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

NASA Astrophysics Data System (ADS)

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

1997-04-01

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

Effects of radiation on crack-initiation and crack-arrest toughness for SA508 Cl. 3 steel

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

Milella, P.P.; Pini, A.; Iskander, S.K.

1995-11-01

An investigation was carried out to determine the effects of neutron irradiation, conducted in several different test-reactors at approximately 280 C, on the mechanical properties of an SA508 Class 3 carbon steel ring forging produced in Italy as a prototype of a pressurized water reactor vessel. The research had two primary objectives: (1) to investigate the effect of a various levels of neutron irradiation (fluences from 1 to 5.5 10{sup 19} n/cm{sup 2} [E>1 MeV]) on the strength, initiation and arrest toughness and ductile-to-brittle transition temperature, and (2) to determine if Charpy data and empirical prediction equations provide conservative estimatesmore » of irradiation effects on the K{sub Ic} and K{sub Ia} transition curves. The paper reports results from tension, Charpy V-notch (CVN) fracture toughness, and crack-arrest tests performed on both unirradiated and irradiated material. It was found that both Charpy V-notch transition temperature shifts and two prediction equations provided conservative estimates of shifts in fracture initiation and fracture arrest transition temperatures for the steel investigated. The 54 C shift of the Charpy V-notch transition curves at a fluence level of 5.5 10{sup 19} n/cm{sup 2} suggests the possibility of extending the component life beyond the common 40 year design life.« 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.

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.

A modified correlation between KJIC and Charpy V-notch impact energy of Chinese SA508-III steel at the upper shelf

NASA Astrophysics Data System (ADS)

Li, Xiangqing; Song, Yuxuan; Ding, Zhenyu; Bao, Shiyi; Gao, Zengliang

2018-07-01

The fracture toughness plays a significant role in the structural integrity assessment of reactor pressure vessels (RPVs) in service temperature. The Charpy V-notch (CVN) impact test is used to estimate fracture toughness (KIC or KJIC) indirectly since universal fracture toughness tests are costly, sophisticated and frequently invalid. In this study, a modified correlation which based on the typical model of KJIC-CVN at the upper shelf was established for Chinese SA508-III steel. Thereinto, the effect of test temperature (T) was directly considered in the correlation. To assess the accuracy of fracture toughness when calculating from the value of Charpy-V notch impact energy by using the modified correlation, both the Charpy-V notch impact tests and fracture toughness tests for Chinese SA508-III steel were conducted at different temperatures (100 °C, 150 °C, 200 °C, 250 °C and 320 °C). The results showed that the modified correlation exhibited the high precision for estimating fracture toughness of Chinese SA508-III steel and the relative error for tested and estimated results is within 8%, which is lower than that of other correlations.

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.

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

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

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

1997-04-01

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

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

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

Logsdon, W.A.

1982-03-01

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

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

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

Using SA508/533 for the HTGR Vessel Material

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

Larry Demick

2012-06-01

This paper examines the influence of High Temperature Gas-cooled Reactor (HTGR) module power rating and normal operating temperatures on the use of SA508/533 material for the HTGR vessel system with emphasis on the calculated times at elevated temperatures approaching or exceeding ASME Code Service Limits (Levels B&C) to which the reactor pressure vessel could be exposed during postulated pressurized and depressurized conduction cooldown events over its design lifetime.

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

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.

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.

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

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

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

2006-07-01

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

Fatigue crack growth in SA508-CL2 steel in a high temperature, high purity water environment

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

Gerber, T.L.; Heald, J.D.; Kiss, E.

1974-10-01

Fatigue crack growth tests were conducted with 1 in. plate specimens of SA508-CL 2 steel in room temperature air, 550$sup 0$F air and in a 550$sup 0$F, high purity, water environment. Zero-tension load controlled tests were run at cyclic frequencies as low as 0.037 CPM. Results show that growth rates in the simulated Boiling Water Reactor (BWR) water environment are faster than growth rates observed in 550$sup 0$F air and these rates are faster than the room temperature rate. In the BWR water environment, lowering the cyclic frequency from 0.37 to 0.037 CPM caused only a slight increase in themore » fatigue crack growth rate. All growth rates measured in these tests were below the upper bound design curve presented in Section XI of the ASME Code. (auth)« less

