr, Mn, and Ni on temper embrittlement in SA508 Gr.4N low alloy steel were evaluated from the viewpoint of thermodynamic parameters such as P diffusivity and C activity. The changes of the ductile-brittle transition temperatures before and after aging were correlated with varying alloying element content, and the diffusivity of P and the activity of C were calculated and correlated with the transition behaviors. The addition of Ni, Cr, and Mn reduce the resistance to temper embrittlement, showing increased Transition-Temperature Shift (TTS) and an increased fraction of intergranular fracture. Although the diffusivity of P is changed by the addition of alloying elements, it does not considerably affect the temper embrittlement. The Mn and Cr content in the matrix significantly reduce the C activity, with showing an inversely proportional relationship to TTS. The change of susceptibility to temper embrittlement caused by Cr and Mn addition could be explained by the variation of C activity. Unlike Cr and Mn, Ni has little effect on the temper embrittlement and C activity.

  3. Effect of microstructure on the impact toughness and temper embrittlement of SA508Gr.4N steel for advanced pressure vessel materials.

    PubMed

    Yang, Zhiqiang; Liu, Zhengdong; He, Xikou; Qiao, Shibin; Xie, Changsheng

    2018-01-09

    The effect of microstructure on the impact toughness and the temper embrittlement of a SA508Gr.4N steel was investigated. Martensitic and bainitic structures formed in this material were examined via scanning electron microscopy, electron backscatter diffraction, transmission electron microscopy, and Auger electron spectroscopy (AES) analysis. The martensitic structure had a positive effect on both the strength and toughness. Compared with the bainitic structure, this structure consisted of smaller blocks and more high-angle grain boundaries (HAGBs). Changes in the ultimate tensile strength and toughness of the martensitic structure were attributed to an increase in the crack propagation path. This increase resulted from an increased number of HAGBs and refinement of the sub-structure (block). The AES results revealed that sulfur segregation is higher in the martensitic structure than in the bainitic structure. Therefore, the martensitic structure is more susceptible to temper embrittlement than the bainitic structure.

  4. Evolution of radiation defect and radiation hardening in heat treated SA508 Gr3 steel

    NASA Astrophysics Data System (ADS)

    Jin, Hyung-Ha; Kwon, Junhyun; Shin, Chansun

    2014-01-01

    The formation of radiation defects and corresponding radiation hardening in heat-treated SA508 Gr3 steel after Fe ion irradiation were investigated by means of transmission electron microscopy and a nano-indentation technique. As the residual dislocation density is increased in the matrix, the formation of radiation defects is considerably weakened. Comparison between the characteristics of the radiation defect and an evaluation of radiation hardening indicates that a large dislocation loop contributes little to the radiation hardening in the heat-treated SA508 Gr3 steel.

  5. Local mechanical properties of Alloy 82/182 dissimilar weld joint between SA508 Gr.1a and F316 SS at RT and 320C

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Byun, Thak Sang; Kim, Jin Weon

    2009-01-01

    This paper presents the variations of local mechanical and microstructural properties in dissimilar metal weld joints consisting of the SA508 Gr.1a ferritic steel, Alloy 82/182 filler metal, and F316 austenitic stainless steel. Flat or round tensile specimens and transmission electron microscopy disks were taken from the base metals, welds, and heat-affected zones (HAZ) of the joints and tested at room temperature (RT) and/or at 320 C. The tensile test results indicated that the mechanical property was relatively uniform within each material zone, but varied considerably between different zones. Further, significant variations were observed both in the austenitic HAZ of F316more » SS and in the ferritic HAZ of SA508 Gr.1a. The yield stress (YS) of the weld metal was under-matched with respect to the HAZs of SA508 Gr.1a and F316 SS by 0.78 to 0.92, although the YS was over-matched with respect to both base metals. The minimum ductility occurred in the HAZ of SA508 Gr.1 at both test temperatures. The plastic instability stress also varied considerably in the weld joints, with minimum values occurring in the SA508 Gr.1a base metal at RT and in the HAZ of F316 SS at 320 C, suggesting that the probability of ductile failure caused by a unstable deformation at the Alloy 82/182 buttering layer is low. Within the HAZ of SA508 Gr.1a, the gradient of the YS and ultimate tensile strength (UTS) was significant, primarily because of the different microstructures produced by the phase transformation during the welding process. The increment of YS was unexpectedly high in the HAZ of F316 SS, which was explained by the strain hardening induced by a strain mismatch between the weldment and the base metal. This was confirmed by the transmission electron micrographs showing high dislocation density in the HAZ.« less

  6. Local mechanical properties of Alloy 82/182 dissimilar weld joint between SA508 Gr.1a and F316 SS at RT and 320 °C

    NASA Astrophysics Data System (ADS)

    Kim, Jin Weon; Lee, Kyoungsoo; Kim, Jong Sung; Byun, Thak Sang

    2009-02-01

    The distributions of mechanical and microstructural properties were investigated for the dissimilar metal weld joints between SA508 Gr.1a ferritic steel and F316 austenitic stainless steel with Alloy 82/182 filler metal using small-size tensile specimens. The material properties varied significantly in different zones while those were relatively uniform within each material. In particular, significant gradient of the mechanical properties were observed near the both heat-affected zones (HAZs) of F316 SS and SA508 Gr.1a. Thus, the yield stress (YS) was under-matched with respect to the both HAZs, although, the YS of the weld metal was over-matched with respect to both base metals. The minimum ductility occurred in the HAZ of SA508 Gr.1a at both test temperatures. The plastic instability stress also varied considerably across the weld joints, with minimum values occurring in the SA508 Gr.1a base metal at RT and in the HAZ of F316 SS at 320 °C. The transmission electron micrographs showed that the strengthening in the HAZ of F316 SS was attributed to the strain hardening, induced by a strain mismatch between the weldment and the base metal, which was evidenced by high dislocation density in the HAZ of F316 SS.

  7. Melanin production by Rhizobium meliloti GR4 is linked to nonsymbiotic plasmid pRmeGR4b: cloning, sequencing, and expression of the tyrosinase gene mepA.

    PubMed Central

    Mercado-Blanco, J; García, F; Fernández-López, M; Olivares, J

    1993-01-01

    Melanin production by Rhizobium meliloti GR4 is linked to nonsymbiotic plasmid pRmeGR4b (140 MDa). Transfer of this plasmid to GR4-cured derivatives or to Agrobacterium tumefaciens enables these bacteria to produce melanin. Sequence analysis of a 3.5-kb PstI fragment of plasmid pRmeGR4b has revealed the presence of a open reading frame 1,481-bp that codes for a protein whose sequence shows strong homology to two conserved regions involved in copper binding in tyrosinases and hemocyanins. In vitro-coupled transcription-translation experiments showed that this open reading frame codes for a 55-kDa polypeptide. Melanin production in GR4 is not under the control of the RpoN-NifA regulatory system, unlike that in R. leguminosarum bv. phaseoli 8002. The GR4 tyrosinase gene could be expressed in Escherichia coli under the control of the lacZ promoter. For avoiding confusion with mel genes (for melibiose), a change of the name of the previously reported mel genes of R. leguminosarum bv. phaseoli and other organisms to mep genes (for melanin production) is proposed. Images PMID:8366027

  8. 12 CFR 508.4 - Contents and service of the Notice or Order.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Contents and service of the Notice or Order. 508.4 Section 508.4 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.4 Contents and service of...

  9. Optimization of the production of thermostable endo-beta-1,4 mannanases from a newly isolated Aspergillus niger gr and Aspergillus flavus gr.

    PubMed

    Kote, Naganagouda V; Patil, Aravind Goud G; Mulimani, V H

    2009-02-01

    The aim of this work was to establish optimal conditions for the maximum production of endo-beta-1,4 mannanases using cheaper sources. Eight thermotolerant fungal strains were isolated from garden soil and compost samples collected in and around the Gulbarga University campus, India. Two strains were selected based on their ability to produce considerable endo-beta-1,4 mannanases activity while growing in liquid medium at 37 degrees C with locust bean gum (LBG) as the only carbon source. They were identified as Aspergillus niger gr and Aspergillus flavus gr. The experiment to evaluate the effect of different carbon sources, nitrogen sources, temperatures and initial pH of the medium on maximal enzyme production was studied. Enzyme productivity was influenced by the type of polysaccharide used as the carbon source. Copra meal defatted with n-hexane showed to be a better substrate than LBG and guar gum for endo-beta-1,4 mannanases production by A. niger gr (40.011 U/ml), but for A. flavus gr (33.532 U/ml), the difference was not significant. Endo-beta-1,4 mannanases produced from A. niger gr and A. flavus gr have high optimum temperature (65 and 60 degrees C) and good thermostability in the absence of any stabilizers (maintaining 50% of residual activity for 8 and 6 h, respectively, at 60 degrees C) and are stable over in a wide pH range. These new strains offer an attractive alternative source of enzymes for the food and feed processing industries.

  10. Characteristic of retained austenite decomposition during tempering and its effect on impact toughness in SA508 Gr.3 steel

    NASA Astrophysics Data System (ADS)

    Yan, Guanghua; Han, Lizhan; Li, Chuanwei; Luo, Xiaomeng; Gu, Jianfeng

    2017-01-01

    Retained austenite(RA) usually presents in the quenched Nuclear Pressure-Vessel SA508 Gr.3 steel. In the present work, the characteristic of RA decomposition and its effect on the impact toughness were investigated by microstructure observation, dilatometric experiments and Charpy impact tests. The results show that the RA transformed into martensite and bainite during tempering at 230 °C and 400 °C respectively, while mixture of long rod carbides and ferrite formed at 650 °C. The long rod carbides formed from RA decomposition decrease the critical cleavage stress for initiation of micro-cracks, and deteriorate the impact toughness of the steel. Pre-tempering at a low temperature such as 230 °C or 400 °C leading to the decomposition of RA into martensite or baintie can eliminate the deterioration of the toughness caused by direct decomposition into long rod carbides. The absorbed energy indicate that pre-tempering at 400 °C can drive dramatically improvement in the toughness of the steel.

  11. [125I]-GR231118: a high affinity radioligand to investigate neuropeptide Y Y1 and Y4 receptors

    PubMed Central

    Dumont, Yvan; Quirion, Rémi

    2000-01-01

    GR231118 (also known as 1229U91 and GW1229), a purported Y1 antagonist and Y4 agonist was radiolabelled using the chloramine T method. [125I]-GR231118 binding reached equilibrium within 10 min at room temperature and remained stable for at least 4 h. Saturation binding experiments showed that [125I]-GR231118 binds with very high affinity (Kd of 0.09–0.24 nM) in transfected HEK293 cells with the rat Y1 and Y4 receptor cDNA and in rat brain membrane homogenates. No specific binding sites could be detected in HEK293 cells transfected with the rat Y2 or Y5 receptor cDNA demonstrating the absence of significant affinity of GR231118 for these two receptor classes. Competition binding experiments revealed that specific [125I]-GR231118 binding in rat brain homogenates is most similar to that observed in HEK293 cells transfected with the rat Y1, but not rat Y4, receptor cDNA. Autoradiographic studies demonstrated that [125I]-GR231118 binding sites were fully inhibited by the Y1 antagonist BIBO3304 in most areas of the rat brain. Interestingly, high percentage of [125I]-GR231118/BIBO3304-insensitive binding sites were detected in few areas. These [125I]-GR231118/BIBO3304-insensitive binding sites likely represent labelling to the Y4 receptor subtype. In summary, [125I]-GR231118 is a new radiolabelled probe to investigate the Y1 and Y4 receptors; its major advantage being its high affinity. Using highly selective Y1 antagonists such as BIBO3304 or BIBP3226 it is possible to block the binding of [125I]-GR231118 to the Y1 receptor allowing for the characterization and visualization of the purported Y4 subtype. PMID:10694200

  12. Sodium 4-phenylbutyrate downregulates Hsc70: implications for intracellular trafficking of DeltaF508-CFTR.

    PubMed

    Rubenstein, R C; Zeitlin, P L

    2000-02-01

    The most common mutation of the cystic fibrosis transmembrane conductance regulator (CFTR), DeltaF508, is a trafficking mutant that has prolonged associations with molecular chaperones and is rapidly degraded, at least in part by the ubiquitin-proteasome system. Sodium 4-phenylbutyrate (4PBA) improves DeltaF508-CFTR trafficking and function in vitro in cystic fibrosis epithelial cells and in vivo. To further understand the mechanism of action of 4PBA, we tested the hypothesis that 4PBA modulates the targeting of DeltaF508-CFTR for ubiquitination and degradation by reducing the expression of Hsc70 in cystic fibrosis epithelial cells. IB3-1 cells (genotype DeltaF508/W1282X) that were treated with 0.05-5 mM 4PBA for 2 days in culture demonstrated a dose-dependent reduction in Hsc70 protein immunoreactivity and mRNA levels. Immunoprecipitation with Hsc70-specific antiserum demonstrated that Hsc70 and CFTR associated under control conditions and that treatment with 4PBA reduced these complexes. Levels of immunoreactive Hsp40, Hdj2, Hsp70, Hsp90, and calnexin were unaffected by 4PBA treatment. These data suggest that 4PBA may improve DeltaF508-CFTR trafficking by allowing a greater proportion of mutant CFTR to escape association with Hsc70.

  13. Complete Genome Sequence of the Alfalfa Symbiont Sinorhizobium/Ensifer meliloti Strain GR4

    PubMed Central

    Martínez-Abarca, Francisco; Martínez-Rodríguez, Laura; López-Contreras, José Antonio; Jiménez-Zurdo, José Ignacio

    2013-01-01

    We present the complete nucleotide sequence of the multipartite genome of Sinorhizobium/Ensifer meliloti GR4, a predominant rhizobial strain in an agricultural field site. The genome (total size, 7.14 Mb) consists of five replicons: one chromosome, two expected symbiotic megaplasmids (pRmeGR4c and pRmeGR4d), and two accessory plasmids (pRmeGR4a and pRmeGR4b). PMID:23409262

  14. Complete Genome Sequence of the Alfalfa Symbiont Sinorhizobium/Ensifer meliloti Strain GR4.

    PubMed

    Martínez-Abarca, Francisco; Martínez-Rodríguez, Laura; López-Contreras, José Antonio; Jiménez-Zurdo, José Ignacio; Toro, Nicolás

    2013-01-01

    We present the complete nucleotide sequence of the multipartite genome of Sinorhizobium/Ensifer meliloti GR4, a predominant rhizobial strain in an agricultural field site. The genome (total size, 7.14 Mb) consists of five replicons: one chromosome, two expected symbiotic megaplasmids (pRmeGR4c and pRmeGR4d), and two accessory plasmids (pRmeGR4a and pRmeGR4b).

  15. X-ray diffraction analysis of 4- and 4'-substituted C n H2 n + 1O-C6H3(OH)-CH=N-C6H4-C m H2 m + 1 ( n/ m = 2/1 and 3/4) salicylideneanilines

    NASA Astrophysics Data System (ADS)

    Kuz'mina, L. G.; Navasardyan, M. A.; Mikhailov, A. A.

    2017-11-01

    X-ray diffraction study of two crystalline modifications of C2H5O-C6H3(OH)-CH=N-C6H4-CH3 ( 1a, sp. gr. P21/ n, and 1b, sp. gr. C2/c) and C3H7O-C6H3(OH)-CH=N-C6H4-C4H9 ( 2, sp. gr. P212121) has been performed. The 1a crystal structure contains two independent molecules. The molecules are conformationally nonrigid with respect to the mutual rotation of benzene rings; the dihedral angles between their planes are 29.19° and 26.00° in the independent molecules of 1a, 18.72° in the molecule of 1b, and 50.35° in the molecule of 2. The crystal packing of the compounds is discussed.

  16. 24 CFR 965.508 - Individual relief.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 4 2010-04-01 2010-04-01 false Individual relief. 965.508 Section 965.508 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued... PHA-OWNED OR LEASED PROJECTS-GENERAL PROVISIONS Resident Allowances for Utilities § 965.508 Individual...

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

    PubMed

    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.

  18. Activation of deltaF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4-phenylbutyrate, genistein and CPX.

    PubMed

    Andersson, C; Roomans, G M

    2000-05-01

    The cellular basis of cystic fibrosis (CF) is a defect in a cyclic adenosine monophosphate (cAMP)-activated chloride channel (CF transmembrane conductance regulator) in epithelial cells that leads to decreased chloride ion transport and impaired water transport across the cell membrane. This study investigated whether it was possible to activate the defective chloride channel in cystic fibrosis respiratory epithelial cells with 4-phenylbutyrate (4PBA), genistein and 8-cyclopentyl-1,3-dipropylxanthine (CPX). The CF bronchial epithelial cell line CFBE41o-, which expresses the deltaF508 mutation, was treated with these agents and loss of Cl-, indicating Cl- efflux, measured by X-ray microanalysis. 8-bromo-cAMP alone did not induce Cl- efflux in CFBE41o- cells, but after incubation with 4PBA a significant efflux of Cl- occurred. Stimulation of cells with a combination of genistein and cAMP also induced Cl- efflux, whereas a combination of pretreatment with 4PBA and a combined stimulation with genistein and cAMP induced an even larger Cl- efflux. Cl- efflux could also be stimulated by CPX, but this effect was not enhanced by 4PBA pretreatment. The deltaF508 mutation leads to impaired processing of the cystic fibrosis transmembrane conductance regulator. The increased efflux of chloride after 4-phenylbutyrate treatment can be explained by the fact that 4-phenylbutyrate allows the deltaF508 cystic fibrosis transmembrane conductance regulator to escape degradation and to be transported to the cell surface. Genistein and 8-cyclopentyl-1,3-dipropylxanthine act by stimulating chloride ion efflux by increasing the probability of the cystic fibrosis transmembrane conductance regulator being open. The combination of 4-phenylbutyrate and genistein may be useful in a potential pharmacological therapy for cystic fibrosis patients with the deltaF508 mutation.

  19. Substrate-Independent Epitaxial Growth of the Metal-Organic Framework MOF-508a.

    PubMed

    Wilson, M; Barrientos-Palomo, S N; Stevens, P C; Mitchell, N L; Oswald, G; Nagaraja, C M; Badyal, J P S

    2018-01-31

    Plasmachemical deposition is a substrate-independent method for the conformal surface functionalization of solid substrates. Structurally well-defined pulsed plasma deposited poly(1-allylimidazole) layers provide surface imidazole linker groups for the directed liquid-phase epitaxial (layer-by-layer) growth of metal-organic frameworks (MOFs) at room temperature. For the case of microporous [Zn (benzene-1,4-dicarboxylate)-(4,4'-bipyridine) 0.5 ] (MOF-508), the MOF-508a polymorph containing two interpenetrating crystal lattice frameworks undergoes orientated Volmer-Weber growth and displays CO 2 gas capture behavior at atmospheric concentrations in proportion to the number of epitaxially grown MOF-508 layers.

  20. 46 CFR 122.508 - Wearing of life jackets.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 4 2010-10-01 2010-10-01 false Wearing of life jackets. 122.508 Section 122.508... Preparations for Emergencies § 122.508 Wearing of life jackets. (a) The master of a vessel shall require passengers to don life jackets when possible hazardous conditions exist, including, but not limited to: (1...

  1. 46 CFR 122.508 - Wearing of life jackets.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 4 2011-10-01 2011-10-01 false Wearing of life jackets. 122.508 Section 122.508... Preparations for Emergencies § 122.508 Wearing of life jackets. (a) The master of a vessel shall require passengers to don life jackets when possible hazardous conditions exist, including, but not limited to: (1...

  2. 46 CFR 122.508 - Wearing of life jackets.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 4 2013-10-01 2013-10-01 false Wearing of life jackets. 122.508 Section 122.508... Preparations for Emergencies § 122.508 Wearing of life jackets. (a) The master of a vessel shall require passengers to don life jackets when possible hazardous conditions exist, including, but not limited to: (1...

  3. 46 CFR 122.508 - Wearing of life jackets.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 4 2014-10-01 2014-10-01 false Wearing of life jackets. 122.508 Section 122.508... Preparations for Emergencies § 122.508 Wearing of life jackets. (a) The master of a vessel shall require passengers to don life jackets when possible hazardous conditions exist, including, but not limited to: (1...

  4. 46 CFR 122.508 - Wearing of life jackets.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 4 2012-10-01 2012-10-01 false Wearing of life jackets. 122.508 Section 122.508... Preparations for Emergencies § 122.508 Wearing of life jackets. (a) The master of a vessel shall require passengers to don life jackets when possible hazardous conditions exist, including, but not limited to: (1...

  5. Tumor cell-released TLR4 ligands stimulate Gr-1+CD11b+F4/80+ cells to induce apoptosis of activated T cells.

    PubMed

    Liu, Yan-Yan; Sun, Ling-Cong; Wei, Jing-Jing; Li, Dong; Yuan, Ye; Yan, Bin; Liang, Zhi-Hui; Zhu, Hui-Fen; Xu, Yong; Li, Bo; Song, Chuan-Wang; Liao, Sheng-Jun; Lei, Zhang; Zhang, Gui-Mei; Feng, Zuo-Hua

    2010-09-01

    Gr-1(+)CD11b(+)F4/80(+) cells play important roles in tumor development and have a negative effect on tumor immunotherapy. So far, the mechanisms underlying the regulation of their immunosuppressive phenotype by classical and alternative macrophage activation stimuli are not well elucidated. In this study, we found that molecules from necrotic tumor cells (NTC-Ms) stimulated Gr-1(+)CD11b(+)F4/80(+) cells to induce apoptosis of activated T cells but not nonstimulated T cells. The apoptosis-inducing capacity was determined by higher expression levels of arginase I and IL-10 relative to those of NO synthase 2 and IL-12 in Gr-1(+)CD11b(+)F4/80(+) cells, which were induced by NTC-Ms through TLR4 signaling. The apoptosis-inducing capacity of NTC-Ms-stimulated Gr-1(+)CD11b(+)F4/80(+) cells could be enhanced by IL-10. IFN-gamma may reduce the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells only if their response to IFN-gamma was not attenuated. However, the potential of Gr-1(+)CD11b(+)F4/80(+) cells to express IL-12 in response to IFN-gamma could be attenuated by tumor, partially due to the existence of active STAT3 in Gr-1(+)CD11b(+)F4/80(+) cells and NTC-Ms from tumor. In this situation, IFN-gamma could not effectively reduce the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells. Tumor immunotherapy with 4-1BBL/soluble programmed death-1 may significantly reduce, but not abolish the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells in local microenvironment. Blockade of TLR4 signaling could further reduce the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells and enhance the suppressive effect of 4-1BBL/soluble form of programmed death-1 on tumor growth. These findings indicate the relationship of distinct signaling pathways with apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells and emphasize the importance of blocking TLR4 signaling to prevent the induction of T cell apoptosis by Gr-1(+)CD11b(+)F4/80(+) cells.

  6. The novel complex allele [A238V;F508del] of the CFTR gene: clinical phenotype and possible implications for cystic fibrosis etiological therapies.

    PubMed

    Diana, Anna; Polizzi, Angela Maria; Santostasi, Teresa; Ratclif, Luigi; Pantaleo, Maria Giuseppina; Leonetti, Giuseppina; Iusco, Danila Rosa; Gallo, Crescenzio; Conese, Massimo; Manca, Antonio

    2016-06-01

    Few mutations in cis have been annotated for F508del homozygous patients. Southern Italy patients who at a first analysis appeared homozygous for the F508del mutation (n=63) or compound heterozygous for the F508del and another mutation in the cystic fibrosis transmembrane conductance regulator gene (n=155) were searched for the A238V mutation in exon 6. The allelic frequency of the complex allele [A238V;F508del] was 0.04. When the whole data set was used (comprised also of 56 F508del/F508del and 34 F508del/other mutation controls), no differences reached the statistical significance in the clinical parameters, except chloride concentrations which were lower in [A238V;F508del]/other mutation compared with F508del/other mutation (P=0.03). The two study groups presented less complications than the control groups. Within the minimal data set (34 F508del/F508del, 27 F508del/other mutation, 4 [A238V;F508del]/F508del cases and 5 [A238V;F508del]/other mutation cases); that is, presenting all the variables in each patient, forced expiratory volume in 1 s and forced vital capacity presented a trend to lower levels in the study groups in comparison with the F508del/F508del group, and C-reactive protein approximated statistically significant higher levels in the [A238V;F508del]/other mutation as compared with F508del/F508del patients (P=0.09). The analysis of statistical dependence among the variables showed a significant anticorrelation between chloride and body mass index in the [A238V;F508del]/other mutation group. In conclusion, the complex allele [A238V;F508del] seems to be associated with less general complications than in the control groups, on the other hand possibly giving a worse pulmonary phenotype and higher systemic/local inflammatory response. These findings have implications for the correct recruitment and clinical response of F508del patients in the clinical trials testing the new etiological drugs for cystic fibrosis.

  7. In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR.

    PubMed Central

    Rubenstein, R C; Egan, M E; Zeitlin, P L

    1997-01-01

    The most common cystic fibrosis transmembrane conductance regulator mutation, delta F508-CFTR, is a partially functional chloride channel that is retained in the endoplasmic reticulum and degraded. We hypothesize that a known transcriptional regulator, sodium 4-phenylbutyrate (4PBA), will enable a greater fraction of delta F508-CFTR to escape degradation and appear at the cell surface. Primary cultures of nasal polyp epithelia from CF patients (delta F508 homozygous or heterozygous), or the CF bronchial epithelial cell line IB3-1 (delta F508/W1282X) were exposed to 4PBA for up to 7 d in culture. 4PBA treatment at concentrations of 0.1 and 2 mM resulted in the restoration of forskolin-activated chloride secretion. Protein kinase A-activated, linear, 10 pS chloride channels appeared at the plasma membrane of IB3-1 cells at the tested concentration of 2.5 mM. Treatment of IB3-1 cells with 0.1-1 mM 4PBA and primary nasal epithelia with 5 mM 4PBA also resulted in the appearance of higher molecular mass forms of CFTR consistent with addition and modification of oligosaccharides in the Golgi apparatus, as detected by immunoblotting of whole cell lysates with anti-CFTR antisera. Immunocytochemistry in CF epithelial cells treated with 4PBA was consistent with increasing amounts of delta F508-CFTR. These data indicate that 4PBA is a promising pharmacologic agent for inducing correction of the CF phenotype in CF patients carrying the delta F508 mutation. PMID:9366560

  8. In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR.

    PubMed

    Rubenstein, R C; Egan, M E; Zeitlin, P L

    1997-11-15

    The most common cystic fibrosis transmembrane conductance regulator mutation, delta F508-CFTR, is a partially functional chloride channel that is retained in the endoplasmic reticulum and degraded. We hypothesize that a known transcriptional regulator, sodium 4-phenylbutyrate (4PBA), will enable a greater fraction of delta F508-CFTR to escape degradation and appear at the cell surface. Primary cultures of nasal polyp epithelia from CF patients (delta F508 homozygous or heterozygous), or the CF bronchial epithelial cell line IB3-1 (delta F508/W1282X) were exposed to 4PBA for up to 7 d in culture. 4PBA treatment at concentrations of 0.1 and 2 mM resulted in the restoration of forskolin-activated chloride secretion. Protein kinase A-activated, linear, 10 pS chloride channels appeared at the plasma membrane of IB3-1 cells at the tested concentration of 2.5 mM. Treatment of IB3-1 cells with 0.1-1 mM 4PBA and primary nasal epithelia with 5 mM 4PBA also resulted in the appearance of higher molecular mass forms of CFTR consistent with addition and modification of oligosaccharides in the Golgi apparatus, as detected by immunoblotting of whole cell lysates with anti-CFTR antisera. Immunocytochemistry in CF epithelial cells treated with 4PBA was consistent with increasing amounts of delta F508-CFTR. These data indicate that 4PBA is a promising pharmacologic agent for inducing correction of the CF phenotype in CF patients carrying the delta F508 mutation.

  9. Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR.

    PubMed

    Donaldson, Scott H; Pilewski, Joseph M; Griese, Matthias; Cooke, Jon; Viswanathan, Lakshmi; Tullis, Elizabeth; Davies, Jane C; Lekstrom-Himes, Julie A; Wang, Linda T

    2018-01-15

    Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor. To evaluate the safety and efficacy of tezacaftor monotherapy and of tezacaftor/ivacaftor combination therapy in subjects with cystic fibrosis homozygous for F508del or compound heterozygous for F508del and G551D. This was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study (NCT01531673). Subjects homozygous for F508del received tezacaftor (10 to 150 mg) every day alone or in combination with ivacaftor (150 mg every 12 h) in a dose escalation phase, as well as in a dosage regimen testing phase. Subjects compound heterozygous for F508del and G551D, taking physician-prescribed ivacaftor, received tezacaftor (100 mg every day). Primary endpoints were safety through Day 56 and change in sweat chloride from baseline through Day 28. Secondary endpoints included change in percent predicted FEV 1 (ppFEV 1 ) from baseline through Day 28 and pharmacokinetics. The incidence of adverse events was similar across treatment arms. Tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h) resulted in a 6.04 mmol/L decrease in sweat chloride and 3.75 percentage point increase in ppFEV 1 in subjects homozygous for F508del, and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV 1 in subjects compound heterozygous for F508del and G551D from baseline through Day 28 (P < 0.05 for all). These results support continued clinical development of tezacaftor (100 mg every day) in combination with ivacaftor (150 mg every 12 h) in subjects with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT01531673).

  10. A chemical corrector modifies the channel function of F508del-CFTR.

    PubMed

    Kim Chiaw, Patrick; Wellhauser, Leigh; Huan, Ling Jun; Ramjeesingh, Mohabir; Bear, Christine E

    2010-09-01

    The deletion of Phe-508 (F508del) constitutes the most prevalent cystic fibrosis-causing mutation. This mutation leads to cystic fibrosis transmembrane conductance regulator (CFTR) misfolding and retention in the endoplasmic reticulum and altered channel activity in mammalian cells. This folding defect can however be partially overcome by growing cells expressing this mutant protein at low (27 degrees C) temperature. Chemical "correctors" have been identified that are also effective in rescuing the biosynthetic defect in F508del-CFTR, thereby permitting its functional expression at the cell surface. The mechanism of action of chemical correctors remains unclear, but it has been suggested that certain correctors [including 4-cyclohexyloxy-2-(1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl)-quinazoline (VRT-325)] may act to promote trafficking by interacting directly with the mutant protein. To test this hypothesis, we assessed the effect of VRT-325 addition on the channel activity of F508del-CFTR after its surface expression had been "rescued" by low temperature. It is noteworthy that short-term pretreatment with VRT-325 [but not with an inactive analog, 4-hydroxy-2-(1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl)-quinazoline (VRT-186)], caused a modest but significant inhibition of cAMP-mediated halide flux. Furthermore, VRT-325 decreased the apparent ATP affinity of purified and reconstituted F508del-CFTR in our ATPase activity assay, an effect that may account for the decrease in channel activity by temperature-rescued F508del-CFTR. These findings suggest that biosynthetic rescue mediated by VRT-325 may be conferred (at least in part) by direct modification of the structure of the mutant protein, leading to a decrease in its ATP-dependent conformational dynamics. Therefore, the challenge for therapy discovery will be the design of small molecules that bind to promote biosynthetic maturation of the major mutant without compromising its activity in

  11. Correlation of the thermodynamic calculation and the experimental observation of Ni-Mo-Cr low alloy steel changing Ni, Mo, and Cr contents

    NASA Astrophysics Data System (ADS)

    Park, Sang-Gyu; Kim, Min-Chul; Lee, Bong-Sang; Wee, Dang-Moon

    2010-12-01

    SA508 Gr.4N Ni-Mo-Cr low alloy steel has improved fracture toughness and strength compared to commercial low alloy steels such as SA508 Gr.3 Mn-Mo-Ni low alloy steel, which has less than 1% Ni. Higher strength and fracture toughness of low alloy steels can be achieved by increasing the Ni and Cr contents. In this study, the effects of the alloying elements of Ni and Cr on the microstructural characteristics and mechanical properties of SA508 Gr.4N Ni-Mo-Cr low alloy steel are evaluated. Changes in the stable phases of SA508 Gr.4N low alloy steel with these alloying elements were evaluated using thermodynamic calculation software. These values were then compared with the observed microstructural results. Additionally, tensile tests and Charpy impact test were carried out to evaluate the mechanical properties. The thermodynamic calculations show that Ni mainly affects the change of the matrix phase of γ and α rather than the carbide phase. Contrary to the Ni effect, Cr and Mo primarily affect the precipitation behavior of the carbide phases of Cr 23C 6, Cr 7C 3 and Mo 2C. In the microscopic observations, the lath martensitic structure becomes finer as the Ni content increases without affecting the carbides. When the Cr content decreases, the Cr carbide becomes unstable and carbide coarsening occurs. Carbide Mo 2C in the form of fine needles were observed in the high-Mo alloy. Greater strength was obtained after additions of Ni and Mo and the transition properties were improved as the Ni and Cr contents increased. These results were correlated with the thermodynamic calculation results.

  12. A synonymous codon change alters the drug sensitivity of ΔF508 cystic fibrosis transmembrane conductance regulator

    PubMed Central

    Bali, Vedrana; Lazrak, Ahmed; Guroji, Purushotham; Fu, Lianwu; Matalon, Sadis; Bebok, Zsuzsanna

    2016-01-01

    Synonymous mutations, such as I507-ATC→ATT, in deletion of Phe508 in cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR), the most frequent disease-associated mutant of CFTR, may affect protein biogenesis, structure, and function and contribute to an altered disease phenotype. Small-molecule drugs are being developed to correct ΔF508 CFTR. To understand correction mechanisms and the consequences of synonymous mutations, we analyzed the effect of mechanistically distinct correctors, corrector 4a (C4) and lumacaftor (VX-809), on I507-ATT and I507-ATC ΔF508 CFTR biogenesis and function. C4 stabilized I507-ATT ΔF508 CFTR band B, but without considerable biochemical and functional correction. VX-809 biochemically corrected ∼10% of both of the variants, leading to stable, forskolin+3-isobutyl-1-methylxanthine (IBMX)-activated whole-cell currents in the presence of the corrector. Omitting VX-809 during whole-cell recordings led to a spontaneous decline of the currents, suggesting posttranslational stabilization by VX-809. Treatment of cells with the C4+VX-809 combination resulted in enhanced rescue and 2-fold higher forskolin+IBMX–activated currents of both I507-ATT and I507-ATC ΔF508 CFTR, compared with VX-809 treatment alone. The lack of an effect of C4 on I507-ATC ΔF508 CFTR, but its additive effect in combination with VX-809, implies that C4 acted on VX-809–modified I507-ATC ΔF508 CFTR. Our results suggest that binding of C4 and VX-809 to ΔF508 CFTR is conformation specific and provide evidence that synonymous mutations can alter the drug sensitivity of proteins.—Bali, V., Lazrak, A., Guroji, P., Fu, L., Matalon, S., Bebok, Z. A synonymous codon change alters the drug sensitivity of ΔF508 cystic fibrosis transmembrane conductance regulator. PMID:26336913

  13. A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in deltaF508-homozygous cystic fibrosis patients: partial restoration of nasal epithelial CFTR function.

    PubMed

    Rubenstein, R C; Zeitlin, P L

    1998-02-01

    Sodium 4-phenylbutyrate (Buphenyl, 4PBA) is a new FDA approved drug for management of urea cycle disorders. We have previously presented data suggesting that 4PBA, at clinically achievable concentrations, induces CFTR channel function on the plasma membrane of deltaF508-expressing cystic fibrosis (CF) airway epithelial cells in vitro (Rubenstein, R. C., and P. L. Zeitlin, 1997. J. Clin. Invest. 100:2457-2463). We hypothesized that 4PBA would induce epithelial CFTR function in vivo in individuals homozygous for deltaF508-CFTR. A randomized, double-blind, placebo-controlled trial in 18 deltaF508-homozygous patients with CF was performed with the maximum approved adult dose of 4PBA, 19 grams p.o. divided t.i.d., given for 1 wk. Nasal potential difference (NPD) response patterns and sweat chloride concentrations were determined before and after study drug treatment, and 4PBA and metabolites were assayed in plasma and urine at the end of study drug treatment. Subjects in the 4PBA group demonstrated small, but statistically significant improvements of the NPD response to perfusion of an isoproterenol/amiloride/chloride-free solution; this measure reflects epithelial CFTR function and is highly discriminatory between patients with and without CF. Subjects who had received 4PBA did not demonstrate significantly reduced sweat chloride concentrations or alterations in the amiloride-sensitive NPD. Side effects due to drug therapy were minimal and comparable in the two groups. These data are consistent with 4PBA therapy inducing CFTR function in the nasal epithelia of deltaF508-homozygous CF patients.

  14. 47 CFR 73.508 - Standards of good engineering practice.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 4 2010-10-01 2010-10-01 false Standards of good engineering practice. 73.508 Section 73.508 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES... engineering practice. (a) All noncommercial educational stations and LPFM stations operating with more than 10...

  15. 47 CFR 73.508 - Standards of good engineering practice.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 4 2014-10-01 2014-10-01 false Standards of good engineering practice. 73.508 Section 73.508 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES... engineering practice. (a) All noncommercial educational stations and LPFM stations operating with more than 10...

  16. 47 CFR 73.508 - Standards of good engineering practice.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 4 2012-10-01 2012-10-01 false Standards of good engineering practice. 73.508 Section 73.508 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES... engineering practice. (a) All noncommercial educational stations and LPFM stations operating with more than 10...

  17. 47 CFR 73.508 - Standards of good engineering practice.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 4 2013-10-01 2013-10-01 false Standards of good engineering practice. 73.508 Section 73.508 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES... engineering practice. (a) All noncommercial educational stations and LPFM stations operating with more than 10...

  18. 47 CFR 73.508 - Standards of good engineering practice.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 4 2011-10-01 2011-10-01 false Standards of good engineering practice. 73.508 Section 73.508 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES... engineering practice. (a) All noncommercial educational stations and LPFM stations operating with more than 10...

  19. 42 CFR 403.508 - Limitations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 2 2014-10-01 2014-10-01 false Limitations. 403.508 Section 403.508 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS SPECIAL PROGRAMS AND PROJECTS Beneficiary Counseling and Assistance Grants § 403.508 Limitations. (a) Use...

  20. 42 CFR 403.508 - Limitations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 2 2013-10-01 2013-10-01 false Limitations. 403.508 Section 403.508 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS SPECIAL PROGRAMS AND PROJECTS Beneficiary Counseling and Assistance Grants § 403.508 Limitations. (a) Use...

  1. 42 CFR 403.508 - Limitations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 2 2010-10-01 2010-10-01 false Limitations. 403.508 Section 403.508 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS SPECIAL PROGRAMS AND PROJECTS Beneficiary Counseling and Assistance Grants § 403.508 Limitations. (a) Use...

  2. 42 CFR 403.508 - Limitations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 2 2012-10-01 2012-10-01 false Limitations. 403.508 Section 403.508 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS SPECIAL PROGRAMS AND PROJECTS Beneficiary Counseling and Assistance Grants § 403.508 Limitations. (a) Use...

  3. 42 CFR 403.508 - Limitations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 2 2011-10-01 2011-10-01 false Limitations. 403.508 Section 403.508 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS SPECIAL PROGRAMS AND PROJECTS Beneficiary Counseling and Assistance Grants § 403.508 Limitations. (a) Use...

  4. 12 CFR 508.8 - Default.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Default. 508.8 Section 508.8 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.8 Default. If the subject individual fails to file a petition for a...

  5. A mouse model for the cystic fibrosis delta F508 mutation.

    PubMed Central

    van Doorninck, J H; French, P J; Verbeek, E; Peters, R H; Morreau, H; Bijman, J; Scholte, B J

    1995-01-01

    Most cystic fibrosis (CF) patients produce a mutant form (delta F508) of the cystic fibrosis transmembrane conductance regulator (CFTR), which is not properly processed in normal cells but is active as a chloride channel in several experimental systems. We used a double homologous recombination ('Hit and Run') procedure to generate a mouse model for the delta F508 mutation. Targeted embryonic stem (ES) cells (Hit clones) were found; of these either 80 or 20% of the clones had lost the delta F508 mutation, depending on the distance between the linearization site in the targeting construct and the delta F508 mutation. Correctly targeted clones underwent a second selection step resulting in ES cell clones (Run clones) heterozygous for the delta F508 mutation with an efficiency of 2-7%. Chimeric mice were generated and offspring homozygous for the delta F508 mutation showed electrophysiological abnormalities in nasal epithelium, gallbladder and in the intestine, and histological abnormalities in the intestine, typical of CF. Our data suggest that the delta F508 mice have residual delta F508 CFTR activity which would explain the mild pathology of the delta F508 mice. The delta F508 mouse may provide a useful model for the study of the processing defect of delta F508 CFTR and for the development of novel therapeutic approaches based on circumvention of the processing block. Images PMID:7556083

  6. 12 CFR 508.1 - Scope.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Scope. 508.1 Section 508.1 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.1 Scope. The rules in this part apply to hearings, which are exempt...

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

    PubMed

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

    2004-03-01

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

  8. Induction of HSP70 promotes DeltaF508 CFTR trafficking.

    PubMed

    Choo-Kang, L R; Zeitlin, P L

    2001-07-01

    The DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) is a temperature-sensitive trafficking mutant that is detected as an immature 160-kDa form (band B) in gel electrophoresis. The goal of this study was to test the hypothesis that HSP70, a member of the 70-kDa heat shock protein family, promotes DeltaF508 CFTR processing to the mature 180-kDa form (band C). Both pharmacological and genetic techniques were used to induce HSP70. IB3-1 cells were treated with sodium 4-phenylbutyrate (4PBA) to promote maturation of DeltaF508 CFTR to band C. A dose-dependent increase in band C and total cellular HSP70 was observed. Under these conditions, HSP70-CFTR complexes were increased and 70-kDa heat shock cognate protein-CFTR complexes were decreased. Increased DeltaF508 CFTR maturation was also seen after transfection with an HSP70 expression plasmid and exposure to glutamine, an inducer of HSP70. With immunofluorescence techniques, the increased appearance of CFTR band C correlated with CFTR distribution beyond the perinuclear regions. These data suggest that induction of HSP70 promotes DeltaF508 CFTR maturation and trafficking.

  9. 48 CFR 419.508 - Solicitation provisions and contract clauses.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Standard and NAICS Code Information, in solicitations that are set aside for small businesses. [61 FR 53646... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Solicitation provisions and contract clauses. 419.508 Section 419.508 Federal Acquisition Regulations System DEPARTMENT OF...

  10. 47 CFR 54.508 - Technology plans.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 3 2013-10-01 2013-10-01 false Technology plans. 54.508 Section 54.508... SERVICE Universal Service Support for Schools and Libraries § 54.508 Technology plans. (a) Applicants must develop a technology plan when requesting discounts for internal connections and basic maintenance for...

  11. Simulation of the reflected blast wave from a C-4 charge

    NASA Astrophysics Data System (ADS)

    Howard, W. Michael; Kuhl, Allen L.; Tringe, Joseph

    2012-03-01

    The reflection of a blast wave from a C4 charge detonated above a planar surface is simulated with our ALE3D code. We used a finely-resolved, fixed Eulerian 2-D mesh (167 μm per cell) to capture the detonation of the charge, the blast wave propagation in nitrogen, and its reflection from the surface. The thermodynamic properties of the detonation products and nitrogen were specified by the Cheetah code. A programmed-burn model was used to detonate the charge at a rate based on measured detonation velocities. Computed pressure histories are compared with pressures measured by Kistler 603B piezoelectric gauges at 7 ranges (GR = 0, 5.08, 10.16, 15.24, 20.32, 25.4, and 30.48 cm) along the reflecting surface. Computed and measured waveforms and positive-phase impulses were similar, except at close-in ranges (GR < 5 cm), which were dominated by jetting effects.

  12. 45 CFR 50.8 - Compliance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 1 2011-10-01 2011-10-01 false Compliance. 50.8 Section 50.8 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION U.S. EXCHANGE VISITOR PROGRAM-REQUEST FOR WAIVER OF THE TWO-YEAR FOREIGN RESIDENCE REQUIREMENT § 50.8 Compliance. If an alien physician acquires H...

  13. 45 CFR 50.8 - Compliance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Compliance. 50.8 Section 50.8 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION U.S. EXCHANGE VISITOR PROGRAM-REQUEST FOR WAIVER OF THE TWO-YEAR FOREIGN RESIDENCE REQUIREMENT § 50.8 Compliance. If an alien physician acquires H...

  14. Study on Material Selection of Reactor Pressure Vessel of SCWR

    NASA Astrophysics Data System (ADS)

    Ma, Shuli; Luo, Ying; Yin, Qinwei; Li, Changxiang; Xie, Guofu

    This paper first analyzes the feasibility of SA-508 Grade 3 Class 1 Steel as an alternative material for Supercritical Water-Cooled Reactor (SCWR) Reactor Pressure Vessel (RPV). This kind of steel is limited to be applied in SCWR RPV due to its quenching property, though large forging could be accomplished by domestic manufacturers in forging aspect. Therefore, steels with higher strength and better quenching property are needed for SWCR RPV. The chemical component of SA-508 Gr.3 Cl.2 steel is similar to that of SA-508 Gr.3 Cl.1 steel, and more appropriate matching of strength and toughness could be achieved by the adjusting the elements contents, as well as proper control of tempering temperature and time. In light of the fact that Cl.2 steel has been successfully applied to steam generator, it could be an alternative material for SWCR RPV. SA-508 Gr.4N steel with high strength and good toughness is another alternative material for SCWR RPV. But large amount of research work before application is still needed for the lack of data on welding and irradiation etc.

