Modeling flow stress constitutive behavior of SA508-3 steel for nuclear reactor pressure vessels

NASA Astrophysics Data System (ADS)

Sun, Mingyue; Hao, Luhan; Li, Shijian; Li, Dianzhong; Li, Yiyi

2011-11-01

Based on the measured stress-strain curves under different temperatures and strain rates, a series of flow stress constitutive equations for SA508-3 steel were firstly established through the classical theories on work hardening and softening. The comparison between the experimental and modeling results has confirmed that the established constitutive equations can correctly describe the mechanical responses and microstructural evolutions of the steel under various hot deformation conditions. We further represented a successful industrial application of this model to simulate a forging process for a large conical shell used in a nuclear steam generator, which evidences its practical and promising perspective of our model with an aim of widely promoting the hot plasticity processing for heavy nuclear components of fission reactors.

Influence of the Strength Mismatch of a Narrow Gap Welded Joint of SA508 on the Plastic η Factor

NASA Astrophysics Data System (ADS)

Koo, J. M.; Huh, Y.; Seok, C. S.

2012-11-01

In this article, the influence of the strength mismatch of a narrow gap welded joint of SA508 on the η factor was evaluated. The η factor is the principal parameter that determines the plastic portion of the J-integral. The specimens for tensile and hardness tests were collected from piping with narrow gap welding and the stress-strain curve and hardness were obtained from those. From these results, the Ramberg-Osgood (R-O) constant was obtained. Also, the finite element analysis was performed with variations in the strength mismatch and the weld width. The η factor equation considering the strength mismatch and the weld width of a narrow gap welded joint was suggested.

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...

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...

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...

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...

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...

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

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...

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...

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.

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

Effects of H content on the tensile properties and fracture behavior of SA508-III steel

NASA Astrophysics Data System (ADS)

Liu, Jia-hua; Wang, Lei; Liu, Yang; Song, Xiu; Luo, Jiong; Yuan, Dan

2015-08-01

SA508-III steel was charged with different hydrogen (H) contents using a high-pressure thermal charging method to study the effects of H content on the tensile properties and evaluate the H embrittlement behavior of the steel. The results indicate that the ultimate tensile strength remains nearly unchanged with the addition of H. In contrast, the yielding strength slightly increases, and the elongation significantly decreases with increasing H content, especially at concentrations exceeding 5.6 × 10-6. On the basis of fractographic analysis, it is clear that the addition of H changes the fracture mode from microvoid coalescence to a mixture of river patterns and dimples. Carbides are strong traps for H; thus, the H atoms easily migrate in the form of Cottrell atmosphere toward the carbides following moving dislocations during tensile deformation. In addition, stress-induced H atoms accumulate at the interface between carbides and the matrix after necking under three-dimensional stress, which weakens the interfacial bonding force. Consequently, when the local H concentration reaches a critical value, microcracks occur at the interface, resulting in fracture.

Calculation of {alpha}/{gamma} equilibria in SA508 grade 3 steels for intercritical heat treatment

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

Lee, B.J.; Kim, H.D.; Hong, J.H.

1998-05-01

An attempt has been made to suggest an optimum temperature for intercritical heat treatment of an SA508 grade 3 steel for nuclear pressure vessels, based on thermodynamic calculation of the {alpha}/{gamma} phase equilibria. A thermodynamic database constructed for the Fe-Mn-Ni-Mo-Cr-Si-V-Al-C-N ten-component system and an empirical criterion that the amount of reformed austenite should be around 40 pct were used for thermodynamic calculation and derivation of the optimum heat-treatment temperature, respectively. The calculated optimum temperature, 720 C, was in good agreement with an experimentally determined temperature of 725 C obtained through an independent experimental investigation of the same steel. The agreementmore » between the calculated and measured fraction of reformed austenite during the intercritical heat treatment was also confirmed. Based on the agreement between calculation and experiment, it could be concluded that thermodynamic calculations can be successfully applied to the materials and/or process design as an additive tool to the already established technology, and that the currently constructed thermodynamic database for steel systems shows an accuracy that makes such applications possible.« less

Dynamic strain aging in the high-temperature low-cycle fatigue of SA508 Cl. 3 forging steel

NASA Astrophysics Data System (ADS)

Lee, Byung Ho; Kim, In Sup

1995-10-01

The effect of dynamic strain aging on cyclic stress response and fatigue resistance of ASME SA508 Cl.3 forging steel for nuclear reactor pressure vessels has been evaluated in the temperature range of room temperature to 500°C. Total strain ranges and strain rates were varied from 0.7 to 2.0% and from 4 × 10 -4 to 1 × 10 -2 s -1, respectively. The cyclic stress response depended on the testing temperature, strain rate, and range. Generally, the initial cyclic hardening was immediately followed by cyclic softening at all strain rates. However, at 300°C, the operating temperature of nuclear reactor pressure vessels, the variation of cyclic stress amplitude showed the primary and secondary hardening stages dependent on the strain rate and strain range. Dynamic strain aging was manifested by enhanced cyclic hardening, distinguished secondary hardening, and negative strain rate sensitivity. A modified cell shutting model was described for the onset of the secondary hardening due to the dynamic strain aging and it was in good agreement with the experimental results. Fatigue life increased in strain rate at all testing temperatures. Specifically the fatigue life was longer at the dynamic strain aging temperature. Further, the dynamic strain aging was easy to initiate the crack, while crack propagation was retarded by crack branching and suppression of plastic zone, hence the dynamic strain aging caused the improvement of fatigue resistance.

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...

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...

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...

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...

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...

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.

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.

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.

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

Fractographic study of a thick wall pressure vessel failure

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

Canonico, D.A.; Crouse, R.S.; Henson, T.J.

1979-01-01

The pressure vessel described in this paper is identified as Intermediate Test Vessel 1 (ITV-1) and was fabricated of SA508, Class 2 Steel. It was tested to failure at 54/sup 0/C (130/sup 0/F). The gross failure appeared to be a brittle fracture although accompanied by a measured strain of 0.9%. Seven regions of the fracture were examined in detail and the observed surfaces were compared to Charpy V-notch (C/sub v/) specimens of SA508, Class 2 steel broken at temperatures above and below the ductile to brittle transition temperature. Three samples from the vessel were taken in the region around themore » fatigue notch and four from areas well removed from the notch. All these were carefully examined both optically and by scanning electron microscopy (SEM). It was established that early crack extension was by ductile mode until a large flaw approximately 500 mm long 83 mm wide was developed. At this point the vessel could no longer contain the internal pressure and final rupture was by brittle fracture.« less

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.

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).

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

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

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...

Cover-gas seal program. Test report - sodium dip-seal wetting study. [at 450/sup 0/F

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

Carnevali, R.

1977-10-20

This report documents the tests conducted to find a reliable surface preparation method of treating the CRBRP dip seal blade (SA508 Class 2 steel) to insure its sodium wettability at 450F or less. Two techniques were established which depressed the sodium wetting temperature of SA 508, Class 2 dip seal blade material to 375F. These techniques were depositing an approx. 60 x 10/sup -6/ inch layer of tin on the blade surface by a brush-on plating process, and, by cleaning the blade surface with ultrasonics while it is immersed in sodium. The tin plating technique is recommended as the initialmore » and primary surface preparation method and ultrasonics as a rewetting and backup technique. This work was conducted in support of the Sodium Dip Seal Feature Test, DRS 32.05.« less

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...

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.

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.

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...

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...

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...

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...

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...

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...

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...

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...

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...

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.

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...

Computational studies of H5N1 hemagglutinin binding with SA-{alpha}-2, 3-Gal and SA-{alpha}-2, 6-Gal

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

Li Minyong; Wang Binghe

2006-09-01

For influenza H5N1 hemagglutinin, a switch from SA-{alpha}-2, 3-Gal to SA-{alpha}-2, 6-Gal receptor specificity is a critical step leading to the conversion from avian-to-human to human-to-human infection. Therefore, the understanding of the binding modes of SA-{alpha}-2, 3-Gal and SA-{alpha}-2, 6-Gal to H5N1 hemagglutinin will be very important for the examination of possible mutations needed for going from an avian to a human flu virus. Based on the available H5N1 hemagglutinin crystal structure, the binding profiles between H5N1 hemagglutinin and two saccharide ligands, SA-{alpha}-2, 3-Gal and SA-{alpha}-2, 6-Gal, were investigated by ab initio quantum mechanics, molecular docking, molecular mechanics, and molecularmore » dynamics simulations. It was found that SA-{alpha}-2, 3-Gal has strong multiple hydrophobic and hydrogen bond interactions in its trans conformation with H5N1 hemagglutinin, whereas the SA-{alpha}-2, 6-Gal only shows weak interactions in a different conformation (cis type)« less

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. ...

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. ...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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.

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...

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...

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...

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...

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 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...

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...

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...

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...

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...

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…

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

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...

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...

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...

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...

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...

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.

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

Closed-loop control of SaO2 in the neonate.

PubMed

Morozoff, P E; Evans, R W

1992-01-01

A microprocessor-based device has been designed to control oxygen saturation (SaO2) in neonates by adjusting the inspired air-oxygen mixture (FiO2) delivered by a mechanical blender. The user sets a target SaO2, which the controller attempts to maintain. Alarms are actuated if the neonate's SaO2 is outside predefined limits. SaO2 levels are extracted from a commercial pulse oximeter and analyzed by an eight-bit microprocessing unit (MPU). Delivered percentages of FiO2 are adjusted by a motorized air-oxygen blender. The controller has a menu-driven user interface and can graphically present four-hour trends of the SaO2, FiO2, or blender setting. Sixteen hours of collected data can be stored and later downloaded to a personal computer. A real-time multitasking operating system forms the nucleus of the controller's software. Major tasks that share MPU time are control, filtering, user display, data collection, data archiving, alarm monitoring, and user input. Analog SaO2 levels are read and converted to digital values, which are then filtered to extract noise. A differential control algorithm is used to determine the required FiO2 blender setting. The blender is then adjusted to the new setting, after which the controller waits to repeat the process of sampling SaO2 and adjusting FiO2. System response time and blender increments are adjustable to allow a user to tune the controller to the patient's needs. Alarm conditions of concern within the device are SaO2 and FiO2 sensor disconnection, blender disconnection, and SaO2 limiting errors. In preliminary trials, for a target of 92.0% SaO2, a prototype controller maintained an average of 91.6% with a standard deviation of 5.0% over a one-hour period.(ABSTRACT TRUNCATED AT 250 WORDS)

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...

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...

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...

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...

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.

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...

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...

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...

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.

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

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...

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...

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...

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

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

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

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...

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...

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...

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...

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...

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.

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.

Qualification of submerged-arc narrow strip cladding process

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

Ayres, P.S.; Gottschling, J.D.; Jeffers, G.K.

1975-08-01

An unique narrow strip cladding process for use on both plate and forging material for nuclear components was developed. The qualification testing of this low-heat input process for cladding nuclear components, including those of SA508 Class 2 material is described. The theory that explains the acceptable results of these tests is also given. (auth)

Qualification of submerged-arc narrow strip cladding process

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

Ayres, P.S.; Gottschling, J.D.; Jeffers, G.K.

1976-03-01

Babcock and Wilcox has developed an unique narrow strip cladding process for use on both plate and forging material for nuclear components. The qualification testing of this low-heat input process for cladding nuclear components is described, including those of SA508 Class 2 material. The theory that explains the acceptable results of these tests is also given.