Mathematical Modeling of High-Temperature Constitutive Equations and Hot Processing Maps for As-Cast SA508-3 Steel

NASA Astrophysics Data System (ADS)

Sui, Dashan; Wang, Tao; Zhu, Lingling; Gao, Liang; Cui, Zhenshan

2016-11-01

The hot deformation behavior and hot workability characteristics of as-cast SA508-3 steel were studied by modeling the constitutive equations and developing hot processing maps. The isothermal compression experiments were carried out at temperatures of 950°C, 1050°C, 1150°C, and 1250°C and strain rates of 0.001 s-1, 0.01 s-1, 0.1 s-1, and 1 s-1 respectively. The two-stage flow stress models were established through the classical theories on work hardening and softening, and the solution of activation energy for hot deformation was 355.0 kJ mol-1 K-1. Based on the dynamic material model, the power dissipation and instability maps were developed separately at strains of 0.2, 0.4, 0.6 and 0.8. The power dissipation rate increases with both the increase of temperature and the decrease of strain rate, and the instable region mainly appears on the conditions of low temperature and high strain rate. The optimal hot working parameters for as-cast SA508-3 steel are 1050-1200°C/0.001-0.1 s-1, with about 25-40% peak efficiency of power dissipation.

Interface bonding of SA508-3 steel under deformation and high temperature diffusion

NASA Astrophysics Data System (ADS)

Xu, Bin; Shao, Chunjuan; Sun, Mingyue

2018-05-01

There are mainly two parameters affecting high temperature interface bonding: deformation and diffusion. To study these two parameters, interface bonding of SA508-3 bainitic steel at 1100°C are simulated by gleeble3500 thermal simulator. The results show that interface of SA508-3 steel can be bonded under deformation and high temperature. For a specimen pressed at 1100°C without further high temperature diffusion, a reduction ratio of 30% can make the interface begun to bond, but the interface is still part of the grain boundary and small grains exist near the interface. When reduction ratio reaches 50%, the interface can be completely bonded and the microstructure near the interface is the same as that of the base material. When deformation is small, long time diffusion can also help the interface bonding. The results show that when the diffusion time is long enough, the interface under small deformation can also be bonded. For a specimen holding for 24h at 1100°C, only 13% reduction ratio is enough for interface bonding.

Effects of Surface Roughness, Oxidation, and Temperature on the Emissivity of Reactor Pressure Vessel Alloys

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

King, J. L.; Jo, H.; Tirawat, R.

Thermal radiation will be an important mode of heat transfer in future high-temperature reactors and in off-normal high-temperature scenarios in present reactors. In this work, spectral directional emissivities of two reactor pressure vessel (RPV) candidate materials were measured at room temperature after exposure to high-temperature air. In the case of SA508 steel, significant increases in emissivity were observed due to oxidation. In the case of Grade 91 steel, only very small increases were observed under the tested conditions. Effects of roughness were also investigated. To study the effects of roughening, unexposed samples of SA508 and Grade 91 steel were roughenedmore » via one of either grinding or shot-peening before being measured. Significant increases were observed only in samples having roughness exceeding the roughness expected of RPV surfaces. While the emissivity increases for SA508 from oxidation were indeed significant, the measured emissivity coefficients were below that of values commonly used in heat transfer models. Based on the observed experimental data, recommendations for emissivity inputs for heat transfer simulations are provided.« less

Fracture toughness and fracture behavior of SA508-III steel at different temperatures

NASA Astrophysics Data System (ADS)

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

2014-12-01

The fracture toughness of SA508-III steel was studied in the temperature range from room temperature to 320°C using the J-integral method. The fracture behavior of the steel was also investigated. It was found that the conditional fracture toughness ( J Q) of the steel first decreased and then increased with increasing test temperature. The maximum and minimum values of J Q were 517.4 kJ/m2 at 25°C and 304.5 kJ/m2 at 180°C, respectively. Dynamic strain aging (DSA) was also observed to occur when the temperature exceeded 260°C with a certain strain rate. Both the dislocation density and the number of small dislocation cells effectively increased because of the occurrence of DSA; as a consequence, crack propagation was more strongly inhibited in the steel. Simultaneously, an increasing number of fine carbides precipitated under high stress at temperatures greater than 260°C. Thus, the deformation resistance of the steel was improved and the J Q was enhanced.

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.