  15. 34 CFR 682.508 - Assignment of a loan.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false Assignment of a loan. 682.508 Section 682.508 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION FEDERAL FAMILY EDUCATION LOAN (FFEL) PROGRAM Federal Guaranteed Student Loan Programs...

  16. 12 CFR 508.11 - Relevant considerations.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Relevant considerations. 508.11 Section 508.11 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.11 Relevant considerations. (a) In determining whether...

  17. 47 CFR 54.508 - Technology plans.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Technology plans. 54.508 Section 54.508... SERVICE Universal Service Support for Schools and Libraries § 54.508 Technology plans. (a) Contents. The technology plans referred to in this subpart must include the following five elements: (1) A clear statement...

  18. 45 CFR 162.508 - Enumeration System.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 1 2012-10-01 2012-10-01 false Enumeration System. 162.508 Section 162.508 Public... ADMINISTRATIVE REQUIREMENTS Standard Unique Health Identifier for Health Plans § 162.508 Enumeration System. The Enumeration System must do all of the following: (a) Assign a single, unique— (1) HPID to a health plan...

  19. 45 CFR 162.508 - Enumeration System.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 1 2014-10-01 2014-10-01 false Enumeration System. 162.508 Section 162.508 Public... ADMINISTRATIVE REQUIREMENTS Standard Unique Health Identifier for Health Plans § 162.508 Enumeration System. The Enumeration System must do all of the following: (a) Assign a single, unique— (1) HPID to a health plan...

  20. 45 CFR 162.508 - Enumeration System.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 false Enumeration System. 162.508 Section 162.508 Public... ADMINISTRATIVE REQUIREMENTS Standard Unique Health Identifier for Health Plans § 162.508 Enumeration System. The Enumeration System must do all of the following: (a) Assign a single, unique— (1) HPID to a health plan...

  1. Learn About Section 508

    EPA Pesticide Factsheets

    Find out about EPA's commitment to making its websites and other electronic and information technology (EIT) products accessible, learn what Section 508 of the Rehabilitation Act covers and why, and how to make your EIT 508 compliant.

  2. Renal proximal tubule function is preserved in Cftrtm2camΔF508 cystic fibrosis mice

    PubMed Central

    Kibble, J D; Balloch, K J D; Neal, A M; Hill, C; White, S; Robson, L; Green, R; Taylor, C J

    2001-01-01

    Changes in proximal tubule function have been reported in cystic fibrosis patients. The aim of this study was to investigate proximal tubule function in the Cftrtm2camΔF508 cystic fibrosis (CF) mouse model. A range of techniques were used including renal clearance studies, in situ microperfusion, RT-PCR and whole-cell patch clamping. Renal Na+ clearance was similar in wild-type (1.4 ± 0.3 μl min−1, number of animals, N= 12) and CF mice (1.6 ± 0.4 μl min−1, N= 7) under control conditions. Acute extracellular volume expansion resulted in significant natriuresis in wild-type (7.0 ± 0.8 μl min−1, N= 8) and CF mice (9.3 ± 1.4 μl min−1, N= 9); no difference between genotypes was observed. In situ microperfusion revealed that fluid absorptive rate (Jv) was similar under control conditions between wild-type (2.2 ± 0.4 nl mm−1 min−1, n= 10) and CF mice (1.9 ± 0.3 nl mm−1 min−1, n= 11). Addition of a forskolin-dibutyryl cAMP (db-cAMP) cocktail to the perfusate caused no significant change in Jv in either wild-type (2.6 ± 0.7 nl mm−1 min−1, n= 10) or Cftrtm2camΔF508 mice (2.0 ± 0.5 nl mm−1 min−1, n= 10). CFTR expression was confirmed in samples of outer cortex using RT-PCR. However, no evidence for functional CFTR was obtained when outer cortical cells were stimulated with protein kinase A or forskolin-db-cAMP using whole-cell patch clamping. In conclusion, no functional deficit in proximal tubule function was found in Cftrtm2camΔF508 mice. This may be a consequence of a lack of whole-cell cAMP-dependent Cl− conductance in mouse proximal tubule cells. PMID:11306663

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

    PubMed Central

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

    2004-01-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel is defective during cystic fibrosis (CF). Activators of the CFTR Cl− channel may be useful for therapy of CF. Here, we demonstrate that a range of general anesthetics like normal-alkanols (n-alkanols) and related compounds can stimulate the Cl− channel activity of wild-type CFTR and delF508-CFTR mutant. The effects of n-alkanols like octanol on CFTR activity were measured by iodide (125I) efflux and patch-clamp techniques on three distinct cellular models: (1) CFTR-expressing Chinese hamster ovary cells, (2) human airway Calu-3 epithelial cells and (3) human airway JME/CF15 epithelial cells which express the delF508-CFTR mutant. Our data show for the first time that n-alkanols activate both wild-type CFTR and delF508-CFTR mutant. Octanol stimulated 125I efflux in a dose-dependent manner in CFTR-expressing cells (wild-type and delF508) but not in cell lines lacking CFTR. 125I efflux and Cl− currents induced by octanol were blocked by glibenclamide but insensitive to 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid, as expected for a CFTR Cl− current. CFTR activation by octanol was neither due to cell-to-cell uncoupling properties of octanol nor to an intracellular cAMP increase. CFTR activation by octanol requires phosphorylation by protein kinase-A (PKA) since it was prevented by H-89, a PKA inhibitor. n-Alkanols chain length was an important determinant for channel activation, with rank order of potencies: 1-heptanol<1-octanol<2-octanol<1-decanol. Our findings may be of valuable interest for developing novel therapeutic strategies for CF. PMID:14967738

  4. 40 CFR 90.508 - Test procedures.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 20 2014-07-01 2013-07-01 true Test procedures. 90.508 Section 90.508....508 Test procedures. (a) For nonroad engines subject to the provisions of this subpart, the prescribed test procedures are the appropriate small SI engine test procedures as described in subpart E of this...

  5. 48 CFR 3045.508 - Physical inventories.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 7 2011-10-01 2011-10-01 false Physical inventories. 3045.508 Section 3045.508 Federal Acquisition Regulations System DEPARTMENT OF HOMELAND SECURITY, HOMELAND... Property in the Possession of Contractors 3045.508 Physical inventories. ...

  6. 48 CFR 3045.508 - Physical inventories.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 7 2010-10-01 2010-10-01 false Physical inventories. 3045.508 Section 3045.508 Federal Acquisition Regulations System DEPARTMENT OF HOMELAND SECURITY, HOMELAND... Property in the Possession of Contractors 3045.508 Physical inventories. ...

  7. Highly preferential association of NonF508del CF mutations with the M470 allele.

    PubMed

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

    2007-01-01

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

  8. 48 CFR 1845.508 - Physical inventories.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Physical inventories. 1845.508 Section 1845.508 Federal Acquisition Regulations System NATIONAL AERONAUTICS AND SPACE... Contractors 1845.508 Physical inventories. NASA contractors shall reconcile inventories with the official...

  9. 50 CFR 600.508 - Fishing operations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 8 2010-10-01 2010-10-01 false Fishing operations. 600.508 Section 600.508 Wildlife and Fisheries FISHERY CONSERVATION AND MANAGEMENT, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE MAGNUSON-STEVENS ACT PROVISIONS Foreign Fishing § 600.508 Fishing...

  10. 40 CFR 35.508 - Funding period.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Funding period. 35.508 Section 35.508... ASSISTANCE Environmental Program Grants for Tribes Preparing An Application § 35.508 Funding period. The Regional Administrator and applicant may negotiate the length of the funding period for environmental...

  11. 40 CFR 35.508 - Funding period.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Funding period. 35.508 Section 35.508... ASSISTANCE Environmental Program Grants for Tribes Preparing An Application § 35.508 Funding period. The Regional Administrator and applicant may negotiate the length of the funding period for environmental...

  12. 40 CFR 35.508 - Funding period.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Funding period. 35.508 Section 35.508... ASSISTANCE Environmental Program Grants for Tribes Preparing An Application § 35.508 Funding period. The Regional Administrator and applicant may negotiate the length of the funding period for environmental...

  13. 40 CFR 35.508 - Funding period.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Funding period. 35.508 Section 35.508... ASSISTANCE Environmental Program Grants for Tribes Preparing An Application § 35.508 Funding period. The Regional Administrator and applicant may negotiate the length of the funding period for environmental...

  14. 40 CFR 35.508 - Funding period.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Funding period. 35.508 Section 35.508... ASSISTANCE Environmental Program Grants for Tribes Preparing An Application § 35.508 Funding period. The Regional Administrator and applicant may negotiate the length of the funding period for environmental...

  15. 7 CFR 1207.508 - USDA costs.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 10 2011-01-01 2011-01-01 false USDA costs. 1207.508 Section 1207.508 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... Rules and Regulations General § 1207.508 USDA costs. Pursuant to § 1207.341 of the Plan the Board shall...

  16. 7 CFR 1207.508 - USDA costs.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 10 2013-01-01 2013-01-01 false USDA costs. 1207.508 Section 1207.508 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... Rules and Regulations General § 1207.508 USDA costs. Pursuant to § 1207.341 of the Plan the Board shall...

  17. 7 CFR 1207.508 - USDA costs.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 10 2014-01-01 2014-01-01 false USDA costs. 1207.508 Section 1207.508 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... Rules and Regulations General § 1207.508 USDA costs. Pursuant to § 1207.341 of the Plan the Board shall...

  18. 7 CFR 1207.508 - USDA costs.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false USDA costs. 1207.508 Section 1207.508 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... Rules and Regulations General § 1207.508 USDA costs. Pursuant to § 1207.341 of the Plan the Board shall...

  19. 7 CFR 1207.508 - USDA costs.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 10 2012-01-01 2012-01-01 false USDA costs. 1207.508 Section 1207.508 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... Rules and Regulations General § 1207.508 USDA costs. Pursuant to § 1207.341 of the Plan the Board shall...

  20. 48 CFR 9.508 - Examples.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Examples. 9.508 Section 9... CONTRACTOR QUALIFICATIONS Organizational and Consultant Conflicts of Interest 9.508 Examples. The examples in... officer apply the general rules in 9.505 to individual contract situations. (a) Company A agrees to...

  1. 12 CFR 508.7 - Conduct of hearings.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Conduct of hearings. 508.7 Section 508.7 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.7 Conduct of hearings. (a) Hearings provided by this...

  2. 12 CFR 508.5 - Petition for hearing.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Petition for hearing. 508.5 Section 508.5 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.5 Petition for hearing. (a) To obtain a hearing, the...

  3. 12 CFR 508.6 - Initiation of hearing.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Initiation of hearing. 508.6 Section 508.6 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.6 Initiation of hearing. (a) Within 10 days of the filing...

  4. 12 CFR 508.9 - Rules of evidence.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Rules of evidence. 508.9 Section 508.9 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.9 Rules of evidence. (a) Formal rules of evidence shall...

  5. Defective Fluid Secretion from Submucosal Glands of Nasal Turbinates from CFTR-/- and CFTRΔF508/ΔF508 Pigs

    PubMed Central

    Cho, Hyung-Ju; Joo, Nam Soo; Wine, Jeffrey J.

    2011-01-01

    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 CFΔF508/ΔF508 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. PMID:21935358

  6. 12 CFR 508.10 - Burden of persuasion.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 5 2011-01-01 2011-01-01 false Burden of persuasion. 508.10 Section 508.10 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.10 Burden of persuasion. The petitioner has the burden of...

  7. 12 CFR 508.10 - Burden of persuasion.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 6 2014-01-01 2012-01-01 true Burden of persuasion. 508.10 Section 508.10 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.10 Burden of persuasion. The petitioner has the burden of...

  8. 12 CFR 508.10 - Burden of persuasion.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 6 2013-01-01 2012-01-01 true Burden of persuasion. 508.10 Section 508.10 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.10 Burden of persuasion. The petitioner has the burden of...

  9. 12 CFR 508.10 - Burden of persuasion.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 6 2012-01-01 2012-01-01 false Burden of persuasion. 508.10 Section 508.10 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.10 Burden of persuasion. The petitioner has the burden of...

  10. 12 CFR 508.10 - Burden of persuasion.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Burden of persuasion. 508.10 Section 508.10 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.10 Burden of persuasion. The petitioner has the burden of...

  11. ETC 408/508: Technical Editing

    ERIC Educational Resources Information Center

    Charlton, Michael

    2013-01-01

    ETC 408/508: Technical Editing is a cross-listed undergraduate and graduate course at Missouri Western State University, an open admissions public university with approximately 6,000 students. 508 is an elective course for students in the Master of Applied Arts in Written Communication degree and highly recommended for those in the Technical…

  12. Tamoxifen inhibits macrophage FABP4 expression through the combined effects of the GR and PPARγ pathways.

    PubMed

    Jiang, Meixiu; Zhang, Ling; Ma, Xingzhe; Hu, Wenquan; Chen, Yuanli; Yu, Miao; Wang, Qixue; Li, Xiaoju; Yin, Zhinan; Zhu, Yan; Gao, Xiumei; Hajjar, David P; Duan, Yajun; Han, Jihong

    2013-09-15

    Macrophage adipocyte fatty acid-binding protein (FABP4) plays an important role in foam cell formation and development of atherosclerosis. Tamoxifen inhibits this disease process. In the present study, we determined whether the anti-atherogenic property of tamoxifen was related to its inhibition of macrophage FABP4 expression. We initially observed that tamoxifen inhibited macrophage/foam cell formation, but the inhibition was attenuated when FABP4 expression was selectively inhibited by siRNA.We then observed that tamoxifen and 4-hydroxytamoxifen inhibited FABP4 protein expression in primary macrophages isolated from both the male and female wild-type mice, suggesting that the inhibition is sex-independent. Tamoxifen and 4-hydroxytamoxifen inhibited macrophage FABP4 protein expression induced either by activation of GR (glucocorticoid receptor) or PPARγ (peroxisome-proliferator-activated receptor γ). Associated with the decreased protein expression, Fabp4 mRNA expression and promoter activity were also inhibited by tamoxifen and 4-hydroxytamoxifen, indicating transcriptional regulation. Analysis of promoter activity and EMSA/ChIP assays indicated that tamoxifen and 4-hydroxytamoxifen activated the nGRE (negative glucocorticoid regulatory element), but inhibited the PPRE (PPARγ regulatory element) in the Fabp4 gene. In vivo, administration of tamoxifen to ApoE (apolipoprotein E)-deficient (apoE-/-) mice on a high-fat diet decreased FABP4 expression in macrophages and adipose tissues as well as circulating FABP4 levels. Tamoxifen also inhibited FABP4 protein expression by human blood monocyte-derived macrophages. Taken together, the results of the present study show that tamoxifen inhibited FABP4 expression through the combined effects of GR and PPARγ signalling pathways. Our findings suggest that the inhibition of macrophage FABP4 expression can be attributed to the antiatherogenic properties of tamoxifen.

  13. Gr/gr deletions on Y-chromosome correlate with male infertility: an original study, meta-analyses, and trial sequential analyses

    NASA Astrophysics Data System (ADS)

    Bansal, Sandeep Kumar; Jaiswal, Deepika; Gupta, Nishi; Singh, Kiran; Dada, Rima; Sankhwar, Satya Narayan; Gupta, Gopal; Rajender, Singh

    2016-02-01

    We analyzed the AZFc region of the Y-chromosome for complete (b2/b4) and distinct partial deletions (gr/gr, b1/b3, b2/b3) in 822 infertile and 225 proven fertile men. We observed complete AZFc deletions in 0.97% and partial deletions in 6.20% of the cases. Among partial deletions, the frequency of gr/gr deletions was the highest (5.84%). The comparison of partial deletion data between cases and controls suggested a significant association of the gr/gr deletions with infertility (P = 0.0004); however, the other partial deletions did not correlate with infertility. In cohort analysis, men with gr/gr deletions had a relatively poor sperm count (54.20 ± 57.45 million/ml) in comparison to those without deletions (72.49 ± 60.06), though the difference was not statistically significant (p = 0.071). Meta-analysis also suggested that gr/gr deletions are significantly associated with male infertility risk (OR = 1.821, 95% CI = 1.39-2.37, p = 0.000). We also performed trial sequential analyses that strengthened the evidence for an overall significant association of gr/gr deletions with the risk of male infertility. Another meta-analysis suggested a significant association of the gr/gr deletions with low sperm count. In conclusion, the gr/gr deletions show a strong correlation with male infertility risk and low sperm count, particularly in the Caucasian populations.

  14. 9 CFR 93.508 - Articles accompanying swine.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Articles accompanying swine. 93.508 Section 93.508 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Swine § 93.508 Articles accompanying swine. No litter...

  15. 9 CFR 93.508 - Articles accompanying swine.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Articles accompanying swine. 93.508 Section 93.508 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Swine § 93.508 Articles accompanying swine. No litter...

  16. 9 CFR 93.508 - Articles accompanying swine.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Articles accompanying swine. 93.508 Section 93.508 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Swine § 93.508 Articles accompanying swine. No litter...

  17. 9 CFR 93.508 - Articles accompanying swine.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Articles accompanying swine. 93.508 Section 93.508 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Swine § 93.508 Articles accompanying swine. No litter...

  18. 9 CFR 93.508 - Articles accompanying swine.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Articles accompanying swine. 93.508 Section 93.508 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Swine § 93.508 Articles accompanying swine. No litter...

  19. Constructing the quantum Hall system on the Grassmannians Gr2(CN)

    NASA Astrophysics Data System (ADS)

    Ballı, F.; Behtash, A.; Kürkçüoğlu, S.; Ünal, G.

    2015-04-01

    In this talk, we give the formulation of Quantum Hall Effects (QHEs) on the complex Grassmann manifolds Gr2(CN). We set up the Landau problem in Gr2(CN), solve it using group theoretical techniques and provide the energy spectrum and the eigenstates in terms of the SU(N) Wigner D-functions for charged particles on Gr2(CN) under the influence of abelian and non-abelian background magnetic monopoles or a combination of these thereof. For the simplest case of Gr2(C4) we provide explicit constructions of the single and many- particle wavefunctions by introducing the Plucker coordinates and show by calculating the two-point correlation function that the lowest Landau level (LLL) at filling factor v = 1 forms an incompressible fluid. Finally, we heuristically identify a relation between the U(1) Hall effect on Gr2(C4) and the Hall effect on the odd sphere S5, which is yet to be investigated in detail, by appealing to the already known analogous relations between the Hall effects on CP3 and CP7 and those on the spheres S4 and S8, respectively. The talk is given by S. Kürkçüoğlu at the Group 30 meeting at Ghent University, Ghent, Belgium in July 2014 and based on the article by F.Ballı, A.Behtash, S. Kürkçüoğlu, G.Ünal [1].

  20. 18 CFR 50.8 - Acceptance/rejection of applications.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... applications. 50.8 Section 50.8 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE FEDERAL POWER ACT APPLICATIONS FOR PERMITS TO SITE INTERSTATE ELECTRIC TRANSMISSION FACILITIES § 50.8 Acceptance/rejection of applications. (a) Applications will be...

  1. 45 CFR 73.735-508 - Other prohibitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 1 2014-10-01 2014-10-01 false Other prohibitions. 73.735-508 Section 73.735-508 Public Welfare Department of Health and Human Services GENERAL ADMINISTRATION STANDARDS OF CONDUCT Gifts, Entertainment, and Favors § 73.735-508 Other prohibitions. Employees shall avoid any action whether or not...

  2. 45 CFR 73.735-508 - Other prohibitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 1 2012-10-01 2012-10-01 false Other prohibitions. 73.735-508 Section 73.735-508 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION STANDARDS OF CONDUCT Gifts, Entertainment, and Favors § 73.735-508 Other prohibitions. Employees shall avoid any action whether or not...

  3. 45 CFR 73.735-508 - Other prohibitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 false Other prohibitions. 73.735-508 Section 73.735-508 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION STANDARDS OF CONDUCT Gifts, Entertainment, and Favors § 73.735-508 Other prohibitions. Employees shall avoid any action whether or not...

  4. 46 CFR 185.508 - Wearing of life jackets.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Wearing of life jackets. 185.508 Section 185.508... TONS) OPERATIONS Preparations for Emergencies § 185.508 Wearing of life jackets. (a) The master of a vessel shall require passengers to don life jackets when possible hazardous conditions exist, including...

  5. 46 CFR 185.508 - Wearing of life jackets.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Wearing of life jackets. 185.508 Section 185.508... TONS) OPERATIONS Preparations for Emergencies § 185.508 Wearing of life jackets. (a) The master of a vessel shall require passengers to don life jackets when possible hazardous conditions exist, including...

  6. 46 CFR 185.508 - Wearing of life jackets.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 7 2012-10-01 2012-10-01 false Wearing of life jackets. 185.508 Section 185.508... TONS) OPERATIONS Preparations for Emergencies § 185.508 Wearing of life jackets. (a) The master of a vessel shall require passengers to don life jackets when possible hazardous conditions exist, including...

  7. 46 CFR 185.508 - Wearing of life jackets.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 7 2014-10-01 2014-10-01 false Wearing of life jackets. 185.508 Section 185.508... TONS) OPERATIONS Preparations for Emergencies § 185.508 Wearing of life jackets. (a) The master of a vessel shall require passengers to don life jackets when possible hazardous conditions exist, including...

  8. 46 CFR 185.508 - Wearing of life jackets.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 7 2013-10-01 2013-10-01 false Wearing of life jackets. 185.508 Section 185.508... TONS) OPERATIONS Preparations for Emergencies § 185.508 Wearing of life jackets. (a) The master of a vessel shall require passengers to don life jackets when possible hazardous conditions exist, including...

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

    PubMed Central

    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

    2014-01-01

    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/cm2) and after isoproterenol stimulation (increased ΔISC from 13.9 to 21.0 μA/cm2) 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.—Blanchard, E., Zlock, L., Lao, A., Mika, D., Namkung, W., Xie, M., Scheitrum, C., Gruenert, D.C., Verkman, A.S., Finkbeiner, W.E., Conti, M., Richter, W. Anchored PDE4 regulates chloride conductance in wild type and ΔF508-CFTR human airway epithelia. PMID:24200884

  10. Missense variations in the cystic fibrosis gene: Heteroduplex formation in the F508C mutation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Macek, M. Jr.; Ladanyi, L.; Buerger, J.

    1992-11-01

    Kobayashi et al. (1990) have described missense variations in the conserved region of exon 10 of the cystic fibrosis (CF) transmembrane conductance regulator gene. In their paper, two [Delta]F508/F508C compound heterozygous individuals were reported. Clinical and epithelial physiological studies in both cases were normal, suggesting that the substitution of cysteine for phenylalanine at position 508, the F508C mutation, is benign. However, Kerem et al. reported a patient with this substitution who had typical symptoms of CF. In routine [Delta]F508 mutation screening by visualization of the 3-bp deletion on a 12% polyacrylamide gel the authors detected an abnormal heteroduplex in themore » father of a CF patient of German origin. Subsequent direct sequencing of the PCR product confirmed that this clinically normal father is a compound heterozygote for the [Delta]F508/F508C mutations. This heteroduplex is slightly different from the usual heteroduplex in [Delta]F508/F508C heteroduplex was not published, it is likely that similar cases can be overseen during the widely performed [Delta]F508 mutation screening by PAGE. Detection of more cases, such as the one presented here, together with careful, standardized clinical examination of the proband, would be valuable to verify the nature of this mutation. 4 refs., 1 fig.« less

  11. airGR: a suite of lumped hydrological models in an R-package

    NASA Astrophysics Data System (ADS)

    Coron, Laurent; Perrin, Charles; Delaigue, Olivier; Andréassian, Vazken; Thirel, Guillaume

    2016-04-01

    Lumped hydrological models are useful and convenient tools for research, engineering and educational purposes. They propose catchment-scale representations of the precipitation-discharge relationship. Thanks to their limited data requirements, they can be easily implemented and run. With such models, it is possible to simulate a number of hydrological key processes over the catchment with limited structural and parametric complexity, typically evapotranspiration, runoff, underground losses, etc. The Hydrology Group at Irstea (Antony) has been developing a suite of rainfall-runoff models over the past 30 years with the main objectives of designing models as efficient as possible in terms of streamflow simulation, applicable to a wide range of catchments and having low data requirements. This resulted in a suite of models running at different time steps (from hourly to annual) applicable for various issues including water balance estimation, forecasting, simulation of impacts and scenario testing. Recently, Irstea has developed an easy-to-use R-package (R Core Team, 2015), called airGR, to make these models widely available. It includes: - the water balance annual GR1A (Mouehli et al., 2006), - the monthly GR2M (Mouehli, 2003) models, - three versions of the daily model, namely GR4J (Perrin et al., 2003), GR5J (Le Moine, 2008) and GR6J (Pushpalatha et al., 2011), - the hourly GR4H model (Mathevet, 2005), - a degree-day snow module CemaNeige (Valéry et al., 2014). The airGR package has been designed to facilitate the use by non-expert users and allow the addition of evaluation criteria, models or calibration algorithms selected by the end-user. Each model core is coded in FORTRAN to ensure low computational time. The other package functions (i.e. mainly the calibration algorithm and the efficiency criteria) are coded in R. The package is already used for educational purposes. The presentation will detail the main functionalities of the package and present a case

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

    PubMed

    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.

  13. Creep of A508/533 Pressure Vessel Steel

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Richard Wright

    2014-08-01

    temperature are allowed by Code Case N-499-2 (now incorporated as an appendix to Section III Division 5 of the Code). This Code Case was developed with a rather sparse data set and focused primarily on rolled plate material (A533 specification). Confirmatory tests of creep behavior of both A508 and A533 are described here that are designed to extend the database in order to build higher confidence in ensuring the structural integrity of the VHTR RPV during off-normal conditions. A number of creep-rupture tests were carried out at temperatures above the 371°C (700°F) Code limit; longer term tests designed to evaluate minimum creep behavior are ongoing. A limited amount of rupture testing was also carried out on welded material. All of the rupture data from the current experiments is compared to historical values from the testing carried out to develop Code Case N-499-2. It is shown that the A508/533 basemetal tested here fits well with the rupture behavior reported from the historical testing. The presence of weldments significantly reduces the time to rupture. The primary purpose of this report is to summarize and record the experimental results in a single document.« less

  14. 12 CFR 508.13 - Decision of the Office.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Decision of the Office. 508.13 Section 508.13 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.13 Decision of the Office. (a) Within 30 days after the recommended decision has been certifie...

  15. 40 CFR 89.508 - Test procedures.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 20 2014-07-01 2013-07-01 true Test procedures. 89.508 Section 89.508... Test procedures. (a)(1) For nonroad engines subject to the provisions of this subpart, the prescribed test procedures are the nonroad engine 8-mode test procedure as described in subpart E of this part...

  16. Specific labelling of serotonin 5-HT(1B) receptors in rat frontal cortex with the novel, phenylpiperazine derivative, [3H]GR125,743. A pharmacological characterization.

    PubMed

    Millan, M J; Newman-Tancredi, A; Lochon, S; Touzard, M; Aubry, S; Audinot, V

    2002-04-01

    Although several tritiated agonists have been used for radiolabelling serotonin (5-hydroxytryptamine, 5-HT)(1B) receptors in rats, data with a selective, radiolabelled antagonist have not been presented. Inasmuch as [3H]GR125,743 specifically labels cloned, human and native guinea pig 5-HT(1B) receptors and has been employed for characterization of cerebral 5-HT(1B) receptor in the latter species [Eur. J. Pharmacol. 327 (1997) 247.], the present study evaluated its utility for characterization of native, cerebral 5-HT(1B) sites in the rat. In homogenates of frontal cortex, [3H]GR125,743 (0.8 nM) showed rapid association (t(1/2)=3.4 min), >90% specific binding and high affinity (K(d)=0.6 nM) for a homogeneous population of receptors with a density (B(max)) of 160 fmol/mg protein. In competition binding studies, affinities were determined for 15 chemically diverse 5-HT(1B) agonists, including 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694,247; pK(i), 10.4), 5-carboxamidotryptamine (5-CT; 9.7), 3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxybenzyl)acrylamide (GR46,611; 9.6), 5-methoxy-3-(1,2,5,6-tetrahydro-4-pyridinyl)-1H-indole (RU24,969; 9.5), dihydroergotamine (DHE; 8.6), 5-H-pyrrolo[3,2-b]pyridin-5-one,1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl (CP93,129; 8.4), anpirtoline (7.9), sumatriptan (7.4), 1-[2-(3-fluorophenyl)ethyl]-4-[3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]piperazine (L775,606; 6.4) and (minus sign)-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-N-methyl-3,4-dihydro-1H-2-benzopyran-6-carboxamide (PNU109,291; <5.0). Similarly, affinities were established for 13 chemically diverse antagonists, including N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide (GR125,743; pK(i), 9.1), (-)cyanopindolol (9.0), (-)-tertatolol (8.2), N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiozol-3-yl)biphenyl-4-carboxamide (GR127,935; 8.2), N-[3-(1,4

  17. 30 CFR 75.508 - Map of electrical system.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Map of electrical system. 75.508 Section 75.508... MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Electrical Equipment-General § 75.508 Map of electrical system. [Statutory Provisions] The location and the electrical rating of all stationary electric...

  18. 30 CFR 75.508 - Map of electrical system.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Map of electrical system. 75.508 Section 75.508... MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Electrical Equipment-General § 75.508 Map of electrical system. [Statutory Provisions] The location and the electrical rating of all stationary electric...

  19. 30 CFR 75.508 - Map of electrical system.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Map of electrical system. 75.508 Section 75.508... MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Electrical Equipment-General § 75.508 Map of electrical system. [Statutory Provisions] The location and the electrical rating of all stationary electric...

  20. 48 CFR 1245.508-2 - Reporting results of inventories.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Reporting results of inventories. 1245.508-2 Section 1245.508-2 Federal Acquisition Regulations System DEPARTMENT OF TRANSPORTATION... 1245.508-2 Reporting results of inventories. The inventory report shall also include the following: (a...

  1. 48 CFR 1245.508-2 - Reporting results of inventories.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Reporting results of inventories. 1245.508-2 Section 1245.508-2 Federal Acquisition Regulations System DEPARTMENT OF TRANSPORTATION... 1245.508-2 Reporting results of inventories. The inventory report shall also include the following: (a...

  2. 48 CFR 1245.508-2 - Reporting results of inventories.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Reporting results of inventories. 1245.508-2 Section 1245.508-2 Federal Acquisition Regulations System DEPARTMENT OF TRANSPORTATION... 1245.508-2 Reporting results of inventories. The inventory report shall also include the following: (a...

  3. 48 CFR 1245.508-2 - Reporting results of inventories.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Reporting results of inventories. 1245.508-2 Section 1245.508-2 Federal Acquisition Regulations System DEPARTMENT OF TRANSPORTATION... 1245.508-2 Reporting results of inventories. The inventory report shall also include the following: (a...

  4. 48 CFR 1245.508-2 - Reporting results of inventories.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Reporting results of inventories. 1245.508-2 Section 1245.508-2 Federal Acquisition Regulations System DEPARTMENT OF TRANSPORTATION... 1245.508-2 Reporting results of inventories. The inventory report shall also include the following: (a...

  5. 50 CFR 600.508 - Fishing operations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 10 2011-10-01 2011-10-01 false Fishing operations. 600.508 Section 600... ADMINISTRATION, DEPARTMENT OF COMMERCE MAGNUSON-STEVENS ACT PROVISIONS Foreign Fishing § 600.508 Fishing.... fishing vessels. These joint venture operations with U.S. fishing vessels may be conducted throughout the...

  6. 50 CFR 600.508 - Fishing operations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 50 Wildlife and Fisheries 12 2013-10-01 2013-10-01 false Fishing operations. 600.508 Section 600... ADMINISTRATION, DEPARTMENT OF COMMERCE MAGNUSON-STEVENS ACT PROVISIONS Foreign Fishing § 600.508 Fishing.... fishing vessels. These joint venture operations with U.S. fishing vessels may be conducted throughout the...

  7. 50 CFR 600.508 - Fishing operations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 50 Wildlife and Fisheries 12 2014-10-01 2014-10-01 false Fishing operations. 600.508 Section 600... ADMINISTRATION, DEPARTMENT OF COMMERCE MAGNUSON-STEVENS ACT PROVISIONS Foreign Fishing § 600.508 Fishing.... fishing vessels. These joint venture operations with U.S. fishing vessels may be conducted throughout the...

  8. 50 CFR 600.508 - Fishing operations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 50 Wildlife and Fisheries 12 2012-10-01 2012-10-01 false Fishing operations. 600.508 Section 600... ADMINISTRATION, DEPARTMENT OF COMMERCE MAGNUSON-STEVENS ACT PROVISIONS Foreign Fishing § 600.508 Fishing.... fishing vessels. These joint venture operations with U.S. fishing vessels may be conducted throughout the...

  9. Synthesis, crystal structure and DFT studies of N-(4-acetyl-5,5-dimethyl-4,5-dihydro-1,3,4-thiadiazol-2-yl)acetamide

    NASA Astrophysics Data System (ADS)

    Gautam, P.; Gautam, D.; Chaudhary, R. P.

    2013-12-01

    The title compound N-(4-acetyl-5,5-dimethyl-4,5-dihydro-1,3,4-thiadiazol-2-yl)acetamide ( III) was obtained from the reaction of 2-(propan-2-ylidene)hydrazinecarbothioamide ( II) with acetic anhydride instead of formation of the desired thiosemcarbazide derivative of Meldrum acid. The structures of II and III were established by elemental analysis, IR, NMR, Mass and X-ray crystallographic studies. II crystallizes in triclinic system, sp. gr. Z = 2; III crystallizes in the monoclinic system, sp. gr. P21/ c, Z = 8. Density functional theory (DFT) calculations have been carried out for III. 1H and 13C NMR of III has been calculated and correlated with experimental results.

  10. 41 CFR 105-72.508 - Contract provisions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... instances in which a contractor violates or breaches the contract terms, and provide for such remedial... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Contract provisions. 105-72.508 Section 105-72.508 Public Contracts and Property Management Federal Property Management...

  11. 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)*

    PubMed Central

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

    2014-01-01

    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 Ser422. SGK1[Ser(P)422] and C4-CER coincidently bind PDK1 and permit PDK1 to autophosphorylate at Ser241. Then PDK1[Ser(P)241] phosphorylates SGK1[Ser(P)422] at Thr256 to generate fully activated SGK1[Ser422, 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. PMID:25384981

  12. 40 CFR 94.508 - Calculation and reporting of test results.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... results. 94.508 Section 94.508 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... Line Testing Programs § 94.508 Calculation and reporting of test results. (a) Manufacturers shall calculate initial test results using the applicable test procedure specified in § 94.506(a). These results...

  13. 40 CFR 94.508 - Calculation and reporting of test results.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... results. 94.508 Section 94.508 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... Line Testing Programs § 94.508 Calculation and reporting of test results. (a) Manufacturers shall calculate initial test results using the applicable test procedure specified in § 94.506(a). These results...

  14. Electrochemical treatment of 2, 4-dichlorophenol using a nanostructured 3D-porous Ti/Sb-SnO2-Gr anode: Reaction kinetics, mechanism, and continuous operation.

    PubMed

    Asim, Sumreen; Zhu, Yunqing; Batool, Aisha; Hailili, Reshalaiti; Luo, Jianmin; Wang, Yuanhao; Wang, Chuanyi

    2017-10-01

    2, 4-dichlorophenol (2, 4-DCP) is considered to be a highly toxic, mutagenic, and possibly carcinogenic pollutant. This study is focused on the electrochemical oxidation of 2, 4-DCP on nanostructured 3D-porous Ti/Sb-SnO 2 -Gr anodes, with the aim of presenting a comprehensive elucidation of mineralization process through the investigation of influential kinetics, the reactivity of hydroxyl radical's and analysis of intermediates. High efficiency was achieved at pH of 3 using Na 2 SO 4 electrolytes at a current density of 30 mA cm -2 . Under the optimized conditions, a maximum removal of 2, 4-DCP of up to 99.9% was reached, whereas a TOC removal of 81% was recorded with the lowest EC TOC (0.49 kW h g -1 ) within 40 min of electrolysis. To explore the stability of the 3D-Ti/Sb-SnO 2 -Gr electrodes, a continuous electrochemical operation was established, and the consistent mineralization results indicated the effectiveness of the 3D-Ti/Sb-SnO 2 -Gr system concerning its durability and practical utilization. EPR studies demonstrated the abundant generation of OH radicals on 3D-Ti/Sb-SnO 2 -Gr, resulting in fast recalcitrant pollutant incineration. From dechlorination and the reactivity of the OH radicals, several intermediates including six cyclic byproducts and three aliphatic carboxylic acids were detected, and two possible degradation pathways were proposed that justify the complete mineralization of 2, 4-DCP. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. A small-molecule modulator interacts directly with deltaPhe508-CFTR to modify its ATPase activity and conformational stability.

    PubMed

    Wellhauser, Leigh; Kim Chiaw, Patrick; Pasyk, Stan; Li, Canhui; Ramjeesingh, Mohabir; Bear, Christine E

    2009-06-01

    The deletion of Phe-508 (DeltaPhe508) constitutes the most prevalent of a number of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that cause cystic fibrosis (CF). This mutation leads to CFTR misfolding and retention in the endoplasmic reticulum, as well as impaired channel activity. The biosynthetic defect can be partially overcome by small-molecule "correctors"; once at the cell surface, small-molecule "potentiators" enhance the channel activity of DeltaPhe508-CFTR. Certain compounds, such as VRT-532, exhibit both corrector and potentiator functions. In the current studies, we confirmed that the inherent chloride channel activity of DeltaPhe508-CFTR (after biosynthetic rescue) is potentiated in studies of intact cells and membrane vesicles. It is noteworthy that we showed that the ATPase activity of the purified and reconstituted mutant protein is directly modulated by binding of VRT-532 [4-methyl-2-(5-phenyl-1H-pyrazol-3-yl)-phenol] ATP turnover by reconstituted DeltaPhe508-CFTR is decreased by VRT-532 treatment, an effect that may account for the increase in channel open time induced by this compound. To determine whether the modification of DeltaPhe508-CFTR function caused by direct VRT-532 binding is associated with structural changes, we evaluated the effect of VRT-532 binding on the protease susceptibility of the major mutant. We found that binding of VRT-532 to DeltaPhe508-CFTR led to a minor but significant decrease in the trypsin susceptibility of the full-length mutant protein and a fragment encompassing the second half of the protein. These findings suggest that direct binding of this small molecule induces and/or stabilizes a structure that promotes the channel open state and may underlie its efficacy as a corrector of DeltaPhe508-CFTR.

  16. Recruitment of Gr1(+)CD11b (+)F4/80 (+) population in the bone marrow and spleen by irradiation-induced pulmonary damage.

    PubMed

    Thanasegaran, Suganya; Ito, Sachiko; Nishio, Naomi; Uddin, Mohammad Nizam; Sun, Yang; Isobe, Ken-ichi

    2015-04-01

    Radiation-induced lung injury is a kind of sterile inflammation, which may lead to morbidity and mortality. The mechanism by which ionizing radiation activate the immune system is not well understood. In the present study, we have investigated the immunological responses induced by local irradiation-induced damage in mouse lung. The left lungs of C57BL/6 mice were irradiated at a high dose of 100 Gy. The histology of the lungs and spleen showed evidences of alveolar inflammation and congestion at 2 weeks after X-ray treatment. Also, prominent increase in cells expressing the cell surface markers, Gr(+)CD11b(+)F4/80(+) and Ly6C(+) Ly6G(+) were observed 2 weeks after X-ray treatment (100 Gy). Gr1(+)CD11b(+)F4/80(+) cell depletion by clodronate treatment reversed the histological effects and also failed to recruit Gr(+)CD11b(+) cells or F4/80(+) cells caused by irradiation. The origin of recruited Gr1(+)CD11b(+) cells was found to be a mixed resident and recruited phenotype.

  17. 40 CFR 92.508 - Calculation and reporting of test results.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... results. 92.508 Section 92.508 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... Remanufacturer Production Line Testing and Audit Programs § 92.508 Calculation and reporting of test results. (a) Manufacturers and remanufacturers shall calculate initial test results using the applicable test procedure...

  18. 40 CFR 92.508 - Calculation and reporting of test results.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... results. 92.508 Section 92.508 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... Remanufacturer Production Line Testing and Audit Programs § 92.508 Calculation and reporting of test results. (a) Manufacturers and remanufacturers shall calculate initial test results using the applicable test procedure...

  19. 48 CFR 3045.508-2 - Reporting results of inventories.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 7 2011-10-01 2011-10-01 false Reporting results of inventories. 3045.508-2 Section 3045.508-2 Federal Acquisition Regulations System DEPARTMENT OF HOMELAND... Management of Government Property in the Possession of Contractors 3045.508-2 Reporting results of...

  20. 48 CFR 3045.508-2 - Reporting results of inventories.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 7 2010-10-01 2010-10-01 false Reporting results of inventories. 3045.508-2 Section 3045.508-2 Federal Acquisition Regulations System DEPARTMENT OF HOMELAND... Management of Government Property in the Possession of Contractors 3045.508-2 Reporting results of...

  1. 48 CFR 3045.508-3 - Quantitative and monetary control.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 7 2010-10-01 2010-10-01 false Quantitative and monetary control. 3045.508-3 Section 3045.508-3 Federal Acquisition Regulations System DEPARTMENT OF HOMELAND... Management of Government Property in the Possession of Contractors 3045.508-3 Quantitative and monetary...

  2. 48 CFR 3045.508-3 - Quantitative and monetary control.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 7 2011-10-01 2011-10-01 false Quantitative and monetary control. 3045.508-3 Section 3045.508-3 Federal Acquisition Regulations System DEPARTMENT OF HOMELAND... Management of Government Property in the Possession of Contractors 3045.508-3 Quantitative and monetary...

  3. J-R fracture characteristics of ferritic steels for RPVs and RCS piping of nuclear power plants

    NASA Astrophysics Data System (ADS)

    Yoon, Ji-Hyun; Lee, Bong-Sang; Hong, Jun-Hwa

    2001-10-01

    J-R fracture resistance tests have been performed on 3 heats of SA508-Gr.3 nuclear reactor pressure vessel (RPV) steel as well as 2 heats of SA516-Gr.70 and a heat of SA508-Gr.1a steels for nuclear reactor coolant system (RCS) piping. For the latter two steels, dynamic in addition to static J-R fracture resistances were investigated. From the test results of the SA508-Gr.3 steels, the J-R fracture resistance was superior in the following order: Si-killing steel, modified VCD steel and VCD steel. Microstructural analyses were carried out to correlate J-R fracture resistances with microstructural characteristics. According to the test results for SA508-Gr.1a and SA516-Gr.70 steels, all of the tested steels showed steep drops in fracture resistance at certain temperature and loading rate combinations. One heat of SA516-Gr.70 steel was very sensitive to dynamic strain aging and its fracture resistance was significantly low. It was concluded that microstructural and chemical factors affect the J-R fracture and DSA characteristics of SA516-Gr.70 steels.

  4. 20 CFR 663.508 - What is a “program of training services”?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false What is a âprogram of training servicesâ? 663.508 Section 663.508 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR ADULT AND DISLOCATED WORKER ACTIVITIES UNDER TITLE I OF THE WORKFORCE INVESTMENT ACT Eligible Training...

  5. 20 CFR 663.508 - What is a “program of training services”?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false What is a âprogram of training servicesâ? 663.508 Section 663.508 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR ADULT AND DISLOCATED WORKER ACTIVITIES UNDER TITLE I OF THE WORKFORCE INVESTMENT ACT Eligible Training...

  6. ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.

    PubMed

    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.

  7. 20 CFR 638.508 - Sale of services or objects.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Sale of services or objects. 638.508 Section 638.508 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR JOB CORPS PROGRAM UNDER TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Center Operations § 638.508 Sale of services...

  8. Effect of neutron irradiation on magnetic properties in the low alloy Ni-Mo steel SA508-3

    NASA Astrophysics Data System (ADS)

    Park, D. G.; Kim, C. G.; Kim, H. C.; Hong, J. H.; Kim, I. S.

    1997-04-01

    The B-H hysteresis loop and Barkhausen noise have been measured in the neutron irradiated SA508 steel of 45 μm thickness. The coercive force of B-H loop showed a slow change up to a neutron dose of 1014 n/cm2 and increased by 15.4% for a 1016 n/cm2 dose sample compared with that of the unirradiated one, related to the domain wall motion hindered by the increased defects. However, the amplitude of Barkhausen noise reflecting the wall motion decreased slowly up to 1014 n/cm2 irradiation, followed by a rapid decrease of 37.5% at 1016 n/cm2.

  9. Cluster Adjacency Properties of Scattering Amplitudes in N =4 Supersymmetric Yang-Mills Theory

    NASA Astrophysics Data System (ADS)

    Drummond, James; Foster, Jack; Gürdoǧan, Ömer

    2018-04-01

    We conjecture a new set of analytic relations for scattering amplitudes in planar N =4 super Yang-Mills theory. They generalize the Steinmann relations and are expressed in terms of the cluster algebras associated to Gr (4 ,n ). In terms of the symbol, they dictate which letters can appear consecutively. We study heptagon amplitudes and integrals in detail and present symbols for previously unknown integrals at two and three loops which support our conjecture.