Creep of A508/533 Pressure Vessel Steel

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

Richard Wright

2014-08-01

ABSTRACT Evaluation of potential Reactor Pressure Vessel (RPV) steels has been carried out as part of the pre-conceptual Very High Temperature Reactor (VHTR) design studies. These design studies have generally focused on American Society of Mechanical Engineers (ASME) Code status of the steels, temperature limits, and allowable stresses. Initially, three candidate materials were identified by this process: conventional light water reactor (LWR) RPV steels A508 and A533, 2¼Cr-1Mo in the annealed condition, and Grade 91 steel. The low strength of 2¼Cr-1Mo at elevated temperature has eliminated this steel from serious consideration as the VHTR RPV candidate material. Discussions with themore » very few vendors that can potentially produce large forgings for nuclear pressure vessels indicate a strong preference for conventional LWR steels. This preference is based in part on extensive experience with forging these steels for nuclear components. It is also based on the inability to cast large ingots of the Grade 91 steel due to segregation during ingot solidification, thus restricting the possible mass of forging components and increasing the amount of welding required for completion of the RPV. Grade 91 steel is also prone to weld cracking and must be post-weld heat treated to ensure adequate high-temperature strength. There are also questions about the ability to produce, and very importantly, verify the through thickness properties of thick sections of Grade 91 material. The availability of large components, ease of fabrication, and nuclear service experience with the A508 and A533 steels strongly favor their use in the RPV for the VHTR. Lowering the gas outlet temperature for the VHTR to 750°C from 950 to 1000°C, proposed in early concept studies, further strengthens the justification for this material selection. This steel is allowed in the ASME Boiler and Pressure Vessel Code for nuclear service up to 371°C (700°F); certain excursions above that

[Pseudo-Bartter syndrome as manifestation of cystic fibrosis with DF508 mutation].

PubMed

Galaviz-Ballesteros, María de Jesús; Acosta-Rodríguez-Bueno, Carlos Patricio; Consuelo-Sánchez, Alejandra; Franco-Álvarez, Isidro; Olalla-Mora, Odilo Iván; Vázquez-Frias, Rodrigo

Pseudo Bartter syndrome (PBS) is defined as hypokalaemic hypochloraemic metabolic alkalosis in the absence of renal tubular pathology. Children with cystic fibrosis (CF) are at risk of developing electrolyte abnormalities and even PBS may occur. 5 months old female infant with a history of two events of dehydration with vomit, refusal to eat, chronic cough, polyuria, malnutrition, metabolic alkalosis, hypokalemia, hyponatremia, hypochloremia and acute renal failure. Chronic cough study was performed, discarding pulmonary tuberculosis, gastroesophageal reflux disease and impaired swallowing. PBS was diagnosed due to hypokalaemic hypochloraemic metabolic alkalosis in the absence of renal tubular pathology. CF was corroborated by electrolytes in sweat and through molecular analysis of the delta F508 mutation. This is one of the few reported cases linking PBS and this mutation. In patients with hyponatremic dehydration episodes with hypokalaemic hypochloraemic metabolic alkalosis, PBS should be considered as differential diagnosis. CF could be presented as PBS, mainly in patients younger than 2 years. Copyright © 2016 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Purification and characterization of native and recombinant SaPIN2a, a plant sieve element-localized proteinase inhibitor.

PubMed

Wang, Zhen-Yu; Ding, Ling-Wen; Ge, Zhi-Juan; Wang, Zhaoyu; Wang, Fanghai; Li, Ning; Xu, Zeng-Fu

2007-01-01

SaPIN2a encodes a proteinase inhibitor in nightshade (Solanum americanum), which is specifically localized to the enucleate sieve elements. It has been proposed to play an important role in phloem development by regulating proteolysis in sieve elements. In this study, we purified and characterized native SaPIN2a from nightshade stems and recombinant SaPIN2a expressed in Escherichia coli. Purified native SaPIN2a was found as a charge isomer family of homodimers, and was weakly glycosylated. Native SaPIN2a significantly inhibited serine proteinases such as trypsin, chymotrypsin, and subtilisin, with the most potent inhibitory activity on subtilisin. It did not inhibit cysteine proteinase papain and aspartic proteinase cathepsin D. Recombinant SaPIN2a had a strong inhibitory effect on chymotrypsin, but its inhibitory activities toward trypsin and especially toward subtilisin were greatly reduced. In addition, native SaPIN2a can effectively inhibit midgut trypsin-like activities from Trichoplusia ni and Spodoptera litura larvae, suggesting a potential for the production of insect-resistant transgenic plants.

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...

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...

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...

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...

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...

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...

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...

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...

∆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.

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...

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

Structure and specificity of a new class of Ca2+-independent housekeeping sortase from Streptomyces avermitilis provide insights into its non-canonical substrate preference

PubMed Central

Das, Sreetama; Pawale, Vijaykumar S.; Dadireddy, Venkatareddy; Singh, Avinash Kumar; Ramakumar, Suryanarayanarao; Roy, Rajendra P.

2017-01-01

Surface proteins in Gram-positive bacteria are incorporated into the cell wall through a peptide ligation reaction catalyzed by transpeptidase sortase. Six main classes (A–F) of sortase have been identified of which class A sortase is meant for housekeeping functions. The prototypic housekeeping sortase A (SaSrtA) from Staphylococcus aureus cleaves LPXTG-containing proteins at the scissile T–G peptide bond and ligates protein-LPXT to the terminal Gly residue of the nascent cross-bridge of peptidoglycan lipid II precursor. Sortase-mediated ligation (“sortagging”) of LPXTG-containing substrates and Gly-terminated nucleophiles occurs in vitro as well as in cellulo in the presence of Ca2+ and has been applied extensively for protein conjugations. Although the majority of applications emanate from SaSrtA, low catalytic efficiency, LPXTG specificity restriction, and Ca2+ requirement (particularly for in cellulo applications) remain a drawback. Given that Gram-positive bacteria genomes encode a variety of sortases, natural sortase mining can be a viable complementary approach akin to engineering of wild-type SaSrtA. Here, we describe the structure and specificity of a new class E sortase (SavSrtE) annotated to perform housekeeping roles in Streptomyces avermitilis. Biochemical experiments define the attributes of an optimum peptide substrate, demonstrate Ca2+-independent activity, and provide insights about contrasting functional characteristics of SavSrtE and SaSrtA. Crystal structure, substrate docking, and mutagenesis experiments have identified a critical residue that dictates the preference for a non-canonical LAXTG recognition motif over LPXTG. These results have implications for rational tailoring of substrate tolerance in sortases. Besides, Ca2+-independent orthogonal specificity of SavSrtE is likely to expand the sortagging toolkit. PMID:28270507

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.

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...

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...

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 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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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.

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...

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...

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...

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...

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...

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...

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...

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

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.

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...

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.

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.

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...

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...

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...

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...

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...

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.

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...

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...

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...

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...

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...

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...

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...

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

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. ...

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...

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...

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...

An x-ray diffraction study of microstructural deformation induced by cyclic loading of selected steels

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

Fourspring, P.M.; Pangborn, R.N.

1997-12-31

X-ray double crystal diffractometry (XRDCD) was used to assess cyclic microstructural deformation in a face centered cubic (fcc) steel (AISI304) and a body centered cubic (bcc) steel (SA508 class 2). The objectives of the investigation were to determine if XRDCD could be used effectively to monitor cyclic microstructural deformation in polycrystalline Fe alloys and to study the distribution of the microstructural deformation induced by cyclic loading in these alloys. The approach used in the investigation was to induce fatigue damage in a material and to characterize the resulting microstructural deformation at discrete fractions of the fatigue life of the material.more » Also, characterization of microstructural deformation was carried out to identify differences in the accumulation of damage from the surface to the bulk, focusing on the following three regions: near surface (0--10 {micro}m), subsurface (10--300 {micro}m), and bulk. Characterization of the subsurface region was performed only on the AISI304 material because of the limited availability of the SA508 material. The results from the XRDCD data indicate a measurable change induced by fatigue from the initial state to subsequent states of both the AISI304 and the SA508 materials. Therefore, the XRDCD technique was shown to be sensitive to the microstructural deformation caused by fatigue in steels; thus, the technique can be used to monitor fatigue damage in steels.« less

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.

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.

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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.

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

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...

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...

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...

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 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...

Vibration analysis of the SA349/2 helicopter

NASA Technical Reports Server (NTRS)

Heffernan, Ruth; Precetti, Dominique; Johnson, Wayne

1991-01-01

Helicopter airframe vibration is examined using calculations and measurements for the SA349/2 research helicopter. The hub loads, which transmit excitations to the fuselage, are predicted using a comprehensive rotorcraft analysis and correlated with measuring hub loads. The predicted and measured hub loads are then coupled with finite element models representing the SA349/2 fuselage. The resulting vertical acceleration at the pilot seat is examined. Adjustments are made to the airframe structural models to examine the sensitivity of predicted vertical acceleration to the model. Changes of a few percent to the damping and frequency of specific models lead to large reductions in predicted vibration, and to major improvements in the correlations with measured pilot-seat vertical acceleration.

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.

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...

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...

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...

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...

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...

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.

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...

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...

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...

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...

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...

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

Chromomycin SA analogs from a marine-derived Streptomyces sp.

PubMed Central

Hu, Youcai; Espindola, Ana Paula D. M; Stewart, Nathan A.; Wei, Shuguang; Posner, Bruce A.; MacMillan, John B.

2011-01-01

Two chromomycin SA analogs, chromomycin SA3 and chromomycin SA2, along with deacetylchromomycin A3 and five previously reported chromomycin analogs were isolated from a marine-derived Streptomyces sp. The structures of the new compounds were determined by spectroscopic methods including 1D and 2D NMR techniques, HRMS and chemical methods. Chromomycin SA3 and chromomycin SA2 are the first naturally occuring chromomycin analogs with truncated side-chains. Biological evaluation of chromomycin analogs for cytotoxicity against two non-small cell lung cancer (NSCLC) cell-lines, A549 and HCC44, demonstrated a decrease in cytotoxicity for the truncated sides chain chromomycin analogs. PMID:21807523

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...

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...

Multiple slips effects on MHD SA-Al2O3 and SA-Cu non-Newtonian nanofluids flow over a stretching cylinder in porous medium with radiation and chemical reaction

NASA Astrophysics Data System (ADS)

Tlili, I.; Khan, W. A.; Khan, I.

2018-03-01

The purpose of this communication is to examine the collective influence of velocity, and thermal slips on magnetohydrodyanmics (MHD) SA-Al2O3 and SA-Cu non-Newtonian nanofluids flow over a stretching cylinder in porous medium together with thermal radiation and chemical reaction effects. Sodium Alginate (SA-NaAlg) is taken as non-Newtonian base fluid. Two types of nanoparticles alumina or aluminum oxide (Al2O3) and copper (Cu) are suspended in sodium alginate (SA) which is taken as base fluid, an example of non-Newtonian Casson fluid. The formulated nonlinear partial differential equations with auxiliary boundary conditions are transformed into non-dimensional form by applying suitable similarity transformations. The resulting dimensionless problem is solved numerically using shooting and fourth order Runge-Kutta method. The impacts of various thermophysical parameters on local skin-friction, local Nusselt number, temperature and velocity are analyzed through graphs as well as in tabular form and discussed in detail. A comparison between SA-Al2O3 and SA-Cu nanofluids is clearly shown and in limiting sense the present results are compared with published results from literature. The results show that with magnetic parameter, skin-friction and Nusselt number both decreased, and Nusselt numbers are the highest in case of Al2O3 than Cu nanoparticles.

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...

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.

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.

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.

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

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.

Detergent enhances binding of a secreted HLA-A2 molecule to solid phase peptides.