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.

Spectral emissivity of candidate alloys for very high temperature reactors in high temperature air environment

NASA Astrophysics Data System (ADS)

Cao, G.; Weber, S. J.; Martin, S. O.; Sridharan, K.; Anderson, M. H.; Allen, T. R.

2013-10-01

Emissivity measurements for candidate alloys for very high temperature reactors were carried out in a custom-built experimental facility, capable of both efficient and reliable measurements of spectral emissivities of multiple samples at high temperatures. The alloys studied include 304 and 316 austenitic stainless steels, Alloy 617, and SA508 ferritic steel. The oxidation of alloys plays an important role in dictating emissivity values. The higher chromium content of 304 and 316 austenitic stainless steels, and Alloy 617 results in an oxide layer only of sub-micron thickness even at 700 °C and consequently the emissivity of these alloys remains low. In contrast, the low alloy SA508 ferritic steel which contains no chromium develops a thicker oxide layer, and consequently exhibits higher emissivity values.

Corrosion inhibition of steam generator tubesheet by Alloy 690 cladding in secondary side environments

NASA Astrophysics Data System (ADS)

Hur, Do Haeng; Choi, Myung Sik; Lee, Deok Hyun; Han, Jung Ho; Shim, Hee Sang

2013-11-01

Denting is a phenomenon that a steam generator tube is distorted by a volume expansion of corrosion products of the tube support and tubesheet materials adjacent to the tube. Although denting has been mitigated by a modification of the design and material of the tube support structures, it has been an inevitable concern in the crevice region of the top of tubesheet. This paper provides a new technology to prevent denting by cladding the secondary surface of the tubesheet with a corrosion resistant material. In this study, Alloy 690 material was cladded onto the surface of an SA508 tubesheet to a thickness of about 9 mm. The corrosion rates of the original SA508 tubesheet and the Alloy 690 clad material were measured in acidic and alkaline simulated environments. Using Alloy 690 cladding, the corrosion rate of the tubesheet within a magnetite sludge pile decreased by a factor of 680 in 0.1 M NiCl2 solution at 300 °C, and by a factor of 58 in 2 M NaOH solution at 315 °C. This means that denting can drastically be prevented by cladding the secondary tubesheet surface with corrosion resistant materials.

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

Current forgings and their properties for steam generator of nuclear plant

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

Tsukada, Hisashi; Suzuki, Komei; Kusuhashi, Mikio

1997-12-31

Current steel forgings for steam generator (SG) of PWR plant are reviewed in the aspect of design and material improvement. The following three items are introduced. The use of integral type steel forgings for the fabrication of steam generator enhances the structural integrity and makes easier fabrication and inspection including in-service inspection. The following examples of current integral type forgings developed by the Japan Steel Works, Ltd. (JSW) are introduced: (1) primary head integrated with nozzles, manways and supports; (2) steam drum head integrated with nozzle and handhole; (3) conical shell integrated with cylindrical sections and handholes. In order tomore » decrease the weight of steam generator, the high strength materials such as SA508, Cl.3a steel have been adopted in some cases. The properties of this steel are introduced and the chemistry and heat treatment condition are discussed. As one of the methods to minimize the macro- and micro-segregations, the use of vacuum carbon deoxidation (VCD), i.e. deoxidization of steel by gaseous CO reaction, with addition of Al for grain refining was investigated. The properties of SA508, Cl.3 steels with Low Si content are compared with those of conventional one.« less

Dynamic strain-aging effect on fracture toughness of vessel steels

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

Kang, S.S.; Kim, I.S.

1992-03-01

In this paper the effect of dynamic strain aging (DSA) on fracture is investigated on the quenched and tempered specimens of American Society of Mechanical Engineers (ASME) standard SA508 class 3 nuclear pressure vessel steel. Serrated flow by DSA is observed between 180 and 340{degrees}C at a tensile strain rate of 2.08 {times} 10{sup {minus}4}/s and 1.25 {times} 10{sup {minus}3}/s. The DSA causes a sharp rise in the ultimate tensile strength and a marked decrease in ductility. The DSA range shifts to higher temperatures with increased strain rates. The temperature and strain rate dependence of the onset of serrations yieldsmore » an activation energy of 16.2 kcal/mol, which suggests that the process is controlled by interstitial diffusion of carbon and nitrogen in ferrite. The J{sub i} value obtained from the direct current potential drop (DCPD) method, for true crack initiation, is lowered by DSA. The drop in J{sub i} at elevated temperatures may be because of the interaction of the interstitial impurities with dislocations at the crack front.« less

Nondestructive evaluation of fatigue damage on low alloy steel by magnetomechanical acoustic emission technique

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

Hiraasawa, T.; Saito, K.; Komura, I.