  10. 7 CFR 1755.508 - Customer access location protection.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 11 2014-01-01 2014-01-01 false Customer access location protection. 1755.508 Section 1755.508 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE TELECOMMUNICATIONS POLICIES ON SPECIFICATIONS, ACCEPTABLE MATERIALS, AND STANDARD...

  11. 7 CFR 1755.508 - Customer access location protection.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 11 2012-01-01 2012-01-01 false Customer access location protection. 1755.508 Section 1755.508 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE TELECOMMUNICATIONS POLICIES ON SPECIFICATIONS, ACCEPTABLE MATERIALS, AND STANDARD...

  12. 7 CFR 1755.508 - Customer access location protection.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 11 2013-01-01 2013-01-01 false Customer access location protection. 1755.508 Section 1755.508 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE TELECOMMUNICATIONS POLICIES ON SPECIFICATIONS, ACCEPTABLE MATERIALS, AND STANDARD...

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

    PubMed

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

    2008-09-01

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

  14. 13 CFR 134.508 - What is the standard of review?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false What is the standard of review? 134.508 Section 134.508 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION RULES OF... Service-Disabled Veteran Owned Small Business Concern Protests § 134.508 What is the standard of review...

  15. 5 CFR 293.508 - Type of folder to be used.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Type of folder to be used. 293.508 Section 293.508 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PERSONNEL RECORDS Employee Medical File System Records § 293.508 Type of folder to be used. Each agency must...

  16. 5 CFR 293.508 - Type of folder to be used.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Type of folder to be used. 293.508 Section 293.508 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PERSONNEL RECORDS Employee Medical File System Records § 293.508 Type of folder to be used. Each agency must...

  17. 5 CFR 293.508 - Type of folder to be used.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Type of folder to be used. 293.508 Section 293.508 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PERSONNEL RECORDS Employee Medical File System Records § 293.508 Type of folder to be used. Each agency must...

  18. 5 CFR 293.508 - Type of folder to be used.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Type of folder to be used. 293.508 Section 293.508 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PERSONNEL RECORDS Employee Medical File System Records § 293.508 Type of folder to be used. Each agency must...

  19. 5 CFR 293.508 - Type of folder to be used.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 5 Administrative Personnel 1 2011-01-01 2011-01-01 false Type of folder to be used. 293.508 Section 293.508 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PERSONNEL RECORDS Employee Medical File System Records § 293.508 Type of folder to be used. Each agency must...

  20. 46 CFR 308.508 - Issuance of an Open Cargo Policy.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 8 2013-10-01 2013-10-01 false Issuance of an Open Cargo Policy. 308.508 Section 308.508 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION EMERGENCY OPERATIONS WAR RISK INSURANCE War Risk Cargo Insurance Ii-Open Policy War Risk Cargo Insurance § 308.508 Issuance of an Open...

  1. 46 CFR 308.508 - Issuance of an Open Cargo Policy.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 8 2010-10-01 2010-10-01 false Issuance of an Open Cargo Policy. 308.508 Section 308.508 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION EMERGENCY OPERATIONS WAR RISK INSURANCE War Risk Cargo Insurance Ii-Open Policy War Risk Cargo Insurance § 308.508 Issuance of an Open...

  2. 46 CFR 308.508 - Issuance of an Open Cargo Policy.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 8 2014-10-01 2014-10-01 false Issuance of an Open Cargo Policy. 308.508 Section 308.508 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION EMERGENCY OPERATIONS WAR RISK INSURANCE War Risk Cargo Insurance Open Policy War Risk Cargo Insurance § 308.508 Issuance of an Open Cargo...

  3. 46 CFR 308.508 - Issuance of an Open Cargo Policy.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 8 2012-10-01 2012-10-01 false Issuance of an Open Cargo Policy. 308.508 Section 308.508 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION EMERGENCY OPERATIONS WAR RISK INSURANCE War Risk Cargo Insurance Ii-Open Policy War Risk Cargo Insurance § 308.508 Issuance of an Open...

  4. 46 CFR 308.508 - Issuance of an Open Cargo Policy.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 8 2011-10-01 2011-10-01 false Issuance of an Open Cargo Policy. 308.508 Section 308.508 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION EMERGENCY OPERATIONS WAR RISK INSURANCE War Risk Cargo Insurance Ii-Open Policy War Risk Cargo Insurance § 308.508 Issuance of an Open...

  5. 32 CFR 508.1 - Utilization of Army bands.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 3 2011-07-01 2009-07-01 true Utilization of Army bands. 508.1 Section 508.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY AID OF CIVIL AUTHORITIES AND... Secretary of Defense. The authority to determine whether the use of an Army band at a public gathering is...

  6. 12 CFR 508.12 - Proposed findings and conclusions and recommended decision.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Proposed findings and conclusions and recommended decision. 508.12 Section 508.12 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY REMOVALS, SUSPENSIONS, AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.12 Proposed...

  7. Section 508 Standards Resources

    EPA Pesticide Factsheets

    Learn which software applications, operating systems, web-based applications, and other electronic and information technology (EIT) products are covered by Section 508 of the Rehabilitation Act; and resources for making sure your EIT products are compliant

  8. The novel GrCEP12 peptide from the plant-parasitic nematode Globodera rostochiensis suppresses flg22-mediated PTI.

    PubMed

    Chen, Shiyan; Chronis, Demosthenis; Wang, Xiaohong

    2013-09-01

    The potato cyst nematode Globodera rostochiensis is a biotrophic pathogen that secretes effector proteins into host root cells to promote successful plant parasitism. In addition to the role in generating within root tissue the feeding cells essential for nematode development, (1) nematode secreted effectors are becoming recognized as suppressors of plant immunity. (2)(-) (4) Recently we reported that the effector ubiquitin carboxyl extension protein (GrUBCEP12) from G. rostochiensis is processed into free ubiquitin and a 12-amino acid GrCEP12 peptide in planta. Transgenic potato lines overexpressing the derived GrCEP12 peptide showed increased susceptibility to G. rostochiensis and to an unrelated bacterial pathogen Streptomyces scabies, suggesting that GrCEP12 has a role in suppressing host basal defense or possibly pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) during the parasitic interaction. (3) To determine if GrCEP12 functions as a PTI suppressor we evaluated whether GrCEP12 suppresses flg22-induced PTI responses in Nicotiana benthamiana. Interestingly, we found that transient expression of GrCEP12 in N. benthamiana leaves suppressed reactive oxygen species (ROS) production and the induction of two PTI marker genes triggered by the bacterial PAMP flg22, providing direct evidence that GrCEP12 indeed has an activity in PTI suppression.

  9. Interplay between gravity and quintessence: a set of new GR solutions

    NASA Astrophysics Data System (ADS)

    Chernin, Arthur D.; Santiago, David I.; Silbergleit, Alexander S.

    2002-02-01

    A set of new exact analytical general relativity (GR) solutions with time-dependent and spatially inhomogeneous quintessence demonstrate (1) a static non-empty space-time with a horizon-type singular surface; (2) time-dependent spatially homogeneous `spheres' which are completely different in geometry from the Friedmann isotropic models; (3) infinitely strong anti-gravity at a `true' singularity where the density is infinitely large. It is also found that (4) the GR solutions allow for an extreme `density-free' form of energy that can generate regular space-time geometries.

  10. Exact period-four solutions of a family of n-dimensional quadratic maps via harmonic balance and Gröbner bases.

    PubMed

    D'Amico, María Belén; Calandrini, Guillermo L

    2015-11-01

    Analytical solutions of the period-four orbits exhibited by a classical family of n-dimensional quadratic maps are presented. Exact expressions are obtained by applying harmonic balance and Gröbner bases to a single-input single-output representation of the system. A detailed study of a generalized scalar quadratic map and a well-known delayed logistic model is included for illustration. In the former example, conditions for the existence of bistability phenomenon are also introduced.

  11. Exact period-four solutions of a family of n-dimensional quadratic maps via harmonic balance and Gröbner bases

    NASA Astrophysics Data System (ADS)

    D'Amico, María Belén; Calandrini, Guillermo L.

    2015-11-01

    Analytical solutions of the period-four orbits exhibited by a classical family of n-dimensional quadratic maps are presented. Exact expressions are obtained by applying harmonic balance and Gröbner bases to a single-input single-output representation of the system. A detailed study of a generalized scalar quadratic map and a well-known delayed logistic model is included for illustration. In the former example, conditions for the existence of bistability phenomenon are also introduced.

  12. 45 CFR 160.508 - Authority of the ALJ.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Authority of the ALJ. 160.508 Section 160.508 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES ADMINISTRATIVE DATA STANDARDS AND RELATED... scope and timing of documentary discovery as permitted by this subpart; (8) Regulate the course of the...

  13. Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508DEL-CFTR.

    PubMed

    Donaldson, Scott H; Solomon, George M; Zeitlin, Pamela L; Flume, Patrick A; Casey, Alicia; McCoy, Karen; Zemanick, Edith T; Mandagere, Arun; Troha, Janice M; Shoemaker, Steven A; Chmiel, James F; Taylor-Cousar, Jennifer L

    2017-05-01

    Cavosonstat (N91115), an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators. A Phase I program evaluated pharmacokinetics, drug-drug interactions and safety of cavosonstat in healthy and cystic fibrosis (CF) subjects homozygous for F508del-CFTR. Exploratory outcomes included changes in sweat chloride in CF subjects. Cavosonstat was rapidly absorbed and demonstrated linear and predictable pharmacokinetics. Exposure was unaffected by a high-fat meal or rifampin-mediated effects on drug metabolism and transport. Cavosonstat was well tolerated, with no dose-limiting toxicities or significant safety findings. At the highest dose, significant reductions from baseline in sweat chloride were observed (-4.1mmol/L; P=0.032) at day 28. The favorable safety and clinical profile warrant further study of cavosonstat in CF. ClinicalTrials.gov Numbers: NCT02275936, NCT02013388, NCT02500667. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  14. 24 CFR 982.508 - Maximum family share at initial occupancy.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 4 2010-04-01 2010-04-01 false Maximum family share at initial... Assistance Payment § 982.508 Maximum family share at initial occupancy. At the time the PHA approves a tenancy for initial occupancy of a dwelling unit by a family with tenant-based assistance under the...

  15. Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex

    PubMed Central

    Hua, Guoqiang; Ganti, Krishna Priya; Chambon, Pierre

    2016-01-01

    Upon binding of a glucocorticoid (GC), the GC receptor (GR) can exert one of three transcriptional regulatory functions. We recently reported that SUMOylation of the GR at position K293 in humans (K310 in mice) within the N-terminal domain is indispensable for GC-induced evolutionary conserved inverted repeated negative GC response element (IR nGRE)-mediated direct transrepression. We now demonstrate that the integrity of this GR SUMOylation site is mandatory for the formation of a GR-small ubiquitin-related modifiers (SUMOs)-SMRT/NCoR1-HDAC3 repressing complex, which is indispensable for NF-κB/AP1-mediated GC-induced tethered indirect transrepression in vitro. Using GR K310R mutant mice or mice containing the N-terminal truncated GR isoform GRα-D3 lacking the K310 SUMOylation site, revealed a more severe skin inflammation than in WT mice. Importantly, cotreatment with dexamethasone (Dex) could not efficiently suppress a 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced skin inflammation in these mutant mice, whereas it was clearly decreased in WT mice. In addition, in mice selectively ablated in skin keratinocytes for either nuclear receptor corepressor 1 (NCoR1)/silencing mediator for retinoid or thyroid-hormone receptors (SMRT) corepressors or histone deacetylase 3 (HDAC3), Dex-induced tethered transrepression and the formation of a repressing complex on DNA-bound NF-κB/AP1 were impaired. We previously suggested that GR ligands that would lack both (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression activities of GCs may preferentially exert the therapeutically beneficial GC antiinflammatory properties. Interestingly, we now identified a nonsteroidal antiinflammatory selective GR agonist (SEGRA) that selectively lacks both Dex-induced (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression functions, while still exerting a tethered indirect transrepression activity and could therefore be clinically lesser

  16. 33 CFR 165.508 - Security Zone; Georgetown Channel, Potomac River, Washington, DC.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., Potomac River, Washington, DC. 165.508 Section 165.508 Navigation and Navigable Waters COAST GUARD... § 165.508 Security Zone; Georgetown Channel, Potomac River, Washington, DC. (a) Definitions. (1) The... zone: All waters of the Georgetown Channel of the Potomac River, from the surface to the bottom, 75...

  17. 33 CFR 165.508 - Security Zone; Georgetown Channel, Potomac River, Washington, DC.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., Potomac River, Washington, DC. 165.508 Section 165.508 Navigation and Navigable Waters COAST GUARD... § 165.508 Security Zone; Georgetown Channel, Potomac River, Washington, DC. (a) Definitions. (1) The... zone: All waters of the Georgetown Channel of the Potomac River, from the surface to the bottom, 75...

  18. 33 CFR 165.508 - Security Zone; Georgetown Channel, Potomac River, Washington, DC.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., Potomac River, Washington, DC. 165.508 Section 165.508 Navigation and Navigable Waters COAST GUARD... § 165.508 Security Zone; Georgetown Channel, Potomac River, Washington, DC. (a) Definitions. (1) The... zone: All waters of the Georgetown Channel of the Potomac River, from the surface to the bottom, 75...

  19. 33 CFR 165.508 - Security Zone; Georgetown Channel, Potomac River, Washington, DC.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., Potomac River, Washington, DC. 165.508 Section 165.508 Navigation and Navigable Waters COAST GUARD... § 165.508 Security Zone; Georgetown Channel, Potomac River, Washington, DC. (a) Definitions. (1) The... zone: All waters of the Georgetown Channel of the Potomac River, from the surface to the bottom, 75...

  20. 33 CFR 165.508 - Security Zone; Georgetown Channel, Potomac River, Washington, DC.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., Potomac River, Washington, DC. 165.508 Section 165.508 Navigation and Navigable Waters COAST GUARD... § 165.508 Security Zone; Georgetown Channel, Potomac River, Washington, DC. (a) Definitions. (1) The... zone: All waters of the Georgetown Channel of the Potomac River, from the surface to the bottom, 75...

  1. 31 CFR 594.508 - Transactions related to telecommunications authorized.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... telecommunications authorized. 594.508 Section 594.508 Money and Finance: Treasury Regulations Relating to Money and... related to telecommunications authorized. All transactions ordinarily incident to the receipt or transmission of telecommunications involving persons whose property or interests in property are blocked...

  2. 31 CFR 594.508 - Transactions related to telecommunications authorized.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... telecommunications authorized. 594.508 Section 594.508 Money and Finance: Treasury Regulations Relating to Money and... related to telecommunications authorized. All transactions ordinarily incident to the receipt or transmission of telecommunications involving persons whose property or interests in property are blocked...

  3. 31 CFR 594.508 - Transactions related to telecommunications authorized.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... telecommunications authorized. 594.508 Section 594.508 Money and Finance: Treasury Regulations Relating to Money and... related to telecommunications authorized. All transactions ordinarily incident to the receipt or transmission of telecommunications involving persons whose property or interests in property are blocked...

  4. 31 CFR 594.508 - Transactions related to telecommunications authorized.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... telecommunications authorized. 594.508 Section 594.508 Money and Finance: Treasury Regulations Relating to Money and... related to telecommunications authorized. All transactions ordinarily incident to the receipt or transmission of telecommunications involving persons whose property or interests in property are blocked...

  5. 31 CFR 545.508 - Transactions related to telecommunications authorized.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... telecommunications authorized. 545.508 Section 545.508 Money and Finance: Treasury Regulations Relating to Money and... related to telecommunications authorized. All transactions ordinarily incident to the receipt or transmission of telecommunications involving the territory of Afghanistan controlled by the Taliban are...

  6. 31 CFR 594.508 - Transactions related to telecommunications authorized.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... telecommunications authorized. 594.508 Section 594.508 Money and Finance: Treasury Regulations Relating to Money and... related to telecommunications authorized. All transactions ordinarily incident to the receipt or transmission of telecommunications involving persons whose property or interests in property are blocked...

  7. Fracture toughness and the master curve for modified 9Cr-1Mo steel

    NASA Astrophysics Data System (ADS)

    Yoon, Ji-Hyun; Yoon, Eui-Pak

    2006-12-01

    Modified 9Cr-1Mo steel is a primary candidate material for the reactor pressure vessel of a Very High Temperature Gas-Cooled Reactor (VHTR) in the Korean Nuclear Hydrogen Development and Demonstration (NHDD) program. In this study, the T0 reference temperature, J-R fracture resistance and Charpy impact properties were evaluated for commercial Grade 91 steel as part of the preliminary testing for a selection of the RPV material for the VHTR. The fracture toughness of the modified 9Cr-1Mo steel was compared with that of SA508-Gr.3. The objective of this study was to obtain the pre-irradiation fracture toughness properties of the modified 9Cr-1Mo steel as reference data for an investigation of radiation effects. Charpy impact properties of the modified 9Cr-1Mo steel were similar to those of SA508-Gr.3. T0 reference temperatures were measured as -67.7 and -72.4°C from the tests with standard PCVN (pre-cracked Charpy V-notch) and half-sized PCVN specimens respectively, which were similar to the results for SA508-Gr.3. The KJc values of the modified 9Cr-1Mo steel with the test temperatures are successfully expressed by the Master Curve. The J-R fracture resistance of the modified 9Cr-1Mo steel at room temperature was nearly identical to that of SA508-Gr.3; in contrast, it was slightly higher at an elevated temperature.

  8. The pharmacology of GR203040, a novel, potent and selective non-peptide tachykinin NK1 receptor antagonist.

    PubMed Central

    Beattie, D. T.; Beresford, I. J.; Connor, H. E.; Marshall, F. H.; Hawcock, A. B.; Hagan, R. M.; Bowers, J.; Birch, P. J.; Ward, P.

    1995-01-01

    1. The in vitro and in vivo pharmacology of GR203040 ((2S, 3S)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), a novel, highly potent and selective non-peptide tachykinin NK1 receptor antagonist, was investigated in the present study. 2. GR203040 potently inhibited [3H]-substance P binding to human NK1 receptors expressed in Chinese hamster ovary (CHO) and U373 MG astrocytoma cells, and NK1 receptors in ferret and gerbil cortex (pKi values of 10.3, 10.5, 10.1 and 10.1 respectively). GR203040 had lower affinity at rat NK1 receptors (pKi = 8.6) and little affinity for human NK2 receptors (pKi < 5.0) in CHO cells and NK3 receptors in guinea-pig cortex (pKi < 6.0). With the exception of the histamine H1 receptor (pIC50 = 7.5). GR203040 had little affinity (pIC50 < 6.0) at all non-NK1 receptors and ion channels examined. Furthermore, GR203040 produced only weak inhibition of Na+ currents in SH-SY5Y neuroblastoma and superior cervical ganglion cells (pIC50 values < 4.0). GR203040 produced only weak antagonism of Ca(2+)-evoked contractions of rat isolated portal vein (pKn = 4.1). The enantiomer of GR203040, GR205608 (2R, 3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), had 10,000 fold lower affinity at the human NK1 receptor expressed in CHO cells (pKi = 6.3). 3. In gerbil ex vivo binding experiments, GR203040 produced a dose-dependent inhibition of the binding of [3H]-substance P to cerebral cortical membranes (ED50 = 15 micrograms kg-1 s.c. and 0.42 mg kg-1 p.o.). At 10 micrograms kg-1 s.c., the inhibition of [3H]-substance P binding was maintained for > 6 h. In the rat, GR203040 was less potent (ED50 = 15.4 mg kg-1 s.c.) probably reflecting, at least in part, its lower affinity at the rat NK1 receptor. 4. In guinea-pig isolated ileum and dog isolated middle cerebral and basilar arteries, GR203040 produced a rightward displacement of the concentration-effect curves to substance P methyl ester (SPOMe) with suppression of the

  9. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

    PubMed Central

    Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Stack, Jeffrey H.; Straley, Kimberly S.; Decker, Caroline J.; Miller, Mark; McCartney, Jason; Olson, Eric R.; Wine, Jeffrey J.; Frizzell, Ray A.; Ashlock, Melissa; Negulescu, Paul A.

    2011-01-01

    Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC50, 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR. PMID:21976485

  10. 31 CFR 576.508 - Judicial process in legal proceedings involving ecological accidents.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... involving ecological accidents. 576.508 Section 576.508 Money and Finance: Treasury Regulations Relating to... § 576.508 Judicial process in legal proceedings involving ecological accidents. The Office of Foreign... accident (including an oil spill) that occurred after May 22, 2003. ...

  11. 41 CFR 101-26.508-3 - Consolidation of requisitions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 2 2010-07-01 2010-07-01 true Consolidation of requisitions. 101-26.508-3 Section 101-26.508-3 Public Contracts and Property Management Federal Property Management Regulations System FEDERAL PROPERTY MANAGEMENT REGULATIONS SUPPLY AND PROCUREMENT 26-PROCUREMENT...

  12. CRTC2 Is a Coactivator of GR and Couples GR and CREB in the Regulation of Hepatic Gluconeogenesis.

    PubMed

    Hill, Micah J; Suzuki, Shigeru; Segars, James H; Kino, Tomoshige

    2016-01-01

    Glucocorticoid hormones play essential roles in the regulation of gluconeogenesis in the liver, an adaptive response that is required for the maintenance of circulating glucose levels during fasting. Glucocorticoids do this by cooperating with glucagon, which is secreted from pancreatic islets to activate the cAMP-signaling pathway in hepatocytes. The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting. We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR). CRTC2 strongly enhances GR-induced transcriptional activity of glucocorticoid-responsive genes. CRTC2 physically interacts with the ligand-binding domain of the GR through a region spanning amino acids 561-693. Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB. CRTC2 is required for the maintenance of blood glucose levels during fasting in mice by enhancing the GR transcriptional activity on both the G6p and phosphoenolpyruvate carboxykinase (Pepck) genes. Finally, CRTC2 modulates the transcriptional activity of the progesterone receptor, indicating that it may influence the transcriptional activity of other steroid/nuclear receptors. Taken together, these results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK.

  13. A Study on Gröbner Basis with Inexact Input

    NASA Astrophysics Data System (ADS)

    Nagasaka, Kosaku

    Gröbner basis is one of the most important tools in recent symbolic algebraic computations. However, computing a Gröbner basis for the given polynomial ideal is not easy and it is not numerically stable if polynomials have inexact coefficients. In this paper, we study what we should get for computing a Gröbner basis with inexact coefficients and introduce a naive method to compute a Gröbner basis by reduced row echelon form, for the ideal generated by the given polynomial set having a priori errors on their coefficients.

  14. 31 CFR 546.508 - Authorization of emergency medical services.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Authorization of emergency medical services. 546.508 Section 546.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY DARFUR SANCTIONS REGULATIONS...

  15. 24 CFR 570.508 - Public access to program records.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 3 2010-04-01 2010-04-01 false Public access to program records. 570.508 Section 570.508 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued) OFFICE OF ASSISTANT SECRETARY FOR COMMUNITY PLANNING AND DEVELOPMENT, DEPARTMENT OF...

  16. Frequent Questions about Section 508

    EPA Pesticide Factsheets

    Reasonable Accommodation addresses the individual's needs in the workplace, while the Rehabilitation Act Section 508 requires accessibility for all people to Information and Communications Technology (ICT) equipment and tools to access information or work.

  17. 31 CFR 593.508 - Authorization of emergency medical services.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Authorization of emergency medical services. 593.508 Section 593.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FORMER LIBERIAN REGIME OF CHARLES...

  18. 31 CFR 593.508 - Authorization of emergency medical services.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Authorization of emergency medical services. 593.508 Section 593.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FORMER LIBERIAN REGIME OF CHARLES...

  19. 31 CFR 593.508 - Authorization of emergency medical services.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Authorization of emergency medical services. 593.508 Section 593.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FORMER LIBERIAN REGIME OF CHARLES...

  20. 31 CFR 593.508 - Authorization of emergency medical services.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Authorization of emergency medical services. 593.508 Section 593.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FORMER LIBERIAN REGIME OF CHARLES...

  1. 31 CFR 593.508 - Authorization of emergency medical services.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Authorization of emergency medical services. 593.508 Section 593.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FORMER LIBERIAN REGIME OF CHARLES...

  2. 31 CFR 547.508 - Authorization of emergency medical services.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Authorization of emergency medical services. 547.508 Section 547.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY DEMOCRATIC REPUBLIC OF THE CONGO...

  3. 31 CFR 547.508 - Authorization of emergency medical services.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Authorization of emergency medical services. 547.508 Section 547.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY DEMOCRATIC REPUBLIC OF THE CONGO...

  4. 31 CFR 547.508 - Authorization of emergency medical services.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Authorization of emergency medical services. 547.508 Section 547.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY DEMOCRATIC REPUBLIC OF THE CONGO...

  5. 31 CFR 547.508 - Authorization of emergency medical services.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Authorization of emergency medical services. 547.508 Section 547.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY DEMOCRATIC REPUBLIC OF THE CONGO...

  6. 31 CFR 547.508 - Authorization of emergency medical services.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Authorization of emergency medical services. 547.508 Section 547.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY DEMOCRATIC REPUBLIC OF THE CONGO...

  7. Effect of neutron irradiation on magnetic properties in the low alloy Ni-Mo steel SA508-3

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Park, D.G.; Kim, C.G.; Kim, H.C.

    1997-04-01

    The B-H hysteresis loop and Barkhausen noise have been measured in the neutron irradiated SA508 steel of 45 {mu}m thickness. The coercive force of B-H loop showed a slow change up to a neutron dose of 10{sup 14} n/cm{sup 2} and increased by 15.4{percent} for a 10{sup 16} n/cm{sup 2} dose sample compared with that of the unirradiated one, related to the domain wall motion hindered by the increased defects. However, the amplitude of Barkhausen noise reflecting the wall motion decreased slowly up to 10{sup 14} n/cm{sup 2} irradiation, followed by a rapid decrease of 37.5{percent} at 10{sup 16} n/cm{supmore » 2}. {copyright} {ital 1997 American Institute of Physics.}« less

  8. Screening for F508del as a first step in the molecular diagnosis of cystic fibrosis.

    PubMed

    Marson, Fernando Augusto de Lima; Bertuzzo, Carmen Silvia; Ribeiro, Maria Ângela Gonçalves de Oliveira; Ribeiro, Antônio Fernando; Ribeiro, José Dirceu

    2013-01-01

    To determine the relevance of screening for the F508del mutation of the cystic fibrosis transmembrane conductance regulator gene as a first step in the genetic diagnosis of cystic fibrosis (CF) by associating the genotype with various clinical variables. We evaluated 180 CF patients regarding the F508del mutation. The clinical data were obtained from the medical records of the patients and from interviews with their parents or legal guardians. Of the 180 patients studied, 65 (36.1%) did not carry the F508del mutation (group 0 [G0]), 67 (37.2%) were F508del heterozygous (G1), and 48 (26.7%) were F508del homozygous (G2). All three groups showed associations with the clinical variables. Homozygosis was associated with younger patients, younger age at CF diagnosis, and younger age at the first isolation of Pseudomonas aeruginosa (PA), as well as with higher prevalence of pancreatic insufficiency (PI) and non-mucoid PA (NMPA) colonization. In comparison with G1+G2 patients, G0 patients were older; first experienced clinical symptoms, digestive disease, and pulmonary disease at an older age; were older at CF diagnosis and at first PA isolation; and had a lower prevalence of PI and meconium ileus, as well as of colonization by NMPA, mucoid PA, and Burkholderia cepacia. In G1 patients, values were intermediate for age at CF diagnosis; age at first PA isolation, first pulmonary symptoms, and first clinical manifestations; MPA colonization; and OR for PI. The identification of F508del in 63.9% of the patients studied showed that this can be a useful tool as a first step in the genetic diagnosis of CF. The F508del genotype was associated with clinical severity of the disease, especially with the variables related to CF onset.

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

    PubMed

    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 ΔF508/ΔF508-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. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Radiosynthesis and radiopharmacological evaluation of [N-methyl-11C]Org 34850 as a glucocorticoid receptor (GR)-binding radiotracer.

    PubMed

    Wuest, Frank; Kniess, Torsten; Henry, Brian; Peeters, Bernardus W M M; Wiegerinck, Peter H G; Pietzsch, Jens; Bergmann, Ralf

    2009-02-01

    The radiosynthesis of [N-methyl-(11)C]Org 34850 as a potential brain glucocorticoid receptor (GR)-binding radiotracer is described. The radiosynthesis was accomplished via N-methylation of the corresponding desmethyl precursor with [(11)C]methyl triflate in a remotely controlled synthesis module to give the desired compound in a radiochemical yield of 23+/-5% (decay-corrected, based upon [(11)C]CO(2)) at a specific activity of 47+/-12 GBq/micromol (n=15) at the end-of-synthesis (EOS). The radiochemical purity after semi-preparative HPLC purification exceeded 95%. The total synthesis time was 35-40 min after end-of-bombardment (EOB). The radiotracer is rapidly metabolized in rat plasma leading to the formation of two more hydrophilic metabolites as the major metabolites. Radiopharmacological evaluation involving biodistribution and small animal PET imaging in normal Wistar rats showed that the compound [N-methyl-(11)C]Org 34850 is not able to sufficiently penetrate the blood-brain barrier. Therefore, compound [N-methyl-(11)C]Org 34850 seems not to be a suitable PET radiotracer for imaging rat brain GRs. However, involvement of Pgp or species differences requires further clarification to establish whether the radiotracer [N-methyl-(11)C]Org 34850 may still represent a suitable candidate for imaging GRs in humans.

  11. 22 CFR 50.8 - Certification of Report of Birth Abroad of a United States Citizen.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Certification of Report of Birth Abroad of a United States Citizen. 50.8 Section 50.8 Foreign Relations DEPARTMENT OF STATE NATIONALITY AND PASSPORTS... payment of the required fee, the Department of State's Passport Office may issue to the citizen, the...

  12. 22 CFR 50.8 - Certification of Report of Birth Abroad of a United States Citizen.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Certification of Report of Birth Abroad of a United States Citizen. 50.8 Section 50.8 Foreign Relations DEPARTMENT OF STATE NATIONALITY AND PASSPORTS... payment of the required fee, the Department of State's Passport Office may issue to the citizen, the...

  13. 22 CFR 50.8 - Certification of Report of Birth Abroad of a United States Citizen.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Certification of Report of Birth Abroad of a United States Citizen. 50.8 Section 50.8 Foreign Relations DEPARTMENT OF STATE NATIONALITY AND PASSPORTS... payment of the required fee, the Department of State's Passport Office may issue to the citizen, the...

  14. 22 CFR 50.8 - Certification of Report of Birth Abroad of a United States Citizen.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Certification of Report of Birth Abroad of a United States Citizen. 50.8 Section 50.8 Foreign Relations DEPARTMENT OF STATE NATIONALITY AND PASSPORTS... payment of the required fee, the Department of State's Passport Office may issue to the citizen, the...

  15. 22 CFR 50.8 - Certification of Report of Birth Abroad of a United States Citizen.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Certification of Report of Birth Abroad of a United States Citizen. 50.8 Section 50.8 Foreign Relations DEPARTMENT OF STATE NATIONALITY AND PASSPORTS... payment of the required fee, the Department of State's Passport Office may issue to the citizen, the...

  16. Microstructure of a safe-end dissimilar metal weld joint (SA508-52-316L) prepared by narrow-gap GTAW

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ming, Hongliang

    The microstructure, residual strain and interfacial chemical composition distribution of a safe-end dissimilar metal weld joint (DMWJ, SA508-52-316L) prepared by narrow-gap gas-tungsten arc welding (NG-GTAW) were studied by optical microscope (OM) and scanning electron microscope equipped with an energy dispersive X-ray microanalysis (SEM/EDX) and an electron back scattering diffraction (EBSD) system. Complex microstructure and chemical composition distribution are found, especially at the SA508-52 interface and the 52-316L interface. In brief, a complicated microstructure transition exists within the SA508 heat affected zone (HAZ); the residual strain, the fraction of high angle random grain boundaries and low angle boundaries decrease with increasingmore » the distance from the fusion boundary in 316L HAZ; neither typical type II boundary nor obvious carbon-depleted zone is found near the SA508-52 interface; dramatic and complicated changes of the contents of the main elements, Fe, Cr and Ni, are observed at the distinct interfaces, especially at the SA508-52 interface. No carbon concentration is found at the SA508-52 interface. - Highlights: •Residual strain and GBCD change as a function of the distance from FB in 316L HAZ. •Neither type II boundary nor obvious carbon-depleted zone is found in SA508 HAZ. •No carbon concentration is found at the SA508-52 interface. •The middle part of the DMWJ has the highest residual strain.« less

  17. 7 CFR 1430.508 - Maintaining records.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS DAIRY PRODUCTS Dairy Market Loss Assistance Program § 1430.508 Maintaining records. Dairy operations making application for benefits under this...

  18. 7 CFR 1430.508 - Maintaining records.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS DAIRY PRODUCTS Dairy Market Loss Assistance Program § 1430.508 Maintaining records. Dairy operations making application for benefits under this...

  19. 7 CFR 1430.508 - Maintaining records.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS DAIRY PRODUCTS Dairy Market Loss Assistance Program § 1430.508 Maintaining records. Dairy operations making application for benefits under this...

  20. 7 CFR 1430.508 - Maintaining records.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS DAIRY PRODUCTS Dairy Market Loss Assistance Program § 1430.508 Maintaining records. Dairy operations making application for benefits under this...

  1. 7 CFR 1430.508 - Maintaining records.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS DAIRY PRODUCTS Dairy Market Loss Assistance Program § 1430.508 Maintaining records. Dairy operations making application for benefits under this...

  2. Rescue of murine F508del CFTR activity in native intestine by low temperature and proteasome inhibitors.

    PubMed

    Wilke, Martina; Bot, Alice; Jorna, Huub; Scholte, Bob J; de Jonge, Hugo R

    2012-01-01

    Most 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 cells. New therapies are therefore aimed at improving the folding and trafficking of F508del CFTR, (CFTR correctors) or at enhancing the open probability of the CFTR chloride channel (CFTR potentiators). Preventing premature breakdown of F508del CFTR is an alternative or additional strategy, which is investigated in this study. We established an ex vivo assay for murine F508del CFTR rescue in native intestinal epithelium that can be used as a pre-clinical test for candidate therapeutics. Overnight incubation of muscle stripped ileum in modified William's E medium at low temperature (26°C), and 4 h or 6 h incubation at 37°C with different proteasome inhibitors (PI: ALLN, MG-132, epoxomicin, PS341/bortezomib) resulted in fifty to hundred percent respectively of the wild type CFTR mediated chloride secretion (forskolin induced short-circuit current). The functional rescue was accompanied by enhanced expression of the murine F508del CFTR protein at the apical surface of intestinal crypts and a gain in the amount of complex-glycosylated CFTR (band C) up to 20% of WT levels. Sustained rescue in the presence of brefeldin A shows the involvement of a post-Golgi compartment in murine F508del CFTR degradation, as was shown earlier for its human counterpart. Our data show that proteasome inhibitors are promising candidate compounds for improving rescue of human F508del CFTR function, in combination with available correctors and potentiators.

  3. ERp29 Regulates ΔF508 and Wild-type Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Trafficking to the Plasma Membrane in Cystic Fibrosis (CF) and Non-CF Epithelial Cells*

    PubMed Central

    Suaud, Laurence; Miller, Katelyn; Alvey, Lora; Yan, Wusheng; Robay, Amal; Kebler, Catherine; Kreindler, James L.; Guttentag, Susan; Hubbard, Michael J.; Rubenstein, Ronald C.

    2011-01-01

    Sodium 4-phenylbutyrate (4PBA) improves the intracellular trafficking of ΔF508-CFTR in cystic fibrosis (CF) epithelial cells. The underlying mechanism is uncertain, but 4PBA modulates the expression of some cytosolic molecular chaperones. To identify other 4PBA-regulated proteins that might regulate ΔF508-CFTR trafficking, we performed a differential display RT-PCR screen on IB3-1 CF bronchiolar epithelial cells exposed to 4PBA. One transcript up-regulated by 4PBA encoded ERp29, a luminal resident of the endoplasmic reticulum (ER) thought to be a novel molecular chaperone. We tested the hypothesis that ERp29 is a 4PBA-regulated ER chaperone that influences ΔF508-CFTR trafficking. ERp29 mRNA and protein expression was significantly increased (∼1.5-fold) in 4PBA-treated IB3-1 cells. In Xenopus oocytes, ERp29 overexpression increased the functional expression of both wild-type and ΔF508-CFTR over 3-fold and increased wild-type cystic fibrosis transmembrane conductance regulator (CFTR) plasma membrane expression. In CFBE41o− WT-CFTR cells, expression of and short circuit currents mediated by CFTR decreased upon depletion of ERp29 as did maturation of newly synthesized CFTR. In IB3-1 cells, ΔF508-CFTR co-immunoprecipitated with endogenous ERp29, and overexpression of ERp29 led to increased ΔF508-CFTR expression at the plasma membrane. These data suggest that ERp29 is a 4PBA-regulated ER chaperone that regulates WT-CFTR biogenesis and can promote ΔF508-CFTR trafficking in CF epithelial cells. PMID:21525008

  4. ERp29 regulates DeltaF508 and wild-type cystic fibrosis transmembrane conductance regulator (CFTR) trafficking to the plasma membrane in cystic fibrosis (CF) and non-CF epithelial cells.

    PubMed

    Suaud, Laurence; Miller, Katelyn; Alvey, Lora; Yan, Wusheng; Robay, Amal; Kebler, Catherine; Kreindler, James L; Guttentag, Susan; Hubbard, Michael J; Rubenstein, Ronald C

    2011-06-17

    Sodium 4-phenylbutyrate (4PBA) improves the intracellular trafficking of ΔF508-CFTR in cystic fibrosis (CF) epithelial cells. The underlying mechanism is uncertain, but 4PBA modulates the expression of some cytosolic molecular chaperones. To identify other 4PBA-regulated proteins that might regulate ΔF508-CFTR trafficking, we performed a differential display RT-PCR screen on IB3-1 CF bronchiolar epithelial cells exposed to 4PBA. One transcript up-regulated by 4PBA encoded ERp29, a luminal resident of the endoplasmic reticulum (ER) thought to be a novel molecular chaperone. We tested the hypothesis that ERp29 is a 4PBA-regulated ER chaperone that influences ΔF508-CFTR trafficking. ERp29 mRNA and protein expression was significantly increased (∼1.5-fold) in 4PBA-treated IB3-1 cells. In Xenopus oocytes, ERp29 overexpression increased the functional expression of both wild-type and ΔF508-CFTR over 3-fold and increased wild-type cystic fibrosis transmembrane conductance regulator (CFTR) plasma membrane expression. In CFBE41o- WT-CFTR cells, expression of and short circuit currents mediated by CFTR decreased upon depletion of ERp29 as did maturation of newly synthesized CFTR. In IB3-1 cells, ΔF508-CFTR co-immunoprecipitated with endogenous ERp29, and overexpression of ERp29 led to increased ΔF508-CFTR expression at the plasma membrane. These data suggest that ERp29 is a 4PBA-regulated ER chaperone that regulates WT-CFTR biogenesis and can promote ΔF508-CFTR trafficking in CF epithelial cells.

  5. Master Curve and Conventional Fracture Toughness of Modified 9Cr-1Mo Steel

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ji-Hyun, Yoon; Sung-Ho, Kim; Bong-Sang, Lee

    2006-07-01

    Modified 9Cr-1Mo steel is a primary candidate material for reactor pressure vessel of Very High Temperature Gas-Cooled Reactor (VHTR) in Korean Nuclear Hydrogen Development and Demonstration (NHDD) program. In this study, T0 reference temperature, J-R fracture resistance and Charpy impact properties were evaluated for commercial Grade 91 steel as preliminary tests for the selection of the RPV material for VHTR. The fracture toughness of the modified 9Cr-1Mo steel was compared with those of SA508-Gr.3. The objective of this study was to obtain pre-irradiation fracture toughness properties of modified 9Cr-1Mo steel as reference data for the radiation effects investigation. The resultsmore » are as follows. Charpy impact properties of the modified 9Cr-1Mo steel were similar to those of SA508-Gr.3. T0 reference temperatures were measured as -67.7 deg C and -72.4 deg C from the tests with standard PCVN (pre-cracked Charpy V-notch) and half sized PCVN specimens respectively, which were similar to results for SA508-Gr.3. The K{sub Jc} values of modified 9Cr-1Mo with test temperatures are successfully expressed with the Master Curve. The J-R fracture resistance of modified 9Cr-1Mo steel at room temperature was almost the same as that of SA508-Gr.3. On the other hand it was a little bit higher at an elevated temperature. (authors)« less

  6. Fertility in Adult Bitches Previously Treated with a 4.7 mg Subcutaneous Deslorelin Implant.

    PubMed

    Borges, P; Fontaine, E; Maenhoudt, C; Payan-Carreira, R; Santos, N; Leblond, E; Fontaine, C; Fontbonne, A

    2015-12-01

    The absence of fertility problems in male dogs after a single treatment with deslorelin acetate (Suprelorin(®)) is well acknowledged. However, reports on the application of deslorelin in the bitch and information concerning fertility after implant treatment are still limited. In this retrospective study, data concerning induced and spontaneous oestruses of 39 bitches from 17 breeds, treated with deslorelin acetate implants (4.7 mg Suprelorin(®), Virbac, France), were retrieved to assess post-treatment fertility (ovulation rate, pregnancy rate and litter size). Animals were grouped according to treatment characteristics: group 1 (Gr1) - females submitted to oestrus induction, showing natural oestruses afterwards (n = 19); group 2 (Gr2) - females re-implanted with 4.7 mg deslorelin acetate to re-induce oestrus, showing subsequent spontaneous post-implant oestruses (n = 7); and group 3 (Gr3) - females submitted to a 4.7 mg deslorelin acetate implant for oestrus suppression, evaluated at subsequent spontaneous post-implant oestruses (n = 13). Comparison of fertility traits between induced and post-treatment spontaneous oestruses in Gr1 and Gr2 (short treatments), or between spontaneous oestruses after long-treatment schedules (Gr 3) revealed a slightly better performance in spontaneous cycles compared with induced cycles: ovulation rate post-treatment was 97.1%, 94.1% and 94.4% and the pregnancy rate post-treatment was 91.2%, 88.9% and 84.6% for groups 1, 2 and 3, respectively. Nevertheless, fertility in induced and post-treatment oestruses was considered normal. Moreover, the individual litter size did not differ within groups between induced and spontaneous cycles. From these findings, we concluded that treatment with 4.7 mg deslorelin implants did not compromise the bitches' fertility in subsequent oestruses. © 2015 The Authors. Reproduction in Domestic Animals Published by Blackwell Verlag GmbH.

  7. Studies of Second Layer Hydrogens on Graphite: Hydrogen/hd/gr and Hd/hd/gr.

    NASA Astrophysics Data System (ADS)

    Liu, Yuanming

    Quasi-adiabatic heat capacity and volumetric vapor pressure isotherm techniques were used to study the thermodynamic properties of monolayer H_2 adsorbed on HD plated graphite (H_2/HD/Gr) and bilayer HD on bare graphite (HD/HD/Gr). Quasielastic neutron scattering (QENS) measurements were performed at the Laboratoire Leon Brillouin (LLB) in Saclay, France, to study the mobility of the bilayer HD films. The three techniques complemented each other. Three types of graphite were used: graphite foam for the heat capacity measurements, more loose and homogeneous graphite 'worms' for the isotherm measurements, and Papyex (similar to Grafoil) with a high surface-to-volume ratio for the QENS measurements. The heat capacity study on the mixture system H_2/HD/Gr is a continuation of the previous study on H_2/D _2/Gr by F. C. Liu et al. The results show three peculiar features which have not been seen in the pure bilayer hydrogen films: a tilted triple line, a distorted liquid(L)-vapor(V) coexistence region, and weak heat capacity anomalies at 10.1K. The triple line tilts backwards, from 6.58K to 6.25K as the H2 coverage increases. The lowest triple point temperature (6.25K) is still higher than both 5.96K of H_2/H _2/Gr (Wiechert et al.) and 5.74K of H_2/D_2/Gr (F. C. Liu et al.). The behavior of the triple line can be semi-quantitatively explained by a model of interlayer mixing which is based on the consideration that interlayer mixing lowers the system's free energy. The distortion of the L-V region and appearance of weak heat capacity anomalies are also believed to be due to interlayer mixing. The heat capacity measurements on HD/HD/Gr show a phase diagram similar to those of H_2 /H_2/MgO, H_2 /H_2/Gr, and 3D van der Waals systems, with the 2D triple and critical points at T _{t} = 8.44K and T_ {c} = 11.45K. The entropy change and heat of fusion at the triple point melting in HD/HD/Gr are comparable with those of H_2/H _2/Gr and D_2/D _2/Gr, but are considerably less

  8. 24 CFR 5.508 - Submission of evidence of citizenship or eligible immigration status.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... citizenship or eligible immigration status. 5.508 Section 5.508 Housing and Urban Development Office of the... Restrictions on Assistance to Noncitizens § 5.508 Submission of evidence of citizenship or eligible immigration... or eligible immigration status, the family members may exercise the election not to contend to have...

  9. 31 CFR 800.508 - Role of the Secretary of Labor.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Role of the Secretary of Labor. 800.508 Section 800.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF INVESTMENT SECURITY, DEPARTMENT OF THE TREASURY REGULATIONS PERTAINING TO MERGERS, ACQUISITIONS...