PubMed

Tussey, L G; Frelinger, J A

1991-11-01

We have constructed a secreted analogue (sA2) of the human class I molecule HLA-A2. sA2 was affinity purified both in the presence and absence of detergent and the effects of detergent on the magnitude and specificity of A2 binding to solid phase peptides tested. sA2 purified in the presence of detergent and detergent-solubilized A2 are shown to function comparably in the binding of the synthetic peptide M.Y + 57-68, a known T-cell epitope derived from the influenza A matrix protein. The molecules binding to M.Y + 57-68 typically represent 8% to 10% of the added protein. In contrast, less than 1% of sA2 protein purified in the absence of detergent binds M.Y + 57-68. This reduced binding is not due to a change in the affinity of sA2 for M.Y + 57-68. Addition of detergent at various stages of the purification and iodination procedures indicates that the longer the sA2 molecules are exposed to detergent the better they bind. However, the concentration of detergent during the actual binding assay does not appear to be critical. We also find that while the sA2-detergent and the sA2-no detergent molecules differ in the extent to which they bind various peptides, they do not differ in their patterns of binding. We conclude that detergent probably does not influence the specificity of class I/peptide binding but does increase the number of sA2 molecules that can participate in the binding of peptide either by generating and stabilizing "empty" sA2 molecules or by stabilizing a structure that is more amenable to binding peptide.

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.

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

Self-Certified Sickness Absence among Young Municipal Employees-Changes from 2002 to 2016 and Occupational Class Differences.

PubMed

Sumanen, Hilla; Pietiläinen, Olli; Mänty, Minna

2017-09-26

We examined changes in self-certified, one-to-three day sickness absence (SA) among young employees from 2002 to 2016 and the magnitude of occupational class differences during that period. All 18-34-year-old employees of the City of Helsinki, Finland were included (2002-2016, n = ~11,725 per year). Employer's personnel and SA registers were used. Occupational class was categorized to four groups. Changes in self-certified SA from 2002 to 2016 were analyzed with Joinpoint regression and the magnitudes of occupational class differences were estimated with the relative index of inequality (RII). Most of the trends first increased and turned to decrease in 2007/2010. Managers and professionals had the least amount of SA, but steadily increasing trends were observed among men. Self-certified SA followed only partially the typical socioeconomic gradient, as routine non-manuals had the highest levels of SA. The magnitude of occupational class differences in self-certified SA was stable during the study period only among women. Self-certified SA and occupational class differences have increased in recent years among men in the lower occupational classes. Socioeconomic differences exist in self-certified SA among young employees, but gradient is only partial. Overall, high amounts of self-certified SA especially in the lower occupational classes require further studies and preventive measures.

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...

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...

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.

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...

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...

A mobile diabetes management and educational system for type-2 diabetics in Saudi Arabia (SAED).

PubMed

Alotaibi, Mohammed M; Istepanian, Robert; Philip, Nada

2016-01-01

Diabetes is a chronic disease, with high prevalence across many nations, which is characterized by elevated level of blood glucose and risk of acute and chronic complication. The Kingdom of Saudi Arabia (KSA) has one of the highest levels of diabetes prevalence globally. It is well-known that the treatment of diabetes is complex process and requires both lifestyle change and clear pharmacologic treatment plan. To avoid the complication from diabetes, the effective behavioural change and extensive education and self-management is one of the key approaches to alleviate such complications. However, this process is lengthy and expensive. The recent studies on the user of smart phone technologies for diabetes self-management have proven to be an effective tool in controlling hemoglobin (HbA1c) levels especially in type-2 diabetic (T2D) patients. However, to date no reported study addressed the effectiveness of this approach in the in Saudi patients. This study investigates the impact of using mobile health technologies for the self-management of diabetes in Saudi Arabia. In this study, an intelligent mobile diabetes management system (SAED), tailored for T2D patients in KSA was developed. A pilot study of the SAED system was conducted in Saudi Arabia with 20 diabetic patients for 6 months duration. The patients were randomly categorized into a control group who did not use the SAED system and an intervention group whom used the SAED system for their diabetes management during this period. At the end of the follow-up period, the HbA1c levels in the patients in both groups were measure together with a diabetes knowledge test was also conducted to test the diabetes awareness of the patients. The results of SAED pilot study showed that the patients in the intervention group were able to significantly decrease their HbA1c levels compared to the control group. The SAED system also enhanced the diabetes awareness amongst the patients in the intervention group during the trial

Structural and functional characterization of methicillin-resistant Staphylococcus aureus's class IIb fructose 1,6-bisphosphate aldolase.

PubMed

Capodagli, Glenn C; Lee, Stephen A; Boehm, Kyle J; Brady, Kristin M; Pegan, Scott D

2014-12-09

Staphylococcus aureus is one of the most common nosocomial sources of soft-tissue and skin infections and has more recently become prevalent in the community setting as well. Since the use of penicillins to combat S. aureus infections in the 1940s, the bacterium has been notorious for developing resistances to antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA). With the persistence of MRSA as well as many other drug resistant bacteria and parasites, there is a growing need to focus on new pharmacological targets. Recently, class II fructose 1,6-bisphosphate aldolases (FBAs) have garnered attention to fill this role. Regrettably, scarce biochemical data and no structural data are currently available for the class II FBA found in MRSA (SaFBA). With the recent finding of a flexible active site zinc-binding loop (Z-Loop) in class IIa FBAs and its potential for broad spectrum class II FBA inhibition, the lack of information regarding this feature of class IIb FBAs, such as SaFBA, has been limiting for further Z-loop inhibitor development. Therefore, we elucidated the crystal structure of SaFBA to 2.1 Å allowing for a more direct structural analysis of SaFBA. Furthermore, we determined the KM for one of SaFBA's substrates, fructose 1,6-bisphosphate, as well as performed mode of inhibition studies for an inhibitor that takes advantage of the Z-loop's flexibility. Together the data offers insight into a class IIb FBA from a pervasively drug resistant bacterium and a comparison of Z-loops and other features between the different subtypes of class II FBAs.

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.

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

Study on underclad cracking in nuclear reactor vessel steels

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

Horiya, T.; Takeda, T.; Yamato, K.

1985-02-01

Susceptibility to underclad cracking in nuclear reactor vessel steels, such as SA533 Grade B Class 1 and SA508 Class 2, was studied in detail. A convenient simulation test method using simulated HAZ specimens of small size has been developed for quantitative evaluation of susceptibility to underclad cracks. The method can predict precisely the cracking behavior in weldments of steels with relative low crack susceptibility. The effect of chemical compositions on susceptibility to the cracking was examined systematically using the developed simulation test method and the following index was obtained from the test results: U = 20(V) + 7(C) + 4(Mo)more » + (Cr) + (Cu) - 0.5(Mn) + 1.5 log(X) X = Al . . . Al/2N less than or equal to 1 X = 2N . . . Al/2N > 1 It was confirmed that the new index (U) is useful for the prediction of crack susceptibility of the nuclear vessel steels; i.e., no crack initiation is detected in weldments in the roller bend test for steels having U value below 0.90.« less

Structural and functional characterization of methicillin-resistant Staphylococcus aureus’s class IIb fructose 1,6-bisphosphate aldolase

DOE PAGES

Capodagli, Glenn C.; Lee, Stephen A.; Boehm, Kyle J.; ...

2014-11-12

Staphylococcus aureus is one of the most common nosocomial sources of soft-tissue and skin infections and has more recently become prevalent in the community setting as well. Since the use of penicillins to combat S. aureus infections in the 1940s, the bacterium has been notorious for developing resistances to antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA). With the persistence of MRSA as well as many other drug resistant bacteria and parasites, there is a growing need to focus on new pharmacological targets. Recently, class II fructose 1,6-bisphosphate aldolases (FBAs) have garnered attention to fill this role. Regrettably, scarce biochemical datamore » and no structural data are currently available for the class II FBA found in MRSA (SaFBA). With the recent finding of a flexible active site zinc-binding loop (Z-Loop) in class IIa FBAs and its potential for broad spectrum class II FBA inhibition, the lack of information regarding this feature of class IIb FBAs, such as SaFBA, has been limiting for further Z-loop inhibitor development. Therefore, we elucidated the crystal structure of SaFBA to 2.1 Å allowing for a more direct structural analysis of SaFBA. Furthermore, we determined the KM for one of SaFBA’s substrates, fructose 1,6-bisphosphate, as well as performed mode of inhibition studies for an inhibitor that takes advantage of the Z-loop’s flexibility. Altogether the data offers insight into a class IIb FBA from a pervasively drug resistant bacterium and a comparison of Z-loops and other features between the different subtypes of class II FBAs.« less

Structural and functional characterization of methicillin-resistant Staphylococcus aureus’s class IIb fructose 1,6-bisphosphate aldolase

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

Capodagli, Glenn C.; Lee, Stephen A.; Boehm, Kyle J.

Staphylococcus aureus is one of the most common nosocomial sources of soft-tissue and skin infections and has more recently become prevalent in the community setting as well. Since the use of penicillins to combat S. aureus infections in the 1940s, the bacterium has been notorious for developing resistances to antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA). With the persistence of MRSA as well as many other drug resistant bacteria and parasites, there is a growing need to focus on new pharmacological targets. Recently, class II fructose 1,6-bisphosphate aldolases (FBAs) have garnered attention to fill this role. Regrettably, scarce biochemical datamore » and no structural data are currently available for the class II FBA found in MRSA (SaFBA). With the recent finding of a flexible active site zinc-binding loop (Z-Loop) in class IIa FBAs and its potential for broad spectrum class II FBA inhibition, the lack of information regarding this feature of class IIb FBAs, such as SaFBA, has been limiting for further Z-loop inhibitor development. Therefore, we elucidated the crystal structure of SaFBA to 2.1 Å allowing for a more direct structural analysis of SaFBA. Furthermore, we determined the KM for one of SaFBA’s substrates, fructose 1,6-bisphosphate, as well as performed mode of inhibition studies for an inhibitor that takes advantage of the Z-loop’s flexibility. Altogether the data offers insight into a class IIb FBA from a pervasively drug resistant bacterium and a comparison of Z-loops and other features between the different subtypes of class II FBAs.« less

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.

saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription.

PubMed

Portnoy, Victoria; Lin, Szu Hua Sharon; Li, Kathy H; Burlingame, Alma; Hu, Zheng-Hui; Li, Hao; Li, Long-Cheng

2016-03-01

Small activating RNAs (saRNAs) targeting specific promoter regions are able to stimulate gene expression at the transcriptional level, a phenomenon known as RNA activation (RNAa). It is known that RNAa depends on Ago2 and is associated with epigenetic changes at the target promoters. However, the precise molecular mechanism of RNAa remains elusive. Using human CDKN1A (p21) as a model gene, we characterized the molecular nature of RNAa. We show that saRNAs guide Ago2 to and associate with target promoters. saRNA-loaded Ago2 facilitates the assembly of an RNA-induced transcriptional activation (RITA) complex, which, in addition to saRNA-Ago2 complex, includes RHA and CTR9, the latter being a component of the PAF1 complex. RITA interacts with RNA polymerase II to stimulate transcription initiation and productive elongation, accompanied by monoubiquitination of histone 2B. Our results establish the existence of a cellular RNA-guided genome-targeting and transcriptional activation mechanism and provide important new mechanistic insights into the RNAa process.

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...

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...

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...

Synergistic streptococcal phage λSA2 and B30 endolysins kill streptococci in cow milk and in a mouse model of mastitis.