1995-08-01

A modified magnetomechanical acoustic emission (MAE) technique, denoted Pulse-MAE, in which the magnetization by current pulse was adopted, was newly developed and its applicability was assessed for the nondestructive detection and evaluation of fatigue damage in reactor pressure vessel steel SFVV2 and SA508 class2. MAE signals were measured with both conventional MAE and Pulse-MAE technique for fatigue damaged specimens having several damage fractions, and peak voltage ratio Vp/Vo, where Vp and Vo were the peak voltage for damaged and undamaged specimen respectively, was chosen as a measure. Vp/Vo was found to increase monotonously at the early stage of fatigue processmore » and the rate of increase in Vp/Vo during the fatigue process was larger in Pulse-MAE than conventional MAE. Therefore, Pulse-MAE technique proved to have higher sensitivity for the detection of fatigue damage compared with the conventional MAE and to have the potential of a practical technique for nondestructive detection and evaluation of fatigue damage in actual components.« less

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

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.

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.

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.

Metallurgical evaluation of a feedwater nozzle to safe-end weld

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

Bowerman, B.S.; Czajkowski, C.J.; Roberts, T.C.

1999-11-01

Weld cracks in safety class systems are a serious concern, because these systems are part of the primary barrier providing containment of radioactive coolant. Loss of weld integrity yields leaks, or, under catastrophic failure, can be the basis for a severe loss of coolant accident. A circumferential indication was found by ultrasonic examination (UT) in the N4A-2 inlet feedwater nozzle to safe-end weld during the second refueling outage of River Bend Station Unit 1 in March 1989. The indication, approximately 15cm (6in) long with a reported maximum depth of 0.5cm (0.1in), was located in the Alloy 182 weld butter onmore » the safe-end side of the weld. (The safe-end base metal was ASME SA 508 Class 1 carbon steel.) The reported characteristics of the UT indication were indicative of intergranular stress corrosion cracking. This indication was reexamined during the second and third fuel cycles in March 1990 and September 1991, respectively, and during the third refuel outage in November 1990. Crack growth was reported during each examination. The safe-end was replaced during the fourth refueling outage in the summer of 1992. The US Nuclear Regulatory Commission (NRC) subsequently contracted with Brookhaven National laboratory (BNL) to conduct a confirmatory investigation to establish the failure mode and determine the root causes of cracking in the safe-end weld.« less

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.

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.

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.

Materials Selection Criteria for Nuclear Power Applications: A Decision Algorithm

NASA Astrophysics Data System (ADS)

Rodríguez-Prieto, Álvaro; Camacho, Ana María; Sebastián, Miguel Ángel

2016-02-01

An innovative methodology based on stringency levels is proposed in this paper and improves the current selection method for structural materials used in demanding industrial applications. This paper describes a new approach for quantifying the stringency of materials requirements based on a novel deterministic algorithm to prevent potential failures. We have applied the new methodology to different standardized specifications used in pressure vessels design, such as SA-533 Grade B Cl.1, SA-508 Cl.3 (issued by the American Society of Mechanical Engineers), DIN 20MnMoNi55 (issued by the German Institute of Standardization) and 16MND5 (issued by the French Nuclear Commission) specifications and determine the influence of design code selection. This study is based on key scientific publications on the influence of chemical composition on the mechanical behavior of materials, which were not considered when the technological requirements were established in the aforementioned specifications. For this purpose, a new method to quantify the efficacy of each standard has been developed using a deterministic algorithm. The process of assigning relative weights was performed by consulting a panel of experts in materials selection for reactor pressure vessels to provide a more objective methodology; thus, the resulting mathematical calculations for quantitative analysis are greatly simplified. The final results show that steel DIN 20MnMoNi55 is the best material option. Additionally, more recently developed materials such as DIN 20MnMoNi55, 16MND5 and SA-508 Cl.3 exhibit mechanical requirements more stringent than SA-533 Grade B Cl.1. The methodology presented in this paper can be used as a decision tool in selection of materials for a wide range of applications.