  10. 19 CFR 351.508 - Debt forgiveness.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Identification and Measurement of Countervailable Subsidies § 351.508 Debt forgiveness. (a) Benefit. In the case of an assumption or forgiveness of a firm's debt obligation, a benefit exists equal to the amount of...

  11. Generation of ΔF508-CFTR T84 cell lines by CRISPR/Cas9-mediated genome editing.

    PubMed

    Chung, Woo Young; Song, Myungjae; Park, Jinhong; Namkung, Wan; Lee, Jinu; Kim, Hyongbum; Lee, Min Goo; Kim, Joo Young

    2016-12-01

    To provide a simple method to make a stable ΔF508-CFTR-expressing T84 cell line that can be used as an efficient screening model system for ΔF508-CFTR rescue. CFTR knockout cell lines were generated by Cas9 with a single-guide RNA (sgRNA) targeting exon 1 of the CFTR genome, which produced indels that abolished CFTR protein expressions. Next, stable ΔF508-CFTR expression was achieved by genome integration of ΔF508-CFTR via the lentivirus infection system. Finally, we showed functional rescue of ΔF508-CFTR not only by growing the cells at a low temperature, but also incubating with VX-809, a ΔF508-CFTR corrector, in the established T84 cells expressing ΔF508-CFTR. This cell system provides an appropriate screening platform for rescue of ΔF508-CFTR, especially related to protein folding, escaped from endoplasmic-reticulum-associated protein degradation, and membrane transport.

  12. 47 CFR 54.508 - Technology plans.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SERVICE Universal Service Support for Schools and Libraries § 54.508 Technology plans. (a) Applicants must... for using telecommunications and information technology to improve education or library services; (2... technologies to improve education or library services; (3) An assessment of the telecommunication services...

  13. 47 CFR 54.508 - Technology plans.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... SERVICE Universal Service Support for Schools and Libraries § 54.508 Technology plans. (a) Applicants must... for using telecommunications and information technology to improve education or library services; (2... technologies to improve education or library services; (3) An assessment of the telecommunication services...

  14. 40 CFR 50.8 - National primary ambient air quality standards for carbon monoxide.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 2 2010-07-01 2010-07-01 false National primary ambient air quality standards for carbon monoxide. 50.8 Section 50.8 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS NATIONAL PRIMARY AND SECONDARY AMBIENT AIR QUALITY STANDARDS § 50.8 National primary ambient air quality standards for...

  15. 40 CFR 50.8 - National primary ambient air quality standards for carbon monoxide.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 2 2014-07-01 2014-07-01 false National primary ambient air quality standards for carbon monoxide. 50.8 Section 50.8 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS NATIONAL PRIMARY AND SECONDARY AMBIENT AIR QUALITY STANDARDS § 50.8 National primary ambient air quality standards for...

  16. 40 CFR 50.8 - National primary ambient air quality standards for carbon monoxide.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 2 2012-07-01 2012-07-01 false National primary ambient air quality standards for carbon monoxide. 50.8 Section 50.8 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS NATIONAL PRIMARY AND SECONDARY AMBIENT AIR QUALITY STANDARDS § 50.8 National primary ambient air quality standards for...

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

    PubMed

    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.

  18. SiglecF+Gr1hi eosinophils are a distinct subpopulation within the lungs of allergen-challenged mice

    PubMed Central

    Percopo, Caroline M.; Brenner, Todd A.; Ma, Michelle; Kraemer, Laura S.; Hakeem, Reem M. A.; Lee, James J.; Rosenberg, Helene F.

    2017-01-01

    Although eosinophils as a group are readily identified by their unique morphology and staining properties, flow cytometry provides an important means for identification of subgroups based on differential expression of distinct surface Ags. Here, we characterize an eosinophil subpopulation defined by high levels of expression of the neutrophil Ag Gr1 (CD45+CD11c−SiglecF+Gr1hi). SiglecF+Gr1hi eosinophils, distinct from the canonical SiglecF+Gr1− eosinophil population, were detected in allergen-challenged wild-type and granule protein-deficient (EPX−/− and MBP-1−/−) mice, but not in the eosinophil-deficient ΔdblGATA strain. In contrast to Gr1+ neutrophils, which express both cross-reacting Ags Ly6C and Ly6G, SiglecF+Gr1hi eosinophils from allergen-challenged lung tissue are uniquely Ly6G+. Although indistinguishable from the more-numerous SiglecF+Gr1− eosinophils under light microscopy, FACS-isolated populations revealed prominent differences in cytokine contents. The lymphocyte-targeting cytokines CXCL13 and IL-27 were identified only in the SiglecF+Gr1hi eosinophil population (at 3.9 and 4.8 pg/106 cells, respectively), as was the prominent proinflammatory mediator IL-13 (72 pg/106 cells). Interestingly, bone marrow-derived (SiglecF+), cultured eosinophils include a more substantial Gr1+ subpopulation (∼50%); Gr1+ bmEos includes primarily a single Ly6C+ and a smaller, double-positive (Ly6C+Ly6G+) population. Taken together, our findings characterize a distinct SiglecF+Gr1hi eosinophil subset in lungs of allergen-challenged, wild-type and granule protein-deficient mice. SiglecF+Gr1hi eosinophils from wild-type mice maintain a distinct subset of cytokines, including those active on B and T lymphocytes. These cytokines may facilitate eosinophil-mediated immunomodulatory responses in the allergen-challenged lung as well as in other distinct microenvironments. PMID:27531929

  19. SiglecF+Gr1hi eosinophils are a distinct subpopulation within the lungs of allergen-challenged mice.

    PubMed

    Percopo, Caroline M; Brenner, Todd A; Ma, Michelle; Kraemer, Laura S; Hakeem, Reem M A; Lee, James J; Rosenberg, Helene F

    2017-01-01

    Although eosinophils as a group are readily identified by their unique morphology and staining properties, flow cytometry provides an important means for identification of subgroups based on differential expression of distinct surface Ags. Here, we characterize an eosinophil subpopulation defined by high levels of expression of the neutrophil Ag Gr1 (CD45 + CD11c - SiglecF + Gr1 hi ). SiglecF + Gr1 hi eosinophils, distinct from the canonical SiglecF + Gr1 - eosinophil population, were detected in allergen-challenged wild-type and granule protein-deficient (EPX -/- and MBP-1 -/- ) mice, but not in the eosinophil-deficient ΔdblGATA strain. In contrast to Gr1 + neutrophils, which express both cross-reacting Ags Ly6C and Ly6G, SiglecF + Gr1 hi eosinophils from allergen-challenged lung tissue are uniquely Ly6G + Although indistinguishable from the more-numerous SiglecF + Gr1 - eosinophils under light microscopy, FACS-isolated populations revealed prominent differences in cytokine contents. The lymphocyte-targeting cytokines CXCL13 and IL-27 were identified only in the SiglecF + Gr1 hi eosinophil population (at 3.9 and 4.8 pg/10 6 cells, respectively), as was the prominent proinflammatory mediator IL-13 (72 pg/10 6 cells). Interestingly, bone marrow-derived (SiglecF + ), cultured eosinophils include a more substantial Gr1 + subpopulation (∼50%); Gr1 + bmEos includes primarily a single Ly6C + and a smaller, double-positive (Ly6C + Ly6G + ) population. Taken together, our findings characterize a distinct SiglecF + Gr1 hi eosinophil subset in lungs of allergen-challenged, wild-type and granule protein-deficient mice. SiglecF + Gr1 hi eosinophils from wild-type mice maintain a distinct subset of cytokines, including those active on B and T lymphocytes. These cytokines may facilitate eosinophil-mediated immunomodulatory responses in the allergen-challenged lung as well as in other distinct microenvironments. © Society for Leukocyte Biology.

  20. Section 508 Electronic Information Accessibility Requirements for Software Development

    NASA Technical Reports Server (NTRS)

    Ellis, Rebecca

    2014-01-01

    Section 508 Subpart B 1194.21 outlines requirements for operating system and software development in order to create a product that is accessible to users with various disabilities. This portion of Section 508 contains a variety of standards to enable those using assistive technology and with visual, hearing, cognitive and motor difficulties to access all information provided in software. The focus on requirements was limited to the Microsoft Windows® operating system as it is the predominant operating system used at this center. Compliance with this portion of the requirements can be obtained by integrating the requirements into the software development cycle early and by remediating issues in legacy software if possible. There are certain circumstances with software that may arise necessitating an exemption from these requirements, such as design or engineering software using dynamically changing graphics or numbers to convey information. These exceptions can be discussed with the Section 508 Coordinator and another method of accommodation used.

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed Central

    Stanton, Bruce A.; Coutermarsh, Bonita; Barnaby, Roxanna; Hogan, Deborah

    2015-01-01

    Background 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. Methods and Results 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. Conclusion 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. PMID:26018799

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

    PubMed

    Stanton, Bruce A; Coutermarsh, Bonita; Barnaby, Roxanna; Hogan, Deborah

    2015-01-01

    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.

  4. Continuous state-space representation of a bucket-type rainfall-runoff model: a case study with the GR4 model using state-space GR4 (version 1.0)

    NASA Astrophysics Data System (ADS)

    Santos, Léonard; Thirel, Guillaume; Perrin, Charles

    2018-04-01

    In many conceptual rainfall-runoff models, the water balance differential equations are not explicitly formulated. These differential equations are solved sequentially by splitting the equations into terms that can be solved analytically with a technique called operator splitting. As a result, only the solutions of the split equations are used to present the different models. This article provides a methodology to make the governing water balance equations of a bucket-type rainfall-runoff model explicit and to solve them continuously. This is done by setting up a comprehensive state-space representation of the model. By representing it in this way, the operator splitting, which makes the structural analysis of the model more complex, could be removed. In this state-space representation, the lag functions (unit hydrographs), which are frequent in rainfall-runoff models and make the resolution of the representation difficult, are first replaced by a so-called Nash cascade and then solved with a robust numerical integration technique. To illustrate this methodology, the GR4J model is taken as an example. The substitution of the unit hydrographs with a Nash cascade, even if it modifies the model behaviour when solved using operator splitting, does not modify it when the state-space representation is solved using an implicit integration technique. Indeed, the flow time series simulated by the new representation of the model are very similar to those simulated by the classic model. The use of a robust numerical technique that approximates a continuous-time model also improves the lag parameter consistency across time steps and provides a more time-consistent model with time-independent parameters.

  5. Mechanism-based corrector combination restores ΔF508-CFTR folding and function

    PubMed Central

    Okiyoneda, Tsukasa; Veit, Guido; Dekkers, Johanna F.; Bagdany, Miklos; Soya, Naoto; Xu, Haijin; Roldan, Ariel; Verkman, Alan S.; Kurth, Mark; Simon, Agnes; Hegedus, Tamas; Beekman, Jeffrey M.; Lukacs, Gergely L.

    2013-01-01

    The most common cystic fibrosis (CF) mutation, ΔF508 in the nucleotide binding domain-1 (NBD1), impairs CFTR coupled-domain folding, plasma membrane (PM) expression, function and stability. VX-809, a promising investigational corrector of ΔF508-CFTR misprocessing, has limited clinical benefit and incompletely understood mechanism, hampering drug development. Based on the effect of second site suppressor mutations, robust ΔF508-CFTR correction likely requires stabilization of NBD1 and the membrane spanning domains (MSDs)-NBD1 interface, both established primary conformational defects. Here, we elucidated the molecular targets of available correctors; class-I stabilizes the NBD1-MSD1/2 interface, class-II targets NBD2, and only chemical chaperones, surrogates of class-III correctors, stabilize the human ΔF508-NBD1. While VX-809 can correct missense mutations primarily destabilizing the NBD1-MSD1/2 interface, functional PM expression of ΔF508-CFTR also requires compounds that counteract the NBD1 and NBD2 stability defects in CF bronchial epithelial cells and intestinal organoids. Thus, structure-guided corrector combination represents an effective approach for CF therapy. PMID:23666117

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

    PubMed

    Luciani, Alessandro; Villella, Valeria Rachela; Esposito, Speranza; Gavina, Manuela; Russo, Ilaria; Silano, Marco; Guido, Stefano; Pettoello-Mantovani, Massimo; Carnuccio, Rosa; Scholte, Bob; De Matteis, Antonella; Maiuri, Maria Chiara; Raia, Valeria; Luini, Alberto; Kroemer, Guido; Maiuri, Luigi

    2012-11-01

    Channel activators (potentiators) of cystic fibrosis (CF) transmembrane conductance regulator (CFTR), can be used for the treatment of the small subset of CF patients that carry plasma membrane-resident CFTR mutants. However, approximately 90% of CF patients carry the misfolded ΔF508-CFTR and are poorly responsive to potentiators, because ΔF508-CFTR is intrinsically unstable at the plasma membrane (PM) even if rescued by pharmacological correctors. We have demonstrated that human and mouse CF airways are autophagy deficient due to functional sequestration of BECN1 and that the tissue transglutaminase-2 inhibitor, cystamine, or antioxidants restore BECN1-dependent autophagy and reduce SQSTM1/p62 levels, thus favoring ΔF508-CFTR trafficking to the epithelial surface. Here, we investigated whether these treatments could facilitate the beneficial action of potentiators on ΔF508-CFTR homozygous airways. Cystamine or the superoxide dismutase (SOD)/catalase-mimetic EUK-134 stabilized ΔF508-CFTR at the plasma membrane of airway epithelial cells and sustained the expression of CFTR at the epithelial surface well beyond drug withdrawal, overexpressing BECN1 and depleting SQSTM1. This facilitates the beneficial action of potentiators in controlling inflammation in ex vivo ΔF508-CFTR homozygous human nasal biopsies and in vivo in mouse ΔF508-CFTR lungs. Direct depletion of Sqstm1 by shRNAs in vivo in ΔF508-CFTR mice synergized with potentiators in sustaining surface CFTR expression and suppressing inflammation. Cystamine pre-treatment restored ΔF508-CFTR response to the CFTR potentiators genistein, Vrx-532 or Vrx-770 in freshly isolated brushed nasal epithelial cells from ΔF508-CFTR homozygous patients. These findings delineate a novel therapeutic strategy for the treatment of CF patients with the ΔF508-CFTR mutation in which patients are first treated with cystamine and subsequently pulsed with CFTR potentiators.

  7. 31 CFR 515.508 - Payments to blocked accounts in domestic banks.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Payments to blocked accounts in domestic banks. 515.508 Section 515.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY CUBAN ASSETS CONTROL...

  8. 31 CFR 500.508 - Payments to blocked accounts in domestic banks.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Payments to blocked accounts in domestic banks. 500.508 Section 500.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN ASSETS CONTROL...

  9. 15 CFR 904.508 - Voluntary forfeiture by abandonment.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... (Continued) NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE GENERAL REGULATIONS CIVIL PROCEDURES Seizure and Forfeiture Procedures § 904.508 Voluntary forfeiture by abandonment. (a) The owner of...

  10. 15 CFR 904.508 - Voluntary forfeiture by abandonment.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... (Continued) NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE GENERAL REGULATIONS CIVIL PROCEDURES Seizure and Forfeiture Procedures § 904.508 Voluntary forfeiture by abandonment. (a) The owner of...

  11. 32 CFR 644.508 - Agreement with Small Business Administration (SBA) on sale of timber.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Agreement with Small Business Administration..., Crops, and Embedded Gravel, Sand and Stone § 644.508 Agreement with Small Business Administration (SBA... development of a program of assistance for small concerns operating in the timber business. This agreement is...

  12. Systemic administration of thrombin peptide TP508 enhances VEGF-stimulated angiogenesis and attenuates effects of chronic hypoxia

    PubMed Central

    Olszewska-Pazdrak, Barbara; Carney, Darrell H.

    2015-01-01

    Revascularization of chronic wounds and ischemic tissue is attenuated by endothelial dysfunction and the inability of angiogenic factors to stimulate angiogenesis. We recently showed that TP508, a nonproteolytic thrombin peptide, increases perfusion and NO-dependent vasodilation in hearts with chronic ischemia and stimulates NO production by endothelial cells. In this study, we investigated systemic in vivo effects of TP508 on VEGF-stimulated angiogenesis in vitro using aortic explants in normoxic and hypoxic conditions. Mice were injected with saline or TP508 and 24h later aortas were removed and cultured to quantify endothelial sprouting. TP508 injection increased endothelial sprouting and potentiated the in vitro response to VEGF. Exposure of control explants to hypoxia inhibited basal and VEGF-stimulated endothelial cell sprouting. This effect of hypoxia was significantly prevented by TP508 injection. Thus, TP508 systemic administration increases responsiveness of aortic endothelial cells to VEGF and diminishes the effect of chronic hypoxia on endothelial cell sprouting. Studies using human endothelial cells in culture suggest that protective effects of TP508 during hypoxia may involve stimulation of endothelial cell NO production. These data suggest potential clinical benefit of using a combination of systemic TP508 and local VEGF as a therapy for revascularization of ischemic tissue. PMID:23594718

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

    PubMed Central

    Luciani, Alessandro; Villella, Valeria Rachela; Esposito, Speranza; Gavina, Manuela; Russo, Ilaria; Silano, Marco; Guido, Stefano; Pettoello-Mantovani, Massimo; Carnuccio, Rosa; Scholte, Bob; De Matteis, Antonella; Maiuri, Maria Chiara; Raia, Valeria; Luini, Alberto; Kroemer, Guido; Maiuri, Luigi

    2012-01-01

    Channel activators (potentiators) of cystic fibrosis (CF) transmembrane conductance regulator (CFTR), can be used for the treatment of the small subset of CF patients that carry plasma membrane-resident CFTR mutants. However, approximately 90% of CF patients carry the misfolded ΔF508-CFTR and are poorly responsive to potentiators, because ΔF508-CFTR is intrinsically unstable at the plasma membrane (PM) even if rescued by pharmacological correctors. We have demonstrated that human and mouse CF airways are autophagy deficient due to functional sequestration of BECN1 and that the tissue transglutaminase-2 inhibitor, cystamine, or antioxidants restore BECN1-dependent autophagy and reduce SQSTM1/p62 levels, thus favoring ΔF508-CFTR trafficking to the epithelial surface. Here, we investigated whether these treatments could facilitate the beneficial action of potentiators on ΔF508-CFTR homozygous airways. Cystamine or the superoxide dismutase (SOD)/catalase-mimetic EUK-134 stabilized ΔF508-CFTR at the plasma membrane of airway epithelial cells and sustained the expression of CFTR at the epithelial surface well beyond drug withdrawal, overexpressing BECN1 and depleting SQSTM1. This facilitates the beneficial action of potentiators in controlling inflammation in ex vivo ΔF508-CFTR homozygous human nasal biopsies and in vivo in mouse ΔF508-CFTR lungs. Direct depletion of Sqstm1 by shRNAs in vivo in ΔF508-CFTR mice synergized with potentiators in sustaining surface CFTR expression and suppressing inflammation. Cystamine pre-treatment restored ΔF508-CFTR response to the CFTR potentiators genistein, Vrx-532 or Vrx-770 in freshly isolated brushed nasal epithelial cells from ΔF508-CFTR homozygous patients. These findings delineate a novel therapeutic strategy for the treatment of CF patients with the ΔF508-CFTR mutation in which patients are first treated with cystamine and subsequently pulsed with CFTR potentiators. PMID:22874563

  14. 32 CFR 644.508 - Agreement with Small Business Administration (SBA) on sale of timber.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Agreement with Small Business Administration (SBA..., Crops, and Embedded Gravel, Sand and Stone § 644.508 Agreement with Small Business Administration (SBA... development of a program of assistance for small concerns operating in the timber business. This agreement is...

  15. 48 CFR 315.7000 - Section 508 accessibility standards.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... CONTRACTING METHODS AND CONTRACT TYPES CONTRACTING BY NEGOTIATION Acquisition of Electronic Information Technology 315.7000 Section 508 accessibility standards. EIT products and services, including EIT...

  16. Intracellular Serine Protease Inhibitor SERPINB4 Inhibits Granzyme M-Induced Cell Death

    PubMed Central

    de Koning, Pieter J. A.; Kummer, J. Alain; de Poot, Stefanie A. H.; Quadir, Razi; Broekhuizen, Roel; McGettrick, Anne F.; Higgins, Wayne J.; Devreese, Bart; Worrall, D. Margaret; Bovenschen, Niels

    2011-01-01

    Granzyme-mediated cell death is the major pathway for cytotoxic lymphocytes to kill virus-infected and tumor cells. In humans, five different granzymes (i.e. GrA, GrB, GrH, GrK, and GrM) are known that all induce cell death. Expression of intracellular serine protease inhibitors (serpins) is one of the mechanisms by which tumor cells evade cytotoxic lymphocyte-mediated killing. Intracellular expression of SERPINB9 by tumor cells renders them resistant to GrB-induced apoptosis. In contrast to GrB, however, no physiological intracellular inhibitors are known for the other four human granzymes. In the present study, we show that SERPINB4 formed a typical serpin-protease SDS-stable complex with both recombinant and native human GrM. Mutation of the P2-P1-P1′ triplet in the SERPINB4 reactive center loop completely abolished complex formation with GrM and N-terminal sequencing revealed that GrM cleaves SERPINB4 after P1-Leu. SERPINB4 inhibited GrM activity with a stoichiometry of inhibition of 1.6 and an apparent second order rate constant of 1.3×104 M−1s−1. SERPINB4 abolished cleavage of the macromolecular GrM substrates α-tubulin and nucleophosmin. Overexpression of SERPINB4 in tumor cells inhibited recombinant GrM-induced as well as NK cell-mediated cell death and this inhibition depended on the reactive center loop of the serpin. As SERPINB4 is highly expressed by squamous cell carcinomas, our results may represent a novel mechanism by which these tumor cells evade cytotoxic lymphocyte-induced GrM-mediated cell death. PMID:21857942

  17. Current transport in graphene/AlGaN/GaN vertical heterostructures probed at nanoscale.

    PubMed

    Fisichella, Gabriele; Greco, Giuseppe; Roccaforte, Fabrizio; Giannazzo, Filippo

    2014-08-07

    Vertical heterostructures combining two or more graphene (Gr) layers separated by ultra-thin insulating or semiconductor barriers represent very promising systems for next generation electronics devices, due to the combination of high speed operation with wide-range current modulation by a gate bias. They are based on the specific mechanisms of current transport between two-dimensional-electron-gases (2DEGs) in close proximity. In this context, vertical devices formed by Gr and semiconductor heterostructures hosting an "ordinary" 2DEG can be also very interesting. In this work, we investigated the vertical current transport in Gr/Al(0.25)Ga(0.75)N/GaN heterostructures, where Gr is separated from a high density 2DEG by a ∼ 24 nm thick AlGaN barrier layer. The current transport from Gr to the buried 2DEG was characterized at nanoscale using conductive atomic force microscopy (CAFM) and scanning capacitance microscopy (SCM). From these analyses, performed both on Gr/AlGaN/GaN and on AlGaN/GaN reference samples using AFM tips with different metal coatings, the Gr/AlGaN Schottky barrier height ΦB and its lateral uniformity were evaluated, as well as the variation of the carrier densities of graphene (ngr) and AlGaN/GaN 2DEG (ns) as a function of the applied bias. A low Schottky barrier (∼ 0.40 eV) with excellent spatial uniformity was found at the Gr/AlGaN interface, i.e., lower compared to the measured values for metal/AlGaN contacts, which range from ∼ 0.6 to ∼ 1.1 eV depending on the metal workfunction. The electrical behavior of the Gr/AlGaN contact has been explained by Gr interaction with AlGaN donor-like surface states located in close proximity, which are also responsible of high n-type Gr doping (∼ 1.3 × 10(13) cm(-2)). An effective modulation of ns by the Gr Schottky contact was demonstrated by capacitance analysis under reverse bias. From this basic understanding of transport properties in Gr/AlGaN/GaN heterostructures, novel vertical field effect

  18. 42 CFR 456.508 - Withdrawal of waiver.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... (CONTINUED) MEDICAL ASSISTANCE PROGRAMS UTILIZATION CONTROL Utilization Review Plans: FFP, Waivers, and Variances for Hospitals and Mental Hospitals Ur Plan: Waiver of Requirements § 456.508 Withdrawal of waiver.... (b) If a waiver is withdrawn by the Administrator, each hospital or mental hospital covered by the...

  19. 17 CFR 249.508 - Form 8-M, consent to service of process by a corporation which is a nonresident broker-dealer.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... to service of process by a corporation which is a nonresident broker-dealer. This form shall be filed... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Form 8-M, consent to service of process by a corporation which is a nonresident broker-dealer. 249.508 Section 249.508 Commodity...

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

    PubMed Central

    Bitam, Sara; 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. PMID:26594334

  1. Application of Gr/PMR-15 to commercial aircraft

    NASA Technical Reports Server (NTRS)

    Postlewaite, J.; Porter, K.; Mclaren, D.

    1985-01-01

    Following from early experience with polyimides on the SST program and Shuttle aft flap studies the Boeing Company is now working on collaborative programs with its principal nacelle suppliers to pursue the development of Gr/PMR-15 nacelle components. Two programs are currently in effect. The first program is directed specifically towards the flight test and service evaluation at the earliest possible date of a 747 nacelle core cowl structure. The second program seeks to firmly establish the producibility and cost of a 757 thrust reverser C duct in a production environment. The near term objectives of these programs include: (1) the comparison of estimated cost and weight of Gr/PMR-15 versus metal structure, (2) the engine test of representative composite structure, (3) the preliminary design and analysis of the C duct structure, and (4) the preparation of cost data and time schedules for the development and producibility program. In addition to powerplant structure, the propulsion ducting system has shown to be a strong candidate for Gr/PMR-15 application. Currently, the Boeing 747 Organization is evaluating the use of PMR-15 matrix composites to replace nearly 800 lbs of titanium ducting per airplane.

  2. The disruption of two salt bridges of the cold-active xylanase XynGR40 results in an increase in activity, but a decrease in thermostability.

    PubMed

    Wang, Guozeng; Wu, Jingjing; Lin, Juan; Ye, Xiuyun; Yao, Bin

    2016-12-02

    Cold-active xylanases are of great interest due to their large potential for application in the food industry. In this study, salt bridges of the eight glycoside hydrolase (GH) family 10 cold-active xylanases reported to date were predicted and the salt bridges specific to the cold-active xylanase XynGR40 were identified. Seven mutants were constructed to disrupt salt bridges specific to XynGR40. The results suggested that five mutants lost their xylanase activity, while the other two mutants, D30N and D83N, displayed different properties when compared with the wild-type XynGR40. First, both mutations showed an obvious decrease in thermostability, with the T 1/2 of D30N and D83N at 50 °C being about one half and one sixth of the wild-type, respectively. Second, both D30N and D83N had a higher specific activity than the wild-type, with activities about 13 and 163% higher, respectively. Third, both D30N and D83N had high k cat and K m values, which resulted in a higher catalytic efficiency of the mutant D83N, but a lower catalytic efficiency of the mutant D30N compared to the wild-type. Our results suggested that salt bridges play important roles in both the activity and thermostability of the cold-active xylanase XynGR40. The mutant D83N had a higher k cat and higher relative activity at low temperatures than the wild-type, and is a good candidate for application in the food industry. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. 31 CFR 535.420 - Transfers of accounts under § 535.508 from demand to interest-bearing status.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Transfers of accounts under § 535.508... IRANIAN ASSETS CONTROL REGULATIONS Interpretations § 535.420 Transfers of accounts under § 535.508 from demand to interest-bearing status. Section 535.508 authorizes transfer of a blocked demand deposit...

  4. 31 CFR 535.420 - Transfers of accounts under § 535.508 from demand to interest-bearing status.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Transfers of accounts under § 535.508... IRANIAN ASSETS CONTROL REGULATIONS Interpretations § 535.420 Transfers of accounts under § 535.508 from demand to interest-bearing status. Section 535.508 authorizes transfer of a blocked demand deposit...

  5. Comparison of Notch Strength between Gr/PEEK (APC-1 and APC-2) and Gr/Epoxy Composite Materials at Elevated Temperature.

    DTIC Science & Technology

    1985-12-01

    J ub. we Jr. Captain, USARt Z712 AFIT/GAE/AA/85D- 12 Iv COMPARISON OF NOTCH STRENGTH BETWEEN GR/PEEK (APC-1 AND APC-2) AND GR/EPOXY COMPOSITE ...85D-12 COMPARISON OF NOTCH STRENGTH BETWEEN GR/PEEK _ (APC-1 AND APC-2) AND GR/EPOXY COMPOSITE MATERIAL AT ELEVATED TEMPERATURE THESIS Presented to the...unlimited Preface In this experimental investigation, the reduction of strength for notched composite laminates of Aromatic Polymer Composite , APC-2

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

    PubMed

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

    2017-06-01

    Several members of the SLC26A family of anion transporters associate with CFTR, forming complexes in which CFTR and SLC26A functions are reciprocally regulated. These associations are 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 is 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 coexpressing SLC26A9 with the trafficking mutant F508del CFTR exhibited a significant reduction in constitutive current compared with cells coexpressing SLC26A9 and wt CFTR. We found that SLC26A9 exhibits complex glycosylation when coexpressed 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 coexpression of wt CFTR. However, coexpression 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 coexpressed with F508del CFTR, its trafficking defect leads to a PDZ motif-sensitive intracellular retention of SLC26A9. Copyright © 2017 the American Physiological Society.

  7. 27 CFR 19.508 - Consignor premises.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... plant or bonded wine cellar; or (ii) the consignor proprietor of an alcohol fuel plant to cover the... alcohol fuel plants qualified under 26 U.S.C. 5181. (3) The consignor proprietor may cover on one transfer... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Consignor premises. 19.508...

  8. Synthesis and Crystal Structure of Dibromido{2-[(4-tert-butylmethylphenyl) iminomethyl]pyridine-κ2 N, N'}Zinc

    NASA Astrophysics Data System (ADS)

    Khalaj, M.; Ghazanfarpour-Darjani, M.; Seftejani, F. B.; Lalegani, A.

    2017-12-01

    The title compound [Zn( dip)Br2] was synthesized using the Schiff base bidentate ligand (E)-4- tert-butyl- N-(pyridine-2-ylmethylene)benzeneamine ( dip) and zinc(II) bromide salts. It has been characterized by elemental analysis, X-ray diffraction, and optical spectroscopy. The X-ray diffraction analysis demonstrates that in this structure, the zinc(II) ion is located on an inversion center and exhibits a ZnN2Br2 tetrahedral geometry. In this structure the dip ligand is coordinated with zinc(II) ion in a cyclic-bidentate fashion forming a five-membered metallocyclic ring. The compound crystallizes in the monoclinic sp. gr. P21/ m with a = 9.2700(13) Å, b = 7.6128(11) Å, c = 12.3880(17) Å, and β = 97.021(3)°.

  9. AME survey-003 A2: on the attractiveness of an medicine career in current China with a survey of 7,508 medical professionals and 443 non-medical professionals

    PubMed Central

    Li, Yáo T.

    2016-01-01

    This is a part of the study of AME survey-003, aiming to understand the motivation and attractiveness of a career in medicine in China. The surveys were conducted on DXY platform with 3,564 medical professionals during October 26 to November 20; on Sojump platform with 1,587 medical professionals during October 28 to December 14, and 443 non-medical professionals during November 15 to December, all in 2015. Similar to our previous result, the not regretted participants vs. regretted participants (N/Y) ratio was 1.1 (P<0.01), and there was no significant difference in N/Y ratio between male and female medical professionals. Medical professionals working in class-IIIA hospitals, small township hospitals, or primary care clinics had a relatively higher job satisfaction than those in hospitals of other classes, while lecturer-level attending doctors (zhuzhi yishi) had a relatively lower job satisfaction than doctors of other grades. A large portion of respondents who replied they regretted entered medical profession said they would still like to be in this profession if they could be in their preferred hospital class and specialty. Public health and basic science research staff, anesthesiologists, oncologists had a relatively higher job satisfaction, while accident and emergency physicians, nurses, and pediatricians had a relatively lower job satisfaction. Medical professionals in Yunnan and Gansu ranked consistently high in job satisfaction than other provinces; despite they were not in the economically advanced regions in China. Similar to our previous result, the majority of the participants favored China to open up medical market to qualified foreign medical organizations to take part in fair competition, as well as favor the government to support regulated private hospitals. Pooled data of 7,508 medical professionals with data from AME survey-003 A1 included showed medicine was the top career choice among medical professionals’ children (104/508, 20

  10. AME survey-003 A2: on the attractiveness of an medicine career in current China with a survey of 7,508 medical professionals and 443 non-medical professionals.

    PubMed

    Wáng, Yì Xiáng J; Li, Yáo T

    2016-02-01

    This is a part of the study of AME survey-003, aiming to understand the motivation and attractiveness of a career in medicine in China. The surveys were conducted on DXY platform with 3,564 medical professionals during October 26 to November 20; on Sojump platform with 1,587 medical professionals during October 28 to December 14, and 443 non-medical professionals during November 15 to December, all in 2015. Similar to our previous result, the not regretted participants vs. regretted participants (N/Y) ratio was 1.1 (P<0.01), and there was no significant difference in N/Y ratio between male and female medical professionals. Medical professionals working in class-IIIA hospitals, small township hospitals, or primary care clinics had a relatively higher job satisfaction than those in hospitals of other classes, while lecturer-level attending doctors (zhuzhi yishi) had a relatively lower job satisfaction than doctors of other grades. A large portion of respondents who replied they regretted entered medical profession said they would still like to be in this profession if they could be in their preferred hospital class and specialty. Public health and basic science research staff, anesthesiologists, oncologists had a relatively higher job satisfaction, while accident and emergency physicians, nurses, and pediatricians had a relatively lower job satisfaction. Medical professionals in Yunnan and Gansu ranked consistently high in job satisfaction than other provinces; despite they were not in the economically advanced regions in China. Similar to our previous result, the majority of the participants favored China to open up medical market to qualified foreign medical organizations to take part in fair competition, as well as favor the government to support regulated private hospitals. Pooled data of 7,508 medical professionals with data from AME survey-003 A1 included showed medicine was the top career choice among medical professionals' children (104/508, 20.5%), followed

  11. Role of microRNA508-3p in melanogenesis by targeting microphthalmia transcription factor in melanocytes of alpaca.

    PubMed

    Zhang, J; Liu, Y; Zhu, Z; Yang, S; Ji, K; Hu, S; Liu, X; Yao, J; Fan, R; Dong, C

    2017-02-01

    It has been demonstrated that microRNAs (miRNAs) play important roles in the control of melanogenesis and hair color in mammals. By comparing miRNA expression profiles between brown and white alpaca skin, we previously identified miR508-3p as a differentially expressed miRNA suggesting its potential role in melanogenesis and hair color formation. The present study was conducted to determine the role of miR508-3p in melanogenesis in alpaca melanocytes. In situ hybridization showed that miR508-3p is abundantly present in the cytoplasma of alpaca melanocytes. miR508-3p was predicted to target the gene encoding microphthalmia transcription factor (MITF) and a luciferase reporter assay indicated that miR508-3p regulates MITF expression by directly targeting its 3'UTR. Overexpression of miR508-3p in alpaca melanocytes down-regulated MITF expression both at the messenger RNA and protein level and resulted in decreased expression of key melanogenic genes including tyrosinase and tyrosinase-related protein 2. Overexpression of miR508-3p in melanocytes also resulted in decreased melanin production including total alkali-soluble melanogenesis, eumelanogenesis and pheomelanogenesis. Results support a functional role of miR508-3p in regulating melanogenesis in alpaca melanocytes by directly targeting MITF.

  12. Allosteric modulation balances thermodynamic stability and restores function of ΔF508 CFTR

    PubMed Central

    Aleksandrov, Andrei A.; Kota, Pradeep; Cui, Liying; Jensen, Tim; Alekseev, Alexey E.; Reyes, Santiago; He, Lihua; Gentzsch, Martina; Aleksandrov, Luba A.; Dokholyan, Nikolay V.; Riordan, John R.

    2013-01-01

    Most cystic fibrosis is caused by a deletion of a single residue (F508) in CFTR that disrupts the folding and biosynthetic maturation of the ion channel protein. Progress towards understanding the underlying mechanisms and overcoming the defect remain incomplete. Here we show that the thermal instability of human ΔF508 CFTR channel activity evident in both cell-attached membrane patches and planar phospholipid bilayers is not observed in corresponding mutant CFTRs of several non-mammalian species. These more stable orthologs are distinguished from their mammalian counterparts by the substitution of proline residues at several key dynamic locations in the first nucleotide domain (NBD1), including the structurally diverse region (SDR), the gamma phosphate switch loop and the Regulatory Insertion (RI). Molecular Dynamic analyses revealed that addition of the prolines could reduce flexibility at these locations and increase the temperatures of unfolding transitions of ΔF508 NBD1 to that of the wild-type. Introduction of these prolines experimentally into full-length human ΔF508 CFTR together with the already recognized I539T suppressor mutation, also in the SDR, restored channel function and thermodynamic stability as well as its trafficking to and lifetime at the cell surface. Thus, while cellular manipulations that circumvent its culling by quality control systems leave ΔF508 CFTR dysfunctional at physiological temperature, restoration of the delicate balance between the dynamic protein’s inherent stability and channel activity returns a near-normal state. PMID:22406676

  13. Nuclear Countermeasure Activity of TP508 Linked to Restoration of Endothelial Function and Acceleration of DNA Repair

    PubMed Central

    Olszewska-Pazdrak, Barbara; McVicar, Scott D.; Rayavara, Kempaiah; Moya, Stephanie M.; Kantara, Carla; Gammarano, Chris; Olszewska, Paulina; Fuller, Gerald M.; Sower, Laurie E.; Carney, Darrell H.

    2016-01-01

    There is increasing evidence that radiation-induced damage to endothelial cells and loss of endothelial function may contribute to both acute radiation syndromes and long-term effects of whole-body nuclear irradiation. Therefore, several drugs are being developed to mitigate the effects of nuclear radiation, most of these drugs will target and protect or regenerate leukocytes and platelets. Our laboratory has demonstrated that TP508, a 23-amino acid thrombin peptide, activates endothelial cells and stem cells to revascularize and regenerate tissues. We now show that TP508 can mitigate radiation-induced damage to endothelial cells in vitro and in vivo. Our in vitro results demonstrate that human endothelial cells irradiation attenuates nitric oxide (NO) signaling, disrupts tube formation and induces DNA double-strand breaks (DSB). TP508 treatment reverses radiation effects on NO signaling, restores tube formation and accelerates the repair of radiation-induced DSB. The radiation-mitigating effects of TP508 on endothelial cells were also seen in CD-1 mice where systemic injection of TP508 stimulated endothelial cell sprouting from aortic explants after 8 Gy irradiation. Systemic doses of TP508 that mitigated radiation-induced endothelial cell damage, also significantly increased survival of CD-1 mice when injected 24 h after 8.5 Gy exposure. These data suggest that increased survival observed with TP508 treatment may be due to its effects on vascular and microvascular endothelial cells. Our study supports the usage of a regenerative drug such as TP508 to activate endothelial cells as a countermeasure for mitigating the effects of nuclear radiation. PMID:27388041

  14. Evidence against Resveratrol as a viable therapy for the rescue of defective ΔF508 CFTR

    PubMed Central

    Jai, Ying; Shah, Kalpit; Bridges, Robert J.; Bradbury, Neil A.

    2015-01-01

    BACKGROUND Resveratrol, a natural phenolic compound, has been reported to rescue mutant ΔF508 CFTR in expression systems and primary epithelial cells. Although this implies a therapeutic benefit to patients with CF, investigations were performed using resveratrol concentrations greatly in excess of those achievable in plasma. We evaluated the efficacy of resveratrol as a CFTR corrector in relevant primary airway cells, using physiologically achievable resveratrol concentrations. METHODS Cells expressing wt or ΔF508 CFTR were exposed to chronic or acute resveratrol. CFTR mRNA and protein expression were monitored. The effects of resveratrol on primary ΔF508 human airway cells were evaluated by equivalent current analysis using modified Ussing chambers. RESULTS Consistent with previously published data in heterologous expression systems, high doses of resveratrol increased CFTR expression; however physiologically relevant concentrations were without effect. In contrast to heterologous expression systems, resveratrol was unable to increase mutant CFTR channel activity in primary airway cells. Elevated amiloride-sensitive currents, indicative of sodium transport and characteristically elevated in CF airway cells, were also unaffected by resveratrol CONCLUSIONS High concentrations of resveratrol can increase CFTR mRNA and protein in some cell types. In addition, acute resveratrol exposure can stimulate CFTR mediated chloride secretion, probably by increasing cellular cAMP levels. Resveratrol at physiologically achievable levels yielded no benefit in primary ΔF508 airway cells, either in terms of amiloride-sensitive currents of CFTR currents. PMID:26342647

  15. The Ricor K508 cryocooler operational experience on Mars

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Johnson, Dean L.; Lysek, Mark J.; Morookian, John Michael

    The Mars Science Laboratory (Curiosity) landed successfully on Mars on August 5, 2012, eight months after launch. The chosen landing site of Gale Crater, located at 4.5 degrees south latitude, 137.4 degrees east longitude, has provided a much more benign environment than was originally planned for during the critical design and integration phases of the MSL Project when all possible landing sites were still being considered. The expected near-surface atmospheric temperatures at the Gale Crater landing site during Curiosity's primary mission (1 Martian year or 687 Earth days) are from −90°C to 0°C. However, enclosed within Curiosity's thermal control fluidmore » loops the Chemistry and Mineralogy (CheMin) instrument is maintained at approximately +20°C. The CheMin instrument uses X-ray diffraction spectroscopy to make precise measurements of mineral constituents of Mars rocks and soil. The instrument incorporated the commercially available Ricor K508 Stirling cycle cryocooler to cool the CCD detector. After several months of brushing itself off, stretching and testing out its subsystems, Curiosity began the exploration of the Mars surface in October 2012. The CheMin instrument on the Mars Science Laboratory (MSL) received its first soil sample from Curiosity on October 24, and successfully analyzed its first soil sample. After a brief review of the rigorous Ricor K508 cooler qualification tests and life tests based on the original MSL environmental requirements this paper presents final pre-launch instrument integration and testing results, and details the operational data of the CheMin cryocooler, providing a snapshot of the resulting CheMin instrument analytical data.« less

  16. 42 CFR 414.508 - Payment for a new clinical diagnostic laboratory test.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 3 2010-10-01 2010-10-01 false Payment for a new clinical diagnostic laboratory... SERVICES Payment for New Clinical Diagnostic Laboratory Tests § 414.508 Payment for a new clinical diagnostic laboratory test. For a new clinical diagnostic laboratory test that is assigned a new or...

  17. 42 CFR 414.508 - Payment for a new clinical diagnostic laboratory test.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 3 2011-10-01 2011-10-01 false Payment for a new clinical diagnostic laboratory... SERVICES Payment for New Clinical Diagnostic Laboratory Tests § 414.508 Payment for a new clinical diagnostic laboratory test. For a new clinical diagnostic laboratory test that is assigned a new or...

  18. Chandra Observations of the Field Containing HESS J1616-508

    NASA Astrophysics Data System (ADS)

    Hare, Jeremy; Kargaltsev, Oleg; Pavlov, George G.; Rangelov, Blagoy; Volkov, Igor

    2017-06-01

    We report the results of three Chandra observations covering most of the extent of the TeV γ-ray source HESS J1616-508 and a search for a lower-energy counterpart to this source. We detect 56 X-ray sources, 37 of which have counterparts at lower frequencies, including a young massive star cluster, but none of them appear to be a particularly promising counterpart to the TeV source. The brightest X-ray source, CXOU J161423.4-505738, with a flux F 0.5-7 keV ≈ 5 × 10-13 erg cm-2 s-1, has a hard spectrum that is well fit by a power-law model with a photon index Γ = 0.2 ± 0.3 and is a likely intermediate polar CV candidate. No counterparts of this source were detected at other wavelengths. CVs are not known to produce extended TeV emission, and the source is also largely offset (19‧) from HESS J1616-508, making them unlikely to be associated. We have also set an upper limit on the X-ray flux of PSR J1614-5048 in the 0.5-8 keV band (F 0.5-8 keV < 5 × 10-15 erg cm-2 s-1 at a 90% confidence level). This makes PSR J1614-5048 one of the least X-ray-efficient pulsars known, with an X-ray efficiency {η }0.5{--8{keV}}={L}0.5{--8{keV}}/\\dot{E}< 2× {10}-5. We find no evidence supporting the association between the pulsar and the TeV source. We rule out a number of X-ray sources as possible counterparts to the TeV emission and do not find a plausible counterpart among the other sources. Lastly, we discuss the possible relation of PSR J1617-5055 to HESS J1616-508 in light of the new observations.