PubMed

Schmelcher, Mathias; Powell, Anne M; Camp, Mary J; Pohl, Calvin S; Donovan, David M

2015-10-01

Bovine mastitis results in billion dollar losses annually in the USA alone. Streptococci are among the most relevant causative agents of this disease. Conventional antibiotic therapy is often unsuccessful and contributes to development of antibiotic resistance. Bacteriophage endolysins represent a new class of antimicrobials against these bacteria. In this work, we characterized the endolysins (lysins) of the streptococcal phages λSA2 and B30 and evaluated their potential as anti-mastitis agents. When tested in vitro against live streptococci, both enzymes exhibited near-optimum lytic activities at ionic strengths, pH, and Ca(2+) concentrations consistent with cow milk. When tested in combination in a checkerboard assay, the lysins were found to exhibit strong synergy. The λSA2 lysin displayed high activity in milk against Streptococcus dysgalactiae (reduction of CFU/ml by 3.5 log units at 100 μg/ml), Streptococcus agalactiae (2 log), and Streptococcus uberis (4 log), whereas the B30 lysin was less effective. In a mouse model of bovine mastitis, both enzymes significantly reduced intramammary concentrations of all three streptococcal species (except for B30 vs. S. dysgalactiae), and the effects on mammary gland wet weights and TNFα concentrations were consistent with these findings. Unexpectedly, the synergistic effect determined for the two enzymes in vitro was not observed in the mouse model. Overall, our results illustrate the potential of endolysins for treatment of Streptococcus-induced bovine mastitis.

Synergistic streptococcal phage λSA2 and B30 endolysins kill streptococci in cow milk and in a mouse model of mastitis

PubMed Central

Schmelcher, Mathias; Powell, Anne M.; Camp, Mary J.; Pohl, Calvin S.; Donovan, David M.

2015-01-01

Bovine mastitis results in billion dollar losses annually in the United States alone. Streptococci are among the most relevant causative agents of this disease. Conventional antibiotic therapy is often unsuccessful and contributes to development of antibiotic resistance. Bacteriophage endolysins represent a new class of antimicrobials against these bacteria. In this work, we characterized the endolysins (lysins) of the streptococcal phages λSA2 and B30 and evaluated their potential as anti-mastitis agents. When tested in vitro against live streptococci, both enzymes exhibited near-optimum lytic activities at ionic strengths, pH, and Ca2+ concentrations consistent with cow milk. When tested in combination in a checkerboard assay, the lysins were found to exhibit strong synergy. The λSA2 lysin displayed high activity in milk against Streptococcus dysgalactiae (reduction of CFU/ml by 3.5 log units at 100 μg/ml), Streptococcus agalactiae (2 log), and Streptococcus uberis (4 log), whereas the B30 lysin was less effective. In a mouse model of bovine mastitis, both enzymes significantly reduced intramammary concentrations of all three streptococcal species (except for B30 vs. S. dysgalactiae), and the effects on mammary gland wet weights and TNFα concentrations were consistent with these findings. Unexpectedly, the synergistic effect determined for the two enzymes in vitro was not observed in the mouse model. Overall, our results illustrate the potential of endolysins for treatment of Streptococcus-induced bovine mastitis. PMID:25895090

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

A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR.

PubMed

Tosco, A; De Gregorio, F; Esposito, S; De Stefano, D; Sana, I; Ferrari, E; Sepe, A; Salvadori, L; Buonpensiero, P; Di Pasqua, A; Grassia, R; Leone, C A; Guido, S; De Rosa, G; Lusa, S; Bona, G; Stoll, G; Maiuri, M C; Mehta, A; Kroemer, G; Maiuri, L; Raia, V

2016-08-01

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts 'on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment.

Application of positron annihilation lineshape analysis to fatigue damage and thermal embrittlement for nuclear plant materials

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

Uchida, M.; Ohta, Y.; Nakamura, N.

1995-08-01

Positron annihilation (PA) lineshape analysis is sensitive to detect microstructural defects such as vacancies and dislocations. The authors are developing a portable system and applying this technique to nuclear power plant material evaluations; fatigue damage in type 316 stainless steel and SA508 low alloy steel, and thermal embrittlement in duplex stainless steel. The PA technique was found to be sensitive in the early fatigue life (up to 10%), but showed a little sensitivity for later stages of the fatigue life in both type 316 stainless steel and SA508 ferritic steel. Type 316 steel showed a higher PA sensitivity than SA508more » since the initial SA508 microstructure already contained a high dislocation density in the as-received state. The PA parameter increased as a fraction of aging time in CF8M samples aged at 350 C and 400 C, but didn`t change much in CF8 samples.« less

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...

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...

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.

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...

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

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

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

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...

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...

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.

77 FR 58002 - Airworthiness Directives; Turbomeca S.A. Turboshaft Engines

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-19

... Airworthiness Directives; Turbomeca S.A. Turboshaft Engines AGENCY: Federal Aviation Administration (FAA), DOT... Turbomeca S.A. Arriel 2B and 2B1 turboshaft engines. That AD currently requires accomplishment of the TU166 modification. This new AD requires adding the Arriel 2S2 and 2C2 engines to the applicability of engines...

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...

An x-ray diffraction study of microstructural deformation induced by cyclic loading of selected steels

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

Fourspring, P.M.; Pangborn, R.N.

1996-06-01

X-ray double crystal diffractometry (XRDCD) was used to assess cyclic microstructural deformation in a face centered cubic (fcc) steel (AISI304) and a body centered cubic (bcc) steel (SA508 class 2). The first objective of the investigation was to determine if XRDCD could be used to effectively monitor cyclic microstructural deformation in polycrystalline Fe alloys. A second objective was to study the microstructural deformation induced by cyclic loading of polycrystalline Fe alloys. The approach used in the investigation was to induce fatigue damage in a material and to characterize the resulting microstructural deformation at discrete fractions of the fatigue life ofmore » the material. Also, characterization of microstructural deformation was carried out to identify differences in the accumulation of damage from the surface to the bulk, focusing on the following three regions: near surface (0--10 {micro}m), subsurface (10--300 {micro}m), and bulk. Characterization of the subsurface region was performed only on the AISI304 material because of the limited availability of the SA508 material. The results from the XRDCD data indicate a measurable change induced by fatigue from the initial state to subsequent states of both the AISI304 and the SA508 materials. Therefore, the XRDCD technique was shown to be sensitive to the microstructural deformation caused by fatigue in steels; thus, the technique can be used to monitor fatigue damage in steels. In addition, for the AISI304 material, the level of cyclic microstructural deformation in the bulk material was found to be greater than the level in the near surface material. In contrast, previous investigations have shown that the deformation is greater in the near surface than the bulk for Al alloys and bcc Fe alloys.« less

An x-ray diffraction study of microstructural deformation induced by cyclic loading of selected steel

NASA Astrophysics Data System (ADS)

Fourspring, Patrick Michael

X-ray double crystal diffractometry (XRDCD) and X-ray scanning diffractometry (XRSD) were used to assess cyclic microstructural deformation in a face centered cubic (fcc) steel (AISI304) and a body centered cubic (bcc) steel (SA508 class 2). The objectives of the investigation were to determine if X-ray diffraction could be used effectively to monitor cyclic microstructural deformation in polycrystalline Fe alloys and to study the distribution of the microstructural deformation induced by cyclic loading in these alloys. The approach used in the investigation was to induce fatigue damage in a material and to characterize the resulting microstructural deformation at discrete fractions of the fatigue life of the material. Also, characterization of microstructural deformation was carried out to identify differences in the accumulation of damage from the surface to the bulk, focusing on the following three regions: near surface (0-10 mum), subsurface (10-300 mum), and bulk. Characterization of the subsurface region was performed only on the AISI304 material because of the limited availability of the SA508 material. The results from the XRDCD data indicate a measurable change induced by fatigue from the initial state to subsequent states of both the AISI304 and the SA508 materials. The results from the XRSD data show similar but less coherent trends than the results from the XRDCD data. Therefore, the XRDCD technique was shown to be sensitive to the microstructural deformation caused by fatigue in steels; thus, the technique can be used to monitor fatigue damage in steels. In addition, for the AISI304 material, the level of cyclic microstructural deformation in the bulk material was found to be greater than the level in the near surface material. In contrast, previous investigations have shown that the deformation is greater in the near surface than the bulk for Al alloys and bcc Fe alloys.

A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR

PubMed Central

Tosco, A; De Gregorio, F; Esposito, S; De Stefano, D; Sana, I; Ferrari, E; Sepe, A; Salvadori, L; Buonpensiero, P; Di Pasqua, A; Grassia, R; Leone, C A; Guido, S; De Rosa, G; Lusa, S; Bona, G; Stoll, G; Maiuri, M C; Mehta, A; Kroemer, G; Maiuri, L; Raia, V

2016-01-01

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts ‘on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment. PMID:27035618

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...

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

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...

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...

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...

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...

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...

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

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...

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...

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...

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...

A novel functional class 2 integron in clinical Proteus mirabilis isolates.

PubMed

Wei, Quhao; Hu, Qingfeng; Li, Shanshan; Lu, Huoyang; Chen, Guoqiang; Shen, Beiqiong; Zhang, Ping; Zhou, Yonglie

2014-04-01

To describe a novel functional class 2 integron that was found in clinical Proteus mirabilis isolates. Class 1 and 2 integrons were screened by PCR in 153 clinical Proteus isolates. The variable regions of class 1 and 2 integrons were determined by restriction analysis and sequencing. The mutations of internal stop codons in class 2 integrons and their common promoters were also determined by sequencing. Enterobacterial repetitive intergenic consensus (ERIC)-PCR was used to analyse the phylogenetic relations of class 2 integron-positive P. mirabilis isolates. Class 1 integrons were detected in 96 (63%) of 153 Proteus isolates: eight different gene cassette arrays were detected, including dfrA32-ereA1-aadA2, which was detected for the first time in P. mirabilis. Class 2 integrons were detected in 101 (66%) of 153 Proteus isolates: four different gene cassette arrays were detected, including dfrA1-catB2-sat2-aadA1, which was detected for the first time in a class 2 integron. A novel functional class 2 integron was detected in 38 P. mirabilis isolates with a common promoter (-35 TTTAAT|16 bp|-10 TAAAGT). The variable region of this functional class 2 integron contained dfrA14 and three novel open reading frames with unknown functions. Very similar ERIC-PCR fingerprinting patterns were detected in these 38 P. mirabilis isolates and were different from other class 2 integron-positive isolates. A novel functional class 2 integron was found for the first time in P. mirabilis. These functional class 2 integron-harbouring P. mirabilis isolates were likely to be clonally spread in our hospital.

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...

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...

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...

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

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.

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...

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...

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...

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...

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...

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...

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

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.

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.

Production of an extracellular thermohalophilic lipase from a moderately halophilic bacterium, Salinivibrio sp. strain SA-2.

PubMed

Amoozegar, Mohammad Ali; Salehghamari, Ensieh; Khajeh, Khosro; Kabiri, Mahbube; Naddaf, Saied

2008-06-01

Fifty strains of moderately halophilic bacteria were isolated from various salty environments in Iran. A strain designated as SA-2 was shown to be the best producer of extracellular lipase and was selected for further studies. Biochemical and physiological characterization along with 16S rDNA sequence analysis placed SA-2 in the genus Salinivibrio. The optimum salt, pH, temperature and aeration for enzyme production were 0.1 M KCl, pH 8, 35 degrees C and 150 rpm, respectively. The enzyme production was synchronized bacterial growth and reached a maximum level during the early-stationary phase in the basal medium containing 1 M NaCl. Triacylglycerols enhanced lipase production, while carbohydrates had inhibitory effects on it. The maximum lipase activity was obtained at pH 7.5, 50 degrees C and CaCl(2) concentration of 0.01 M. The enzyme was stable at pH range of 7.5-8 and retained 90% of its activity at 80 degrees C for 30 min. Different concentrations of NaNO(3), Na(2)SO(4), KCl and NaCl had no affect on lipase stability for 3 h. These results suggest that the lipase secreted by Salinivibrio sp. strain SA-2 is industrially important from the perspective of its tolerance to a broad temperature range, its moderate thermoactivity and its high tolerance to a wide range of salt concentrations (0-3 M NaCl).