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.

Fracture resistance of welded thick-walled high-pressure vessels in power plants. Report No. 2. Approach to evaluating static strength

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

Gorynin, I.V.; Filatov, V.M.; Ignatov, V.A.

1986-07-01

The authors examine data on the effect of defects on the fracture resistance of high-pressure vessels and their models obtained within the framework of the HSST program. Results of internal-pressure tests of two types of vessels with a wall thickness of 152 mm made from forgings of steels SA508 and SA533, as well as small vessels with a wall thickness of 11.5 and 23mm made of steel SA533 are shown. The authors state that testing thick-walled welded high-pressure vessels and thin-walled vessels with surface defects of different sizes has demonstrated that there are substantial static-strength reserves in structures designed bymore » existing domestic and foreign standards on the strength of power-plant equipment. A correction was proposed for the presently used method of calculating the resistance of highpressure vessels to brittle fracture that allows for the dimensions of the defects in relation to the type of vessel, the manufacturing technology, and the method of inspection.« less

Preparation of reconstituted Charpy V-notch impact specimens for generating pressure vessel steel fracture toughness data

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

Perrin, J.S.; Fromm, E.O.; Server, W.L.

1982-01-01

The arc stud welding process has been adapted for use in producing reconstituted Charpy V-notch impact specimens. In this process, each half of a tested and fractured Charpy specimen is used as the central region of a reconstituted specimen. End tabs are joined to one half of a fractured specimen by a specially designed stud welding apparatus. SA533B-1 and SA508-2 unirradiated and irradiated pressure vessel steel specimens have been produced. Both conventional and precracked reconstituted specimen data have been produced. Both types of data have been shown to be in excellent agreement with original specimen data. The arc stud weldingmore » process can therefore be used to increase the amount of data obtainable from a limited number of specimens or to obtain Charpy data when full size specimens cannot otherwise be obtained.« less

A morphometric assessment and classification of coral reef spur and groove morphology

NASA Astrophysics Data System (ADS)

Duce, S.; Vila-Concejo, A.; Hamylton, S. M.; Webster, J. M.; Bruce, E.; Beaman, R. J.

2016-07-01

Spurs and grooves (SaGs) are a common and important feature of coral reef fore slopes worldwide. However, they are difficult to access and hence their morphodynamics and formation are poorly understood. We use remote sensing, with extensive ground truthing, to measure SaG morphometrics and environmental factors at 11,430 grooves across 17 reefs in the southern Great Barrier Reef, Australia. We revealed strong positive correlations between groove length, orientation and wave exposure with longer, more closely-spaced grooves oriented easterly reflecting the dominant swell regime. Wave exposure was found to be the most important factor controlling SaG distribution and morphology. Gradient of the upper reef slope was also an important limiting factor, with SaGs less likely to develop in steeply sloping (> 5°) areas. We used a subset of the morphometric data (11 reefs) to statistically define four classes of SaG. This classification scheme was tested on the remaining six reefs. SaGs in the four classes differ in morphology, groove substrate and coral cover. These differences provide insights into SaG formation mechanisms with implications to reef platform growth and evolution. We hypothesize SaG formation is dominated by coral growth processes at two classes and erosion processes at one class. A fourth class may represent relic features formed earlier in the Holocene transgression. The classes are comparable with SaGs elsewhere, suggesting the classification could be applied globally with the addition of new classes if necessary. While further research is required, we show remotely sensed SaG morphometrics can provide useful insights into reef platform evolution.

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.

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

Additive effect of multiple pharmacological chaperones on maturation of CFTR processing mutants

PubMed Central

Wang, Ying; Loo, Tip W.; Bartlett, M. Claire; Clarke, David M.