  19. GrB TWEAK: A Potential Novel Biologic for NSCLC Therapy

    DTIC Science & Technology

    2017-07-01

    saline (control) or GrB-Fc-IT4 at 20 mg...intravenously   treated  with   saline  or  MRT-­‐101  construct  (Qod  X  5).  On  average,  tumors  from   saline -­‐treated...also   demonstrated   >50%   tumor   suppression   vs   saline   controls.   Overall,   treatment  with  MRT-­‐101

  20. Cystic fibrosis in the Basque country: high frequency of mutation delta F508 in patients of Basque origin.

    PubMed Central

    Casals, T; Vázquez, C; Lázaro, C; Girbau, E; Giménez, F J; Estivill, X

    1992-01-01

    The Basque population is one of the oldest populations of Europe. It has been suggested that the Basques arose from a population established in western Europe during the late Paleolithic Age. The Basque language (Euskera) is a supposedly pre-Indo-European language that originates from the first settlers of Europe. The variable distribution of the major cystic fibrosis (CF) mutation (delta F508 deletion) in Europe, with higher frequencies of the mutation in northern Europe and lower frequencies in southern Europe, has suggested that the delta F508 mutation was spread by early farmers migrating from the Middle East during the Neolithic period. We have studied 45 CF families from the Basque Country, where the incidence of CF is approximately 1/4,500. The birthplaces of the parents and grandparents have been traced and are distributed according to their origin as Basque or Mixed Basque. The frequency of the delta F508 mutation in the chromosomes of Basque origin is 87%, compared with 58% in those of Mixed Basque origin. The analysis of haplotypes, both with markers closely linked to the CF gene and with intragenic markers, suggests that the delta F508 mutation was not spread by the Indo-European invasions but was already present in Europe more than 10,000 years ago, during the Paleolithic period. PMID:1370875

  1. 12 CFR 508.3 - Issuance of Notice or Order.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ..., AND PROHIBITIONS WHERE A CRIME IS CHARGED OR PROVEN § 508.3 Issuance of Notice or Order. (a) The..., or complaint with the commission of or participation in a crime involving dishonesty or breach of...

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

    PubMed Central

    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.

    2015-01-01

    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. PMID:25101887

  3. CD11b+Gr-1dim Tolerogenic Dendritic Cell-Like Cells Are Expanded in Interstitial Lung Disease in SKG Mice.

    PubMed

    Sendo, Sho; Saegusa, Jun; Okano, Takaichi; Takahashi, Soshi; Akashi, Kengo; Morinobu, Akio

    2017-12-01

    SKG mice develop interstitial lung disease (ILD) resembling rheumatoid arthritis-associated ILD in humans. The aim of this study was to clarify the mechanism underlying the lung pathology by analyzing lung-infiltrating cells in SKG mice with ILD. We assessed the severity of zymosan A (ZyA)-induced ILD in SKG mice histologically, and we examined lung-infiltrating cells by flow cytometry. Total lung cells and isolated monocytic myeloid-derived suppressor cells (MDSCs) were cultured in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. The proliferation of 5,6-carboxyfluorescein diacetate N-succinimidyl ester-labeled naive T cells cocultured with isolated CD11b+Gr-1 dim cells and MDSCs was evaluated by flow cytometry. CD11b+Gr-1 dim cells were adoptively transferred to ZyA-treated SKG mice. MDSCs, Th17 cells, and group 1 and 3 innate lymphoid cells (ILC1s and ILC3s) were increased in the lungs; the proportion of these cells varied with ILD severity. In this process, we found that a unique cell population, CD11b+Gr-1 dim cells, was expanded in the severely inflamed lungs. Approximately half of the CD11b+Gr-1 dim cells expressed CD11c. CD11b+Gr-1 dim cells were induced from monocytic MDSCs with GM-CSF in vitro and were considered tolerogenic because they suppressed T cell proliferation. These CD11b+Gr-1 dim cells have never been described previously, and we termed them CD11b+Gr-1 dim tolerogenic dendritic cell (DC)-like cells. Th17 cells, ILC1s, and ILC3s in the inflamed lung produced GM-CSF, which may have expanded CD11b+Gr-1 dim tolerogenic DC-like cells in vivo. Furthermore, adoptive transfer of CD11b+Gr-1 dim tolerogenic DC-like cells significantly suppressed progression of ILD in SKG mice. We identified unique suppressive myeloid cells that were differentiated from monocytic MDSCs in SKG mice with ILD, and we termed them CD11b+Gr-1 dim tolerogenic DC-like cells. © 2017, American College of Rheumatology.

  4. Octopamine Neuromodulation Regulates Gr32a-Linked Aggression and Courtship Pathways in Drosophila Males

    PubMed Central

    Andrews, Jonathan C.; Fernández, María Paz; Yu, Qin; Leary, Greg P.; Leung, Adelaine K. W.; Kavanaugh, Michael P.; Kravitz, Edward A.; Certel, Sarah J.

    2014-01-01

    Chemosensory pheromonal information regulates aggression and reproduction in many species, but how pheromonal signals are transduced to reliably produce behavior is not well understood. Here we demonstrate that the pheromonal signals detected by Gr32a-expressing chemosensory neurons to enhance male aggression are filtered through octopamine (OA, invertebrate equivalent of norepinephrine) neurons. Using behavioral assays, we find males lacking both octopamine and Gr32a gustatory receptors exhibit parallel delays in the onset of aggression and reductions in aggression. Physiological and anatomical experiments identify Gr32a to octopamine neuron synaptic and functional connections in the suboesophageal ganglion. Refining the Gr32a-expressing population indicates that mouth Gr32a neurons promote male aggression and form synaptic contacts with OA neurons. By restricting the monoamine neuron target population, we show that three previously identified OA-FruM neurons involved in behavioral choice are among the Gr32a-OA connections. Our findings demonstrate that octopaminergic neuromodulatory neurons function as early as a second-order step in this chemosensory-driven male social behavior pathway. PMID:24852170

  5. Converging shock flows for a Mie-Grüneisen equation of state

    NASA Astrophysics Data System (ADS)

    Ramsey, Scott D.; Schmidt, Emma M.; Boyd, Zachary M.; Lilieholm, Jennifer F.; Baty, Roy S.

    2018-04-01

    Previous work has shown that the one-dimensional (1D) inviscid compressible flow (Euler) equations admit a wide variety of scale-invariant solutions (including the famous Noh, Sedov, and Guderley shock solutions) when the included equation of state (EOS) closure model assumes a certain scale-invariant form. However, this scale-invariant EOS class does not include even simple models used for shock compression of crystalline solids, including many broadly applicable representations of Mie-Grüneisen EOS. Intuitively, this incompatibility naturally arises from the presence of multiple dimensional scales in the Mie-Grüneisen EOS, which are otherwise absent from scale-invariant models that feature only dimensionless parameters (such as the adiabatic index in the ideal gas EOS). The current work extends previous efforts intended to rectify this inconsistency, by using a scale-invariant EOS model to approximate a Mie-Grüneisen EOS form. To this end, the adiabatic bulk modulus for the Mie-Grüneisen EOS is constructed, and its key features are used to motivate the selection of a scale-invariant approximation form. The remaining surrogate model parameters are selected through enforcement of the Rankine-Hugoniot jump conditions for an infinitely strong shock in a Mie-Grüneisen material. Finally, the approximate EOS is used in conjunction with the 1D inviscid Euler equations to calculate a semi-analytical Guderley-like imploding shock solution in a metal sphere and to determine if and when the solution may be valid for the underlying Mie-Grüneisen EOS.

  6. Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80+CD11bhighGr1low macrophages

    PubMed Central

    Schiechl, Gabriela; Bauer, Bernhard; Fuss, Ivan; Lang, Sven A.; Moser, Christian; Ruemmele, Petra; Rose-John, Stefan; Neurath, Markus F.; Geissler, Edward K.; Schlitt, Hans-Jürgen; Strober, Warren; Fichtner-Feigl, Stefan

    2011-01-01

    Patients with prolonged ulcerative colitis (UC) frequently develop colorectal adenocarcinoma for reasons that are not fully clear. To analyze inflammation-associated colonic tumorigenesis, we developed a chronic form of oxazolone-induced colitis in mice that, similar to UC, was distinguished by the presence of IL-13–producing NKT cells. In this model, the induction of tumors using azoxymethane was accompanied by the coappearance of F4/80+CD11bhighGr1low M2 macrophages, cells that undergo polarization by IL-13 and are absent in tumors that lack high level IL-13 production. Importantly, this subset of macrophages was a source of tumor-promoting factors, including IL-6. Similar to dextran sodium sulfate–induced colitis, F4/80+CD11bhighGr1intermediate macrophages were present in the mouse model of chronic oxazolone-induced colitis and may influence tumor development through production of TGF-β1, a cytokine that inhibits tumor immunosurveillance. Finally, while robust chronic oxazolone-induced colitis developed in myeloid differentiation primary response gene 88–deficient (Myd88–/–) mice, these mice did not support tumor development. The inhibition of tumor development in Myd88–/– mice correlated with cessation of IL-6 and TGF-β1 production by M2 and F4/80+CD11bhighGr1intermediate macrophages, respectively, and was reversed by exogenous IL-6. These data show that an UC-like inflammation may facilitate tumor development by providing a milieu favoring development of MyD88-dependent tumor-supporting macrophages. PMID:21519141

  7. 32 CFR 48.508 - Certain 100 percent disability retirement.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., MILITARY AND CIVILIAN RETIRED SERVICEMAN'S FAMILY PROTECTION PLAN Annuity § 48.508 Certain 100 percent... duty as a direct result of armed conflict, or (b) His widow or children are not entitled to dependency...

  8. 41 CFR 101-26.508 - Electronic data processing (EDP) tape and instrumentation tape (wide and intermediate band).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... processing (EDP) tape and instrumentation tape (wide and intermediate band). 101-26.508 Section 101-26.508... Programs § 101-26.508 Electronic data processing (EDP) tape and instrumentation tape (wide and intermediate band). Procurement by Federal agencies of EDP tape and instrumentation tape (wide and intermediate band...

  9. 41 CFR 101-26.508 - Electronic data processing (EDP) tape and instrumentation tape (wide and intermediate band).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... processing (EDP) tape and instrumentation tape (wide and intermediate band). 101-26.508 Section 101-26.508... Programs § 101-26.508 Electronic data processing (EDP) tape and instrumentation tape (wide and intermediate band). Procurement by Federal agencies of EDP tape and instrumentation tape (wide and intermediate band...

  10. 41 CFR 101-26.508 - Electronic data processing (EDP) tape and instrumentation tape (wide and intermediate band).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... processing (EDP) tape and instrumentation tape (wide and intermediate band). 101-26.508 Section 101-26.508... Programs § 101-26.508 Electronic data processing (EDP) tape and instrumentation tape (wide and intermediate band). Procurement by Federal agencies of EDP tape and instrumentation tape (wide and intermediate band...

  11. 41 CFR 101-26.508 - Electronic data processing (EDP) tape and instrumentation tape (wide and intermediate band).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... processing (EDP) tape and instrumentation tape (wide and intermediate band). 101-26.508 Section 101-26.508... Programs § 101-26.508 Electronic data processing (EDP) tape and instrumentation tape (wide and intermediate band). Procurement by Federal agencies of EDP tape and instrumentation tape (wide and intermediate band...

  12. 41 CFR 101-26.508 - Electronic data processing (EDP) tape and instrumentation tape (wide and intermediate band).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... processing (EDP) tape and instrumentation tape (wide and intermediate band). 101-26.508 Section 101-26.508... Programs § 101-26.508 Electronic data processing (EDP) tape and instrumentation tape (wide and intermediate band). Procurement by Federal agencies of EDP tape and instrumentation tape (wide and intermediate band...

  13. J{sub IC} evaluation of the smooth and the side-grooved CT specimen in the reactor pressure vessel steel (SA508-3)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Oh, S.W.; Lim, M.B.; Kim, T.H.

    1993-12-31

    The elastic-plastic fracture toughness J{sub IC} of SA508-3 forging steel was investigated by using CT-type specimens. The thickness of the smooth specimen is B{sub 0} = 25.4 mm and the side groove specimen is B{sub N} = 20.4 mm and the side groove deep is S{center_dot}G = [(B{sub 0} {minus} B{sub N})/B{sub 0}] {times} 100 = 19.7% and the groove angle is 90{degree}. The J{sub IC} tests estimated according to the method proposed in the ASTM E813-81 and JSME S001-81. The side-grooved specimen have the advantage of J{sub IC} estimation, it is much easier to determine the onset of ductilemore » tearing by the R-curve method and it improved accuracy and scatter of the toughness values thus determined, provided all the size-requirements for the specimen prescribed in the JSME method were satisfied. But it is difficult to find by the ASTM method. The critical stretched zone width (SZW{sub C}) of the side-grooved specimens found to be smaller than that previously determined for the standard CT specimens without side-grooves. This was attributed to higher triaxiality produced by the side-grooves. The stretched zone width method gave slightly larger J{sub IC} values than those by the R-curve method for SA508-3, as has been observed for the standard specimen without side-groove.« less

  14. 23 CFR 636.508 - Can price or cost be an issue in discussions?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 23 Highways 1 2013-04-01 2013-04-01 false Can price or cost be an issue in discussions? 636.508 Section 636.508 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND... Can price or cost be an issue in discussions? You may inform an offeror that its price is considered...

  15. 23 CFR 636.508 - Can price or cost be an issue in discussions?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 23 Highways 1 2012-04-01 2012-04-01 false Can price or cost be an issue in discussions? 636.508 Section 636.508 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND... Can price or cost be an issue in discussions? You may inform an offeror that its price is considered...

  16. 23 CFR 636.508 - Can price or cost be an issue in discussions?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 23 Highways 1 2011-04-01 2011-04-01 false Can price or cost be an issue in discussions? 636.508 Section 636.508 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND... Can price or cost be an issue in discussions? You may inform an offeror that its price is considered...

  17. 23 CFR 636.508 - Can price or cost be an issue in discussions?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 23 Highways 1 2014-04-01 2014-04-01 false Can price or cost be an issue in discussions? 636.508 Section 636.508 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND... Can price or cost be an issue in discussions? You may inform an offeror that its price is considered...

  18. 48 CFR 311.7001 - Section 508 accessibility standards for HHS Web site content and communications materials.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Section 508 accessibility... Acquisition Regulations System HEALTH AND HUMAN SERVICES COMPETITION AND ACQUISITION PLANNING DESCRIBING... acquisition of communications products and services, including content in any format, such as reports...

  19. 32 CFR 508.1 - Utilization of Army bands.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... PUBLIC RELATIONS COMPETITION WITH CIVILIAN BANDS § 508.1 Utilization of Army bands. (a) General... Secretary of Defense. The authority to determine whether the use of an Army band at a public gathering is... Forces, veterans, and patriotic organizations. (3) At public rallies and parades intended to stimulate...

  20. 30 CFR 77.508 - Lightning arresters, ungrounded and exposed power conductors and telephone wires.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... power conductors and telephone wires. 77.508 Section 77.508 Mineral Resources MINE SAFETY AND HEALTH... arresters, ungrounded and exposed power conductors and telephone wires. All ungrounded, exposed power conductors and telephone wires shall be equipped with suitable lightning arresters which are adequately...

  1. 30 CFR 77.508 - Lightning arresters, ungrounded and exposed power conductors and telephone wires.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... power conductors and telephone wires. 77.508 Section 77.508 Mineral Resources MINE SAFETY AND HEALTH... arresters, ungrounded and exposed power conductors and telephone wires. All ungrounded, exposed power conductors and telephone wires shall be equipped with suitable lightning arresters which are adequately...

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

    PubMed

    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. Copyright © 2014, American Association for the Advancement of Science.

  3. 23 CFR 636.508 - Can price or cost be an issue in discussions?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 23 Highways 1 2010-04-01 2010-04-01 false Can price or cost be an issue in discussions? 636.508... TRAFFIC OPERATIONS DESIGN-BUILD CONTRACTING Discussions, Proposal Revisions and Source Selection § 636.508 Can price or cost be an issue in discussions? You may inform an offeror that its price is considered...

  4. 38 CFR 17.508 - Access to quality assurance records and documents within the agency.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Access to quality assurance records and documents within the agency. 17.508 Section 17.508 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS MEDICAL Confidentiality of Healthcare Quality Assurance Review...

  5. 38 CFR 17.508 - Access to quality assurance records and documents within the agency.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Access to quality assurance records and documents within the agency. 17.508 Section 17.508 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS MEDICAL Confidentiality of Healthcare Quality Assurance Review...

  6. 38 CFR 17.508 - Access to quality assurance records and documents within the agency.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Access to quality assurance records and documents within the agency. 17.508 Section 17.508 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS MEDICAL Confidentiality of Healthcare Quality Assurance Review...

  7. 38 CFR 17.508 - Access to quality assurance records and documents within the agency.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Access to quality assurance records and documents within the agency. 17.508 Section 17.508 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS MEDICAL Confidentiality of Healthcare Quality Assurance Review...

  8. 38 CFR 17.508 - Access to quality assurance records and documents within the agency.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Access to quality assurance records and documents within the agency. 17.508 Section 17.508 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS MEDICAL Confidentiality of Healthcare Quality Assurance Review...

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

    PubMed Central

    Stefano, Daniela De; Villella, Valeria R; Esposito, Speranza; Tosco, Antonella; Sepe, Angela; Gregorio, Fabiola De; Salvadori, Laura; Grassia, Rosa; Leone, Carlo A; Rosa, Giuseppe De; 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 CftrF508del 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. PMID:25350163

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

    PubMed

    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.

  11. Structural, Electronic, and Thermodynamic Properties of Tetragonal t-SixGe3−xN4

    PubMed Central

    Han, Chenxi; Chai, Changchun; Fan, Qingyang; Yang, Jionghao; Yang, Yintang

    2018-01-01

    The structural, mechanical, anisotropic, electronic, and thermal properties of t-Si3N4, t-Si2GeN4, t-SiGe2N4, and t-Ge3N4 in the tetragonal phase are systematically investigated in the present work. The mechanical stability is proved by the elastic constants of t-Si3N4, t-Si2GeN4, t-SiGe2N4, and t-Ge3N4. Moreover, they all demonstrate brittleness, because B/G < 1.75, and v < 0.26. The elastic anisotropy of t-Si3N4, t-Si2GeN4, t-SiGe2N4, and t-Ge3N4 is characterized by Poisson’s ratio, Young’s modulus, the percentage of elastic anisotropy for bulk modulus AB, the percentage of elastic anisotropy for shear modulus AG, and the universal anisotropic index AU. The electronic structures of t-Si3N4, t-Si2GeN4, t-SiGe2N4, and t-Ge3N4 are all wide band gap semiconductor materials, with band gaps of 4.26 eV, 3.94 eV, 3.83 eV, and 3.25 eV, respectively, when using the Heyd-Scuseria-Ernzerhof (HSE06) hybrid functional. Moreover, t-Ge3N4 is a quasi-direct gap semiconductor material. The thermodynamic properties of t-Si3N4, t-Si2GeN4, t-SiGe2N4, and t-Ge3N4 are investigated utilizing the quasi-harmonic Debye model. The effects of temperature and pressure on the thermal expansion coefficient, heat capacity, Debye temperature, and Grüneisen parameters are discussed in detail. PMID:29518943

  12. 49 CFR 599.508 - Statements of matters in dispute and submission of supporting information.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 7 2010-10-01 2010-10-01 false Statements of matters in dispute and submission of supporting information. 599.508 Section 599.508 Transportation Other Regulations Relating to Transportation (Continued) NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) REQUIREMENTS AND PROCEDURES FOR CONSUME...

  13. Chlorpyrifos promotes colorectal adenocarcinoma H508 cell growth through the activation of EGFR/ERK1/2 signaling pathway but not cholinergic pathway.

    PubMed

    Suriyo, Tawit; Tachachartvanich, Phum; Visitnonthachai, Daranee; Watcharasit, Piyajit; Satayavivad, Jutamaad

    2015-12-02

    Aside from the effects on neuronal cholinergic system, epidemiological studies suggest an association between chlorpyrifos (CPF) exposure and cancer risk. This in vitro study examined the effects of CPF and its toxic metabolite, chlorpyrifos oxon (CPF-O), on the growth of human colorectal adenocarcinoma H508, colorectal adenocarcinoma HT-29, normal colon epithelial CCD841, liver hepatocellular carcinoma HepG2, and normal liver hepatocyte THLE-3 cells. The results showed that CPF (5-100 μM) concentration-dependently increased viability of H508 and CCD841 cells in serum-free conditions. This increasing trend was not found in HT-29, HepG2 and THLE-3 cells. In contrast, CPF-O (50-100 μM) reduced the viability of all cell lines. Cell cycle analysis showed the induction of cells in the S phase, and EdU incorporation assay revealed the induction of DNA synthesis in CPF-treated H508 cells indicating that CPF promotes cell cycle progression. Despite the observation of acetylcholinesterase activity inhibition and reactive oxygen species (ROS) generation, atropine (a non-selective muscarinic acetylcholine receptor antagonist) and N-acetylcysteine (a potent antioxidant) failed to inhibit the growth-promoting effect of CPF. CPF increased the phosphorylation of epidermal growth factor receptor (EGFR) and its downstream effector, extracellular signal regulated kinase (ERK1/2), in H508 cells. AG-1478 (a specific EGFR tyrosine kinase inhibitor) and U0126 (a specific MEK inhibitor) completely mitigated the growth promoting effect of CPF. Altogether, these results suggest that EGFR/ERK1/2 signaling pathway but not cholinergic pathway involves in CPF-induced colorectal adenocarcinoma H508 cell growth. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. Combined effects of VX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels.

    PubMed

    Kopeikin, Z; Yuksek, Z; Yang, H-Y; Bompadre, S G

    2014-09-01

    The most common cystic fibrosis-associated mutation, the deletion of phenylalanine 508 (F508del), results in channels with poor membrane expression and impaired function. VX-770, a clinically approved drug for treatment of CF patients carrying the G551D mutation, and VX-809, a corrector shown in vitro to increase membrane expression of mutant channels, are currently undergoing clinical trials, but functional data at the molecular level is still lacking. The effect of VX-770 and VX-809 on the multiple functional defects of F508del-CFTR was assessed via excised inside-out patch-clamp experiments. VX-770 completely restores the low opening-rate of F508del-CFTR, with smaller open-time increase, in temperature-corrected and VX-809-treated channels. The shorter locked-open time of hydrolysis-deficient F508del-CFTR is also prolonged by VX-770. VX-809 does not improve channel function by itself as previously reported. The results from these studies can be interpreted as an equilibrium shift toward the open-channel conformation of F508del-CFTR channels. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  15. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.

    PubMed

    Wainwright, Claire E; Elborn, J Stuart; Ramsey, Bonnie W; Marigowda, Gautham; Huang, Xiaohong; Cipolli, Marco; Colombo, Carla; Davies, Jane C; De Boeck, Kris; Flume, Patrick A; Konstan, Michael W; McColley, Susanna A; McCoy, Karen; McKone, Edward F; Munck, Anne; Ratjen, Felix; Rowe, Steven M; Waltz, David; Boyle, Michael P

    2015-07-16

    Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation. We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. These data show that lumacaftor in

  16. 10 CFR 434.508 - Determination of the design energy consumption and design energy cost.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 3 2010-01-01 2010-01-01 false Determination of the design energy consumption and design energy cost. 434.508 Section 434.508 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY CODE FOR NEW FEDERAL COMMERCIAL AND MULTI-FAMILY HIGH RISE RESIDENTIAL BUILDINGS Building Energy Cost Compliance...

  17. 10 CFR 434.508 - Determination of the design energy consumption and design energy cost.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 3 2014-01-01 2014-01-01 false Determination of the design energy consumption and design energy cost. 434.508 Section 434.508 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY CODE FOR NEW FEDERAL COMMERCIAL AND MULTI-FAMILY HIGH RISE RESIDENTIAL BUILDINGS Building Energy Cost Compliance...

  18. 10 CFR 434.508 - Determination of the design energy consumption and design energy cost.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 3 2013-01-01 2013-01-01 false Determination of the design energy consumption and design energy cost. 434.508 Section 434.508 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY CODE FOR NEW FEDERAL COMMERCIAL AND MULTI-FAMILY HIGH RISE RESIDENTIAL BUILDINGS Building Energy Cost Compliance...

  19. 10 CFR 434.508 - Determination of the design energy consumption and design energy cost.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 3 2012-01-01 2012-01-01 false Determination of the design energy consumption and design energy cost. 434.508 Section 434.508 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY CODE FOR NEW FEDERAL COMMERCIAL AND MULTI-FAMILY HIGH RISE RESIDENTIAL BUILDINGS Building Energy Cost Compliance...

  20. 10 CFR 434.508 - Determination of the design energy consumption and design energy cost.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 3 2011-01-01 2011-01-01 false Determination of the design energy consumption and design energy cost. 434.508 Section 434.508 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY CODE FOR NEW FEDERAL COMMERCIAL AND MULTI-FAMILY HIGH RISE RESIDENTIAL BUILDINGS Building Energy Cost Compliance...

  1. Effect of the F508del genotype on outcomes of endoscopic sinus surgery in children with cystic fibrosis.

    PubMed

    Do, Bao Anh Julie; Lands, Larry C; Saint-Martin, Christine; Mascarella, Marco A; Manoukian, John J; Daniel, Sam J; Nguyen, Lily H P

    2014-07-01

    Numerous authors have sought to describe genotype-phenotype correlations in cystic fibrosis (CF), notably to pancreatic insufficiency and lung disease. However, few studies have focused on the association between the F508del genotype and response to sinus surgery. The objective of this study is to assess the effect of the F508del genotype on sinonasal disease severity and outcomes following functional endoscopic sinus surgery (FESS) in a pediatric population. A retrospective chart review of 153 children with CF seen at a tertiary care pediatric hospital from 1995 to 2008 was performed. Patients were classified into one of three groups according to F508del genotype, either as homozygous, heterozygous or not carrying a F508del mutation. The sinonasal disease phenotype of the three groups was compared based on clinical and radiological findings, extent of endoscopic sinus surgery and rate of revision surgery. The relationship between the F508del genotype and pancreatic insufficiency was confirmed (p<0.05). There was no association between the F508del genotype and increased need for FESS (p=0.75). Moreover, no association was established between F508del homozygosity and presence of nasal polyps, Lund-Mackay score, extent of surgery or length of postoperative hospitalization. The rates of revision surgery did not differ significantly among the three genotypes analyzed (p=0.59). There is no clear association between the F508del genotype and an increased need for FESS, extent of surgery, or revision surgery. Given the phenotypic variability of sinonasal disease in patients with CF, a prospective study is needed to better understand outcomes following FESS and the contribution of gene modifiers to this effect. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  2. Accumulation of CD11b+Gr-1+ cells in the lung, blood and bone marrow of mice infected with highly pathogenic H5N1 and H1N1 influenza viruses

    PubMed Central

    Kotur, Mark S.; Stark, Gregory V.; Warren, Richard L.; Kasoji, Manjula; Craft, Jeremy L.; Albrecht, Randy A.; García-Sastre, Adolfo; Katze, Michael G.; Waters, Katrina M.; Vasconcelos, Daphne; Sabourin, Patrick J.; Bresler, Herbert S.; Sabourin, Carol L.

    2017-01-01

    Infection with pathogenic influenza viruses isassociated with intense inflammatory disease. Here, we investigated the innate immune response in mice infectedwith H5N1 A/Vietnam/1203/04 and with reassortanthuman H1N1 A/Texas/36/91 viruse s containing the virulence genes hemagglutinin (HA), neuraminidase (NA) and NS1 of the 1918 pandemic virus. Inclusion of the 1918 HAand NA glycoproteins rendered a seasonal H1N1 virus capable of inducing an exacerbated host innate immuneresponse similar to that observed for highly pathogenicA/Vietnam/1203/04 virus. Infection with 1918 HA/NA:Tx/91 and A/Vietnam/1203/04 were associated with severelung pathology, increased cytokine and chemokine production, and significant immune cell changes, including the presence of CD11b+Gr-1+cells in the blood, lung and bone marrow. Significant differential gene expression in the lung included pathways for cell death, apoptosis, production and response to reactive oxygen radicals, as well asarginine and proline meta bolism and chemokines associated with monocyte and neutrophil/granulocyte accumulation and/or activation. Arginase was produced in the lungof animals infected with A/Vietnam/1204. These results demonstrate that the innate immune cell response resultsin t he accumulation of CD11b+Gr-1+cells and products that have previously been shown to contribute to T cellsuppression. PMID:23397329

  3. Functional genomic responses to cystic fibrosis transmembrane conductance regulator (CFTR) and CFTR(delta508) in the lung.

    PubMed

    Xu, Yan; Liu, Cong; Clark, Jean C; Whitsett, Jeffrey A

    2006-04-21

    Cystic fibrosis (CF), a common lethal pulmonary disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) that disturbs fluid homeostasis and host defense in target organs. The effects of CFTR and delta508-CFTR were assessed in transgenic mice that 1) lack CFTR expression (Cftr-/-); 2) express the human delta508 CFTR (CFTR(delta508)); 3) overexpress the normal human CFTR (CFTR(tg)) in respiratory epithelial cells. Genes were selected from Affymetrix Murine Gene-Chips analysis and subjected to functional classification, k-means clustering, promoter cis-elements/modules searching, literature mining, and pathway exploring. Genomic responses to Cftr-/- were not corrected by expression of CFTR(delta508). Genes regulating host defense, inflammation, fluid and electrolyte transport were similarly altered in Cftr-/- and CFTR(delta508) mice. CFTR(delta508) induced a primary disturbance in expression of genes regulating redox and antioxidant systems. Genomic responses to CFTR(tg) were modest and were not associated with lung pathology. CFTR(tg) and CFTR(delta508) induced genes encoding heat shock proteins and other chaperones but did not activate the endoplasmic reticulum-associated degradation pathway. RNAs encoding proteins that directly interact with CFTR were identified in each of the CFTR mouse models, supporting the hypothesis that CFTR functions within a multiprotein complex whose members interact at the level of protein-protein interactions and gene expression. Promoters of genes influenced by CFTR shared common regulatory elements, suggesting that their co-expression may be mediated by shared regulatory mechanisms. Genes and pathways involved in the response to CFTR may be of interest as modifiers of CF.

  4. 14 CFR 1204.508 - Delegation of authority of certain civil rights functions to Department of Health, Education, and...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... rights functions to Department of Health, Education, and Welfare. 1204.508 Section 1204.508 Aeronautics... Delegations and Designations § 1204.508 Delegation of authority of certain civil rights functions to... responsible NASA official under Title VI, Civil Rights Act of 1964 (78 Stat. 252) (42 U.S.C. 2000d), with...

  5. 14 CFR 1204.508 - Delegation of authority of certain civil rights functions to Department of Health, Education, and...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... rights functions to Department of Health, Education, and Welfare. 1204.508 Section 1204.508 Aeronautics... Delegations and Designations § 1204.508 Delegation of authority of certain civil rights functions to... responsible NASA official under Title VI, Civil Rights Act of 1964 (78 Stat. 252) (42 U.S.C. 2000d), with...

  6. 14 CFR 1204.508 - Delegation of authority of certain civil rights functions to Department of Health, Education, and...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... rights functions to Department of Health, Education, and Welfare. 1204.508 Section 1204.508 Aeronautics... Delegations and Designations § 1204.508 Delegation of authority of certain civil rights functions to... responsible NASA official under Title VI, Civil Rights Act of 1964 (78 Stat. 252) (42 U.S.C. 2000d), with...

  7. 14 CFR 1204.508 - Delegation of authority of certain civil rights functions to Department of Health, Education, and...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... rights functions to Department of Health, Education, and Welfare. 1204.508 Section 1204.508 Aeronautics... Delegations and Designations § 1204.508 Delegation of authority of certain civil rights functions to... responsible NASA official under Title VI, Civil Rights Act of 1964 (78 Stat. 252) (42 U.S.C. 2000d), with...

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

    PubMed

    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.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26171232

  10. Potentiator Ivacaftor Abrogates Pharmacological Correction of ΔF508 CFTR in Cystic Fibrosis

    PubMed Central

    Cholon, Deborah M.; Quinney, Nancy L.; Fulcher, M. Leslie; Esther, Charles R.; Das, Jhuma; Dokholyan, Nikolay V.; Randell, Scott H.; Boucher, Richard C.; Gentzsch, Martina

    2014-01-01

    Cystic Fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR). Newly developed “correctors” such as lumacaftor (VX-809) that improve CFTR maturation and trafficking and “potentiators” such as ivacaftor (VX-770) that enhance channel activity may provide important advances in CF therapy. Although VX-770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation (G551D) that affects only channel activity, a single compound is not sufficient to treat patients with the more common CFTR mutation, ΔF508. Thus, patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit. However, whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro, the impact of chronic therapy has not been established. In studies of human primary airway epithelial cells, we found that both acute and chronic treatment with VX-770 improved CFTR function in cells with the G551D mutation, consistent with clinical studies. In contrast, chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated CFTR correction in ΔF508 homozygous cultures. This result reflected the destabilization of corrected ΔF508 CFTR by VX-770, dramatically increasing its turnover rate. Chronic VX-770 treatment also reduced mature wild-type CFTR levels and function. These findings demonstrate that chronic treatment with CFTR potentiators and correctors may have unexpected effects that cannot be predicted from short-term studies. Combining of these drugs to maximize rescue of ΔF508 CFTR may require changes in dosing and/or development of new potentiator compounds that do not interfere with CFTR stability. PMID:25101886

  11. 33 CFR 150.508 - What are the maintenance and repair requirements for inflatable rescue boats?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... repair requirements for inflatable rescue boats? 150.508 Section 150.508 Navigation and Navigable Waters... repair requirements for inflatable rescue boats? The operator must perform the maintenance and repair of inflatable rescue boats according to the manufacturer's instructions. Operational Tests and Inspections...

  12. 33 CFR 150.508 - What are the maintenance and repair requirements for inflatable rescue boats?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... repair requirements for inflatable rescue boats? 150.508 Section 150.508 Navigation and Navigable Waters... repair requirements for inflatable rescue boats? The operator must perform the maintenance and repair of inflatable rescue boats according to the manufacturer's instructions. Operational Tests and Inspections...

  13. 33 CFR 150.508 - What are the maintenance and repair requirements for inflatable rescue boats?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... repair requirements for inflatable rescue boats? 150.508 Section 150.508 Navigation and Navigable Waters... repair requirements for inflatable rescue boats? The operator must perform the maintenance and repair of inflatable rescue boats according to the manufacturer's instructions. Operational Tests and Inspections...

  14. 33 CFR 150.508 - What are the maintenance and repair requirements for inflatable rescue boats?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... repair requirements for inflatable rescue boats? 150.508 Section 150.508 Navigation and Navigable Waters... repair requirements for inflatable rescue boats? The operator must perform the maintenance and repair of inflatable rescue boats according to the manufacturer's instructions. Operational Tests and Inspections...

  15. 33 CFR 150.508 - What are the maintenance and repair requirements for inflatable rescue boats?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... repair requirements for inflatable rescue boats? 150.508 Section 150.508 Navigation and Navigable Waters... repair requirements for inflatable rescue boats? The operator must perform the maintenance and repair of inflatable rescue boats according to the manufacturer's instructions. Operational Tests and Inspections...

  16. 41 CFR 302-3.508 - What relocation expenses are not authorized for new appointees or student trainees?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 41 Public Contracts and Property Management 4 2012-07-01 2012-07-01 false What relocation expenses... Contracts and Property Management Federal Travel Regulation System RELOCATION ALLOWANCES RELOCATION ALLOWANCES 3-RELOCATION ALLOWANCE BY SPECIFIC TYPE Agency Responsibilities New Appointees § 302-3.508 What...

  17. 41 CFR 302-3.508 - What relocation expenses are not authorized for new appointees or student trainees?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 41 Public Contracts and Property Management 4 2014-07-01 2014-07-01 false What relocation expenses... Contracts and Property Management Federal Travel Regulation System RELOCATION ALLOWANCES RELOCATION ALLOWANCES 3-RELOCATION ALLOWANCE BY SPECIFIC TYPE Agency Responsibilities New Appointees § 302-3.508 What...

  18. 41 CFR 302-3.508 - What relocation expenses are not authorized for new appointees or student trainees?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 41 Public Contracts and Property Management 4 2011-07-01 2011-07-01 false What relocation expenses... Contracts and Property Management Federal Travel Regulation System RELOCATION ALLOWANCES RELOCATION ALLOWANCES 3-RELOCATION ALLOWANCE BY SPECIFIC TYPE Agency Responsibilities New Appointees § 302-3.508 What...

  19. 41 CFR 302-3.508 - What relocation expenses are not authorized for new appointees or student trainees?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 41 Public Contracts and Property Management 4 2013-07-01 2012-07-01 true What relocation expenses... Contracts and Property Management Federal Travel Regulation System RELOCATION ALLOWANCES RELOCATION ALLOWANCES 3-RELOCATION ALLOWANCE BY SPECIFIC TYPE Agency Responsibilities New Appointees § 302-3.508 What...

  20. The role of cystic fibrosis transmembrane conductance regulator phenylalanine 508 side chain in ion channel gating

    PubMed Central

    Cui, Liying; Aleksandrov, Luba; Hou, Yue-Xian; Gentzsch, Martina; Chen, Jey-Hsin; Riordan, John R; Aleksandrov, Andrei A

    2006-01-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel employing the ABC transporter structural motif. Deletion of a single residue (Phe508) in the first nucleotide-binding domain (NBD1), which occurs in most patients with cystic fibrosis, impairs both maturation and function of the protein. However, substitution of the Phe508 with small uncharged amino acids, including cysteine, is permissive for maturation. To explore the possible role of the phenylalanine aromatic side chain in channel gating we introduced a cysteine at this position in cysless CFTR, enabling its selective chemical modification by sulfhydryl reagents. Both cysless and wild-type CFTR ion channels have identical mean open times when activated by different nucleotide ligands. Moreover, both channels could be locked in an open state by introducing an ATPase inhibiting mutation (E1371S). However, the introduction of a single cysteine (F508C) prevented the cysless E1371S channel from maintaining the permanently open state, allowing closing to occur. Chemical modification of cysless E1371S/F508C by sulfhydryl reagents was used to probe the role of the side chain in ion channel function. Specifically, benzyl-methanethiosulphonate modification of this variant restored the gating behaviour to that of cysless E1371S containing the wild-type phenylalanine at position 508. This provides the first direct evidence that a specific interaction of the Phe508 aromatic side chain plays a role in determining the residency time in the closed state. Thus, despite the fact that this aromatic side chain is not essential for CFTR folding, it is important in the ion channel function. PMID:16484308

  1. Gr-GDHP: A New Architecture for Globalized Dual Heuristic Dynamic Programming.

    PubMed

    Zhong, Xiangnan; Ni, Zhen; He, Haibo

    2017-10-01

    Goal representation globalized dual heuristic dynamic programming (Gr-GDHP) method is proposed in this paper. A goal neural network is integrated into the traditional GDHP method providing an internal reinforcement signal and its derivatives to help the control and learning process. From the proposed architecture, it is shown that the obtained internal reinforcement signal and its derivatives can be able to adjust themselves online over time rather than a fixed or predefined function in literature. Furthermore, the obtained derivatives can directly contribute to the objective function of the critic network, whose learning process is thus simplified. Numerical simulation studies are applied to show the performance of the proposed Gr-GDHP method and compare the results with other existing adaptive dynamic programming designs. We also investigate this method on a ball-and-beam balancing system. The statistical simulation results are presented for both the Gr-GDHP and the GDHP methods to demonstrate the improved learning and controlling performance.

  2. On the Computation of Comprehensive Boolean Gröbner Bases

    NASA Astrophysics Data System (ADS)

    Inoue, Shutaro

    We show that a comprehensive Boolean Gröbner basis of an ideal I in a Boolean polynomial ring B (bar A,bar X) with main variables bar X and parameters bar A can be obtained by simply computing a usual Boolean Gröbner basis of I regarding both bar X and bar A as variables with a certain block term order such that bar X ≫ bar A. The result together with a fact that a finite Boolean ring is isomorphic to a direct product of the Galois field mathbb{GF}_2 enables us to compute a comprehensive Boolean Gröbner basis by only computing corresponding Gröbner bases in a polynomial ring over mathbb{GF}_2. Our implementation in a computer algebra system Risa/Asir shows that our method is extremely efficient comparing with existing computation algorithms of comprehensive Boolean Gröbner bases.

  3. A Glycine-Rich RNA-Binding Protein, CsGR-RBP3, Is Involved in Defense Responses Against Cold Stress in Harvested Cucumber (Cucumis sativus L.) Fruit

    PubMed Central

    Wang, Bin; Wang, Guang; Shen, Fei; Zhu, Shijiang

    2018-01-01

    Plant glycine-rich RNA-binding proteins (GR-RBPs) have been shown to play important roles in response to abiotic stresses in actively proliferating organs such as young plants, root tips, and flowers, but their roles in chilling responses of harvested fruit remains largely unknown. Here, we investigated the role of CsGR-RBP3 in the chilling response of cucumber fruit. Pre-storage cold acclimation at 10°C (PsCA) for 3 days significantly enhanced chilling tolerance of cucumber fruit compared with the control fruit that were stored at 5°C. In the control fruit, only one of the six cucumber CsGR-RBP genes, CsGR-RBP2, was enhanced whereas the other five, i.e., CsGR-RBP3, CsGR-RBP4, CsGR-RBP5, CsGR-RBP-blt801, and CsGR-RBP-RZ1A were not. However, in the fruit exposed to PsCA before storage at 5°C, CsGR-RBP2 transcript levels were not obviously different from those in the controls, whereas the other five were highly upregulated, with CsGR-RBP3 the most significantly induced. Treatment with endogenous ABA and NO biosynthesis inhibitors, tungstate and L-nitro-arginine methyl ester, respectively, prior to PsCA treatment, clearly downregulated CsGR-RBP3 expression and significantly aggravated chilling injury. These results suggest a strong connection between CsGR-RBP3 expression and chilling tolerance in cucumber fruit. Transient expression in tobacco suggests CsGR-RBP3 was located in the mitochondria, implying a role for CsGR-RBP3 in maintaining mitochondria-related functions under low temperature. Arabidopsis lines overexpressing CsGR-RBP3 displayed faster growth at 23°C, lower electrolyte leakage and higher Fv/Fm ratio at 0°C, and higher survival rate at -20°C, than wild-type plants. Under cold stress conditions, Arabidopsis plants overexpressing CsGR-RBP3 displayed lower reactive oxygen species levels, and higher catalase and superoxide dismutase expression and activities, compared with the wild-type plants. In addition, overexpression of CsGR-RBP3 significantly

  4. Wear and friction behavior of Al-TiB2-nano-Gr hybrid composites fabricated through ultrasonic cavitation assisted stir casting

    NASA Astrophysics Data System (ADS)

    Poria, Suswagata; Sutradhar, Goutam; Sahoo, Prasanta

    2018-05-01

    The present study reports the role of nano-graphite particles in determining wear and friction behavior of Al-TiB2-nano-Gr hybrid composites. Ultrasonic cavitation assisted stir casting method has been used for fabrication of composites. Al-Si5Cu3 alloy is used as base alloy along with micro sized TiB2 hard ceramic particles (2.5 and 5.5 wt%) as reinforcement and nano-Gr particles (2 and 4 wt%) as solid lubricant additives. SEM micrographs, EDAX spectrum and optical images are considered to observe uniform dispersion of reinforcing phases. Micro-hardness is evaluated using Vicker’s microhardness tester. Hardness is seen to increase with incorporation of TiB2 while the same decreases with incorporation of graphite. Wear and friction of composites are tested for varying load (10 to 40 N) and sliding speed (0.2 to 0.4 m s‑1) using a pin-on-disk tribometer. Worn surfaces are characterized using SEM and EDAX analysis. Wear resistance of composites increases with incorporation of reinforcing phases together. Nano-Gr particles are easily sheared out from the sub-surface and provide a layer over the tribo-surface of composite that enhances friction and wear behavior. Wear mechanism in composites is predominantly adhesion while abrasion and ploughing is prominent in base alloy.

  5. 9 CFR 590.508 - Candling and transfer-room operations.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ..., Processing, and Facility Requirements § 590.508 Candling and transfer-room operations. (a) Candling and transfer rooms and equipment shall be kept clean, free from cobwebs, dust, objectionable odors, and excess... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Candling and transfer-room operations...

  6. 9 CFR 590.508 - Candling and transfer-room operations.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., Processing, and Facility Requirements § 590.508 Candling and transfer-room operations. (a) Candling and transfer rooms and equipment shall be kept clean, free from cobwebs, dust, objectionable odors, and excess... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Candling and transfer-room operations...

  7. 9 CFR 590.508 - Candling and transfer-room operations.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ..., Processing, and Facility Requirements § 590.508 Candling and transfer-room operations. (a) Candling and transfer rooms and equipment shall be kept clean, free from cobwebs, dust, objectionable odors, and excess... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Candling and transfer-room operations...

  8. 9 CFR 590.508 - Candling and transfer-room operations.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., Processing, and Facility Requirements § 590.508 Candling and transfer-room operations. (a) Candling and transfer rooms and equipment shall be kept clean, free from cobwebs, dust, objectionable odors, and excess... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Candling and transfer-room operations...

  9. 9 CFR 590.508 - Candling and transfer-room operations.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ..., Processing, and Facility Requirements § 590.508 Candling and transfer-room operations. (a) Candling and transfer rooms and equipment shall be kept clean, free from cobwebs, dust, objectionable odors, and excess... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Candling and transfer-room operations...

  10. Application of the Rehabilitation Act Section 508 to the NPFC

    DOT National Transportation Integrated Search

    2001-04-09

    This paper provides a brief summary of Section 508 and its associated technical standards in layman's terms. It identifies the elements of the NPFC information technology (IT) that are affected by the technical standards and a brief discussion of how...

  11. SDSS (g--r) colors of isolated galaxies

    NASA Astrophysics Data System (ADS)

    Fernández Lorenzo, M.; Sulentic, J.; Verdes-Montenegro, L.; Ruiz, J. E.; Sabater, J.; Sánchez-Expósito, S.