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...

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.

Interrelationships between education, occupational class and income as determinants of sickness absence among young employees in 2002-2007 and 2008-2013.

PubMed

Sumanen, Hilla; Pietiläinen, Olli; Lahti, Jouni; Lahelma, Eero; Rahkonen, Ossi

2015-04-08

A low socioeconomic position (SEP) is consistently associated with ill health, sickness absence (SA) and permanent disability, but studies among young employees are lacking. We examined the interrelationships between education, occupational class and income as determinants of SA among 25-34-year-old employees. We also examined, whether the association between SEP and SA varied over time in 2002-2007 and 2008-2013. The analyses covered young, 25-34-year-old women and men employed by the City of Helsinki over the time periods 2002-2007 and 2008-2013. Four-level education and occupational class classifications were used, as well as income quartiles. The outcome measure was the number of annual SA days. Education had the strongest and most consistent independent association with SA among women and men in both periods under study. Occupational class had weaker independent and less consistent association with SA. Income had an independent association with SA, which strengthened over time among the men. The interrelationships between the SEP indicators and SA were partly explained by prior or mediated through subsequent SEP indicators. Socioeconomic differences followed only partially a gradient for occupational class and also for income among men. Preventive measures to reduce the risk of SA should be considered, especially among young employees with a basic or lower-secondary education.

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...

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...

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...

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...

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...

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.

78 FR 34284 - Airworthiness Directives; Turbomeca S.A. Turboshaft Engines

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-07

... Turbomeca S.A. Arriel 2D turboshaft engines. The existing AD currently requires replacing the..., MA. For information on the availability of this material at the FAA, call 781-238-7125. Examining the..., January 31, 2013), for all Turbomeca S.A. Arriel 2D turboshaft engines. That AD requires replacing the HMU...

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

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...

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...

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...

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...

Biodegradable mixed MPEG-SS-2SA/TPGS micelles for triggered intracellular release of paclitaxel and reversing multidrug resistance

PubMed Central

Dong, Kai; Yan, Yan; Wang, Pengchong; Shi, Xianpeng; Zhang, Lu; Wang, Ke; Xing, Jianfeng; Dong, Yalin

2016-01-01

In this study, a type of multifunctional mixed micelles were prepared by a novel biodegradable amphiphilic polymer (MPEG-SS-2SA) and a multidrug resistance (MDR) reversal agent (d-α-tocopheryl polyethylene glycol succinate, TPGS). The mixed micelles could achieve rapid intracellular drug release and reversal of MDR. First, the amphiphilic polymer, MPEG-SS-2SA, was synthesized through disulfide bonds between poly (ethylene glycol) monomethyl ether (MPEG) and stearic acid (SA). The structure of the obtained polymer was similar to poly (ethylene glycol)-phosphatidylethanolamine (PEG-PE). Then the mixed micelles, MPEG-SS-2SA/TPGS, were prepared by MPEG-SS-2SA and TPGS through the thin film hydration method and loaded paclitaxel (PTX) as the model drug. The in vitro release study revealed that the mixed micelles could rapidly release PTX within 24 h under a reductive environment because of the breaking of disulfide bonds. In cell experiments, the mixed micelles significantly inhibited the activity of mitochondrial respiratory complex II, also reduced the mitochondrial membrane potential, and the content of adenosine triphosphate, thus effectively inhibiting the efflux of PTX from cells. Moreover, in the confocal laser scanning microscopy, cellular uptake and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assays, the MPEG-SS-2SA/TPGS micelles achieved faster release and more uptake of PTX in Michigan Cancer Foundation-7/PTX cells and showed better antitumor effects as compared with the insensitive control. In conclusion, the biodegradable mixed micelles, MPEG-SS-2SA/TPGS, could be potential vehicles for delivering hydrophobic chemotherapeutic drugs in MDR cancer therapy. PMID:27785018

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

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).

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.

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...

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...

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...

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...

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...

75 FR 59060 - Airworthiness Directives; Turboméca S.A. ARRIEL 2B Turboshaft Engines

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-27

... Airworthiness Directives; Turbom[eacute]ca S.A. ARRIEL 2B Turboshaft Engines AGENCY: Federal Aviation... turboshaft engines. That AD currently requires initial and repetitive inspections, cleaning, lubrication, and... engines that incorporate modification TU 132. That AD also provides an optional terminating action for the...

Immunogenicity of a Japanese encephalitis chimeric virus vaccine as a booster dose after primary vaccination with SA14-14-2 vaccine in Thai children.

PubMed

Janewongwirot, Pakpoom; Puthanakit, Thanyawee; Anugulruengkitt, Suvaporn; Jantarabenjakul, Watsamon; Phasomsap, Chayapa; Chumket, Sompong; Yoksan, Sutee; Pancharoen, Chitsanu

2016-10-17

Japanese Encephalitis chimeric virus vaccine (JE-CV) and SA14-14-2 vaccine are live-attenuated JE vaccines produced from the same virus strain. Data on interchangeability is limited. To evaluate the immunogenicity and safety of JE-CV booster after primary vaccination with SA14-14-2 vaccine. This study was an open-label clinical trial in Thai children who had received a primary SA14-14-2 vaccination at 12-24monthsbefore enrollment (ClinicalTrials.gov NCT02602652). JE-CV was administered. A 50% plaque reduction neutralization test (PRNT 50 ) against three virus strains; JE-CV, SA-14-14-2andwild-type JE virus was measured before and 28-days post vaccination. The laboratory was performed at PRNT 50 titers ⩾10 (1/dil) were considered seroprotective against JE. Geometric mean titer (GMT) of PRNT 50 was calculated. Adverse events were observed for 28days. From March 2014 to June 2015, 50 children (64% male) were enrolled. Mean age and duration after primary vaccination was 26.9 (SD 4.6) and 12.8 (SD 2.7) months, respectively. The proportion of participants who had PRNT 50 pre and post-booster vaccination were 92% and 96% against JE-CV virus, 56% and 98% against SA-14-14-2 strain and 70% and 98% against wild-type JE virus, respectively. Solicited injection site reactions including erythema, pain and swelling occurred in 18%, 10% and 4% of subjects, respectively. Four children (8%) had fever (⩾37.7Celsius). Eight children (16%) had adverse events, which were not related to the vaccine. AJE-CV booster dose is highly immunogenic and safe among children who previously received SA14-14-2 vaccine. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

Genetic determinants restricting the reassortment of heterologous NSP2 genes into the simian rotavirus SA11 genome.

PubMed

Mingo, Rebecca; Zhang, Shu; Long, Courtney P; LaConte, Leslie E W; McDonald, Sarah M

2017-08-24

Rotaviruses (RVs) can evolve through the process of reassortment, whereby the 11 double-stranded RNA genome segments are exchanged among strains during co-infection. However, reassortment is limited in cases where the genes or encoded proteins of co-infecting strains are functionally incompatible. In this study, we employed a helper virus-based reverse genetics system to identify NSP2 gene regions that correlate with restricted reassortment into simian RV strain SA11. We show that SA11 reassortants with NSP2 genes from human RV strains Wa or DS-1 were efficiently rescued and exhibit no detectable replication defects. However, we could not rescue an SA11 reassortant with a human RV strain AU-1 NSP2 gene, which differs from that of SA11 by 186 nucleotides (36 amino acids). To map restriction determinants, we engineered viruses to contain chimeric NSP2 genes in which specific regions of AU-1 sequence were substituted with SA11 sequence. We show that a region spanning AU-1 NSP2 gene nucleotides 784-820 is critical for the observed restriction; yet additional determinants reside in other gene regions. In silico and in vitro analyses were used to predict how the 784-820 region may impact NSP2 gene/protein function, thereby informing an understanding of the reassortment restriction mechanism.

Suppression or knockout of SaF/SaM overcomes the Sa-mediated hybrid male sterility in rice.

PubMed

Xie, Yongyao; Niu, Baixiao; Long, Yunming; Li, Gousi; Tang, Jintao; Zhang, Yaling; Ren, Ding; Liu, Yao-Guang; Chen, Letian

2017-09-01

Hybrids between the indica and japonica subspecies of rice (Oryza sativa) are usually sterile, which hinders utilization of heterosis in the inter-subspecific hybrid breeding. The complex locus Sa comprises two adjacently located genes, SaF and SaM, which interact to cause abortion of pollen grains carrying the japonica allele in japonica-indica hybrids. Here we showed that silencing of SaF or SaM by RNA interference restored male fertility in indica-japonica hybrids with heterozygous Sa. We further used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-based genome editing to knockout the SaF and SaM alleles, respectively, of an indica rice line to create hybrid-compatible lines. The resultant artificial neutral alleles did not affect pollen viability and other agricultural traits, but did break down the reproductive barrier in the hybrids. We found that some rice lines have natural neutral allele Sa-n, which was compatible with the typical japonica or indica Sa alleles in hybrids. Our results demonstrate that SaF and SaM are required for hybrid male sterility, but are not essential for pollen development. This study provides effective approaches for the generation of hybrid-compatible lines by knocking out the Sa locus or using the natural Sa-n allele to overcome hybrid male sterility in rice breeding. © 2017 The Authors. Bioelectromagnetics published by Wiley Periodicals, Inc. © 2017 Institute of Botany, Chinese Academy of Sciences.

SaOS-2 cell response to macro-porous boron-incorporated TiO2 coating prepared by micro-arc oxidation on titanium.

PubMed

Huang, Qianli; Elkhooly, Tarek A; Liu, Xujie; Zhang, Ranran; Yang, Xing; Shen, Zhijian; Feng, Qingling

2016-10-01

The aims of the present study were to develop boron-incorporated TiO2 coating (B-TiO2 coating) through micro-arc oxidation (MAO) and subsequently evaluate the effect of boron incorporation on the in vitro biological performance of the coatings. The physicochemical properties of B-TiO2 coating and its response to osteoblast like cells (SaOS-2) were investigated compared to the control group without boron (TiO2 coating). The morphological and X-ray diffraction results showed that both coatings exhibited similar surface topography and phase composition, respectively. However, the incorporation of B led to an enhancement in the surface hydrophilicity of B-TiO2 coating. The spreading of SaOS-2 cells on B-TiO2 coating was faster than that on TiO2 coating. The proliferation rate of SaOS-2 cells cultured on B-TiO2 decreased after 5days of culture compared to that on TiO2 coating. SaOS-2 cells cultured on B-TiO2 coating exhibited an enhanced alkaline phosphatase (ALP) activity, Collagen I synthesis and in vitro mineralization compared to those on TiO2 coating. The present findings suggest that B-TiO2 coating is a promising candidate surface for orthopedic implants. Copyright © 2016 Elsevier B.V. All rights reserved.

Cellular Immune Responses to Live Attenuated Japanese Encephalitis (JE) Vaccine SA14-14-2 in Adults in a JE/Dengue Co-Endemic Area.

PubMed

Turtle, Lance; Tatullo, Filippo; Bali, Tanushka; Ravi, Vasanthapuram; Soni, Mohammed; Chan, Sajesh; Chib, Savita; Venkataswamy, Manjunatha M; Fadnis, Prachi; Yaïch, Mansour; Fernandez, Stefan; Klenerman, Paul; Satchidanandam, Vijaya; Solomon, Tom

2017-01-01

Japanese encephalitis (JE) virus (JEV) causes severe epidemic encephalitis across Asia, for which the live attenuated vaccine SA14-14-2 is being used increasingly. JEV is a flavivirus, and is closely related to dengue virus (DENV), which is co-endemic in many parts of Asia, with clinically relevant interactions. There is no information on the human T cell response to SA14-14-2, or whether responses to SA14-14-2 cross-react with DENV. We used live attenuated JE vaccine SA14-14-2 as a model for studying T cell responses to JEV infection in adults, and to determine whether these T cell responses are cross-reactive with DENV, and other flaviviruses. We conducted a single arm, open label clinical trial (registration: clinicaltrials.gov NCT01656200) to study T cell responses to SA14-14-2 in adults in South India, an area endemic for JE and dengue. Ten out of 16 (62.5%) participants seroconverted to JEV SA14-14-2, and geometric mean neutralising antibody (NAb) titre was 18.5. Proliferation responses were commonly present before vaccination in the absence of NAb, indicating a likely high degree of previous flavivirus exposure. Thirteen of 15 (87%) participants made T cell interferon-gamma (IFNγ) responses against JEV proteins. In four subjects tested, at least some T cell epitopes mapped cross-reacted with DENV and other flaviviruses. JEV SA14-14-2 was more immunogenic for T cell IFNγ than for NAb in adults in this JE/DENV co-endemic area. The proliferation positive, NAb negative combination may represent a new marker of long term immunity/exposure to JE. T cell responses can cross-react between JE vaccine and DENV in a co-endemic area, illustrating a need for greater knowledge on such responses to inform the development of next-generation vaccines effective against both diseases. clinicaltrials.gov (NCT01656200).

Measurements by a Vector Network Analyzer at 325 to 508 GHz

NASA Technical Reports Server (NTRS)

Fung, King Man; Samoska, Lorene; Chattopadhyay, Goutam; Gaier, Todd; Kangaslahti, Pekka; Pukala, David; Lau, Yuenie; Oleson, Charles; Denning, Anthony

2008-01-01

Recent experiments were performed in which return loss and insertion loss of waveguide test assemblies in the frequency range from 325 to 508 GHz were measured by use of a swept-frequency two-port vector network analyzer (VNA) test set. The experiments were part of a continuing effort to develop means of characterizing passive and active electronic components and systems operating at ever increasing frequencies. The waveguide test assemblies comprised WR-2.2 end sections collinear with WR-3.3 middle sections. The test set, assembled from commercially available components, included a 50-GHz VNA scattering- parameter test set and external signal synthesizers, augmented with recently developed frequency extenders, and further augmented with attenuators and amplifiers as needed to adjust radiofrequency and intermediate-frequency power levels between the aforementioned components. The tests included line-reflect-line calibration procedures, using WR-2.2 waveguide shims as the "line" standards and waveguide flange short circuits as the "reflect" standards. Calibrated dynamic ranges somewhat greater than about 20 dB for return loss and 35 dB for insertion loss were achieved. The measurement data of the test assemblies were found to substantially agree with results of computational simulations.

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...

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...

78 FR 39339 - Importer of Controlled Substances; Notice of Registration; SA INTL GMBH C/O., Sigma Aldrich Co., LLC

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-01

... Registration; SA INTL GMBH C/O., Sigma Aldrich Co., LLC By Notice dated March 20, 2013, and published in the Federal Register on March 28, 2013, 78 FR 19015, SA INTL GMBH C/O., Sigma Aldrich Co. LLC., 3500 Dekalb... registration of SA INTL GMBH C/O., Sigma Aldrich Co. LLC., to import the basic classes of controlled substances...

Effects of silica–gentamicin nanohybrids on osteogenic differentiation of human osteoblast-like SaOS-2 cells

PubMed Central

He, Wei; Mosselhy, Dina A; Li, Xiaoning; Yang, Xing; Yue, Lina; Hannula, Simo-Pekka

2018-01-01

Introduction In recent years, there has been an increasing interest in silica (SiO2) nanoparticles (NPs) as drug delivery systems. This interest is mainly attributed to the ease of their surface functionalization for drug loading. In orthopedic applications, gentamicin-loaded SiO2 NPs (nanohybrids) are frequently utilized for their prolonged antibacterial effects. Therefore, the possible adverse effects of SiO2–gentamicin nanohybrids on osteogenesis of bone-related cells should be thoroughly investigated to ensure safe applications. Materials and methods The effects of SiO2–gentamicin nanohybrids on the cell viability and osteogenic differentiation of human osteoblast-like SaOS-2 cells were investigated, together with native SiO2 NPs and free gentamicin. Results The results of Cell Count Kit-8 (CCK-8) assay show that both SiO2–gentamicin nanohybrids and native SiO2 NPs reduce cell viability of SaOS-2 cells in a dose-dependent manner. Regarding osteogenesis, SiO2–gentamicin nanohybrids and native SiO2 NPs at the concentration range of 31.25–125 μg/mL do not influence the osteogenic differentiation capacity of SaOS-2 cells. At a high concentration (250 μg/mL), both materials induce a lower expression of alkaline phosphatase (ALP) but an enhanced mineralization. Free gentamicin at concentrations of 6.26 and 9.65 μg/mL does not significantly influence the cell viability and osteogenic differentiation capacity of SaOS-2 cells. Conclusions The results of this study suggest that both SiO2–gentamicin nanohybrids and SiO2 NPs show cytotoxic effects to SaOS-2 cells. Further investigation on the effects of SiO2–gentamicin nanohybrids on the behaviors of stem cells or other regular osteoblasts should be conducted to make a full evaluation of the safety of SiO2–gentamicin nanohybrids in orthopedic applications. PMID:29445277

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

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...

77 FR 71491 - Airworthiness Directives; Turbomeca S.A. Turboshaft Engines

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-03

... Airworthiness Directives; Turbomeca S.A. Turboshaft Engines AGENCY: Federal Aviation Administration (FAA), DOT... Turbomeca S.A. Arriel 1E2, 1S, and 1S1 turboshaft engines. That AD currently requires a one-time inspection... 74 45 15. You may view this service information at the FAA, Engine & Propeller Directorate, 12 New...

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...

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...

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...

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...

Correlation of SA349/2 helicopter flight-test data with a comprehensive rotorcraft model

NASA Technical Reports Server (NTRS)

Yamauchi, Gloria K.; Heffernan, Ruth M.; Gaubert, Michel

1986-01-01

A comprehensive rotorcraft analysis model was used to predict blade aerodynamic and structural loads for comparison with flight test data. The data were obtained from an SA349/2 helicopter with an advanced geometry rotor. Sensitivity of the correlation to wake geometry, blade dynamics, and blade aerodynamic effects was investigated. Blade chordwise pressure coefficients were predicted for the blade transonic regimes using the model coupled with two finite-difference codes.

40 CFR 2.207 - Class determinations.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Confidentiality of Business Information § 2.207 Class determinations. (a) The General Counsel may make and issue a... items of business information; (2) One or more characteristics common to all such items of information... § 2.204(b)(1), § 2.204(d), § 2.205(d), or § 2.206. However, the existence of a class determination...

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...

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.

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...

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...

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...

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...

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...

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...

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.

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.

Microstructural examination of

NASA Astrophysics Data System (ADS)

Fukuoka, C.; Yoshizawa, H.; Nakagawa, Y. G.; Lapides, M. E.

1993-10-01

Fatigue tests were performed to examine how microstructural conditioning influences crack initiation and propagation in SA508 class 3 low-carbon steel. A 3-mm-long crack was introduced in compact tension (CT) fatigue test specimens under four different loads in order to obtain crack tip plastic zones at different stress intensity factor ranges, ΔK = 18, 36, 54, and 72 MPa√m. The microstructure of the plastic zones around the crack tip were examined by trans- mission electron microscopy (TEM) and selected area electron diffraction (SAD). Micro- orientation of the dislocation cells in the plastic zones of all of the CT samples increased to 4 deg from the level of an as-received sample. Four-point bending fatigue tests were performed for plate shape samples with a large cyclic strain range. The SAD value of the bending samples was also 4 deg in the damaged area where cracks already initiated at an early stage of the fatigue process. These test results indicate that the microstructural conditioning is a prerequisite for the fatigue crack initiation and propagation in SA508. These observations may lead to better under- standing of how fatigue initiation processes transit to cracks.

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...

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...

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...

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.

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...

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...

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...

25 CFR 502.2 - Class I gaming.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 25 Indians 2 2011-04-01 2011-04-01 false Class I gaming. 502.2 Section 502.2 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS DEFINITIONS OF THIS CHAPTER § 502.2 Class I gaming. Class I gaming means: (a) Social games played solely for prizes of minimal value...

25 CFR 502.2 - Class I gaming.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 2 2010-04-01 2010-04-01 false Class I gaming. 502.2 Section 502.2 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS DEFINITIONS OF THIS CHAPTER § 502.2 Class I gaming. Class I gaming means: (a) Social games played solely for prizes of minimal value...

25 CFR 502.2 - Class I gaming.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 25 Indians 2 2012-04-01 2012-04-01 false Class I gaming. 502.2 Section 502.2 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS DEFINITIONS OF THIS CHAPTER § 502.2 Class I gaming. Class I gaming means: (a) Social games played solely for prizes of minimal value...

25 CFR 502.2 - Class I gaming.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 25 Indians 2 2013-04-01 2013-04-01 false Class I gaming. 502.2 Section 502.2 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS DEFINITIONS OF THIS CHAPTER § 502.2 Class I gaming. Class I gaming means: (a) Social games played solely for prizes of minimal value...

25 CFR 502.2 - Class I gaming.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 25 Indians 2 2014-04-01 2014-04-01 false Class I gaming. 502.2 Section 502.2 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS DEFINITIONS OF THIS CHAPTER § 502.2 Class I gaming. Class I gaming means: (a) Social games played solely for prizes of minimal value...

Enhanced CO2 sequestration by a novel microalga: Scenedesmus obliquus SA1 isolated from bio-diversity hotspot region of Assam, India.

PubMed

Basu, Samarpita; Roy, Abhijit Sarma; Mohanty, Kaustubha; Ghoshal, Aloke K

2013-09-01

The present study aimed to isolate a high CO2 and temperature tolerant microalga capable of sequestering CO2 from flue gas. Microalga strain SA1 was isolated from a freshwater body of Assam and identified as Scenedesmus obliquus (KC733762). At 13.8±1.5% CO2 and 25 °C, maximum biomass (4.975±0.003 g L(-1)) and maximum CO2 fixation rate (252.883±0.361 mg L(-1) d(-1)) were obtained which were higher than most of the relevant studies. At elevated temperature (40 °C) and 13.8±1.5% CO2 maximum biomass (0.883±0.001 g L(-1)) was obtained. The carbohydrate, protein, lipid, and chlorophyll content of the CO2 treated SA1 were 30.87±0.64%, 9.48±1.65%, 33.04±0.46% and 6.03±0.19% respectively, which were higher than previous reports. Thus, SA1 could prove to be a potential candidate for CO2 sequestration from flue gas as well as for the production of value added substances. Copyright © 2013 Elsevier Ltd. All rights reserved.

Entry, Descent and Landing Systems Analysis: Exploration Class Simulation Overview and Results

NASA Technical Reports Server (NTRS)

DwyerCianciolo, Alicia M.; Davis, Jody L.; Shidner, Jeremy D.; Powell, Richard W.