    2013-05-01

    Several processes can affect a galaxy over its lifetime. If effects of interaction with companions are minimized, it is possible to focus on secular evolutionary processes. We present a study of the SDSS (g--r) colors of isolated galaxies in the AMIGA project (Analysis of the interstellar Medium of Isolated GAlaxies; http://www.amiga.iaa.es). Assuming that color is an indicator of the star formation history, this work better records the signature of passive star formation via pure secular evolution. We focused on median values for the main morphological subtypes found in the AMIGA sample (66% Sb--Sc and 14% E/S0) and compared them with equivalent measures of galaxies in denser environments. The main results of this study include: 1) a tendency for AMIGA spiral galaxies to be redder than similar type galaxies in close pairs, but 2) no clear difference when we compare with galaxies in other (e.g. group) environments; 3) a Gaussian distribution of the (g--r) color of isolated galaxies, as might be expected in the case of pure secular evolution; and 4) a smaller median absolute deviation in colors for isolated galaxies compared to both wide and close pairs.

  12. 14 CFR § 1204.508 - Delegation of authority of certain civil rights functions to Department of Health, Education, and...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... rights functions to Department of Health, Education, and Welfare. § 1204.508 Section § 1204.508... Delegations and Designations § 1204.508 Delegation of authority of certain civil rights functions to... responsible NASA official under Title VI, Civil Rights Act of 1964 (78 Stat. 252) (42 U.S.C. 2000d), with...

  13. Impact of the F508del mutation on ovine CFTR, a Cl− channel with enhanced conductance and ATP-dependent gating

    PubMed Central

    Cai, Zhiwei; Palmai-Pallag, Timea; Khuituan, Pissared; Mutolo, Michael J; Boinot, Clément; Liu, Beihui; Scott-Ward, Toby S; Callebaut, Isabelle; Harris, Ann; Sheppard, David N

    2015-01-01

    Cross-species comparative studies are a powerful approach to understanding the epithelial Cl− channel cystic fibrosis transmembrane conductance regulator (CFTR), which is defective in the genetic disease cystic fibrosis (CF). Here, we investigate the single-channel behaviour of ovine CFTR and the impact of the most common CF mutation, F508del-CFTR, using excised inside-out membrane patches from transiently transfected CHO cells. Like human CFTR, ovine CFTR formed a weakly inwardly rectifying Cl− channel regulated by PKA-dependent phosphorylation, inhibited by the open-channel blocker glibenclamide. However, for three reasons, ovine CFTR was noticeably more active than human CFTR. First, single-channel conductance was increased. Second, open probability was augmented because the frequency and duration of channel openings were increased. Third, with enhanced affinity and efficacy, ATP more strongly stimulated ovine CFTR channel gating. Consistent with these data, the CFTR modulator phloxine B failed to potentiate ovine CFTR Cl− currents. Similar to its impact on human CFTR, the F508del mutation caused a temperature-sensitive folding defect, which disrupted ovine CFTR protein processing and reduced membrane stability. However, the F508del mutation had reduced impact on ovine CFTR channel gating in contrast to its marked effects on human CFTR. We conclude that ovine CFTR forms a regulated Cl− channel with enhanced conductance and ATP-dependent channel gating. This phylogenetic analysis of CFTR structure and function demonstrates that subtle changes in structure have pronounced effects on channel function and the consequences of the CF mutation F508del. Key points Malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), a gated pathway for chloride movement, causes the common life-shortening genetic disease cystic fibrosis (CF). Towards the development of a sheep model of CF, we have investigated the function of sheep CFTR. We found that

  14. Characterization of microstructure of A508III/309L/308L weld and oxide films formed in deaerated high-temperature water

    NASA Astrophysics Data System (ADS)

    Xiong, Qi; Li, Hongjuan; Lu, Zhanpeng; Chen, Junjie; Xiao, Qian; Ma, Jiarong; Ru, Xiangkun

    2018-01-01

    The microstructure of A508III/309L/308L weld clad and the properties of the oxide films formed in simulated pressurized water reactor primary water at 290 °C were characterized. The A508III heat-affected zone (HAZ) consisted primarily of a decarburization zone with ferrite near the fusion line and a following pearlite structure with fine grains. A high hardness region in the HAZ could be the result of C-enrichment. M23C6 and M7C3 precipitates were observed in element transition zone. 308L stainless steel (SS) containing ∼ 12% ferrites exhibited both ferritic-austenitic solidification mode (FA mode, δ→γ) and austenitic-ferritic solidification mode (AF mode, γ→δ), whereas 309L SS containing ∼ 9% ferrites exhibited only FA mode. The A508III surface oxide film was mainly Fe3O4 in deaerated high-temperature water. The coarse grain zone covered with few oxide particles was different from other types of film on the other region of HAZ and the bulk zone. More pitting appears on 309L SS after immersion in deaerated high-temperature water due to the dissolution of inclusions. SS surface oxide films consisted primarily of spinels. The oxide film on SS was divided into two layers. Ni was concentrated mainly at the oxide/substrate interface. The oxide film formed on 309L was thicker than that on the 308L. The ferrite in the stainless steel could improve the oxidation resistance.

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

    PubMed

    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 (ΔF508/ΔF508) 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. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Low free drug concentration prevents inhibition of F508del CFTR functional expression by the potentiator VX-770 (ivacaftor).

    PubMed

    Matthes, Elizabeth; Goepp, Julie; Carlile, Graeme W; Luo, Yishan; Dejgaard, Kurt; Billet, Arnaud; Robert, Renaud; Thomas, David Y; Hanrahan, John W

    2016-02-01

    The most common cystic fibrosis (CF) mutation F508del inhibits the gating and surface expression of CFTR, a plasma membrane anion channel. Optimal pharmacotherapies will probably require both a 'potentiator' to increase channel open probability and a 'corrector' that improves folding and trafficking of the mutant protein and its stability at the cell surface. Interaction between CF drugs has been reported but remains poorly understood. CF bronchial epithelial cells were exposed to the corrector VX-809 (lumacaftor) and potentiator VX-770 (ivacaftor) individually or in combination. Functional expression of CFTR was assayed as the forskolin-stimulated short-circuit current (Isc ) across airway epithelial monolayers expressing F508del CFTR. The potentiated Isc response during forskolin stimulation was increased sixfold after pretreatment with VX-809 alone and reached ~11% that measured across non-CF monolayers. VX-770 (100 nM) and genistein (50 μM) caused similar levels of potentiation, which were not additive and were abolished by the CFTR inhibitor CFTRinh -172. The unbound fraction of VX-770 in plasma was 0.13 ± 0.04%, which together with previous measurements in patients given 250 mg p.o. twice daily, suggests a peak free plasma concentration of 1.5-8.5 nM. Chronic exposure to high VX-770 concentrations (>1 μM) inhibited functional correction by VX-809 but not in the presence of physiological protein levels (20-40 mg·mL(-1) ). Chronic exposure to a low concentration of VX-770 (100 nM) together with VX-809 (1 μM) also did not reduce the forskolin-stimulated Isc , relative to cells chronically exposed to VX-809 alone, provided it was assayed acutely using the same, clinically relevant concentration of potentiator. Chronic exposure to clinically relevant concentrations of VX-770 did not reduce F508del CFTR function. Therapeutic benefit of VX-770 + VX-809 (Orkambi) is probably limited by the efficacy of VX-809 rather than by inhibition by VX-770. © 2015

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

    PubMed

    Saussereau, Emilie Lyne; Roussel, Delphine; Diallo, Siradiou; Debarbieux, Laurent; Edelman, Aleksander; Sermet-Gaudelus, Isabelle

    2013-01-01

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

  18. High pressure behavior of complex phosphate K2Ce[PO4]2: Grüneisen parameter and anharmonicity properties

    NASA Astrophysics Data System (ADS)

    Mishra, Karuna Kara; Bevara, Samatha; Ravindran, T. R.; Patwe, S. J.; Gupta, Mayanak K.; Mittal, Ranjan; Krishnan, R. Venkata; Achary, S. N.; Tyagi, A. K.

    2018-02-01

    Herein we reported structural stability, vibrational and thermal properties of K2Ce[PO4]2, a relatively underexplored complex phosphate of tetravalent Ce4+ from in situ high-pressure Raman spectroscopic investigations up to 28 GPa using a diamond anvil cell. The studies identified the soft phonons that lead to a reversible phase transformation above 8 GPa, and a phase coexistence of ambient (PI) and high pressure (PII) phases in a wider pressure region 6-11 GPa. From a visual representation of the computed eigen vector displacements, the Ag soft mode at 82 cm-1 is assigned as a lattice mode of K+ cation. Pressure-induced positional disorder is apparent from the substantial broadening of internal modes and the disappearance of low frequency lattice and external modes in phase PII above 18 GPa. Isothermal mode Grüneisen parameters γi of the various phonon modes are calculated and compared for several modes. Using these values, thermal properties such as average Grüneisen parameter, and thermal expansion coefficient are estimated as 0.47, and 2.5 × 10-6 K-1, respectively. The specific heat value was estimated from all optical modes obtained from DFT calculations as 314 J-mol-1 K-1. Our earlier reported temperature dependence of phonon frequencies is used to decouple the "true anharmonic" (explicit contribution at constant volume) and "quasi harmonic" (implicit contribution brought out by volume change) contributions from the total anharmonicity. In addition to the 81 cm-1 Ag lattice mode, several other lattice and external modes of PO43- ions are found to be strongly anharmonic.

  19. 20 CFR 702.508 - Vocational rehabilitation; confidentiality of information.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Vocational rehabilitation; confidentiality of... PROCEDURE Vocational Rehabilitation § 702.508 Vocational rehabilitation; confidentiality of information. The... which it is provided; (b) Interested persons and agencies have been advised that any information...

  20. 30 CFR 7.508 - Harmful gas removal components.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... chemical used for removal of harmful gas shall be— (1) Contained such that when stored or used it cannot... for disposal of used chemical. (c) Each harmful gas removal component shall be tested to determine its... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Harmful gas removal components. 7.508 Section 7...

  1. 30 CFR 7.508 - Harmful gas removal components.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... chemical used for removal of harmful gas shall be— (1) Contained such that when stored or used it cannot... for disposal of used chemical. (c) Each harmful gas removal component shall be tested to determine its... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Harmful gas removal components. 7.508 Section 7...

  2. 30 CFR 7.508 - Harmful gas removal components.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... chemical used for removal of harmful gas shall be— (1) Contained such that when stored or used it cannot... for disposal of used chemical. (c) Each harmful gas removal component shall be tested to determine its... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Harmful gas removal components. 7.508 Section 7...

  3. 31 CFR 535.420 - Transfers of accounts under § 535.508 from demand to interest-bearing status.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Transfers of accounts under § 535... TREASURY IRANIAN ASSETS CONTROL REGULATIONS Interpretations § 535.420 Transfers of accounts under § 535.508 from demand to interest-bearing status. Section 535.508 authorizes transfer of a blocked demand deposit...

  4. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.

    PubMed

    Clancy, J P; Rowe, Steven M; Accurso, Frank J; Aitken, Moira L; Amin, Raouf S; Ashlock, Melissa A; Ballmann, Manfred; Boyle, Michael P; Bronsveld, Inez; Campbell, Preston W; De Boeck, Kris; Donaldson, Scott H; Dorkin, Henry L; Dunitz, Jordan M; Durie, Peter R; Jain, Manu; Leonard, Anissa; McCoy, Karen S; Moss, Richard B; Pilewski, Joseph M; Rosenbluth, Daniel B; Rubenstein, Ronald C; Schechter, Michael S; Botfield, Martyn; Ordoñez, Claudia L; Spencer-Green, George T; Vernillet, Laurent; Wisseh, Steve; Yen, Karl; Konstan, Michael W

    2012-01-01

    VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. NCT00865904.

  5. 31 CFR 585.508 - Importation of household and personal effects from the FRY (S&M) authorized.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Importation of household and personal effects from the FRY (S&M) authorized. 585.508 Section 585.508 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY...

  6. 31 CFR 50.8 - Procedure for requesting determinations of controlling influence.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... the Treasury TERRORISM RISK INSURANCE PROGRAM General Provisions § 50.8 Procedure for requesting... controlling influence. Such submissions shall be made to the Terrorism Risk Insurance Program Office...

  7. 31 CFR 50.8 - Procedure for requesting determinations of controlling influence.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... the Treasury TERRORISM RISK INSURANCE PROGRAM General Provisions § 50.8 Procedure for requesting... controlling influence. Such submissions shall be made to the Terrorism Risk Insurance Program Office...

  8. 31 CFR 50.8 - Procedure for requesting determinations of controlling influence.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... the Treasury TERRORISM RISK INSURANCE PROGRAM General Provisions § 50.8 Procedure for requesting... controlling influence. Such submissions shall be made to the Terrorism Risk Insurance Program Office...

  9. 31 CFR 50.8 - Procedure for requesting determinations of controlling influence.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... the Treasury TERRORISM RISK INSURANCE PROGRAM General Provisions § 50.8 Procedure for requesting... controlling influence. Such submissions shall be made to the Terrorism Risk Insurance Program Office...

  10. 31 CFR 50.8 - Procedure for requesting determinations of controlling influence.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... the Treasury TERRORISM RISK INSURANCE PROGRAM General Provisions § 50.8 Procedure for requesting... controlling influence. Such submissions shall be made to the Terrorism Risk Insurance Program Office...

  11. 30 CFR 285.508 - What rent payments must I pay on ROW grants or RUE grants associated with renewable energy projects?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... RUE grants associated with renewable energy projects? 285.508 Section 285.508 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF... § 285.508 What rent payments must I pay on ROW grants or RUE grants associated with renewable energy...

  12. In vitro cytotoxicity evaluation of a 50.8% NiTi single crystal.

    PubMed

    Manceur, Aziza; Chellat, Fatiha; Merhi, Yahye; Chumlyakov, Yuriy; Yahia, L'Hocine

    2003-11-01

    To our knowledge, the biocompatibility of nickel-titanium (NiTi) single crystals has not been reported. Yet certain orientations of single crystals present several advantages over the polycrystalline form in terms of maximal strain, fatigue resistance, and temperature range of superelasticity. Therefore we tested the in vitro biocompatibility of 50.8% NiTi single crystals in the orientation <001> after four different heat treatments in a helium atmosphere followed by mechanical polishing. The study was performed on the material extracts after immersion of the specimens in cell culture medium (DMEM) for 7 days at 37 degrees C. Cytotoxicity studies were performed on L-929 mouse fibroblasts using the MTT assay. J-774 macrophages were used to assess the potential inflammatory effect of the extracts by IL1-beta and TNF-alpha dosages (sandwich ELISA method). Exposure of L-929 to material extracts did not affect cell viability. In addition, IL1-beta and TNF-alpha secretion was not stimulated after incubation with NiTi extracts compared to the negative controls. These results were predictable since atomic absorption spectroscopy did not detect nickel ions in the extracts with a resolution of 1 ppm. Within the limits of in vitro testing, our results demonstrate that the TiNi(50.8%) single crystals do not trigger a cytotoxic reaction. Copyright 2003 Wiley Periodicals, Inc.

  13. Maternal betaine supplementation during gestation modifies hippocampal expression of GR and its regulatory miRNAs in neonatal piglets

    PubMed Central

    SUN, Qinwei; LI, Xi; JIA, Yimin; PAN, Shifeng; LI, Runsheng; YANG, Xiaojing; ZHAO, Ruqian

    2016-01-01

    Methyl donor nutrients are critical for embryonic development of brain. Hippocampus is the most susceptible brain region to various factors including prenatal supply of methyl donors. Glucocorticoid receptor (GR) expressed in hippocampus is involved in the regulation of energy homeostasis and stress sensitivity. Hippocampal GR expression is highly susceptible to epigenetic regulation, yet the effect of maternal methyl donor supplementation on epigenetic regulation of GR transcription in offspring hippocampus remains unclear. In this study, we fed sows with betaine (3 g/kg) throughout the gestation and analyzed the hippocampal expression of GR mRNA and its variants, as well as the CpG methylation status of the promoter and the microRNAs predicted to target 3’ UTR of porcine GR gene in neonatal piglets. Total GR mRNA (P<0.01) and its variants GR 1-4 (P<0.05) and 1-9,10 (P<0.01), were significantly higher in the hippocampus of betaine-treated piglets, while the content of GR protein was not significantly changed. The CpGs located in the –1650 ~ –1515 segment of GR gene were hypermethylated (P<0.05). The hippocampal expression of miR-130b (P<0.05), miR-181a (P<0.05) and miR-181d (P<0.01) was significantly up-regulated. The targeting efficacy of miR-130b and miR-181d was validated in vitro using dual-luciferase reporter assay system. Our results demonstrate that maternal betaine supplementation during gestation enhances GR mRNA expression in offspring hippocampus, which involves alterations in miRNAs expression. PMID:26875838

  14. Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis

    PubMed Central

    Robben, Paul M.; LaRegina, Marie; Kuziel, William A.; Sibley, L. David

    2005-01-01

    Circulating murine monocytes comprise two largely exclusive subpopulations that are responsible for seeding normal tissues (Gr-1−/CCR2−/CX3CR1high) or responding to sites of inflammation (Gr-1+/CCR2+/CX3CR1lo). Gr-1+ monocytes are recruited to the site of infection during the early stages of immune response to the intracellular pathogen Toxoplasma gondii. A murine model of toxoplasmosis was thus used to examine the importance of Gr-1+ monocytes in the control of disseminated parasitic infection in vivo. The recruitment of Gr-1+ monocytes was intimately associated with the ability to suppress early parasite replication at the site of inoculation. Infection of CCR2−/− and MCP-1−/− mice with typically nonlethal, low doses of T. gondii resulted in the abrogated recruitment of Gr-1+ monocytes. The failure to recruit Gr-1+ monocytes resulted in greatly enhanced mortality despite the induction of normal Th1 cell responses leading to high levels of IL-12, TNF-α, and IFN-γ. The profound susceptibility of CCR2−/− mice establishes Gr-1+ monocytes as necessary effector cells in the resistance to acute toxoplasmosis and suggests that the CCR2-dependent recruitment of Gr-1+ monocytes may be an important general mechanism for resistance to intracellular pathogens. PMID:15928200

  15. Cystic fibrosis Δf508 mutation screening in Brazilian women with altered fertility.

    PubMed

    Brunoro, G V F; Wolfgramm, E V; Louro, I D; Degasperi, I I; Busatto, V C W; Perrone, A M S; Batitucci, M C P

    2011-10-01

    Cystic Fibrosis (CF) is an autosomal recessive disease, caused by mutations in the Cystic Fibrosis Transmembrane Regulator gene (CFTR). The most frequent mutation in CF is ΔF508. The disease is clinically characterized by elevated concentrations of sweat chlorides and abnormally thick mucus. It affects organs such as lung, pancreas, gastrointestinal and reproductive tract. Women with CF commonly present delayed puberty and amenorrhea due to malnutrition. Our objective was to screen the presence of ΔF508 mutation in 24 women with altered fertility. Nine of these women presented reduced fertility without a known cause, four showed polycystic ovaries and two had early menopause. One woman with early menopause was a carrier of the ΔF508 mutation. Our study demonstrates that it is possible that the frequency of CF mutations among patients with altered fertility may be higher than expected. Previous data showed that fibrocystic women can show reduced fertility, maternal mortality associated with pregnancy and increased incidence of spontaneous abortion. We therefore recommend that women with reduced fertility undertake genetic tests for a better evaluation of pregnancy risks and clinical monitoring.

  16. 31 CFR 560.508 - Telecommunications and mail transactions authorized.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Telecommunications and mail... REGULATIONS Licenses, Authorizations and Statements of Licensing Policy § 560.508 Telecommunications and mail... telecommunications and mail between the United States and Iran are authorized. For purposes of this section, the term...

  17. 31 CFR 560.508 - Telecommunications and mail transactions authorized.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Telecommunications and mail... REGULATIONS Licenses, Authorizations and Statements of Licensing Policy § 560.508 Telecommunications and mail... telecommunications and mail between the United States and Iran are authorized. For purposes of this section, the term...

  18. 31 CFR 560.508 - Telecommunications and mail transactions authorized.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Telecommunications and mail... REGULATIONS Licenses, Authorizations and Statements of Licensing Policy § 560.508 Telecommunications and mail... telecommunications and mail between the United States and Iran are authorized. For purposes of this section, the term...

  19. Epithelial IgG and its relationship to the loss of F508 in the common mutant form of the cystic fibrosis transmembrane conductance regulator.

    PubMed

    Treharne, Kate J; Cassidy, Diane; Goddard, Catharine; Colledge, William H; Cassidy, Andrew; Mehta, Anil

    2009-08-06

    The most debilitating feature of cystic fibrosis (CF) disease is uncontrolled inflammation of respiratory epithelium. The relationship between the commonest mutated form of CFTR (F508del or DeltaF508) and inflammation has not yet been elucidated. Here, we present a new paradigm suggesting that CFTR can interact with intra-epithelial IgG, establishing a direct link between normal CFTR and the immune system. Further, our data show that the amino-acid sequence local to F508 can bind IgG with high affinity, dependent on F508, such that loss of F508 abolishes this link both in vitro and in the intact cell.

  20. 30 CFR 585.508 - What rent payments must I pay on ROW grants or RUE grants associated with renewable energy projects?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... RUE grants associated with renewable energy projects? 585.508 Section 585.508 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES... Payments § 585.508 What rent payments must I pay on ROW grants or RUE grants associated with renewable...

  1. 30 CFR 585.508 - What rent payments must I pay on ROW grants or RUE grants associated with renewable energy projects?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... RUE grants associated with renewable energy projects? 585.508 Section 585.508 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES... Payments § 585.508 What rent payments must I pay on ROW grants or RUE grants associated with renewable...

  2. 30 CFR 585.508 - What rent payments must I pay on ROW grants or RUE grants associated with renewable energy projects?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... RUE grants associated with renewable energy projects? 585.508 Section 585.508 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES... Payments § 585.508 What rent payments must I pay on ROW grants or RUE grants associated with renewable...

  3. 41 CFR 302-3.508 - What relocation expenses are not authorized for new appointees or student trainees?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... are not authorized for new appointees or student trainees? 302-3.508 Section 302-3.508 Public Contracts and Property Management Federal Travel Regulation System RELOCATION ALLOWANCES RELOCATION... relocation expenses are not authorized for new appointees or student trainees? You must not pay any expenses...

  4. Key algorithms used in GR02: A computer simulation model for predicting tree and stand growth

    Treesearch

    Garrett A. Hughes; Paul E. Sendak; Paul E. Sendak

    1985-01-01

    GR02 is an individual tree, distance-independent simulation model for predicting tree and stand growth over time. It performs five major functions during each run: (1) updates diameter at breast height, (2) updates total height, (3) estimates mortality, (4) determines regeneration, and (5) updates crown class.

  5. α Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation and Transrepression in Podocytes*

    PubMed Central

    Zhao, Xuan; Khurana, Simran; Charkraborty, Sharmistha; Tian, Yuqian; Sedor, John R.; Bruggman, Leslie A.; Kao, Hung-Ying

    2017-01-01

    Glucocorticoids are a general class of steroids that possess renoprotective activity in glomeruli through their interaction with the glucocorticoid receptor. However, the mechanisms by which glucocorticoids ameliorate proteinuria and glomerular disease are not well understood. In this study, we demonstrated that α actinin 4 (ACTN4), an actin-cross-linking protein known to coordinate cytoskeletal organization, interacts with the glucocorticoid receptor (GR) in the nucleus of human podocytes (HPCs), a key cell type in the glomerulus critical for kidney filtration function. The GR-ACTN4 complex enhances glucocorticoid response element (GRE)-driven reporter activity. Stable knockdown of ACTN4 by shRNA in HPCs significantly reduces dexamethasone-mediated induction of GR target genes and GRE-driven reporter activity without disrupting dexamethasone-induced nuclear translocation of GR. Synonymous mutations or protein expression losses in ACTN4 are associated with kidney diseases, including focal segmental glomerulosclerosis, characterized by proteinuria and podocyte injury. We found that focal segmental glomerulosclerosis-linked ACTN4 mutants lose their ability to bind liganded GR and support GRE-mediated transcriptional activity. Mechanistically, GR and ACTN4 interact in the nucleus of HPCs. Furthermore, disruption of the LXXLL nuclear receptor-interacting motif present in ACTN4 results in reduced GR interaction and dexamethasone-mediated transactivation of a GRE reporter while still maintaining its actin-binding activity. In contrast, an ACTN4 isoform, ACTN4 (Iso), that loses its actin-binding domain is still capable of potentiating a GRE reporter. Dexamethasone induces the recruitment of ACTN4 and GR to putative GREs in dexamethasone-transactivated promoters, SERPINE1, ANGPLT4, CCL20, and SAA1 as well as the NF-κB (p65) binding sites on GR-transrepressed promoters such as IL-1β, IL-6, and IL-8. Taken together, our data establish ACTN4 as a transcriptional co

  6. GrDHP: a general utility function representation for dual heuristic dynamic programming.

    PubMed

    Ni, Zhen; He, Haibo; Zhao, Dongbin; Xu, Xin; Prokhorov, Danil V

    2015-03-01

    A general utility function representation is proposed to provide the required derivable and adjustable utility function for the dual heuristic dynamic programming (DHP) design. Goal representation DHP (GrDHP) is presented with a goal network being on top of the traditional DHP design. This goal network provides a general mapping between the system states and the derivatives of the utility function. With this proposed architecture, we can obtain the required derivatives of the utility function directly from the goal network. In addition, instead of a fixed predefined utility function in literature, we conduct an online learning process for the goal network so that the derivatives of the utility function can be adaptively tuned over time. We provide the control performance of both the proposed GrDHP and the traditional DHP approaches under the same environment and parameter settings. The statistical simulation results and the snapshot of the system variables are presented to demonstrate the improved learning and controlling performance. We also apply both approaches to a power system example to further demonstrate the control capabilities of the GrDHP approach.

  7. Chronic corticosterone administration facilitates aversive memory retrieval and increases GR/NOS immunoreactivity.

    PubMed

    Santos, Thays B; Céspedes, Isabel C; Viana, Milena B

    2014-07-01

    Glucocorticoids are stress hormones that mediate the organism's reaction to stress. It has been previously proposed that the facilitation of emotional aversive conditioning induced by these hormones may involve nitric oxide-pathways. The purpose of the present study was to address this question. For that, male Wistar rats were surgically implanted with slow-release corticosterone (CORT) pellets (21 days) and tested in a step-down inhibitory avoidance task. Additional groups of animals were also submitted to the same treatment conditions and on the 21st day of treatment assayed for GR (glucocorticoid receptors)-nNOS (neuronal nitric oxide synthase) immunoreactivity (GRi-nNOSi) or measurements of plasma CORT. Results showed that CORT treatment induced facilitation of step-down inhibitory avoidance. This same treatment also significantly increased CORT plasma levels and GRi in the medial, basolateral and basomedial amygdala, in the paraventricular hypothalamic nucleus (PVN), in the ventral and dorsal dentate gyrus, in the ventral CA1 region and in the dorsal CA1 and CA3 regions. Furthermore, nNOSi and GRi-nNOSi were significantly increased by CORT treatment in the medial amygdala and basolateral amygdaloid complex, in the PVN, subiculum, in the dorsal CA3 region and in the ventral CA1 and CA3 regions. These results indicate that the facilitation of aversive conditioning induced by CORT involves GR-nNOS pathways activation, what may be of relevance for a better understanding of stress-related psychiatric conditions. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Presence of S100A8/Gr1-Positive Myeloid-Derived Suppressor Cells in Primary Tumors and Visceral Organs Invaded by Breast Carcinoma Cells.

    PubMed

    Tanriover, Gamze; Eyinc, Mehmet Berk; Aliyev, Elnur; Dilmac, Sayra; Erin, Nuray

    2018-04-26

    Increased S100A8/A9 expression in Gr1-positive cells has been shown in myeloid-derived suppressor cells and may play a role in the formation of a metastatic milieu. We aimed to determine S100A8/A9 expression alone and with coexpression of Gr1 (a myeloid marker) in primary tumor and visceral tissues invaded by metastatic breast carcinoma. Female BALB/c mice were injected with 4TLM, 4THM, and 67NR orthotopically. Confluent cells (75%-80%) were used. Primary tumor, lung, liver, and spleen tissue samples were removed 26 days after injection. Peripheral blood smears and metastasis assay were performed, as was immunohistochemistry and staining. S100A8/A9 immunoreactivity alone or coexpressed with Gr1 was found in primary tumors formed by 4TLM and 4THM cells, which was markedly higher than in primary tumors formed by nonmetastatic 67NR cells. Similarly, liver and lung tissues obtained from mice injected with 4TLM or 4THM cells were invaded by S100A8/A9-positive and Gr1-positive cells. Double-positive cells were markedly fewer in liver and lung tissues of animals injected with 67NR cells. S100A8/A9-positive cells were mostly localized in red pulp of spleens. We observed an increased number of neutrophils in the peripheral blood of mice injected with metastatic breast carcinoma cells. Tumor-derived factors may increase S100A8/A9-positive cells locally and systemically, and S100A8/A9-positive cells may provide an appropriate milieu for the formation of metastasis. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Microstructural characterization of an SA508–309L/308L–316L domestic dissimilar metal welded safe-end joint

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ming, Hongliang; Zhang, Zhiming; Wang, Jianqiu, E-mail: wangjianqiu@imr.ac.cn

    2014-11-15

    The microstructure of an SA508–309L/308L–316L domestic dissimilar metal welded safe-end joint was characterized in this work by optical microscopy, scanning electron microscopy (with electron back scattering diffraction) and micro-hardness testing. Epitaxial growth and competitive growth are evident in the 308L–316L fusion boundary regions. A martensite layer, carbon-depleted zones, and type-II and type-I boundaries are found in the SA508–309L fusion boundary regions, while only martensite and austenite mixed zones are observed in the SA508–308L fusion boundary regions. The microstructure near the fusion boundary and the microstructure transition in the SA508 heat affected zone are quite complex. Both for SA508–309L/308L and 308L–316L,more » the highest residual strain is located on the outside of the weldment. The residual strain and the grain boundary character distribution change with increasing distance from the fusion boundary in the heat affected zone of 316L. Micro-hardness measurements also reveal non-uniform mechanical properties across the weldment. - Highlights: • The microstructure of SA508 HAZ, especially near the FB, is very complex. • The outside of the dissimilar metal welded joint has the highest residual. • The micro-hardness distributions along the DMWJ are non-uniform.« less

  10. Acoustic performance of a 50.8-cm (20-inch) diameter variable-pitch fan and inlet. Volume 2: Acoustic data

    NASA Technical Reports Server (NTRS)

    Bilwakesh, K. R.; Clemons, A.; Stimpert, D. L.

    1979-01-01

    Results from acoustic tests on a 50.8 cm (20 inch) QCSEE Under-the-Wing (UTW) engine, variable pitch fan and inlet simulator are tabulated. Tests were run in both forward and reverse thrust mdoes with a bellmouth inlet, five accelerating inlets (one hardwall and four treated), and four low Mach number inlets (one hardwall and three treated). The 1/3 octave-band acoustic data are presented for the model size on the measured 5.2 m (17.0 ft) arc and also data scaled to full QCSEE size 71:20 on a 152.4 m (500 ft) sideline.

  11. Computing Gröbner Bases within Linear Algebra

    NASA Astrophysics Data System (ADS)

    Suzuki, Akira

    In this paper, we present an alternative algorithm to compute Gröbner bases, which is based on computations on sparse linear algebra. Both of S-polynomial computations and monomial reductions are computed in linear algebra simultaneously in this algorithm. So it can be implemented to any computational system which can handle linear algebra. For a given ideal in a polynomial ring, it calculates a Gröbner basis along with the corresponding term order appropriately.

  12. 508 Compliance: Preparing Presentations, Excel Files, Websites, and Multimedia Products

    ERIC Educational Resources Information Center

    Regional Educational Laboratory, 2014

    2014-01-01

    PowerPoint presentations, Excel documents, Web pages, and videos posted on federal websites must meet the requirements of the 1998 amendment to Section 508 of the Rehabilitation Act. Doing so ensures that these materials are accessible to a wide range of people with disabilities, including visual, auditory, sensory, and motor impairments. These…

  13. Influence of long-time stress relief treatments on the dynamic fracture toughness properties of ASME SA508 C1 2a and ASME SA533 GR B C12 pressure vessel steels

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Logsdon, W.A.

    1982-03-01

    Dynamic fracture toughness tests were performed on materials which had been subjected to one of three long-time post weld type stress relief heat treatments: 48 hours at 1000/degree/F (538/degree/C), 24 hours at 1125/degree/F (607/degree/C), and 48 hours at 1125/degree/F (607/degree/C). Linear elastic K/sub Id/ results were obtained at low temperatures while J-integral techniques were utilized to evaluate dynamic fracture toughness over the transition and upper shelf temperature ranges. Tensile, Charpy impact, and drop weight nil-ductility transition tests as well as room temperature, air environment fatigue crack growth rate tests (SA508 Cl 2a only) were also performed. The fracture toughness ofmore » both materials exceeded the ASME specified minimum reference toughness K/sub IR/ curve. 17 refs.« less

  14. Tuning near-gap electronic structure, interface charge transfer and visible light response of hybrid doped graphene and Ag3PO4 composite: Dopant effects

    PubMed Central

    He, Chao-Ni; Huang, Wei-Qing; Xu, Liang; Yang, Yin-Cai; Zhou, Bing-Xin; Huang, Gui-Fang; Peng, P.; Liu, Wu-Ming

    2016-01-01

    The enhanced photocatalytic performance of doped graphene (GR)/semiconductor nanocomposites have recently been widely observed, but an understanding of the underlying mechanisms behind it is still out of reach. As a model system to study the dopant effects, we investigate the electronic structures and optical properties of doped GR/Ag3PO4 nanocomposites using the first-principles calculations, demonstrating that the band gap, near-gap electronic structure and interface charge transfer of the doped GR/Ag3PO4(100) composite can be tuned by the dopants. Interestingly, the doping atom and C atoms bonded to dopant become active sites for photocatalysis because they are positively or negatively charged due to the charge redistribution caused by interaction. The dopants can enhance the visible light absorption and photoinduced electron transfer. We propose that the N atom may be one of the most appropriate dopants for the GR/Ag3PO4 photocatalyst. This work can rationalize the available experimental results about N-doped GR-semiconductor composites, and enriches our understanding on the dopant effects in the doped GR-based composites for developing high-performance photocatalysts. PMID:26923338

  15. 42 CFR 422.508 - Modification or termination of contract by mutual consent.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICARE PROGRAM MEDICARE ADVANTAGE PROGRAM Application Procedures and Contracts for Medicare Advantage Organizations § 422.508 Modification or termination of contract...

  16. Probing Conformational Rescue Induced by a Chemical Corrector of F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutant*

    PubMed Central

    Yu, Wilson; Chiaw, Patrick Kim; Bear, Christine E.

    2011-01-01

    Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that cause loss of function of the CFTR channel on the apical surface of epithelial cells. The major CF-causing mutation, F508del-CFTR, is misfolded, retained in the endoplasmic reticulum, and degraded. Small molecule corrector compounds have been identified using high throughput screens, which partially rescue the trafficking defect of F508del-CFTR, allowing a fraction of the mutant protein to escape endoplasmic reticulum retention and traffic to the plasma membrane, where it exhibits partial function as a cAMP-regulated chloride channel. A subset of such corrector compounds binds directly to the mutant protein, prompting the hypothesis that they rescue the biosynthetic defect by inducing improved protein conformation. We tested this hypothesis directly by evaluating the consequences of a corrector compound on the conformation of each nucleotide binding domain (NBD) in the context of the full-length mutant protein in limited proteolytic digest studies. Interestingly, we found that VRT-325 was capable of partially restoring compactness in NBD1. However, VRT-325 had no detectable effect on the conformation of the second half of the molecule. In comparison, ablation of the di-arginine sequence, R553XR555 (F508del-KXK-CFTR), modified protease susceptibility of NBD1, NBD2, and the full-length protein. Singly, each intervention led to a partial correction of the processing defect. Together, these interventions restored processing of F508del-CFTR to near wild type. Importantly, however, a defect in NBD1 conformation persisted, as did a defect in channel activation after the combined interventions. Importantly, this defect in channel activation can be fully corrected by the addition of the potentiator, VX-770. PMID:21602569

  17. 30 CFR 77.508-1 - Lightning arresters; wires entering buildings.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Lightning arresters; wires entering buildings... OF UNDERGROUND COAL MINES Electrical Equipment-General § 77.508-1 Lightning arresters; wires entering buildings. Lightning arresters protecting exposed telephone wires entering buildings shall be provided at...

  18. 30 CFR 77.508-1 - Lightning arresters; wires entering buildings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Lightning arresters; wires entering buildings... OF UNDERGROUND COAL MINES Electrical Equipment-General § 77.508-1 Lightning arresters; wires entering buildings. Lightning arresters protecting exposed telephone wires entering buildings shall be provided at...

  19. 30 CFR 77.508-1 - Lightning arresters; wires entering buildings.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Lightning arresters; wires entering buildings... OF UNDERGROUND COAL MINES Electrical Equipment-General § 77.508-1 Lightning arresters; wires entering buildings. Lightning arresters protecting exposed telephone wires entering buildings shall be provided at...

  20. 30 CFR 77.508-1 - Lightning arresters; wires entering buildings.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Lightning arresters; wires entering buildings... OF UNDERGROUND COAL MINES Electrical Equipment-General § 77.508-1 Lightning arresters; wires entering buildings. Lightning arresters protecting exposed telephone wires entering buildings shall be provided at...

  1. 30 CFR 77.508-1 - Lightning arresters; wires entering buildings.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Lightning arresters; wires entering buildings... OF UNDERGROUND COAL MINES Electrical Equipment-General § 77.508-1 Lightning arresters; wires entering buildings. Lightning arresters protecting exposed telephone wires entering buildings shall be provided at...

  2. Continuous Cooling Transformations in Nuclear Pressure Vessel Steels

    NASA Astrophysics Data System (ADS)

    Pous-Romero, Hector; Bhadeshia, Harry K. D. H.

    2014-10-01

    A class of low-alloy steels often referred to as SA508 represent key materials for the manufacture of nuclear reactor pressure vessels. The alloys have good properties, but the scatter in properties is of prime interest in safe design. Such scatter can arise from microstructural variations but most studies conclude that large components made from such steels are, following heat treatment, fully bainitic. In the present work, we demonstrate with the help of a variety of experimental techniques that the microstructures of three SA508 Gr.3 alloys are far from homogeneous when considered in the context of the cooling rates encountered in practice. In particular, allotriomorphic ferrite that is expected to lead to a deterioration in toughness, is found in the microstructure for realistic combinations of austenite grain size and the cooling rate combination. Parameters are established to identify the domains in which SA508 Gr.3 steels transform only into the fine bainitic microstructures.

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

    PubMed

    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 < 5 µM. Eight chemical scaffolds showed synergy with 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. Copyright © 2014 by The

  4. Extending Clause Learning of SAT Solvers with Boolean Gröbner Bases

    NASA Astrophysics Data System (ADS)

    Zengler, Christoph; Küchlin, Wolfgang

    We extend clause learning as performed by most modern SAT Solvers by integrating the computation of Boolean Gröbner bases into the conflict learning process. Instead of learning only one clause per conflict, we compute and learn additional binary clauses from a Gröbner basis of the current conflict. We used the Gröbner basis engine of the logic package Redlog contained in the computer algebra system Reduce to extend the SAT solver MiniSAT with Gröbner basis learning. Our approach shows a significant reduction of conflicts and a reduction of restarts and computation time on many hard problems from the SAT 2009 competition.

  5. EDITORIAL: 19th International Conference on General Relativity and Gravitation (GR19), México, 4-9 July 2010 19th International Conference on General Relativity and Gravitation (GR19), México City, México, 4-9 July 2010

    NASA Astrophysics Data System (ADS)

    Marolf, Don; Sudarsky, Daniel

    2011-06-01

    The GR19 meeting was held in México City from 6-9 July 2010. The decision to have the meeting in México was taken during the GR18 meeting in Sydney, Australia in 2007, and represented a great milestone for the scientific community working in the fields related to gravitation in México. This fact was evidenced by the commitment of the most important institutions in México where the field is developed, by the support the meeting received at various governmental levels, and also by a promotional campaign dedicated to educate the public about our subject, which was undertaken by important segments of the gravitational physics community in Mexico. This campaign was named 'El Mes de Einstein' or 'The Einsteinian Month', and consisted of a series of presentations, talks and movies about topics related to General Relativity which culminated with the public talk of the GR19 meeting (now a traditional aspect of the GR events). This talk was given by George Smoot, Nobel laureate in physics 2006, on the amazing developments around the detailed studies of the Cosmic Microwave Background, and was held at the Nezahualc'oyotl Hall in the main campus of the National Autonomous University of México, which was filled to capacity by enthusiastic crowds of lay people fascinated with the subject. The meeting itself was a very successful one with participants from dozens of countries spanning the five continents, with a rich, varied and informative plenary program. Highlights, featured in this issue, were perhaps the talk by Veronika Hubeny on the fluid/gravity correspondence, a subject that has grown dramatically during the last few years, the lecture by Tarun Souradeep on the enormous potential for discovery offered by the ever increasing accuracy of cosmological observations, the presentation by Jeffrey McClintock, about accreting black holes and the exciting possibility of measuring their spins, the informative review about Loop Quantum Gravity from one of the pioneers of the

  6. 5'-adenosine monophosphate mediated cooling treatment enhances ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) stability in vivo.

    PubMed

    Zhang, Yueqiang; O'Brien, William G; Zhao, Zhaoyang; Lee, Cheng Chi

    2015-09-04

    Gene mutations that produce misprocessed proteins are linked to many human disorders. Interestingly, some misprocessed proteins retained their biological function when stabilized by low temperature treatment of cultured cells in vitro. Here we investigate whether low temperature treatment in vivo can rescue misfolded proteins by applying 5'-AMP mediated whole body cooling to a Cystic Fibrosis (CF) mouse model carrying a mutant cystic fibrosis transmembrane conductance regulator (CFTR) with a deletion of the phenylalanine residue in position 508 (ΔF508-CFTR). Low temperature treatment of cultured cells was previously shown to be able to alleviate the processing defect of ΔF508-CFTR, enhancing its plasma membrane localization and its function in mediating chloride ion transport. Here, we report that whole body cooling enhanced the retention of ΔF508-CFTR in intestinal epithelial cells. Functional analysis based on β-adrenergic dependent salivary secretion and post-natal mortality rate revealed a moderate but significant improvement in treated compared with untreated CF mice. Our findings demonstrate that temperature sensitive processing of mutant proteins can be responsive to low temperature treatment in vivo.

  7. 5 CFR 531.508 - Evaluation of quality step increase authority.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Evaluation of quality step increase... REGULATIONS PAY UNDER THE GENERAL SCHEDULE Quality Step Increases § 531.508 Evaluation of quality step... grant quality step increases. The agency shall take any corrective action required by the Office. [60 FR...

  8. 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.

    PubMed

    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 C18, a small

  9. The ΔF508 Mutation in the Cystic Fibrosis Transmembrane Conductance Regulator Is Associated With Progressive Insulin Resistance and Decreased Functional β-Cell Mass in Mice.

    PubMed

    Fontés, Ghislaine; Ghislain, Julien; Benterki, Isma; Zarrouki, Bader; Trudel, Dominique; Berthiaume, Yves; Poitout, Vincent

    2015-12-01

    Cystic fibrosis (CF) is the result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF-related diabetes affects 50% of adult CF patients. How CFTR deficiency predisposes to diabetes is unknown. Herein, we examined the impact of the most frequent cftr mutation in humans, deletion of phenylalanine at position 508 (ΔF508), on glucose homeostasis in mice. We compared ΔF508 mutant mice with wild-type (WT) littermates. Twelve-week-old male ΔF508 mutants had lower body weight, improved oral glucose tolerance, and a trend toward higher insulin tolerance. Glucose-induced insulin secretion was slightly diminished in ΔF508 mutant islets, due to reduced insulin content, but ΔF508 mutant islets were not more sensitive to proinflammatory cytokines than WT islets. Hyperglycemic clamps confirmed an increase in insulin sensitivity with normal β-cell function in 12- and 18-week-old ΔF508 mutants. In contrast, 24-week-old ΔF508 mutants exhibited insulin resistance and reduced β-cell function. β-Cell mass was unaffected at 11 weeks of age but was significantly lower in ΔF508 mutants versus controls at 24 weeks. This was not associated with gross pancreatic pathology. We conclude that the ΔF508 CFTR mutation does not lead to an intrinsic β-cell secretory defect but is associated with insulin resistance and a β-cell mass deficit in aging mutants. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  10. Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR.

    PubMed

    Milla, Carlos E; Ratjen, Felix; Marigowda, Gautham; Liu, Fang; Waltz, David; Rosenfeld, Margaret

    2017-04-01

    Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del-CFTR, but it has not been assessed in younger patients. In this open-label phase III trial, we evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis who were homozygous for F508del-CFTR. Patients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications. Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug-related adverse events: elevated liver transaminases, n = 1; rash, n = 1). No safety concerns were associated with spirometry. No significant changes in percent predicted FEV 1 were observed (change from baseline at Week 24, +2.5 percentage points; 95% confidence interval [CI], -0.2 to 5.2; P = 0.0671). At Week 24, significant improvements from baseline were observed in sweat chloride (-24.8 mmol/L; 95% CI, -29.1 to -20.5; P < 0.0001), body mass index z score (+0.15; 95% CI, 0.08 to 0.22; P < 0.0001), Cystic Fibrosis Questionnaire-Revised respiratory domain score (+5.4; 95% CI, 1.4 to 9.4; P = 0.0085), and lung clearance index based on lung volume turnover required to reach 2.5% of starting N 2 concentration (-0.88; 95% CI, -1.40 to -0.37; P = 0.0018). Lumacaftor/ivacaftor was well tolerated in this young population; no new safety concerns were identified. Improvements in lung clearance index, sweat chloride, nutritional status, and health-related quality of life were observed after 24 weeks of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT01897233).

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

    PubMed

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

    2017-08-01

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

  12. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial.

    PubMed

    Ratjen, Felix; Hug, Christopher; Marigowda, Gautham; Tian, Simon; Huang, Xiaohong; Stanojevic, Sanja; Milla, Carlos E; Robinson, Paul D; Waltz, David; Davies, Jane C

    2017-07-01

    visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473. Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI 2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was -1·09 units (95% CI -1·43 to -0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was -20·8 mmol/L (95% CI -23·4 to -18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV 1 from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4-4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the

  13. Single Nucleotide Variations of the Human GR Gene Manifested as Pathologic Mutations or Polymorphisms.

    PubMed

    Kino, Tomoshige

    2018-05-11

    The human genome contains numerous single nucleotide variations (SNVs), and the human GR gene harbors ∼450 of these genetic changes. Among them, extremely rare non-synonymous variants known as pathologic GR gene mutations develop a characteristic pathologic condition, familial/sporadic generalized glucocorticoid resistance syndrome, by replacing the amino acids critical for GR protein structure and functions, whereas others known as pathologic polymorphisms develop mild manifestations recognized mainly at population bases by changing the GR activities slightly. Recent progress on the structural analysis to the GR protein and subsequent computer-based structural simulation revealed details of the molecular defects caused by such pathologic GR gene mutations, including their impact on the receptor interaction to ligands, nuclear receptor coactivators (NCoAs) or DNA glucocorticoid response elements (GREs). Indeed, those found in the GR ligand-binding domain significantly damage protein structure of the ligand-binding pocket and/or the activation function-2 transactivation domain and change their molecular interaction to glucocorticoids or the LxxLL signature motif of NCoAs. Two mutations found in GR DBD also affect interaction of the mutant receptors to GRE DNA by affecting the critical amino acid for the interaction or changing local hydrophobic circumstance. In this review, we discuss recent findings on the structural simulation of the pathologic GR mutants in connection to their functional and clinical impacts along with brief explanation to recent research achievement on the GR polymorphisms.

  14. Effect of Cutting Parameters on Thrust Force and Surface Roughness in Drilling of Al-2219/B4C/Gr Metal Matrix Composites

    NASA Astrophysics Data System (ADS)

    Ravindranath, V. M.; Basavarajappa, G. S. Shiva Shankar S.; Suresh, R.

    2016-09-01

    In aluminium matrix composites, reinforcement of hard ceramic particle present inside the matrix which causes tool wear, high cutting forces and poor surface finish during machining. This paper focuses on effect of cutting parameters on thrust force, surface roughness and burr height during drilling of MMCs. In the present work, discuss the influence of spindle speed and feed rate on drilling the pure base alloy (Al-2219), mono composite (Al- 2219+8% B4C) and hybrid composite (Al-2219+8%B4C+3%Gr). The composites were fabricated using liquid metallurgy route. The drilling experiments were conducted by CNC machine with TiN coated HSS tool, M42 (Cobalt grade) and carbide tools at various spindle speeds and feed rates. The thrust force, surface roughness and burr height of the drilled hole were investigated in mono composite and hybrid composite containing graphite particles, the experimental results show that the feed rate has more influence on thrust force and surface roughness. Lesser thrust force and discontinuous chips were produced during machining of hybrid composites when compared with mono and base alloy during drilling process. It is due to solid lubricant property of graphite which reduces the lesser thrust force, burr height and lower surface roughness. When machining with Carbide tool at low feed and high speeds good surface finish was obtained compared to other two types of cutting tool materials.

  15. Quantification of sensitivity and resistance of breast cancer cell lines to anti-cancer drugs using GR metrics

    PubMed Central

    Hafner, Marc; Heiser, Laura M.; Williams, Elizabeth H.; Niepel, Mario; Wang, Nicholas J.; Korkola, James E.; Gray, Joe W.; Sorger, Peter K.

    2017-01-01

    Traditional means for scoring the effects of anti-cancer drugs on the growth and survival of cell lines is based on relative cell number in drug-treated and control samples and is seriously confounded by unequal division rates arising from natural biological variation and differences in culture conditions. This problem can be overcome by computing drug sensitivity on a per-division basis. The normalized growth rate inhibition (GR) approach yields per-division metrics for drug potency (GR50) and efficacy (GRmax) that are analogous to the more familiar IC50 and Emax values. In this work, we report GR-based, proliferation-corrected, drug sensitivity metrics for ~4,700 pairs of breast cancer cell lines and perturbagens. Such data are broadly useful in understanding the molecular basis of therapeutic response and resistance. Here, we use them to investigate the relationship between different measures of drug sensitivity and conclude that drug potency and efficacy exhibit high variation that is only weakly correlated. To facilitate further use of these data, computed GR curves and metrics can be browsed interactively at http://www.GRbrowser.org/. PMID:29112189

  16. 4,4\\'-Methylene bis(N,N\\'-dimethyl)aniline

    Integrated Risk Information System (IRIS)

    4,4 ' - Methylene bis ( N , N ' - dimethyl ) aniline ; CASRN 101 - 61 - 1 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Haz

  17. Novel Regenerative Peptide TP508 Mitigates Radiation-Induced Gastrointestinal Damage By Activating Stem Cells and Preserving Crypt Integrity

    PubMed Central

    Kantara, Carla; Moya, Stephanie M.; Houchen, Courtney W.; Umar, Shahid; Ullrich, Robert L.; Singh, Pomila; Carney, Darrell H.

    2015-01-01

    In recent years, increasing threats of radiation exposure and nuclear disasters have become a significant concern for the United States and countries worldwide. Exposure to high doses of radiation triggers a number of potentially lethal effects. Among the most severe is the gastrointestinal (GI) toxicity syndrome caused by the destruction of the intestinal barrier, resulting in bacterial translocation, systemic bacteremia, sepsis and death. The lack of effective radioprotective agents capable of mitigating radiation-induced damage has prompted a search for novel countermeasures that can mitigate the effects of radiation post-exposure, accelerate tissue repair in radiation-exposed individuals, and prevent mortality. We report that a single injection of regenerative peptide TP508 (rusalatide acetate, Chrysalin®) 24h after lethal radiation exposure (9Gy, LD100/15) appears to significantly increase survival and delay mortality by mitigating radiation-induced intestinal and colonic toxicity. TP508 treatment post-exposure prevents the disintegration of gastrointestinal crypts, stimulates the expression of adherens junction protein E-cadherin, activates crypt cell proliferation, and decreases apoptosis. TP508 post-exposure treatment also up-regulates the expression of DCLK1 and LGR5 markers of stem cells that have been shown to be responsible for maintaining and regenerating intestinal crypts. Thus, TP508 appears to mitigate the effects of GI toxicity by activating radioresistant stem cells and increasing the stemness potential of crypts to maintain and restore intestinal integrity. These results suggest that TP508 may be an effective emergency nuclear countermeasure that could be delivered within 24h post-exposure to increase survival and delay mortality, giving victims time to reach clinical sites for advanced medical treatment. PMID:26280221

  18. GR-891: a novel 5-fluorouracil acyclonucleoside prodrug for differentiation therapy in rhabdomyosarcoma cells

    PubMed Central

    Marchal, J A; Prados, J; Melguizo, C; Gómez, J A; Campos, J; Gallo, M A; Espinosa, A; Arena, N; Aránega, A

    1999-01-01

    Differentiation therapy provides an alternative treatment of cancer that overcomes the undesirable effects of classical chemotherapy, i.e. cytotoxicity and resistance to drugs. This new approach to cancer therapy focuses on the development of specific agents designed to selectively engage the process of terminal differentiation, leading to the elimination of tumorigenic cells and recovery of normal cell homeostasis. A series of new anti-cancer pyrimidine acyclonucleoside-like compounds were designed and synthesized by structural modifications of 5-fluorouracil, a drug which causes considerable cell toxicity and morbidity, and we evaluated their applicability for differentiation therapy in human rhabdomyosarcoma cells. We tested the pyrimidine derivative GR-891, (RS)-1-{[3-(2-hydroxyethoxy)-1-isopropoxy]propyl}-5-fluorouracil, an active drug which shows low toxicity in vivo and releases acrolein which is an aldehyde with anti-tumour activity. Both GR-891 and 5-fluorouracil caused time- and dose-dependent growth inhibition in vitro; however, GR-891 showed no cytotoxicity at low doses (22.5 μmol l−1 and 45 μmol l−1) and induced terminal myogenic differentiation in RD cells (a rhabdomyosarcoma cell line) treated for 6 days. Changes in morphological features and in protein organization indicated re-entry in the pathway of muscular maturation. Moreover, GR-891 increased adhesion capability mediated by the expression of fibronectin, and did not induce overexpression of P-glycoprotein, the mdr1 gene product, implicated in multidrug resistance. New acyclonucleoside-like compounds such as GR-891 have important potential advantages over 5-fluorouracil because of their lower toxicity and their ability to induce myogenic differentiation in rhabdomyosarcoma cells. Our results suggest that this drug may be useful for differentiation therapy in this type of tumour. 1999 Cancer Research Campaign PMID:10070873

  19. Lateral assembly of oxidized graphene flakes into large-scale transparent conductive thin films with a three-dimensional surfactant 4-sulfocalix[4]arene

    PubMed Central

    Sundramoorthy, Ashok K.; Wang, Yilei; Wang, Jing; Che, Jianfei; Thong, Ya Xuan; Lu, Albert Chee W.; Chan-Park, Mary B.

    2015-01-01

    Graphene is a promising candidate material for transparent conductive films because of its excellent conductivity and one-carbon-atom thickness. Graphene oxide flakes prepared by Hummers method are typically several microns in size and must be pieced together in order to create macroscopic films. We report a macro-scale thin film fabrication method which employs a three-dimensional (3-D) surfactant, 4-sulfocalix[4]arene (SCX), as a lateral aggregating agent. After electrochemical exfoliation, the partially oxidized graphene (oGr) flakes are dispersed with SCX. The SCX forms micelles, which adsorb on the oGr flakes to enhance their dispersion, also promote aggregation into large-scale thin films under vacuum filtration. A thin oGr/SCX film can be shaved off from the aggregated oGr/SCX cake by immersing the cake in water. The oGr/SCX thin-film floating on the water can be subsequently lifted from the water surface with a substrate. The reduced oGr (red-oGr) films can be as thin as 10−20 nm with a transparency of >90% and sheet resistance of 890 ± 47 kΩ/sq. This method of electrochemical exfoliation followed by SCX-assisted suspension and hydrazine reduction, avoids using large amounts of strong acid (unlike Hummers method), is relatively simple and can easily form a large scale conductive and transparent film from oGr/SCX suspension. PMID:26040436

  20. MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis

    PubMed Central

    Delano, Matthew J.; Scumpia, Philip O.; Weinstein, Jason S.; Coco, Dominique; Nagaraj, Srinivas; Kelly-Scumpia, Kindra M.; O'Malley, Kerri A.; Wynn, James L.; Antonenko, Svetlana; Al-Quran, Samer Z.; Swan, Ryan; Chung, Chun-Shiang; Atkinson, Mark A.; Ramphal, Reuben; Gabrilovich, Dmitry I.; Reeves, Wesley H.; Ayala, Alfred; Phillips, Joseph; LaFace, Drake; Heyworth, Paul G.; Clare-Salzler, Michael; Moldawer, Lyle L.

    2007-01-01

    Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1+CD11b+ population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1+ cells effectively suppress antigen-specific CD8+ T cell interferon (IFN) γ production but only modestly suppress antigen-specific and nonspecific CD4+ T cell proliferation. GR-1+ cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell–dependent and depression of Th1 cell–dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain–containing adaptor-inducing IFN-β, or the IFN-α/β receptor, is required for complete GR-1+CD11b+ expansion. GR-1+CD11b+ cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization. PMID:17548519

  1. A modified correlation between KJIC and Charpy V-notch impact energy of Chinese SA508-III steel at the upper shelf

    NASA Astrophysics Data System (ADS)

    Li, Xiangqing; Song, Yuxuan; Ding, Zhenyu; Bao, Shiyi; Gao, Zengliang

    2018-07-01

    The fracture toughness plays a significant role in the structural integrity assessment of reactor pressure vessels (RPVs) in service temperature. The Charpy V-notch (CVN) impact test is used to estimate fracture toughness (KIC or KJIC) indirectly since universal fracture toughness tests are costly, sophisticated and frequently invalid. In this study, a modified correlation which based on the typical model of KJIC-CVN at the upper shelf was established for Chinese SA508-III steel. Thereinto, the effect of test temperature (T) was directly considered in the correlation. To assess the accuracy of fracture toughness when calculating from the value of Charpy-V notch impact energy by using the modified correlation, both the Charpy-V notch impact tests and fracture toughness tests for Chinese SA508-III steel were conducted at different temperatures (100 °C, 150 °C, 200 °C, 250 °C and 320 °C). The results showed that the modified correlation exhibited the high precision for estimating fracture toughness of Chinese SA508-III steel and the relative error for tested and estimated results is within 8%, which is lower than that of other correlations.

  2. Synthesis, characterization and single crystal x-ray analysis of a complex of iron(II) bis(2,4-dimethylphenyl)dithiophosphate with 4-ethylpyridine

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kumar, Sandeep; Andotra, Savit; Kaur, Mandeep

    2016-09-15

    Complex of iron(II) bis(2,4-dimethylphenyl)dithiophosphate with 4-ethylpyridine [((2,4- (CH{sub 3}){sub 2}C{sub 6}H{sub 3}O)2PS2)2Fe(NC{sub 5}H{sub 4}(C{sub 2}H{sub 5})-4){sub 2}] is synthesized and characterized by elemental analysis, magnetic moment, IR spectroscopy and single crystal X-ray analysis. Complex crystallizes in the monoclinic sp. gr. P2{sub 1}/n, Z = 2. Crystal structure consists of mononuclear units with Fe(II) ion chelated by four S atoms of the two diphenyldithiophosphate ligands in bidentate manner. N atoms from two 4-ethylpyridine ligands are axially coordinated to the Fe(II) atom leading to an octahedral geometry.

  3. 30 CFR 285.508 - What rent payments must I pay on ROW grants or RUE grants associated with renewable energy projects?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... RUE grants associated with renewable energy projects? 285.508 Section 285.508 Mineral Resources BUREAU... RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Payments and Financial... associated with renewable energy projects? (a) For each ROW grant MMS approves under subpart C of this part...

  4. N-terminal domain of the dual-targeted pea glutathione reductase signal peptide controls organellar targeting efficiency.

    PubMed

    Rudhe, Charlotta; Clifton, Rachel; Whelan, James; Glaser, Elzbieta

    2002-12-06

    Import of nuclear-encoded proteins into mitochondria and chloroplasts is generally organelle specific and its specificity depends on the N-terminal signal peptide. Yet, a group of proteins known as dual-targeted proteins have a targeting peptide capable of leading the mature protein to both organelles. We have investigated the domain structure of the dual-targeted pea glutathione reductase (GR) signal peptide by using N-terminal truncations. A mutant of the GR precursor (pGR) starting with the second methionine residue of the targeting peptide, pGRdelta2-4, directed import into both organelles, negating the possibility that dual import was controlled by the nature of the N terminus. The deletion of the 30 N-terminal residues (pGRdelta2-30) inhibited import efficiency into chloroplasts substantially and almost completely into mitochondria, whereas the removal of only 16 N-terminal amino acid residues (pGRdelta2-16) resulted in the strongly stimulated mitochondrial import without significantly affecting chloroplast import. Furthermore, N-terminal truncations of the signal peptide (pGRdelta2-16 and pGRdelta2-30) greatly stimulated the mitochondrial processing activity measured with the isolated processing peptidase. These results suggest a domain structure for the dual-targeting peptide of pGR and the existence of domains controlling organellar import efficiency therein.

  5. Purification and characterization of thermostable alpha-galactosidase from Aspergillus terreus (GR).

    PubMed

    Shankar, S K; Dhananjay, S K; Mulimani, V H

    2009-02-01

    An extracellular thermostable alpha-galactosidase producing Aspergillus terreus (GR) strain was isolated from soil sample using guar gum as sole source of carbon. It was purified to apparent homogeneity by acetone precipitation, gel filtration followed by DEAE-Sephacel chromatographic step. The purified enzyme showed a single band after sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The molecular weight of the purified enzyme after SDS-PAGE was 108 kDa. The enzyme showed optimum pH and temperature of 5.0 and 65 degrees C, respectively, for artificial substrate pNPalphaGal. alpha-Galactosidase from A. terreus (GR) is found to be thermostable, as it was not inactivated after heating at 65 degrees C for 40 min. The K (m) for pNPalphaGal, oNPalphaGal, raffinose, and stachyose are 0.1, 0.28, 0.42, and 0.33 mM, respectively. Inhibitors such as 1,10-phenanthroline, phenylmethylsulfonyl fluoride, ethylenediaminetetraacetic acid, mercaptoethanol, and urea have no effect, whereas N-bromosuccinamide inhibited enzyme activity by 100%. Among metal ions tested, Mg(2+), Ni(2+), Ca(2+), Co(2+), and Mn(2+) had no effect on enzyme activity, but Ag(+), Hg(2+), and Cu(2+) have inhibited complete activity.

  6. Crystal Structure of Two V-shaped Ligands with N-Heterocycles

    NASA Astrophysics Data System (ADS)

    Wang, Gao-Feng; Sun, Shu-Wen; Zhang, Xiao; Sun, Shu-Gang

    2017-12-01

    Two V-shaped ligands with N-heterocycles, bis(4-(1 H-imidazol-1-yl) phenyl)methanone ( 1), and bis(4-(1 H-benzo[d]imidazol-1-yl)phenyl)methanone ( 2) have been synthesized and characterized by elemental analyses, IR and 1 H NMR spectroscopy. Crystal structures of 1 and 2 have been determined by X-ray diffraction. The crystal of 1 is monoclinic, sp. gr. P21/ c, Z = 4. The crystal of 2 is orthorhombic, sp. gr. Fdd2, Z = 8. X-ray diffraction analyses show that the V-shaped angles of 1 and 2 are 122.72(15)° and 120.7(4)°, respectively. Intermolecular C-H···O, C-H···N, C-H···π, and π···π interactions link the components into three-dimensional networks in the crystal structures.

  7. Using SA508/533 for the HTGR Vessel Material

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Larry Demick

    2012-06-01

    This paper examines the influence of High Temperature Gas-cooled Reactor (HTGR) module power rating and normal operating temperatures on the use of SA508/533 material for the HTGR vessel system with emphasis on the calculated times at elevated temperatures approaching or exceeding ASME Code Service Limits (Levels B&C) to which the reactor pressure vessel could be exposed during postulated pressurized and depressurized conduction cooldown events over its design lifetime.

  8. 24 CFR 3280.508 - Heat loss, heat gain and cooling load calculations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Thermal Protection § 3280.508 Heat loss, heat gain and cooling load calculations. (a) Information, values... Loads—Manufactured Homes—February 1992-PNL 8006, HUD User No. 0005945. (c) Areas where the insulation... 24 Housing and Urban Development 5 2013-04-01 2013-04-01 false Heat loss, heat gain and cooling...

  9. 24 CFR 3280.508 - Heat loss, heat gain and cooling load calculations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Thermal Protection § 3280.508 Heat loss, heat gain and cooling load calculations. (a) Information, values... Loads—Manufactured Homes—February 1992-PNL 8006, HUD User No. 0005945. (c) Areas where the insulation... 24 Housing and Urban Development 5 2010-04-01 2010-04-01 false Heat loss, heat gain and cooling...

  10. 24 CFR 3280.508 - Heat loss, heat gain and cooling load calculations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Thermal Protection § 3280.508 Heat loss, heat gain and cooling load calculations. (a) Information, values... Loads—Manufactured Homes—February 1992-PNL 8006, HUD User No. 0005945. (c) Areas where the insulation... 24 Housing and Urban Development 5 2011-04-01 2011-04-01 false Heat loss, heat gain and cooling...

  11. 24 CFR 3280.508 - Heat loss, heat gain and cooling load calculations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Thermal Protection § 3280.508 Heat loss, heat gain and cooling load calculations. (a) Information, values... Loads—Manufactured Homes—February 1992-PNL 8006, HUD User No. 0005945. (c) Areas where the insulation... 24 Housing and Urban Development 5 2012-04-01 2012-04-01 false Heat loss, heat gain and cooling...

  12. 24 CFR 3280.508 - Heat loss, heat gain and cooling load calculations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Thermal Protection § 3280.508 Heat loss, heat gain and cooling load calculations. (a) Information, values... Loads—Manufactured Homes—February 1992-PNL 8006, HUD User No. 0005945. (c) Areas where the insulation... 24 Housing and Urban Development 5 2014-04-01 2014-04-01 false Heat loss, heat gain and cooling...

  13. Purification and characterization of endo-beta-1,4 mannanase from Aspergillus niger gr for application in food processing industry.

    PubMed

    Naganagouda, K; Salimath, P V; Mulimani, V H

    2009-10-01

    A thermostable extracellular beta-mannanase from the culture supernatant of a fungus Aspergillus niger gr was purified to homogeneity. SDS-PAGE of the purified enzyme showed a single protein band of molecular mass 66 kDa. The beta- mannanase exhibited optimum catalytic activity at pH 5.5 and 55 degrees C. It was thermostable at 55 degrees C, and retained 50% activity after 6 h at 55 degrees C. The enzyme was stable at a pH range of 3.0 to 7.0. The metal ions Hg(2+), Cu(2+), and Ag(2+) inhibited complete enzyme activity. The inhibitors tested, EDTA, PMSF, and 1,10-phenanthroline, did not inhibit the enzyme activity. N-Bromosuccinimide completely inhibited enzyme activity. The relative substrate specificity of enzyme towards the various mannans is in the order of locust bean gum>guar gum>copra mannan, with K(m) of 0.11, 0.28, and 0.33 mg/ml, respectively. Since the enzyme is active over a wide range of pH and temperature, it could find potential use in the food-processing industry.

  14. Cirrhosis could be associated with severe mutations of the cystic fibrosis gene

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lenaerts, C.; Piussan, C.; Soto, B.

    1994-09-01

    Previous studies failed to demonstrate a genetic predisposition to liver disease in cystic fibrosis. In order to characterize patients with cirrhosis defined on the basis of either hepatosplenomegaly, portal hypertension or liver biopsy, we analyzed a total number of 110 cirrhotic CF patients from different CF centers in France. Of them, 71 are males, which is not different from the overall CF french population. All but 2 are pancreatic insufficient. A history of meconium ileus {plus_minus} meconium ileus equivalent seems to be a risk factor for cirrhosis since these complications are present in 29% of the cirrhotic patients vs. 19%more » in the non-cirrhotic population (p = 0.03). This confirms our previous data in a postmortem study. Genotype analysis was performed in all the patients. {Delta}F508 represents 70% of the identified mutations with a higher proportion of {Delta}F508 +/+ in the cirrhotic than in the non-cirrhotic population (52% vs. 42%, p=0.003), 35% {Delta}F508 +/- vs. 42% and 13% {Delta}F508 -/- vs. 16%. Sixty percent of the other mutations associated with cirrhosis are identified, usually in {Delta}F508 +/- and include 1303 N-K, 542 G-X, 1078 del T, 1282 W-X, 1313 Q-X, 827 E-X, 1061 G-R, 1301 N-H, 14 K-X, 1717-1 G-A, 1918 delGC, 2183 A-G, 2184 delA, 405+1 G-A, 507 {Delta}l, 574 delA, 621+1 G-T, 85 G-E and 1303 N-K/other, 227 L-R/other. None of the cirrhotic patients bear one of the dominant missense mutations regarded as mild with respect to pancreatic function (117 R-H, 334 R-W, 347 R-P, 455 A-E, 574 P-H) or both the {Delta}F508 and the 5512 G-A mutations associated with a decreased risk of meconium ileus. Cirrhosis could thus be linked to the presence of 2 of the severe mutations of the CF gene associated with pancreatic insufficiency.« less

  15. Bacillus amyloliquefaciens subsp. plantarum GR53, a potent biocontrol agent resists Rhizoctonia disease on Chinese cabbage through hormonal and antioxidants regulation.

    PubMed

    Kang, Sang-Mo; Radhakrishnan, Ramalingam; Lee, In-Jung

    2015-10-01

    The fungus Rhizoctonia solani is one of the causal agents of numerous diseases that affect crop growth and yield. The aim of this present investigation was to identify a biocontrol agent that acts against R. solani and to determine the agent's protective effect through phytohormones and antioxidant regulation in experimentally infected Chinese cabbage plants. Four rhizospheric soil bacterial isolates GR53, GR169, GR786, and GR320 were tested for their antagonistic activity against R. solani. Among these isolates, GR53 significantly suppressed fungal growth. GR53 was identified as Bacillus amyloliquefaciens subsp. plantarum by phylogenetic analysis of the 16S rDNA sequence. The biocontrol activity of B. amyloliquefaciens subsp. plantarum GR53 was tested in Chinese cabbage plants under controlled conditions. Results showed that R. solani inhibited plant growth (length, width, fresh and dry weight of leaves) by reducing chlorophyll and total phenolic content, as well as by increasing the levels of salicylic acid, jasmonic acid, abscisic acid, and DPPH scavenging activity. By regulating the levels of these compounds, the co-inoculation of B. amyloliquefaciens subsp. plantarum GR53 heightened induced systemic resistance in infected Chinese cabbage, effectively mitigating R. solani-induced damaging effects and improving plant growth. The results obtained from this study suggest that B. amyloliquefaciens subsp. plantarum GR53 is an effective biocontrol agent to prevent the damage caused by R. solani in Chinese cabbage plants.

  16. Synthesis, structure, and properties of nickel complexes with nitrilotris(methylenephosphonic acid) [Ni(H{sub 2}O)3N(CH2PO{sub 3}H){sub 3}] and Na{sub 4}[Ni(H{sub 2}O)N(CH{sub 2}PO{sub 3}){sub 3}] ∙ 11H{sub 2}O

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Somov, N. V., E-mail: somov@phys.unn.ru; Chausov, F. F., E-mail: chaus@yandex.ru; Zakirova, R. M.

    2016-03-15

    Nitrilotris(methylenephosphonato)triaquanickel and tetrasodium nitrilotris(methylenephosphonato) aquanickelate undecahydrate were synthesized and characterized. The crystal of [Ni(H{sub 2}O){sub 3}N(CH{sub 2}PO{sub 3}H){sub 3}] is composed of linear coordination polymers and belongs to sp. gr. P2{sub 1}/c, Z = 4, a = 9.17120(10) Å, b = 16.05700(10) Å, c = 9.70890(10) Å, β = 115.830(2)°. The Ni atom is in an octahedral coordination formed by two oxygen atoms of one phosphonate ligand, one oxygen atom of another ligand molecule, and three water molecules in a meridional configuration. The crystal of Na{sub 4}[Ni(H{sub 2}O)N(CH{sub 2}PO{sub 3}){sub 3}] ∙ 11H{sub 2}O has an island dimeric chelate structuremore » and belongs to sp. gr. C2/c, Z = 8, a = 18.7152(2) Å, b = 12.05510(10) Å, c = 21.1266(2) Å, β = 104.4960(10)°. The Ni atom has a slightly distorted octahedral coordination involving one nitrogen atom and closes three five-membered N–C–P–O–Ni rings sharing the Ni–N bond.« less

  17. Draft genome sequence of a multidrug-resistant Aeromonas hydrophila ST508 strain carrying rmtD and blaCTX-M-131 isolated from a bloodstream infection.

    PubMed

    Moura, Quézia; Fernandes, Miriam R; Cerdeira, Louise; Santos, Ana Carolina M; de Souza, Tiago A; Ienne, Susan; Pignatari, Antonio Carlos C; Gales, Ana C; Silva, Rosa M; Lincopan, Nilton

    2017-09-01

    Here we report the draft genome sequence of a multidrug-resistant (MDR) Aeromonas hydrophila strain belonging to sequence type 508 (ST508) isolated from a human bloodstream infection. Assembly and annotation of this draft genome resulted in 5028498bp and revealed the presence of 16S rRNA methylase rmtD and bla CTX-M-131 genes encoding high-level resistance to aminoglycosides and cephalosporins, respectively, as well as multiple virulence genes. This draft genome can provide significant information for understanding mechanisms on the establishment and treatment of infections caused by this pathogen. Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

  18. Some Applications of Gröbner Bases in Robotics and Engineering

    NASA Astrophysics Data System (ADS)

    Abłamowicz, Rafał

    Gröbner bases in polynomial rings have numerous applications in geometry, applied mathematics, and engineering. We show a few applications of Gröbner bases in robotics, formulated in the language of Clifford algebras, and in engineering to the theory of curves, including Fermat and Bézier cubics, and interpolation functions used in finite element theory.

  19. CD11b+ Gr1+ Bone Marrow Cells Ameliorate Liver Fibrosis by Producing Interleukin-10 in Mice

    PubMed Central

    Suh, Yang-Gun; Kim, Ja Kyung; Byun, Jin-Seok; Yi, Hyon-Seung; Lee, Young-Sun; Eun, Hyuk Soo; Kim, So Yeon; Han, Kwang-Hyub; Lee, Kwan Sik; Duester, Gregg; Friedman, Scott L.; Jeong, Won-Il

    2012-01-01

    Clinical trials and animal models suggest that infusion of bone marrow cells (BMC) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMC. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMC showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMC and activated hepatic stellate cells (HSCs) was investigated using in vitro co-culturing system. Within 24 hours, infused BMC were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10−/−) BMC failed to reproduce these effects in the fibrotic livers. Intriguingly, in isolated cells, CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ BMC expressed more IL-10 after co-culturing with activated HSCs, leading to suppressed expression of collagen and α-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMC were co-cultured with IL-6−/− and retinaldehyde dehydrogenase 1−/− HSCs. Similar to murine data, human BMC expressed more IL-10 after co-culturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. Conclusion Activated HSCs increase IL-10 expression in BMC (CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis. PMID:22544759

  20. Constitutive neuropeptide Y Y4 receptor expression in human colonic adenocarcinoma cell lines

    PubMed Central

    Cox, Helen M; Tough, Iain R; Zandvliet, Dorothea W J; Holliday, Nicholas D

    2001-01-01

    Three human adenocarcinoma cell lines, Colony-24 (Col-24), Col-6 and Col-1 have been studied as confluent epithelial layers able to transport ions vectorially in response to basolateral vasoactive intestinal polypeptide (VIP) and pancreatic polypeptides (PP). Different species PP stimulated responses in Col-24 with Y4-like pharmacology. Bovine (b)PP, human (h)PP and porcine (p)PP were equipotent (EC50 values 3.0 – 5.0 nM) while rat (r)PP, avian (a)PP and [Leu31, Pro34]PYY (Pro34PYY) were significantly less potent. PYY was inactive. The PP pharmacology in Col-1 was comparable with Col-24. However, Col-6 cells were different; pPP had an EC50 intermediate (22.0 nM) between that of bPP (3.0 nM) and hPP (173.2 nM), with aPP and rPP being at least a further fold less potent. Deamidation of Tyr36 in bPP (by O-methylation or hydroxylation) or removal of the residue resulted in significant loss of activity in Col-24. GR231118 (1 μM) had no PP-like effects. In Col-24 and Col-1, GR231118 significantly attenuated bPP (30 nM) or hPP (100 nM) responses, but it did not alter bPP responses in Col-6. BIBP3226 and GR231118 both inhibited Y1-mediated responses which were only present in Col-6. RT – PCR analysis confirmed the presence of hY4 receptor mRNA in Col-24 and Col-1 epithelia but a barely visible hY4 product was observed in Col-6 and we suggest that an atypical Y4 receptor is expressed in this cell line. PMID:11156595

  1. A topological extension of GR: Black holes induce dark energy

    NASA Astrophysics Data System (ADS)

    Spaans, M.

    2013-02-01

    A topological extension of general relativity is presented. The superposition principle of quantum mechanics, as formulated by the Feynman path integral, is taken as a starting point. It is argued that the trajectories that enter this path integral are distinct and thus that space-time topology is multiply connected. Specifically, space-time at the Planck scale consists of a lattice of three-tori that facilitates many distinct paths for particles to travel along. To add gravity, mini black holes are attached to this lattice. These mini black holes represent Wheeler's quantum foam and result from the fact that GR is not conformally invariant. The number of such mini black holes in any time-slice through four-space is found to be equal to the number of macroscopic (so long-lived) black holes in the entire universe. This connection, by which macroscopic black holes induce mini black holes, is a topological expression of Mach's principle. The proposed topological extension of GR can be tested because, if correct, the dark energy density of the universe should be proportional the total number of macroscopic black holes in the universe at any time. This prediction, although strange, agrees with current astrophysical observations.

  2. The Grid Analysis and Display System (GrADS)

    NASA Technical Reports Server (NTRS)

    Kinter, James L., III

    1994-01-01

    During the period 1 September 1993 - 31 August 1994, further development of the Grid Analysis and Display System (GrADS) was conducted at the Center for Ocean-Land-Atmosphere Studies (COLA) of the Institute of Global Environment and Society, Inc. (IGES) under subcontract 5555-31 from the University Space Research Association (USRA) administered by The Center of Excellence in Space Data and Information Sciences (CESDIS). This final report documents progress made under this subcontract and provides directions on how to access the software and documentation developed therein. A short description of GrADS is provided followed by summary of progress completed and a summary of the distribution of the software to date and the establishment of research collaborations.

  3. Fatigue and fracture mechanical behavior for Chinese A508-3 steel at room temperature

    NASA Astrophysics Data System (ADS)

    Shi, K. K.; Xie, H.; Zheng, B.; Fu, X. L.

    2018-06-01

    Material, A508-3 steel, has been used in nuclear reactor vessels. In the present study, fatigue and fracture mechanical behavior of Chinese A5083 steel at room temperature are studied by mechanical material testing machine (MTS). Test data of material’s mechanical behavior including uniaxial tension, low cycle fatigue (LCF), threshold value of stress intensity factor (SIF) range, fatigue crack growth (FCG), and fracture toughness is generated and given for further study. It is worth noting that the model in predicting FCG of material from LCF parameters is verified and discussed.

  4. 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.

    PubMed

    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. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. 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*

    PubMed Central

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

    2015-01-01

    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. PMID:26060255

  6. Role of N-linked oligosaccharides in the biosynthetic processing of the cystic fibrosis membrane conductance regulator

    PubMed Central

    Chang, Xiu-bao; Mengos, April; Hou, Yue-xian; Cui, Liying; Jensen, Timothy J.; Aleksandrov, Andrei; Riordan, John R.; Gentzsch, Martina

    2009-01-01

    Summary The epithelial chloride channel CFTR is a glycoprotein that is modified by two N-linked oligosaccharides. The most common mutant CFTR protein in patients with cystic fibrosis, ΔF508, is misfolded and retained by ER quality control. As oligosaccharide moieties of glycoproteins are known to mediate interactions with ER lectin chaperones, we investigated the role of N-linked glycosylation in the processing of wild-type and ΔF508 CFTR. We found that N-glycosylation and ER lectin interactions are not major determinants of trafficking of wild-type and ΔF508 from the ER to the plasma membrane. Unglycosylated CFTR, generated by removal of glycosylation sites or treatment of cells with the N-glycosylation inhibitor tunicamycin, did not bind calnexin, but did traffic to the cell surface and exhibited chloride channel activity. Most importantly, unglycosylated Δ F508 CFTR still could not escape quality control in the early secretory pathway and remained associated with the ER. However, the absence of N-linked oligosaccharides did reduce the stability of wild-type CFTR, causing significantly more-rapid turnover in post-ER compartments. Surprisingly, the individual N-linked carbohydrates do not play equivalent roles and modulate the fate of the wild-type protein in different ways in its early biosynthetic pathway. PMID:18682497

  7. Role of N-linked oligosaccharides in the biosynthetic processing of the cystic fibrosis membrane conductance regulator.

    PubMed

    Chang, Xiu-Bao; Mengos, April; Hou, Yue-Xian; Cui, Liying; Jensen, Timothy J; Aleksandrov, Andrei; Riordan, John R; Gentzsch, Martina

    2008-09-01

    The epithelial chloride channel CFTR is a glycoprotein that is modified by two N-linked oligosaccharides. The most common mutant CFTR protein in patients with cystic fibrosis, DeltaF508, is misfolded and retained by ER quality control. As oligosaccharide moieties of glycoproteins are known to mediate interactions with ER lectin chaperones, we investigated the role of N-linked glycosylation in the processing of wild-type and DeltaF508 CFTR. We found that N-glycosylation and ER lectin interactions are not major determinants of trafficking of wild-type and DeltaF508 from the ER to the plasma membrane. Unglycosylated CFTR, generated by removal of glycosylation sites or treatment of cells with the N-glycosylation inhibitor tunicamycin, did not bind calnexin, but did traffic to the cell surface and exhibited chloride channel activity. Most importantly, unglycosylated DeltaF508 CFTR still could not escape quality control in the early secretory pathway and remained associated with the ER. However, the absence of N-linked oligosaccharides did reduce the stability of wild-type CFTR, causing significantly more-rapid turnover in post-ER compartments. Surprisingly, the individual N-linked carbohydrates do not play equivalent roles and modulate the fate of the wild-type protein in different ways in its early biosynthetic pathway.

  8. GR712RC- Dual-Core Processor- Product Status

    NASA Astrophysics Data System (ADS)

    Sturesson, Fredrik; Habinc, Sandi; Gaisler, Jiri

    2012-08-01

    The GR712RC System-on-Chip (SoC) is a dual core LEON3FT system suitable for advanced high reliability space avionics. Fault tolerance features from Aeroflex Gaisler’s GRLIB IP library and an implementation using Ramon Chips RadSafe cell library enables superior radiation hardness.The GR712RC device has been designed to provide high processing power by including two LEON3FT 32- bit SPARC V8 processors, each with its own high- performance IEEE754 compliant floating-point-unit and SPARC reference memory management unit.This high processing power is combined with a large number of serial interfaces, ranging from high-speed links for data transfers to low-speed control buses for commanding and status acquisition.

  9. Ghrelin accelerates wound healing through GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways in combined radiation and burn injury in rats.

    PubMed

    Liu, Cong; Huang, Jiawei; Li, Hong; Yang, Zhangyou; Zeng, Yiping; Liu, Jing; Hao, Yuhui; Li, Rong

    2016-06-07

    The therapeutic effect of ghrelin on wound healing was assessed using a rat model of combined radiation and burn injury (CRBI). Rat ghrelin, anti-rat tumor necrosis factor (TNF) α polyclonal antibody (PcAb), or selective antagonists of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and growth hormone secretagogue receptor (GHS-R) 1a (SB203580, SP600125, and [D-Lys3]-GHRP-6, respectively), were administered for seven consecutive days. Levels of various signaling molecules were assessed in isolated rat peritoneal macrophages. The results showed that serum ghrelin levels and levels of macrophage glucocorticoid receptor (GR) decreased, while phosphorylation of p38MAPK, JNK, and p65 nuclear factor (NF) κB increased. Ghrelin inhibited the serum induction of proinflammatory mediators, especially TNF-α, and promoted wound healing in a dose-dependent manner. Ghrelin treatment decreased phosphorylation of p38MAPK, JNK, and p65NF-κB, and increased GR levels in the presence of GHS-R1a. SB203580 or co-administration of SB203580 and SP600125 decreased TNF-α level, which may have contributed to the inactivation of p65NF-κB and increase in GR expression, as confirmed by western blotting. In conclusion, ghrelin enhances wound recovery in CRBI rats, possibly by decreasing the induction of TNF-α or other proinflammatory mediators that are involved in the regulation of GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways.

  10. The C.A.M.S. 54 G.R. transatlantic seaplane (French)

    NASA Technical Reports Server (NTRS)

    Ide, John Jay

    1928-01-01

    Tested at the end of March, 1928, the C.A.M.S. 54 G.R. was built for the purpose of crossing the Atlantic from Europe by way of the azores. It has a biplane construction with wings mounted above the hull. It is powered by two new series 500 HP. geared Hispano Suiza V type engines.

  11. Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1

    PubMed Central

    Catena, Raúl; Bhattacharya, Nandita; Rayes, Tina El; Wang, Suming; Choi, Hyejin; Gao, Dingcheng; Ryu, Seongho; Joshi, Natasha; Bielenberg, Diane; Lee, Sharrell B.; Haukaas, Svein A.; Gravdal, Karsten; Halvorsen, Ole J.; Akslen, Lars A.; Watnick, Randolph S.; Mittal, Vivek

    2013-01-01

    Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow (BM)- derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations the otherwise pro-metastatic Gr1+ myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. (BM)-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by BM transplant from Tsp-1+ donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacological inducer of Tsp-1 in Gr1+ BM cells, which dramatically suppresses metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1+ myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1+ cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. PMID:23633432

  12. 76 FR 61376 - NIMS Public Works Resources: Typed Resource Definitions (FEMA 508-7)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-04

    ...] NIMS Public Works Resources: Typed Resource Definitions (FEMA 508-7) AGENCY: Federal Emergency... Management Agency (FEMA) is requesting public comments on the NIMS Public Works Resources: Typed Resource..., nongovernmental organizations, and the private sector to work together to prevent, protect against, respond to...

  13. 40 CFR 721.1085 - Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Benzenamine,4,4â²-methylenebis[N-ethyl-N-methyl-. 721.1085 Section 721.1085 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1085 Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-. (a) Chemical...

  14. 40 CFR 721.1085 - Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Benzenamine,4,4â²-methylenebis[N-ethyl-N-methyl-. 721.1085 Section 721.1085 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1085 Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-. (a) Chemical...

  15. NRIP enhances HPV gene expression via interaction with either GR or E2

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chang, Szu-Wei; Lu, Pei-Yu; Guo, Jih-Huong

    We previously identified a gene, nuclear receptor-interaction protein (NRIP), which functions as a transcription cofactor in glucocorticoid receptor (GR) and human papillomavirus E2 (HPV E2)-driven gene expression. Here, we comprehensively evaluated the role of NRIP in HPV-16 gene expression. NRIP acts as a transcription cofactor to enhance GR-regulated HPV-16 gene expression in the presence of hormone. NRIP also can form complex with E2 that caused NRIP-induced HPV gene expression via E2-binding sites in a hormone-independent manner. Furthermore, NRIP can associate with GR and E2 to form tri-protein complex to activate HPV gene expression via GRE, not the E2-binding site, inmore » a hormone-dependent manner. These results indicate that NRIP and GR are viral E2-binding proteins and that NRIP regulates HPV gene expression via GRE and/or E2 binding site in the HPV promoter in a hormone-dependent or independent manner, respectively.« less

  16. A Convenient, TiCl4/SnCl4-Mediated Synthesis of N-Phenyl or N-Aryl Benzamidines and N-Phenylpicolinamidines

    PubMed Central

    Patil, Umesh D.; Mahulikar, Pramod P.

    2012-01-01

    A new, TiCl4-or SnCl4-mediated, solvent-free method was developed for the synthesis of N-Aryl benzamidines and N-phenylpicolinamidines, in moderate-to-good yield, using suitable amines and nitriles as starting materials. PMID:24052858

  17. Biomass Burning and the 2012 Greenland Ice Sheet (GrIS) melt

    NASA Astrophysics Data System (ADS)

    Choi, H. D.; Soja, A. J.; Polashenski, C.; Fairlie, T. D.; Winker, D. M.; Trepte, C. R.

    2017-12-01

    This study is the part of the Sunlight Absorption on the Greenland ice sheet Experiment (SAGE) project investigating the impact of light absorbing impurities (e.g., aerosols) on the Greenland Ice Sheet (GrIS). Satellite observations, [e.g. Oceansat-2 (OS2) and the Moderate-resolution Imaging Spectroradionmeter (MODIS)] discovered an unusually large melt event in July 2012. NASA sensors showed that nearly 98.6% of the GrIS experienced melting at or near surface [Nghiem et al., 2012]. In this study, we question the extent to which biomass burning derived aerosols enhanced melting across the GrIS. Random points [59 total, 13 coincident with snow pit sites and 46 gridded] are selected across the entire extent of the GrIS from April 1st to August 31st 2012, and then the NASA Langley Trajectory Model (LaTM) is used to simulate the transport of potentially smoke-filled air parcels backwards for 5 days form these points, evaluation the back trajectory for coincidence with active fire detections. The trajectory model is initialized for 24-hour sustained injection from each site, and air parcels are released from the surface to 2 km at 200m intervals. With the trajectory model outputs, we are able to identify trajectories that have coincidences with fires. We focus on events in April through July when the GrIS albedo was dramatically decreased. We also utilize Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) data to verify smoke-aerosol signatures in boreal regions based on the NASA LaTM results. The results of this study will help us better understand the transport of biomass burning plumes and black carbon deposition that could lead to enhanced GrIS melting.