2010-01-01

NASA senior management commissioned the Entry, Descent and Landing Systems Analysis (EDL-SA) Study in 2008 to identify and roadmap the Entry, Descent and Landing (EDL) technology investments that the agency needed to make in order to successfully land large payloads at Mars for both robotic and exploration or human-scale missions. The year one exploration class mission activity considered technologies capable of delivering a 40-mt payload. This paper provides an overview of the exploration class mission study, including technologies considered, models developed and initial simulation results from the EDL-SA year one effort.

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...

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...

Comparison between instrumented precracked Charpy and compact specimen tests of carbon steels

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

Nanstad, R.K.

1980-01-01

The General Atomic Company High Temperature Gas-Cooled Reactor (HTGR) is housed within a prestressed concrete reactor vessel (PCRV). Various carbon steel structural members serve as closures at penetrations in the vessel. A program of testing and evaluation is underway to determine the need for reference fracture toughness (K/sub IR/) and indexing procedures for these materials as described in Appendix G to Section III, ASME Code for light water reactor steels. The materials of interest are carbon steel forgings (SA508, Class 1) and plates (SA537, Classes 1 and 2) as well as weldments of these steels. The fracture toughness behavior ismore » characterized with instrumented precracked Charpy V-votch specimens (PCVN) - slow-bend and dynamic - and compact specimens (10-mm and 25-mm thicknesses) using both linear elastic (ASTM E399) and elastic-plastic (equivalent Energy and J-Integral) analytical procedures. For the dynamic PCVN tests, force-time traces are analyzed according to the procedures of the Pressure Vessel Research Council (PVRC)/Metal Properties Council (MPC). Testing and analytical procedures are discussed and PCVN results are compared to those obtained with compact specimens.« less

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

PubMed Central

2013-01-01

Background Many genetic diseases are due to defects in protein trafficking where the mutant protein is recognized by the quality control systems, retained in the endoplasmic reticulum (ER), and degraded by the proteasome. In many cases, the mutant protein retains function if it can be trafficked to its proper cellular location. We have identified structurally diverse correctors that restore the trafficking and function of the most common mutation causing cystic fibrosis, F508del-CFTR. Most of these correctors do not act directly as ligands of CFTR, but indirectly on other pathways to promote folding and correction. We hypothesize that these proteostasis regulators may also correct other protein trafficking diseases. Methods To test our hypothesis, we used stable cell lines or transient transfection to express 2 well-studied trafficking disease mutations in each of 3 different proteins: the arginine-vasopressin receptor 2 (AVPR2, also known as V2R), the human ether-a-go-go-related gene (KCNH2, also known as hERG), and finally the sulfonylurea receptor 1 (ABCC8, also known as SUR1). We treated cells expressing these mutant proteins with 9 structurally diverse F508del-CFTR correctors that function through different cellular mechanisms and assessed whether correction occurred via immunoblotting and functional assays. Results were deemed significantly different from controls by a one-way ANOVA (p < 0.05). Results Here we show that F508del-CFTR correctors RDR1, KM60 and KM57 also correct some mutant alleles of other protein trafficking diseases. We also show that one corrector, the cardiac glycoside ouabain, was found to alter the glycosylation of all mutant alleles tested. Conclusions Correctors of F508del-CFTR trafficking might have broader applications to other protein trafficking diseases. PMID:23316740

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…

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...

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...

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...

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...

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...

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...

Spectroscopic Investigation of the Mechanisms Responsible for the Superior Stability of Hybrid Class 1/Class 2 CO 2 Sorbents: A New Class 4 Category

DOE PAGES

Wilfong, Walter Christopher; Kail, Brian W.; Jones, Christopher W.; ...

2016-05-04

Hybrid Class 1/Class 2 supported amine CO 2 sorbents demonstrate superior performance under practical steam conditions, yet their amine immobilization and stabilization mechanisms are unclear. Uncovering the interactions responsible for the sorbents’ robust features is critical for further improvements and can facilitate practical applications. We employ solid state 29Si CP-MAS and 2-D FSLG 1H– 13C CP HETCOR NMR spectroscopies to probe the overall molecular interactions of aminosilane/silica, polyamine [poly(ethylenimine), PEI]/silica, and hybrid aminosilane/PEI/silica sorbents. A unique, sequential impregnation sorbent preparation method is executed in a diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) setup to decouple amine binding mechanisms at themore » amine–silica interface from those within bulk amine layers. These mechanisms are correlated with each sorbents’ resistance to accelerated liquid H 2O and TGA steam treatments (H 2O stability) and to oxidative degradation (thermal stability). High percentages of CO 2 capture retained (PCR) and organic content retained (OCR) values after H 2O testing of N-(3-(trimethoxysilyl)propyl)ethylenediamine (TMPED)/PEI and (3-aminopropyl)trimethoxysilane (APTMS)/PEI hybrid sorbents are associated with a synergistic stabilizing effect of the amine species observed during oxidative degradation (thermal gravimetric analysis-differential scanning calorimetry, TGA-DSC). Solid state NMR spectroscopy reveals that the synergistic effect of the TMPED/PEI mixture is manifested by the formation of hydrogen-bonded PEI–NH 2···NH 2–TMPED and PEI–NH 2···HO–Si/O–Si–O (TMPED, T 2) linkages within the sorbent. DRIFTS further determines that PEI enhances the grafting of TMPED to silica and that PEI is dispersed among a stable network of polymerized TMPED in the bulk, utilizing H-bonded linkages. These findings provide the scientific basis for establishing a Class 4 category for aminosilane

On the validity of specific rate constants (kSA) in Fe0/H2O systems.

PubMed

Noubactep, C

2009-05-30

The validity of the specific reaction rate constants (k(SA)) in modelling contaminant removal in Fe(0)/H(2)O systems is questioned. It is shown that the current k(SA)-model does not consider the large reactive surface area provided by the in-situ formed oxide film, and thus the adsorptive interactions between contaminants and film materials. Furthermore, neither the dynamic nature of film formation nor the fact that the Fe(0) surface is shielded by the film is considered. Suggestions are made how the k(SA)-model could be further developed to meet its original goal.

MimoSA: a system for minimotif annotation

PubMed Central

2010-01-01

Background Minimotifs are short peptide sequences within one protein, which are recognized by other proteins or molecules. While there are now several minimotif databases, they are incomplete. There are reports of many minimotifs in the primary literature, which have yet to be annotated, while entirely novel minimotifs continue to be published on a weekly basis. Our recently proposed function and sequence syntax for minimotifs enables us to build a general tool that will facilitate structured annotation and management of minimotif data from the biomedical literature. Results We have built the MimoSA application for minimotif annotation. The application supports management of the Minimotif Miner database, literature tracking, and annotation of new minimotifs. MimoSA enables the visualization, organization, selection and editing functions of minimotifs and their attributes in the MnM database. For the literature components, Mimosa provides paper status tracking and scoring of papers for annotation through a freely available machine learning approach, which is based on word correlation. The paper scoring algorithm is also available as a separate program, TextMine. Form-driven annotation of minimotif attributes enables entry of new minimotifs into the MnM database. Several supporting features increase the efficiency of annotation. The layered architecture of MimoSA allows for extensibility by separating the functions of paper scoring, minimotif visualization, and database management. MimoSA is readily adaptable to other annotation efforts that manually curate literature into a MySQL database. Conclusions MimoSA is an extensible application that facilitates minimotif annotation and integrates with the Minimotif Miner database. We have built MimoSA as an application that integrates dynamic abstract scoring with a high performance relational model of minimotif syntax. MimoSA's TextMine, an efficient paper-scoring algorithm, can be used to dynamically rank papers with

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.

WRC bulletin. A review of underclad cracking in pressure-vessel components

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

Vinckier, A.G.; Pense, A.W.

1974-01-01

This review of cracking underneath the weld cladding is to determine what factors contribute to this condition, and to outline means for alleviating or eliminating this condition. Considerable data on manufacture, heat treatment, and cladding of heavy-section pressure-vessel steels for nuclear service are also included. Three factors in combination that promote underclad cracking are susceptible microstructure, favorable residual-stress pattern, and a thermal treatment bringing the steel into a critical temperature region (600-650/sup 0/C) where creep ductility is low. High-heat-input weld-overlay cladding produces the susceptible microstructure and residual-stress pattern and postweld heat treatment produces the critical temperature. Most underclad cracking wasmore » found in SA508 Class 2 steel forgings clad with one-layer submerged-arc strip electrodes or multi-electrode processes. It was not produced in SA533 Grade B plate or when multilayer overlay processes were used. Underclad cracking can be reduced or eliminated by a two-layer cladding technique, by controlling welding process variables (low heat input), renormalizing the sensitive HAZ region prior to heat treatment, by use of nonsusceptible materials, or by eliminating the postweld heat treatment. Results of a questionnaire survey are also included. 50 references. (DLC)« less

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...

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.

NEW YOUNG STAR CANDIDATES IN CG4 AND Sa101

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

Rebull, L. M.; Laine, S.; Laher, R.

2011-07-15

The CG4 and Sa101 regions together cover a region of {approx}0.5 deg{sup 2} in the vicinity of a 'cometary globule' that is part of the Gum Nebula. There are seven previously identified young stars in this region; we have searched for new young stars using mid- and far-infrared data (3.6-70 {mu}m) from the Spitzer Space Telescope, combined with ground-based optical data and near-infrared data from the Two Micron All Sky Survey. We find infrared excesses in all six of the previously identified young stars in our maps and identify 16 more candidate young stars based on apparent infrared excesses. Mostmore » (73%) of the new young stars are Class II objects. There is a tighter grouping of young stars and young star candidates in the Sa101 region, in contrast to the CG4 region, where there are fewer young stars and young star candidates, and they are more dispersed. Few likely young objects are found in the 'fingers' of the dust being disturbed by the ionization front from the heart of the Gum Nebula.« less

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

Revista de Saúde Pública in scientific publications on Violence and Health (1967-2015).

PubMed

Schraiber, Lilia Blima; Barros, Claudia; d'Oliveira, Ana Flávia Pires Lucas; Peres, Maria Fernanda Tourinho

2016-11-10

This article retrieved the publications from the Revista de Saúde Pública journal (from 1967 to 2015) on violence and health, on the SciELO and PubMed bases, by searching for the terms "violence", "suicide", "aggression", "bullying", and "external causes", registered in any part of the text. We found 130 articles (the first one published in 1974). We observed: increase of publications over time, with decrease in the last five years; similar production volume in lethal and non-lethal violence; later publication of the latter; few studies in qualitative research; mostly descriptive production; and visualization of the problem more by the acts than by contexts or motivations and aggressors. Social markers were little approached, appearing, from largest to smallest frequency, social class, gender, race/ethnicity, and generation. Human rights were little used and only recently used as analytical framework, connected more to gender than to social class. Although Revista de Saúde Pública has registered the theme in its publications, consolidating it as scientific production line, there is still great explanatory theoretical rarefaction and little intersectionality between violence, social inequalities, and human rights. RESUMO A produção da Revista de Saúde Pública (de 1967 até 2015) sobre violência e saúde foi recuperada nas bases SciELO e PubMed utilizando-se os termos "violência", "suicídio", "agressões", "bullying" e "causas externas", registrados em qualquer parte do texto. Foram encontrados 130 artigos (o primeiro deles publicado em 1974). Constatou-se: aumento das publicações no tempo, com decréscimo nos últimos cinco anos; volume similar de produção em violência letal e não letal; publicação mais tardia desta última; poucos estudos em pesquisa qualitativa; produção majoritariamente descritiva; e visibilização do problema, mais pelos atos que pelos contextos ou motivações e agressores. Os marcadores sociais foram pouco tematizados

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.