  18. Bottom-up substitution assembly of AuF4-n0,-+nPO3 (n = 1-4): a theoretical study of novel oxyfluoride hyperhalogen molecules and anions AuF4-n(PO3)n0,-

    NASA Astrophysics Data System (ADS)

    Yang, Yi-fan; Cui, Zhong-hua; Ding, Yi-hong

    2014-06-01

    Compounds with high electron affinity, i.e. superhalogens, have continued to attract chemists' attention, due to their potential importance in fundamental chemistry and materials science. It has now proven very effective to build up novel superhalogens with multi-positively charged centres, which are usually called 'hyperhalogens'. Herein, using AuF4- and PO3 as the model building blocks, we made the first attempt to design the Au,P-based hyperhalogen anions AuF4-n(PO3)n- (n = 1-4) at the B3LYP/6-311+G(d)&SDD and CCSD(T)/6-311+G(d)&SDD (single-point) levels (6-311+G(d) for O, F, P and SDD for Au). Notably, for all the considered Au,P systems, the ground state bears a dioxo-bonded structure with n ≤ 3, which is significantly more stable than the usually presumed mono-oxo-bonded one. Moreover, the clustering of the -PO3 moieties becomes energetically favoured for n ≥ 3. The ground states of AuP4O120,- are the first reported cage-like oxide hyperhalogens. Thus, the -PO3 moiety cannot be retained during the 'bottom-up' assembly. The vertical detachment energy (VDE) value of the most stable AuF4-n(PO3)n- (n = 1-4) ranges from 7.16 to 8.20 eV, higher than the VDE values of the corresponding building blocks AuF4- (7.08 eV) and PO3- (4.69 eV). The adiabatic detachment energy values of these four hyperhalogens exceed 6.00 eV. Possible generation routes for AuF4-n(PO3)n- (n = 1-4) were discussed. The presently designed oxyfluorides not only enriches the family of hyperhalogens, but also demonstrates the great importance of considering the structural transformation during the superhalogen → hyperhalogen design such as for the present Au-P based systems.

  19. Interface bonding of SA508-3 steel under deformation and high temperature diffusion

    NASA Astrophysics Data System (ADS)

    Xu, Bin; Shao, Chunjuan; Sun, Mingyue

    2018-05-01

    There are mainly two parameters affecting high temperature interface bonding: deformation and diffusion. To study these two parameters, interface bonding of SA508-3 bainitic steel at 1100°C are simulated by gleeble3500 thermal simulator. The results show that interface of SA508-3 steel can be bonded under deformation and high temperature. For a specimen pressed at 1100°C without further high temperature diffusion, a reduction ratio of 30% can make the interface begun to bond, but the interface is still part of the grain boundary and small grains exist near the interface. When reduction ratio reaches 50%, the interface can be completely bonded and the microstructure near the interface is the same as that of the base material. When deformation is small, long time diffusion can also help the interface bonding. The results show that when the diffusion time is long enough, the interface under small deformation can also be bonded. For a specimen holding for 24h at 1100°C, only 13% reduction ratio is enough for interface bonding.

  20. CFTR DeltaF508 mutation detection from dried blood samples in the first trimester of pregnancy: a possible routine prenatal screening strategy for cystic fibrosis?

    PubMed

    Konialis, Christopher P; Hagnefelt, Birgitta; Kazamia, Constantina; Karapanou, Sophia; Pangalos, Constantinos

    2007-01-01

    The implementation and evaluation of a proposed wide-scale prenatal screening strategy, based on DNA isolated from dried blood spots in the first trimester of pregnancy, for the early detection of pregnancies at risk for cystic fibrosis (CF). The screening was performed in conjunction with routine biochemical marker screening for Down's syndrome risk in the first trimester of pregnancy. DNA was isolated from 1,233 dried blood spots and analyzed for the presence of the CF transmembrane regulator DeltaF508 mutation. Women carriers were offered and accepted the option for additional full testing of their partners in order to assess the risk for the fetus. All 1,233 samples were successfully analyzed, identifying 23 DeltaF508 carriers, corresponding to a DeltaF508 carrier rate of approximately 1/55 (1.8%). All partners of the women carriers were further tested without revealing any need for further prenatal testing in this group. This study reveals the relatively high frequency of the DeltaF508 CF mutation in the Greek population. More importantly, we demonstrate that the proposed prenatal screening strategy, based on the ease and cost-effectiveness of the analysis for the detection of a single common mutation, can be considered as a feasible and practical approach for wide-scale prenatal screening for CF, following the sequential model. It is applied early on in pregnancy, allowing for the timely management of families at risk for the corresponding genetic disorders. Finally, it can easily be extended to include screening for other common genetic disorders in specific population groups.

  1. Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD.

    PubMed

    Sabbagh, Jonathan J; Cordova, Ricardo A; Zheng, Dali; Criado-Marrero, Marangelie; Lemus, Andrea; Li, Pengfei; Baker, Jeremy D; Nordhues, Bryce A; Darling, April L; Martinez-Licha, Carlos; Rutz, Daniel A; Patel, Shreya; Buchner, Johannes; Leahy, James W; Koren, John; Dickey, Chad A; Blair, Laura J

    2018-06-19

    Genetic and epigenetic alterations in FK506-binding protein 5 ( FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression.

  2. Mathematical Modeling of High-Temperature Constitutive Equations and Hot Processing Maps for As-Cast SA508-3 Steel

    NASA Astrophysics Data System (ADS)

    Sui, Dashan; Wang, Tao; Zhu, Lingling; Gao, Liang; Cui, Zhenshan

    2016-11-01

    The hot deformation behavior and hot workability characteristics of as-cast SA508-3 steel were studied by modeling the constitutive equations and developing hot processing maps. The isothermal compression experiments were carried out at temperatures of 950°C, 1050°C, 1150°C, and 1250°C and strain rates of 0.001 s-1, 0.01 s-1, 0.1 s-1, and 1 s-1 respectively. The two-stage flow stress models were established through the classical theories on work hardening and softening, and the solution of activation energy for hot deformation was 355.0 kJ mol-1 K-1. Based on the dynamic material model, the power dissipation and instability maps were developed separately at strains of 0.2, 0.4, 0.6 and 0.8. The power dissipation rate increases with both the increase of temperature and the decrease of strain rate, and the instable region mainly appears on the conditions of low temperature and high strain rate. The optimal hot working parameters for as-cast SA508-3 steel are 1050-1200°C/0.001-0.1 s-1, with about 25-40% peak efficiency of power dissipation.

  3. Iceland's Grímsvötn volcano erupts

    NASA Astrophysics Data System (ADS)

    Showstack, Randy

    2011-05-01

    About 13 months after Iceland's Eyjafjallajökull volcano began erupting on 14 April 2010, which led to extensive air traffic closures over Europe, Grímsvötn volcano in southeastern took its turn. Iceland's most active volcano, which last erupted in 2004 and lies largely beneath the Vatnajökull ice cap, began its eruption activity on 21 May, with the ash plume initially reaching about 20 kilometers in altitude, according to the Icelandic Meteorological Office. Volcanic ash from Grímsvötn has cancelled hundreds of airplane flights and prompted U.S. president Barack Obama to cut short his visit to Ireland. As Eos went to press, activity at the volcano was beginning to subside.

  4. 77 FR 40511 - Safety Zone; GR Symphony Fireworks Display, Kalamazoo Lake, Saugatuck, MI

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-10

    ...-AA00 Safety Zone; GR Symphony Fireworks Display, Kalamazoo Lake, Saugatuck, MI AGENCY: Coast Guard, DHS... Kalamazoo Lake during the GR Symphony Fireworks display. This temporary safety zone is necessary to protect spectators and vessels from the hazards associated with a fireworks display. DATES: This rule will be...

  5. Variable stars in the dwarf galaxy GR 8 (DDO 155)

    NASA Technical Reports Server (NTRS)

    Tolstoy, Eline; Saha, A.; Hoessel, John G.; Danielson, G. Edward

    1995-01-01

    Observations of the resolved stars in dwarf galaxy GR 8, obtained over the period 1980 February to 1994 March, are presented. Thirty-four separate epochs were searched for variable stars, and a total of six were found, of which one has Cepheid characteristics. After correction for Galactic extinction this single Cepheid yields a distance modulus of m - M = 26.75 +/- 0.35. This corresponds to a distance of 2.24 Mpc, placing GR 8 near the Local Group (LG) zero-velocity surface. The other five variable stars are very red, and possibly have long periods of order 100 days or more.

  6. Structure of complexes of nitrilo tris methylene phosphonic acid with copper, [CuN(CH{sub 2}PO{sub 3}){sub 3}(H{sub 2}O){sub 3}] and Na{sub 4}[CuN(CH{sub 2}PO{sub 3}){sub 3}]{sub 2} · 19H{sub 2}O, as bactericides and inhibitors of scaling and corrosion

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Somov, N. V., E-mail: somov@phys.unn.ru; Chausov, F. F., E-mail: chaus@uni.udm.ru

    2015-03-15

    Nitrilotris methylene phosphonate triaqua copper and octasodium bis(nitrilotris methylene phosphonate cuprate(II)) nonadecahydrate have been synthesized and investigated. [CuN(CH{sub 2}PO{sub 3}){sub 3}(H{sub 2}O){sub 3}] is crystallized in the sp. gr. P2{sub 1}/c, Z = 4, a = 9.2506(2) Å, b = 15.9815(2) Å, c = 9.5474(2) Å, β = 113.697(2)°. The copper atom is coordinated by oxygen atoms in the configuration of elongated octahedron; the ligand (of bridge type) links neighboring copper atoms. Na{sub 8}[CuN(CH{sub 2}PO{sub 3}){sub 3}]{sub 2} · 19H{sub 2}O is crystallized in the sp. gr. P2{sub 1}/c, Z = 2, a = 11.24550(10) Å, b = 17.38980(10) Å,more » c = 13.5852(2) Å, β = 127.8120(10)°. This complex is chelating; the copper atom closes three five-membered N-C-P-O-Cu cycles with a shared Cu-N bond. Copper is coordinated in a distorted trigonal-bipyramidal configuration.« less

  7. Iceland: Grímsvötn Volcano

    Atmospheric Science Data Center

    2013-04-17

    article title:  Grímsvötn Volcano Injects Ash into the Stratosphere     ... p.m. local time (1730 UTC) on Saturday, May 21, 2011. The volcano, located approximately 140 miles (220 kilometers) east of the capital ...

  8. Matrine in association with FD-2 stimulates F508del-cystic fibrosis transmembrane conductance regulator activity in the presence of corrector VX809

    PubMed Central

    Marengo, Barbara; Speciale, Andrea; Senatore, Lisa; Garibaldi, Silvano; Musumeci, Francesca; Nieddu, Erika; Pollarolo, Benedetta; Pronzato, Maria Adelaide; Schenone, Silvia; Mazzei, Mauro; Domenicotti, Cinzia

    2017-01-01

    Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and the predominant mutation is termed Phe508del (F508del). Therapy for F508del-CFTR patients is based on the use of Orkambi®, a combination of VX809 and VX770. However, though Orkambi leads to an improvement in the lung function of patients, a progressive reduction in its efficacy has been observed. In order to overcome this effect, the aim of the present study was to investigate the role of matrine and the in-house compound FD-2 in increasing the action of VX809 and VX770. Fischer rat thyroid cells overexpressing F508del-CFTR were treated with matrine, VX809 (corrector) and/or with a number of potentiators (VX770, FD-1 and FD-2). The results demonstrated that matrine was able to stimulate CFTR activity and, in association with FD-2, increased the functionality of the channel in the presence of VX809. Based on these results, it may be hypothesized that FD-2 may be a novel and more effective potentiator compared with VX770. PMID:29039559

  9. Section 508: Its Effect on States Funded under P.L. 100-407. Q & A. RESNA Technical Assistance Project.

    ERIC Educational Resources Information Center

    RESNA: Association for the Advancement of Rehabilitation Technology, Washington, DC.

    This guide contains questions and answers about Section 508 of the Rehabilitation Act, as amended in 1986 by Public Law 99-506, which required the federal government to establish, in consultation with industry, guidelines to ensure that individuals with disabilities may use electronic office equipment with or without special peripherals. The guide…

  10. HPA axis dysregulation and behavioral analysis of mouse mutants with altered GR or MR function

    PubMed Central

    Kolber, Benedict J.; Wieczorek, Lindsay; Muglia, Louis J.

    2009-01-01

    Corticosteroid receptors are critical for the maintenance of homeostasis after both psychological and physiological stress. To properly understand the different roles and interactions of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) during stress, it is necessary to dissect the role of corticosteroid signaling at both the system and sub-system level. A variety of GR transgenic mouse lines have recently been used to characterize the role of GR in the CNS as a whole and particularly in the forebrain. We will describe both the behavioral and cellular/molecular implications of disrupting GR function in these animal models and describe the implications of this data for our understanding of normal endocrine function and stress adaptation. MRs in tight epithelia have a long established role in sodium homeostasis. Recently however, evidence has suggested that limbic MRs also play an important role in psychological stress. Just as with GR, targeted mutations in MR induce a variety of behavioral changes associated with stress adaptation. In this review, we will discuss the implications of this work on MR. Finally, we will discuss the possible interaction between MR and GR and how future work using double mutants (through conventional means or virus based gene alteration) will be needed to fully understand how signaling through these two steroid receptors provides the adaptive mechanisms to deal with a variety of stressors. PMID:18609295

  11. Theoretical and Experimental Studies of N,N-Dimethyl-N'-Picryl-4,4'-Stilbenediamine.

    PubMed

    Papper, Vladislav; Wu, Yuanyuan; Kharlanov, Vladimir; Sukharaharja, Ayrine; Steele, Terry W J; Marks, Robert S

    2018-01-01

    N,N-dimethyl-N'-picryl-4,4'-stilbenediamine (DMPSDA) was prepared, purified and crystallised in a form of black lustrous crystals, and its absorption and fluorescence spectra were recorded in cyclohexane, acetonitrile and dimethyl sulfoxide. Non-emissive intramolecular charge transfer state (ICT) was clearly observed in this molecule in all three solvents. Theoretical calculations demonstrating a betaine electronic structure of the trinitrophenyl group in the ground state of the molecule and a charge transfer nature of the long wavelength transition S 0  → S 1 supported the experimental observations of the ICT formation in the molecule.

  12. Multi-band photometric study of the short-period eclipsing binary GR Boo

    NASA Astrophysics Data System (ADS)

    Wang, Daimei; Zhang, Liyun; Han, Xianming L.; Lu, Hongpeng

    2017-05-01

    We present BVRI light curves with complete phase coverage for the short-period (p = 0.377day) eclipsing binary star GR Boo. We carried out the observations using the SARA 90 cm telescope located at Kitt Peak National Observatory. We obtained six new light curve minimum times. By fitting all of the available O-C minimum times, we obtained an updated ephemeris that shows the orbital period of GR Boo is decreasing at a rate of P˙ = - 2.36 ×10-7 days/year. This decrease in its period can be explained by either mass transfer from the more massive component to the less massive one, or angular momentum exchange due to magnetic activities. We also obtained a set of revised orbital parameters using the Wilson & Devinney program. And finally, we concluded that GR Boo is a contact binary with a dark spot.

  13. 31 CFR 586.508 - Entries in certain accounts for normal service charges authorized.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... institution by the owner of such blocked account. (b) As used in this section, the term normal service charge..., and Statements of Licensing Policy § 586.508 Entries in certain accounts for normal service charges... by way of limitation, minimum balance charges, notary and protest fees, and charges for reference...

  14. Uptake of algal carbon and the synthesis of an "essential" fatty acid by Uvigerina ex. gr. semiornata (Foraminifera) within the Pakistan margin oxygen minimum zone: evidence from fatty acid biomarker and 13C tracer experiments

    NASA Astrophysics Data System (ADS)

    Larkin, K. E.; Gooday, A. J.; Woulds, C.; Jeffreys, R.; Schwartz, M.; Cowie, G.; Whitcraft, C.; Levin, L.; Dick, J. R.; Pond, D. W.

    2014-01-01

    Foraminifera are an important component of benthic communities in oxygen depleted settings, where they potentially play a~significant role in the processing of organic matter. We tracked the uptake of a 13C-labeled algal food source into individual fatty acids in the benthic foraminiferal species, Uvigerina ex. gr. semiornata, from the Arabian Sea oxygen minimum zone (OMZ). The tracer experiments were conducted on the Pakistan Margin during the late/post monsoon period (August-October 2003). A monoculture of the diatom Thalassiosira weisflogii was 13C-labeled and used to simulate a pulse of phytoplankton in two complementary experiments. A lander system was used for in situ incubations at 140 m and for 2.5 days duration, whilst a laboratory incubation used an oxystat system to maintain ambient dissolved oxygen concentrations. These shipboard experiments were terminated after 5 days. Uptake of diatoms was rapid, with high incorporation of diatom fatty acids into foraminifera after ~2 days in both experiments. Ingestion of the diatom food source was indicated by the increase over time in the quantity of diatom biomarker fatty acids in the foraminifera and by the high percentage of 13C in many of the fatty acids present at the endpoint of both in~situ and laboratory-based experiments. These results indicate that U. ex. gr. semiornata rapidly ingested the diatom food source and that this foraminifera will play an important role in the short-term cycling of organic matter within this OMZ environment. The experiments also suggested that U. ex. gr. semiornata consumed non-labeled bacterial food items, particularly bacteria, and synthesised the polyunsaturated fatty acid 20:4(n-6) de novo. 20:4(n-6) is often abundant in benthic fauna yet its origins and function have remained unclear. This study demonstrates that U. ex. gr. semiornata is capable of de novo synthesis of this "essential fatty acid" and is potentially a major source of this dietary nutrient in benthic food

  15. Uptake of algal carbon and the likely synthesis of an "essential" fatty acid by Uvigerina ex. gr. semiornata (Foraminifera) within the Pakistan margin oxygen minimum zone: evidence from fatty acid biomarker and 13C tracer experiments

    NASA Astrophysics Data System (ADS)

    Larkin, K. E.; Gooday, A. J.; Woulds, C.; Jeffreys, R. M.; Schwartz, M.; Cowie, G.; Whitcraft, C.; Levin, L.; Dick, J. R.; Pond, D. W.

    2014-07-01

    Foraminifera are an important component of benthic communities in oxygen-depleted settings, where they potentially play a significant role in the processing of organic matter. We tracked the uptake of a 13C-labelled algal food source into individual fatty acids in the benthic foraminiferal species Uvigerina ex. gr. semiornata from the Arabian Sea oxygen minimum zone (OMZ). The tracer experiments were conducted on the Pakistan margin during the late/post monsoon period (August-October 2003). A monoculture of the diatom Thalassiosira weisflogii was 13C-labelled and used to simulate a pulse of phytoplankton in two complementary experiments. A lander system was used for in situ incubations at 140 m water depth and for 2.5 days in duration. Shipboard laboratory incubations of cores collected at 140 m incorporated an oxystat system to maintain ambient dissolved oxygen concentrations and were terminated after 5 days. Uptake of diatoms was rapid, with a high incorporation of diatom fatty acids into foraminifera after ~ 2 days in both experiments. Ingestion of the diatom food source was indicated by the increase over time in the quantity of diatom biomarker fatty acids in the foraminifera and by the high percentage of 13C in many of the fatty acids present at the endpoint of both in situ and laboratory-based experiments. These results indicate that gr. semiornata rapidly ingested the diatom food source and that these foraminifera will play an important role in the short-term cycling of organic matter within this OMZ environment. The presence of 18:1(n-7) in the experimental foraminifera suggested that U. ex. gr. semiornata also consumed non-labelled bacterial food items. In addition, levels of 20:4(n-6), a PUFA only present in low amounts in the diatom food, increased dramatically in the foraminifera during both the in situ and shipboard experiments, possibly because it was synthesised de novo. This "essential fatty acid" is often abundant in benthic fauna, yet

  16. Hydroxylation of the herbicide isoproturon by fungi isolated from agricultural soil.

    PubMed

    Rønhede, Stig; Jensen, Bo; Rosendahl, Søren; Kragelund, Birthe B; Juhler, René K; Aamand, Jens

    2005-12-01

    Several asco-, basidio-, and zygomycetes isolated from an agricultural field were shown to be able to hydroxylate the phenylurea herbicide isoproturon [N-(4-isopropylphenyl)-N',N'-dimethylurea] to N-(4-(2-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea and N-(4-(1-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea. Bacterial metabolism of isoproturon has previously been shown to proceed by an initial demethylation to N-(4-isopropylphenyl)-N'-methylurea. In soils, however, hydroxylated metabolites have also been detected. In this study we identified fungi as organisms that potentially play a major role in the formation of these hydroxylated metabolites in soils treated with isoproturon. Isolates of Mortierella sp. strain Gr4, Phoma cf. eupyrena Gr61, and Alternaria sp. strain Gr174 hydroxylated isoproturon at the first position of the isopropyl side chain, yielding N-(4-(2-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea, while Mucor sp. strain Gr22 hydroxylated the molecule at the second position, yielding N-(4-(1-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea. Hydroxylation was the dominant mode of isoproturon transformation in these fungi, although some cultures also produced traces of the N-demethylated metabolite N-(4-isopropylphenyl)-N'-methylurea. A basidiomycete isolate produced a mixture of the two hydroxylated and N-demethylated metabolites at low concentrations. Clonostachys sp. strain Gr141 and putative Tetracladium sp. strain Gr57 did not hydroxylate isoproturon but N demethylated the compound to a minor extent. Mortierella sp. strain Gr4 also produced N-(4-(2-hydroxy-1-methylethyl)phenyl)-N'-methylurea, which is the product resulting from combined N demethylation and hydroxylation.

  17. Results of crack-arrest tests on irradiated a 508 class 3 steel

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Iskander, S.K.; Milella, P.P.; Pini, M.A.

    1998-02-01

    Ten crack-arrest toughness values for irradiated specimens of A 508 class 3 forging steel have been obtained. The tests were performed according to the American Society for Testing and Materials (ASTM) Standard Test Method for Determining Plane-Strain Crack-Arrest Fracture Toughness, K{sub la} of Ferritic Steels, E 1221-88. None of these values are strictly valid in all five ASTM E 1221-88 validity criteria. However, they are useful when compared to unirradiated crack-arrest specimen toughness values since they show the small (averaging approximately 10{degrees}C) shifts in the mean and lower-bound crack-arrest toughness curves. This confirms that a low copper content in ASTMmore » A 508 class 3 forging material can be expected to result in small shifts of the transition toughness curve. The shifts due to neutron irradiation of the lower bound and mean toughness curves are approximately the same as the Charpy V-notch (CVN) 41-J temperature shift. The nine crack-arrest specimens were irradiated at temperatures varying from 243 to 280{degrees}C, and to a fluence varying from 1.7 to 2.7 x 10{sup 19} neutrons/cm{sup 2} (> 1 MeV). The test results were normalized to reference values that correspond to those of CVN specimens irradiated at 284{degrees}C to a fluence of 3.2 x 10{sup 19} neutrons/cm{sup 2} (> 1 MeV) in the same capsule as the crack-arrest specimens. This adjustment resulted in a shift to lower temperatures of all the data, and in particular moved two data points that appeared to lie close to or lower than the American Society of Mechanical Engineers K{sub la} curve to positions that seemed more reasonable with respect to the remaining data. A special fixture was designed, fabricated, and successfully used in the testing. For reasons explained in the text, special blocks to receive the Oak Ridge National Laboratory clip gage were designed, and greater-than-standard crack-mouth opening displacements measured were accounted for. 24 refs., 13 figs., 12 tabs.« less

  18. 30 CFR 77.508 - Lightning arresters, ungrounded and exposed power conductors and telephone wires.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Lightning arresters, ungrounded and exposed... AND SURFACE WORK AREAS OF UNDERGROUND COAL MINES Electrical Equipment-General § 77.508 Lightning... conductors and telephone wires shall be equipped with suitable lightning arresters which are adequately...

  19. 30 CFR 77.508 - Lightning arresters, ungrounded and exposed power conductors and telephone wires.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Lightning arresters, ungrounded and exposed... AND SURFACE WORK AREAS OF UNDERGROUND COAL MINES Electrical Equipment-General § 77.508 Lightning... conductors and telephone wires shall be equipped with suitable lightning arresters which are adequately...

  20. 30 CFR 77.508 - Lightning arresters, ungrounded and exposed power conductors and telephone wires.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Lightning arresters, ungrounded and exposed... AND SURFACE WORK AREAS OF UNDERGROUND COAL MINES Electrical Equipment-General § 77.508 Lightning... conductors and telephone wires shall be equipped with suitable lightning arresters which are adequately...

  1. A comparative study of functional 5-HT4 receptors in human colon, rat oesophagus and rat ileum.

    PubMed

    McLean, P G; Coupar, I M; Molenaar, P

    1995-05-01

    1. The pharmacological properties of 5-hydroxytryptamine (5-HT), the 5-HT4 receptor agonists, DAU 6236 and SC 53116 and the 5-HT4 receptor antagonist, GR 1130808, were studied in the rat oesophagus, rat ileum and human colon. 2. 5-HT relaxed the longitudinal muscle of the rat oesophagus and rat ileum and the circular muscle of the human colon. Absolute values of relaxation were measured and showed the order of the maximum responses, rat oesophagus > human colon > rat ileum with EC50 values of 189 +/- 15 nM, 157 +/- 4 nM, 306 +/- 72 nM, respectively. 5-HT also inhibited the spontaneous contractions of the human colon with an EC50 value of 119 +/- 1 nM. The effect of 5-HT on the human colon was not affected by methysergide (10 microM) or ondansetron (1 microM). 3. The use of the uptake and metabolism inhibitors, cocaine (30 microM) and pargyline (100 microM), did not increase the potency of 5-HT in the rat oesophagus or human colon. In the rat oesophagus, cocaine (30 microM) produced a reduction in carbachol-induced tone of 22.2 +/- 0.6% and reduced the 5-HT maximum effect by 52.0 +/- 0.4%. 4. The compounds, DAU 6236 and SC 53116, showed a different pattern of potencies and efficacies in the rat oesophagus, rat ileum and human colon compared to 5-HT. DAU 6236 relaxed the human colonic circular muscle with an EC50 value of 129 +/- 16 nM but its efficacy was less than that of 5-HT. DAU 6236 (1 microM) also antagonized the 5-HT-induced relaxation of the human colon with a dose-ratio of 9.9. In the rat oesophagus and rat ileum, DAU 6236 was inactive in the majority of tissues. In the minority of oesophagus tissues that did respond the EC50 value was 1.2 +/- 0.7 microM. DAU 6236 also antagonized the effect of 5-HT in the rat oesophagus in a non-surmountable fashion. SC 53116 relaxed the rat oesophagus with an EC50 value of 91 +/- 4 nM, with an efficacy less than that observed to 5-HT; however, at 200 nM it did not antagonize the 5-HT-induced relaxation of the rat

  2. Superconductivity at 33-37 K in A L n2Fe4As4O2 (A =Kand Cs;L n =lanthanides)

    NASA Astrophysics Data System (ADS)

    Wu, Si-Qi; Wang, Zhi-Cheng; He, Chao-Yang; Tang, Zhang-Tu; Liu, Yi; Cao, Guang-Han

    2017-09-01

    We have synthesized ten iron oxyarsenides, K L n2Fe4As4O2 (L n =Gd,Tb,Dy, and Ho) and Cs L n2Fe4As4O2 (L n =Nd,Sm,Gd,Tb,Dy, and Ho) , with the aid of the lattice-match approach. The resultant compounds possess hole-doped conducting double FeAs layers [AFe4As4] 2 - that are separated by the insulating [Ln2O2] 2 + slabs. Measurements of electrical resistivity and dc magnetic susceptibility demonstrate bulk superconductivity at Tc=33 -37 K. We find that Tc correlates with the axial ratio c /a for all 12442-type superconductors discovered. Also, Tc tends to increase with the lattice mismatch, implying that lattice instability plays a role in the enhancement of superconductivity.

  3. 49 CFR 236.508 - Interference with application of brakes by means of brake valve.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... GOVERNING THE INSTALLATION, INSPECTION, MAINTENANCE, AND REPAIR OF SIGNAL AND TRAIN CONTROL SYSTEMS, DEVICES, AND APPLIANCES Automatic Train Stop, Train Control and Cab Signal Systems Standards § 236.508 Interference with application of brakes by means of brake valve. The automatic train stop, train control, or...

  4. 49 CFR 236.508 - Interference with application of brakes by means of brake valve.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... GOVERNING THE INSTALLATION, INSPECTION, MAINTENANCE, AND REPAIR OF SIGNAL AND TRAIN CONTROL SYSTEMS, DEVICES, AND APPLIANCES Automatic Train Stop, Train Control and Cab Signal Systems Standards § 236.508 Interference with application of brakes by means of brake valve. The automatic train stop, train control, or...

  5. N-doped graphene-carbon nanotube hybrid networks attaching with gold nanoparticles for glucose non-enzymatic sensor.

    PubMed

    Jeong, Hun; Nguyen, Dang Mao; Lee, Min Sang; Kim, Hong Gun; Ko, Sang Cheol; Kwac, Lee Ku

    2018-09-01

    Herein, we successfully developed a novel three dimensional (3D) opened networks based on nitrogen doped graphene‑carbon nanotubes attaching with gold nanoparticles (N-GR-CNTs/AuNPs) to apply for non-enzymatic glucose determination. It was demonstrated that the N-GR-CNTs/AuNPs modified electrode exhibited good behavior for glucose detection with a long linear range of 2 μM to 19.6 mM, high sensitivity of 0.9824 μA·mM -1 ·cm -2 , low detection limit of 500 nM, and negligible interference effect. The high performance of the N-GR-CNTs/AuNPs based sensor was assumed due to the outstanding catalytic activity of AuNPs well dispersing on N-GR-CNTs networks, which exhibited as a perfect supporting scaffold due to the enhanced electrical conductivity and large surface area. The obtained results indicated that the N-GR-CNTs/AuNPs hybrid is highly promising for sensitive and selective detection of glucose in sensor application. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. Incomplete Gröbner basis as a preconditioner for polynomial systems

    NASA Astrophysics Data System (ADS)

    Sun, Yang; Tao, Yu-Hui; Bai, Feng-Shan

    2009-04-01

    Precondition plays a critical role in the numerical methods for large and sparse linear systems. It is also true for nonlinear algebraic systems. In this paper incomplete Gröbner basis (IGB) is proposed as a preconditioner of homotopy methods for polynomial systems of equations, which transforms a deficient system into a system with the same finite solutions, but smaller degree. The reduced system can thus be solved faster. Numerical results show the efficiency of the preconditioner.

  7. [Knowledge of the "Gräfenberg zone" and female ejaculation in ancient Indian sexual science. A medical history contribution].

    PubMed

    Syed, R

    1999-01-01

    Ancient Indian texts in sexology (kamaśastra) from the 11th century onwards prove that their authors knew about the area later termed the "Gräfenberg zone" in Europe, as well as about the female ejaculation connected with the stimulation of this area. The Gräfenberg zone is a sexually arousable zone in the front part of the vagina, stimulation of which can lead to the discharge of liquid from the urethra, a phenomenon which is described as female ejaculation. The german gynaecologist Ernst Gräfenberg, who worked in America, described this zone, situated beneath the clitoris, for the first time (at least in this century) in Western medicine in an article published in 1950. (There are, however, evidences, that the 17th-century anatomist Regnier de Graaf had knowledge about the mentioned erogenous zone as well as female ejaculation.) Since the 1980s the so-called Gräfenberg zone, popularly termed "G-spot", and female ejaculation have been controversially discussed medically as well as in popular science, first in the United States, then in Europe; both phenomena have meanwhile been accepted as facts in medical manuals and reference books (e.g. the "Pschyrembel"). Whereas the oldest and most well-known sexological-erotological work of Ancient India, the Kamasutra, dating probably from the third century A.D., apparently did not know the Gräfenberg zone and female ejaculation, texts such as the Pañcasayaka (11th century), Jayamangala (Yaśodhara's commentary on the Kamasutra from the 13th century), the Ratirahasya (13th century), as well as the late kamaśastra-works Smaradipika and Anangaranga (16th century?) demonstrably describe both, the Gräfenberg zone and female ejaculation, in great detail. The female ejaculation is described already in the 7th century in a non-kamaśastra-text, in a work of the poet Amaru called the Amaruśataka.

  8. Validation of the German revised version of the program in palliative care education and practice questionnaire (PCEP-GR).

    PubMed

    Fetz, Katharina; Wenzel-Meyburg, Ursula; Schulz-Quach, Christian

    2017-12-28

    The evaluation of the effectiveness of undergraduate palliative care education (UPCE) programs is an essential foundation to providing high-quality UPCE programs. Therefore, the implementation of valid evaluation tools is indispensable. Until today, there has been no general consensus regarding concrete outcome parameters and their accurate measurement. The Program in Palliative Care Education and Practice Questionnaire (German Revised Version; PCEP-GR) is a promising assessment tool for UPCE. The aim of the current study was to evaluate the psychometric properties of PCEP-GR and to demonstrate its feasibility for the evaluation of UPCE programs. The practical feasibility of the PCEP-GR and its acceptance in medical students were investigated in a pilot study with 24 undergraduate medical students at Heinrich Heine University Dusseldorf, Germany. Subsequently, the PCEP-GR was surveyed in a representative sample (N = 680) of medical students in order to investigate its psychometric properties. Factorial validity was investigated by means of principal component analysis (PCA). Reliability was examined by means of split-half-reliability analysis and analysis of internal consistency. After taking into consideration the PCA and distribution analysis results, an evaluation instruction for the PCEP-GR was developed. The PCEP-GR proved to be feasible and well-accepted in medical students. PCA revealed a four-factorial solution indicating four PCEP-GR subscales: preparation to provide palliative care, attitudes towards palliative care, self-estimation of competence in communication with dying patients and their relatives and self-estimation of knowledge and skills in palliative care. The PCEP-GR showed good split-half-reliability and acceptable to good internal consistency of subscales. Attitudes towards palliative care slightly missed the criterion of acceptable internal consistency. The evaluation instruction suggests a global PCEP-GR index and four subscales. The

  9. The Response of the Root Proteome to the Synthetic Strigolactone GR24 in Arabidopsis*

    PubMed Central

    Walton, Alan; Stes, Elisabeth; Goeminne, Geert; Braem, Lukas; Vuylsteke, Marnik; Matthys, Cedrick; De Cuyper, Carolien; Staes, An; Vandenbussche, Jonathan; Boyer, François-Didier; Vanholme, Ruben; Fromentin, Justine; Boerjan, Wout; Gevaert, Kris; Goormachtig, Sofie

    2016-01-01

    Strigolactones are plant metabolites that act as phytohormones and rhizosphere signals. Whereas most research on unraveling the action mechanisms of strigolactones is focused on plant shoots, we investigated proteome adaptation during strigolactone signaling in the roots of Arabidopsis thaliana. Through large-scale, time-resolved, and quantitative proteomics, the impact of the strigolactone analog rac-GR24 was elucidated on the root proteome of the wild type and the signaling mutant more axillary growth 2 (max2). Our study revealed a clear MAX2-dependent rac-GR24 response: an increase in abundance of enzymes involved in flavonol biosynthesis, which was reduced in the max2–1 mutant. Mass spectrometry-driven metabolite profiling and thin-layer chromatography experiments demonstrated that these changes in protein expression lead to the accumulation of specific flavonols. Moreover, quantitative RT-PCR revealed that the flavonol-related protein expression profile was caused by rac-GR24-induced changes in transcript levels of the corresponding genes. This induction of flavonol production was shown to be activated by the two pure enantiomers that together make up rac-GR24. Finally, our data provide much needed clues concerning the multiple roles played by MAX2 in the roots and a comprehensive view of the rac-GR24-induced response in the root proteome. PMID:27317401

  10. Dexamethasone-Mediated Changes in Adipose Triacylglycerol Metabolism Are Exaggerated, Not Diminished, in the Absence of a Functional GR Dimerization Domain

    PubMed Central

    Roohk, Donald J.; Mascharak, Smita; Khambatta, Cyrus; Leung, Ho; Hellerstein, Marc

    2013-01-01

    The glucocorticoid (GC) receptor (GR) has multiple effector mechanisms, including dimerization-mediated transactivation of target genes via DNA binding and transcriptional repression mediated by protein-protein interactions. Much attention has been focused on developing selective GR modulators that would dissociate adverse effects from therapeutic anti-inflammatory effects. The GRdim/dim mouse has a mutation in the dimerization domain of GR and has been shown to have attenuated transactivation with intact repression. To understand the role of GR dimerization-dependent targets in multiple tissues, we measured metabolic fluxes through several disease-relevant GC target pathways using heavy water labeling and mass spectrometry in wild-type and GRdim/dim mice administered the potent GC dexamethasone (DEX). Absolute triglyceride synthesis was increased in both wild-type and GRdim/dim mice by DEX in the inguinal and epididymal fat depots. GRdim/dim mice showed an exaggerated response to DEX in both depots. De novo lipogenesis was also greatly increased in both depots in response to DEX in GRdim/dim, but not wild-type mice. In contrast, the inhibitory effect of DEX on bone and skin collagen synthesis rates was greater in wild-type compared with GRdim/dim mice. Wild-type mice were more sensitive to DEX-dependent decreases in insulin sensitivity than GRdim/dim mice. Wild-type and GRdim/dim mice were equally sensitive to DEX-dependent decreases in muscle protein synthesis. Chronic elevation of GCs in GRdim/dim mice results in severe runting and lethality. In conclusion, some metabolic effects of GC treatment are exaggerated in adipose tissue of GRdim/dim mice, suggesting that selective GR modulators based on dissociating GR transactivation from repression should be evaluated carefully. PMID:23493372

  11. The elastocaloric effect of Ni50.8Ti49.2 shape memory alloys

    NASA Astrophysics Data System (ADS)

    Zhou, Min; Li, Yushuang; Zhang, Chen; Li, Shaojie; Wu, Erfu; Li, Wei; Li, Laifeng

    2018-04-01

    Solid-state cooling technologies are considered as possible alternatives for vapor compression cooling systems. The elastocaloric cooling (whose caloric effects are driven by uniaxial stress) technology, as an efficient and clean solid-state cooling technology, is receiving a great deal of attention very recently. Herein, a NiTi-based elastocaloric bulk material was reported. A large coefficient-of-performance of the material (COPmater) of 4.5 was obtained, which was even higher than that of other NiTi bulk materials. The temperature changes (ΔT) increased with increasing applied strain (ɛ), and reached 18 K upon loading and  -11 K upon unloading when the ɛ value increased to 4%. The high temperature changes were attributed to the large stress-induced entropy changes (the maximum ΔS σ value was 37 J kg-1 K-1). The temperature changes decreased with loading-unloading tensile cycles, and stabilized at 6.5 K upon loading and  -6 K upon unloading after tens of mechanical cycles. The Ni50.8Ti49.2 shape memory alloy showed great promise for application in solid-state refrigeration (or as heat pumps).

  12. Convergence of glycogen synthase kinase 3β and GR signaling in response to fluoxetine treatment in chronically stressed female and male rats.

    PubMed

    Mitic, Milos; Brkic, Zeljka; Lukic, Iva; Adzic, Miroslav

    2017-08-30

    Accumulating evidence strongly suggest that impaired glucocorticoid receptor (GR) signaling is involved in stress-related mood disorders, and nominate GR as a potential target for antidepressants (ADs). It is known that different classes of ADs affects the GR action via modifying its phosphorylation, while the mechanism through which ADs alter GR phosphorylation targeted by GSK3β, a kinase modulated via serotonin neurotransmission, are unclear. On this basis, we investigated whether GSK3β-GR signaling could be a convergence point of fluoxetine action on brain function and behavior, by examining its effect on GSK3β targeted-GR phosphorylation on threonine 171 (pGR171), and expression of GR-regulated genes in the hippocampus of female and male rats exposed to chronic isolation stress. Stress induced sex-specific GSK3β-targeted phosphorylation of pGR171 in the nucleus of the hippocampus of stressed animals. Namely, while in females stress triggered coupled action of GSK3β-pGR171 signaling, in males changes in pGR171 levels did not correspond to GSK3β activity. On the other hand, fluoxetine managed to up-regulate this pathway in sex-unbiased manner. Furthermore, fluoxetine reverted stress-induced changes in most of the analyzed genes in males, CRH, 5-HT1a and p11, while in females its effect was limited to CRH. These data further suggest that pGR171 signaling affects cellular localization of GR in response to chronic stress and fluoxetine in both sexes. Collectively, our results describe a novel convergence point between GR signaling and GSK3β pathway in rat hippocampus in response to stress and fluoxetine in both sexes and its involvement in fluoxetine-regulated brain function in males. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. 25 CFR 20.508 - What must the social services agency do when a child is placed in foster care, residential care...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false What must the social services agency do when a child is... INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR HUMAN SERVICES FINANCIAL ASSISTANCE AND SOCIAL SERVICES PROGRAMS Child Assistance Foster Care § 20.508 What must the social services agency do when a child is...

  14. 25 CFR 20.508 - What must the social services agency do when a child is placed in foster care, residential care...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false What must the social services agency do when a child is... INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR HUMAN SERVICES FINANCIAL ASSISTANCE AND SOCIAL SERVICES PROGRAMS Child Assistance Foster Care § 20.508 What must the social services agency do when a child is...

  15. 46 CFR 508.101 - Cross-referrence to employee ethical conduct standards and financial disclosure regulations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 9 2011-10-01 2011-10-01 false Cross-referrence to employee ethical conduct standards... GENERAL AND ADMINISTRATIVE PROVISIONS EMPLOYEE ETHICAL CONDUCT STANDARDS AND FINANCIAL DISCLOSURE REGULATIONS § 508.101 Cross-referrence to employee ethical conduct standards and financial disclosure...

  16. 46 CFR 508.101 - Cross-referrence to employee ethical conduct standards and financial disclosure regulations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 9 2010-10-01 2010-10-01 false Cross-referrence to employee ethical conduct standards... GENERAL AND ADMINISTRATIVE PROVISIONS EMPLOYEE ETHICAL CONDUCT STANDARDS AND FINANCIAL DISCLOSURE REGULATIONS § 508.101 Cross-referrence to employee ethical conduct standards and financial disclosure...

  17. 46 CFR 508.101 - Cross-referrence to employee ethical conduct standards and financial disclosure regulations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 9 2014-10-01 2014-10-01 false Cross-referrence to employee ethical conduct standards... GENERAL AND ADMINISTRATIVE PROVISIONS EMPLOYEE ETHICAL CONDUCT STANDARDS AND FINANCIAL DISCLOSURE REGULATIONS § 508.101 Cross-referrence to employee ethical conduct standards and financial disclosure...

  18. 46 CFR 508.101 - Cross-referrence to employee ethical conduct standards and financial disclosure regulations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 9 2012-10-01 2012-10-01 false Cross-referrence to employee ethical conduct standards... GENERAL AND ADMINISTRATIVE PROVISIONS EMPLOYEE ETHICAL CONDUCT STANDARDS AND FINANCIAL DISCLOSURE REGULATIONS § 508.101 Cross-referrence to employee ethical conduct standards and financial disclosure...

  19. 46 CFR 508.101 - Cross-referrence to employee ethical conduct standards and financial disclosure regulations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 9 2013-10-01 2013-10-01 false Cross-referrence to employee ethical conduct standards... GENERAL AND ADMINISTRATIVE PROVISIONS EMPLOYEE ETHICAL CONDUCT STANDARDS AND FINANCIAL DISCLOSURE REGULATIONS § 508.101 Cross-referrence to employee ethical conduct standards and financial disclosure...

  20. gr-MRI: A software package for magnetic resonance imaging using software defined radios

    NASA Astrophysics Data System (ADS)

    Hasselwander, Christopher J.; Cao, Zhipeng; Grissom, William A.

    2016-09-01

    The goal of this work is to develop software that enables the rapid implementation of custom MRI spectrometers using commercially-available software defined radios (SDRs). The developed gr-MRI software package comprises a set of Python scripts, flowgraphs, and signal generation and recording blocks for GNU Radio, an open-source SDR software package that is widely used in communications research. gr-MRI implements basic event sequencing functionality, and tools for system calibrations, multi-radio synchronization, and MR signal processing and image reconstruction. It includes four pulse sequences: a single-pulse sequence to record free induction signals, a gradient-recalled echo imaging sequence, a spin echo imaging sequence, and an inversion recovery spin echo imaging sequence. The sequences were used to perform phantom imaging scans with a 0.5 Tesla tabletop MRI scanner and two commercially-available SDRs. One SDR was used for RF excitation and reception, and the other for gradient pulse generation. The total SDR hardware cost was approximately 2000. The frequency of radio desynchronization events and the frequency with which the software recovered from those events was also measured, and the SDR's ability to generate frequency-swept RF waveforms was validated and compared to the scanner's commercial spectrometer. The spin echo images geometrically matched those acquired using the commercial spectrometer, with no unexpected distortions. Desynchronization events were more likely to occur at the very beginning of an imaging scan, but were nearly eliminated if the user invoked the sequence for a short period before beginning data recording. The SDR produced a 500 kHz bandwidth frequency-swept pulse with high fidelity, while the commercial spectrometer produced a waveform with large frequency spike errors. In conclusion, the developed gr-MRI software can be used to develop high-fidelity, low-cost custom MRI spectrometers using commercially-available SDRs.