Saturn 1B launch vehicle flight evaluation report, SA-206, Skylab-2

NASA Technical Reports Server (NTRS)

1973-01-01

The performance evaluation of the SA-206 launch vehicle for the Skylab 2 launch is presented. Flight problems are identified, the causes are determined, and recommendations are made for appropriate corrective action. Summaries of launch operations and spacecraft performance are included. The significant events, failures, and anomalies are tabulated.

The Magnitude of Occupational Class Differences in Sickness Absence: 15-Year Trends among Young and Middle-Aged Municipal Employees.

PubMed

Sumanen, Hilla; Lahelma, Eero; Pietiläinen, Olli; Rahkonen, Ossi

2017-06-09

Background : Our aim was to examine the magnitude of relative occupational class differences in sickness absence (SA) days over a 15-year period among female and male municipal employees in two age-groups. Methods : 18-34 and 35-59-year-old employees of the City of Helsinki from 2002 to 2016 were included in our data ( n = ~37,500 per year). Occupational class was classified into four groups. The magnitude of relative occupational class differences in SA was studied using the relative index of inequality (RII). Results : The relative occupational class differences were larger among older than younger employees; the largest differences were among 35-59-year-old men. Among women in both age-groups the relative class differences remained stable during 2002-2016. Among younger and older men, the differences were larger during the beginning of study period than in the end. Among women in both age-groups the RII values were between 2.19 (95% confidence intervals (CI) 1.98, 2.42) and 3.60 (95% CI 3.28, 3.95). The corresponding differences varied from 3.74 (95% CI 3.13, 4.48) to 1.68 (95% CI 1.44, 1.97) among younger and from 6.43 (95% CI 5.85, 7.06) to 3.31 (95% CI 2.98, 3.68) among older men. Relative occupational class differences were persistent among employees irrespective of age group and gender. Preventive measures should be started at young age.

Four Distinct Subgroups of Self-Injurious Behavior among Chinese Adolescents: Findings from a Latent Class Analysis

PubMed Central

Xin, Xiuhong; Ming, Qingsen; Zhang, Jibiao; Wang, Yuping; Liu, Mingli; Yao, Shuqiao

2016-01-01

Self-injurious behavior (SIB) among adolescents is an important public health issue worldwide. It is still uncertain whether homogeneous subgroups of SIB can be identified and whether constellations of SIBs can co-occur due to the high heterogeneity of these behaviors. In this study, a cross-sectional study was conducted on a large school-based sample and latent class analysis was performed (n = 10,069, mean age = 15 years) to identify SIB classes based on 11 indicators falling under direct SIB (DSIB), indirect SIB (ISIB), and suicide attempts (SAs). Social and psychological characteristics of each subgroup were examined after controlling for age and gender. Results showed that a four-class model best fit the data and each class had a distinct pattern of co-occurrence of SIBs and external measures. Class 4 (the baseline/normative group, 65.3%) had a low probability of SIB. Class 3 (severe SIB group, 3.9%) had a high probability of SIB and the poorest social and psychological status. Class 1 (DSIB+SA group, 14.2%) had similar scores for external variables compared to class 3, and included a majority of girls [odds ratio (OR) = 1.94]. Class 2 (ISIB group, 16.6%) displayed moderate endorsement of ISIB items, and had a majority of boys and older adolescents (OR = 1.51). These findings suggest that SIB is a heterogeneous entity, but it may be best explained by four homogenous subgroups that display quantitative and qualitative differences. Findings in this study will improve our understanding on SIB and may facilitate the prevention and treatment of SIB. PMID:27392132

32 CFR 1639.2 - The claim for Class 2-D.

Code of Federal Regulations, 2011 CFR

2011-07-01

... National Defense Other Regulations Relating to National Defense SELECTIVE SERVICE SYSTEM CLASSIFICATION OF REGISTRANTS PREPARING FOR THE MINISTRY § 1639.2 The claim for Class 2-D. A claim to classification in Class 2-D must be made by the registrant in writing, such document being placed in his file folder. ...

32 CFR 1639.2 - The claim for Class 2-D.

Code of Federal Regulations, 2010 CFR

2010-07-01

... National Defense Other Regulations Relating to National Defense SELECTIVE SERVICE SYSTEM CLASSIFICATION OF REGISTRANTS PREPARING FOR THE MINISTRY § 1639.2 The claim for Class 2-D. A claim to classification in Class 2-D must be made by the registrant in writing, such document being placed in his file folder. ...

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

Microstructural examination of fatigue crack tip in high strength steel

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

Fukuoka, C.; Yoshizawa, H.; Nakagawa, Y.G.

1993-10-01

Fatigue tests were performed to examine how microstructural conditioning influences crack initiation and propagation in SA508 class 3 low-carbon steel. A 3-mm-long crack was introduced in compact tension (CT) fatigue test specimens under four different loads in order to obtain crack tip plastic zones at different stress intensity factor ranges, [Delta]K = 18, 36, 54, and 72 MPa[radical]m. The microstructure of the plastic zones around the crack tip were examined by transmission electron microscopy (TEM) and selected area electron diffraction (SAD). Micro-orientation of the dislocation cells in the plastic zones of all of the CT samples increased to 4 degmore » from the level of an as-received sample. Four-point bending fatigue tests were performed for plate shape samples with a large cyclic strain range. The SAD value of the bending samples was also 4 deg in the damaged area where cracks already initiated at an early stage of the fatigue process. These test results indicate that the microstructural conditioning is a prerequisite for the fatigue crack initiation and propagation in SA508. These observations may lead to better understanding of how fatigue initiation processes transit to cracks.« less

Bioremediation potential of a highly mercury resistant bacterial strain Sphingobium SA2 isolated from contaminated soil.

PubMed

Mahbub, Khandaker Rayhan; Krishnan, Kannan; Megharaj, Mallavarapu; Naidu, Ravi

2016-02-01

A mercury resistant bacterial strain, SA2, was isolated from soil contaminated with mercury. The 16S rRNA gene sequence of this isolate showed 99% sequence similarity to the genera Sphingobium and Sphingomonas of α-proteobacteria group. However, the isolate formed a distinct phyletic line with the genus Sphingobium suggesting the strain belongs to Sphingobium sp. Toxicity studies indicated resistance to high levels of mercury with estimated EC50 values 4.5 mg L(-1) and 44.15 mg L(-1) and MIC values 5.1 mg L(-1) and 48.48 mg L(-1) in minimal and rich media, respectively. The strain SA2 was able to volatilize mercury by producing mercuric reductase enzyme which makes it potential candidate for remediating mercury. ICP-QQQ-MS analysis of Hg supplemented culture solutions confirmed that almost 79% mercury in the culture suspension was volatilized in 6 h. A very small amount of mercury was observed to accumulate in cell pellets which was also evident according to ESEM-EDX analysis. The mercuric reductase gene merA was amplified and sequenced. The deduced amino acid sequence demonstrated sequence homology with α-proteobacteria and Ascomycota group. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice.

PubMed

Wilkerson, Jenny L; Ghosh, Sudeshna; Mustafa, Mohammed; Abdullah, Rehab A; Niphakis, Micah J; Cabrera, Roberto; Maldonado, Rafael L; Cravatt, Benjamin F; Lichtman, Aron H

2017-03-01

Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB) 1 and CB 2 receptors; however, only CB 2 receptors were necessary for the anti-edematous effects in the carrageenan assay. Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects. Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin. In conclusion, the results of the present

The Endocannabinoid Hydrolysis Inhibitor SA-57: Intrinsic Antinociceptive Effects, Augmented Morphine-induced Antinociception, and Attenuated Heroin Seeking Behavior in Mice

PubMed Central

Wilkerson, Jenny L.; Ghosh, Sudeshna; Mustafa, Mohammed; Abdullah, Rehab A.; Niphakis, Micah J.; Cabrera, Roberto; Maldonado, Rafael L.; Cravatt, Benjamin F.; Lichtman, Aron H.

2017-01-01

Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB)1 and CB2 receptors; however, only CB2 receptors were necessary for the anti-edematous effects in the carrageenan assay. Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects. Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin. In conclusion, the results of the present

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...

An Actin Depolymerizing Factor from the Halophyte Smooth Cordgrass, Spartina alterniflora (SaADF2) is Superior to its Rice homolog (OsADF2) in Conferring Drought and Salt Tolerance when Constitutively Overexpressed in Rice.

PubMed

Sengupta, Sonali; Mangu, Venkata; Sanchez, Luis; Bedre, Renesh; Joshi, Rohit; Rajasekaran, Kanniah; Baisakh, Niranjan

2018-05-31

Actin depolymerizing factors (ADFs) maintain the cellular actin network dynamics by regulating severing and disassembly of actin filaments in response to environmental cues. An ADF isolated from a monocot halophyte, Spartina alterniflora (SaADF2) imparted significantly higher level of drought and salinity tolerance when expressed in rice than its rice homologue OsADF2. SaADF2 differs from OsADF2 by a few amino acid residues, including a substitution in the regulatory phosphorylation site serine-6, which accounted for its weak interaction with OsCDPK6 (calcium dependent protein kinase), thus resulting in an increased efficacy of SaADF2 and enhanced cellular actin dynamics. SaADF2 overexpression preserved the actin filament organization better in rice protoplasts under desiccation stress. The predicted tertiary structure of SaADF2 showed a longer F-loop than OsADF2 that could have contributed to higher actin-binding affinity and rapid F-actin depolymerization in vitro by SaADF2. Rice transgenics constitutively overexpressing SaADF2 (SaADF2-OE) showed better growth, relative water content, and photosynthetic and agronomic yield under drought conditions than wild-type (WT) and OsADF2 overexpressers (OsADF2-OE). SaADF2-OE preserved intact grana structure after prolonged drought stress, whereas WT and OsADF2-OE presented highly damaged and disorganized grana stacking. The possible role of ADF2 in transactivation was hypothesized from the comparative transcriptome analyses, which showed significant differential expression of stress-related genes including interacting partners of ADF2 in overexpressers. Identification of a complex, differential interactome decorating or regulating stress-modulated cytoskeleton driven by ADF isoforms will lead us to key pathways that could be potential target for genome engineering to improve abiotic stress tolerance in agricultural crops. This article is protected by copyright. All rights reserved. This article is protected by copyright

Aerodynamic effect of a honeycomb rotor tip shroud on a 50.8-centimeter-tip-diameter core turbine

NASA Technical Reports Server (NTRS)

Moffitt, T. P.; Whitney, W. J.

1983-01-01

A 50.8-cm-tip-diameter turbine equipped with a rotor tip shroud of hexagonal cell (or honeycomb) cross section has been tested in warm air (416 K) for a range of shroud coolant to primary flow rates. Test results were also obtained for the same turbine operated with a solid shroud for comparison. The results showed that the combined effect of the honeycomb shroud and the coolant flow was to cause a reduction of 2.8 points in efficiency at design speed, pressure ratio, and coolant flow rate. With the coolant system inactivated, the honeycomb shroud caused a decrease in efficiency of 2.3 points. These results and those obtained from a small reference turbine indicate that the dominant factor governing honeycomb tip shroud loss is the ratio of honeycomb depth to blade span. The loss results of the two shrouds could be correlated on this basis. The same honeycomb and coolant effects are expected to occur for the hot (2200 K) version of this turbine.

Upregulation of cell proliferation via Shc and ERK1/2 MAPK signaling in SaOS-2 osteoblasts grown on magnesium alloy surface coating with tricalcium phosphate.

PubMed

Jiang, Tianlong; Guo, Lei; Ni, Shenghui; Zhao, Yuyan

2015-04-01