2007-01-01

The most common cause of CF (cystic fibrosis) is the deletion of Phe508 (ΔF508) in the CFTR [CF TM (transmembrane) conductance regulator] chloride channel. One major problem with ΔF508 CFTR is that the protein is defective in folding so that little mature protein is delivered to the cell surface. Expression of ΔF508 CFTR in the presence of small molecules known as correctors or pharmacological chaperones can increase the level of mature protein. Unfortunately, the efficiency of corrector-induced maturation of ΔF508 CFTR is probably too low to have therapeutic value and approaches are needed to increase maturation efficiency. We postulated that expression of ΔF508 CFTR in the presence of multiple correctors that bound to different sites may have an additive effect on maturation. In support of this mechanism, we found that expression of P-glycoprotein (CFTR's sister protein) processing mutants in the presence of two compounds that bind to different sites (rhodamine B and Hoechst 33342) had an additive effect on maturation. Therefore we tested whether expression of ΔF508 CFTR in the presence of combinations of three different classes of corrector molecules would increase its maturation efficiency. It was found that the combination of the quinazoline VRT-325 together with the thiazole corr-2b or bisaminomethylbithiazole corr-4a doubled the steady-state maturation efficiency of ΔF508 CFTR (approx. 40% of total CFTR was mature protein) compared with expression in the presence of a single compound. The additive effect of the correctors on ΔF508 CFTR maturation suggests that they directly interact at different sites of the protein. PMID:17535157

Development of two socioeconomic indices for Saudi Arabia.

PubMed

AlOmar, Reem S; Parslow, Roger C; Law, Graham R

2018-06-26

Health and socioeconomic status (SES) are linked in studies worldwide. Measures of SES exist for many countries, however not for Saudi Arabia (SA). We describe two indices of area-based SES for SA. Routine census data has been used to construct two indices of SES at the geographically-delimited administrative region of Governorates in SA (n = 118). The data used included indicators of educational status, employment status, car and material ownership. A continuous measure of SES was constructed using exploratory factor analysis (EFA) and a categorical measure of SES using latent class analysis (LCA). Both indices were mapped by Governorates. The EFA identified three factors: The first explained 51.58% of the common variance within the interrelated factors, the second 15.14%, and the third 14.26%. These proportions were used in the formulation of the standard index. The scores were fixed to range from 100 for the affluent Governorate and 0 for the deprived. The LCA found a 4 class model as the best model fit. Class 1 was termed "affluent" and included 11.01% of Governorates, class 2 "upper middle class" (44.91%), class 3 "lower middle class" (33.05%) and class 4 "deprived" (11.01%). The populated urbanised Governorates were found to be the most affluent whereas the smaller rural Governorates were the most deprived. This is the first description of measures of SES in SA at a geographical level. Two measures have been successfully constructed and mapped. The maps show similar patterns suggesting validity. Both indices support the common perception of SES in SA.

Scalability of Robotic Controllers: Effects of Progressive Autonomy on Intelligence, Surveillance, and Reconnaissance Robotic Tasks

DTIC Science & Technology

2012-09-01

away from the MOCU. The semi-autonomous mode was preferred over the teleoperated mode for multitasking , maintaining SA, avoiding obstacles, and...0 23 Software with icons 0 0 0 0 2 25 Pull-down menu * 0 0 0 0 3 24 Graphics/drawing features in software packages* 3 8 1 4 3 8 Email 1 0 0 0 1...r. Navigate to the next waypoint or set of hash lines 5.27 5.08 6.25 s. Ability to multitask (operate/monitor robot and communicate on the radio

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

Conditioning monitoring by microstructural evaluation of cumulative fatigue damage

NASA Astrophysics Data System (ADS)

Fukuoka, C.; Nakagawa, Y. G.; Lance, J. J.; Pangborn, R. N.

1996-12-01

The objective of this work is to evaluate the damage induced below and above the fatigue limit (Δ σ t =360 MPa) in pressure vessel steels, such as SA508. Fatigue damage was induced in samples taken from an SA508 steel plate by various loading histories in order to examine the influence of prior cyclic loading below the fatigue limit. Cell-to-cell misorientation differences were measured by the selected area diffraction (SAD) method. Surface cracking was also studied by the replication method. Small cracks were observed after precycling both below and above the fatigue limit. It was, however, found that fatigue test bars had a longer lifetime after precycling below the fatigue limit, while precycling above the fatigue limit caused other specimens to fail even when subsequently cycled below the fatigue limit. Cell-to-cell misorientation usually increases with accumulation of fatigue damage, but it was found that the misorientations measured after precycling below the fatigue limit decreased again at the beginning of the subsequent cycling above the fatigue limit. It should be noted that the misorientation at failure was always about 4 to 5 deg, regardless of loading histories. Misorientation showed good correlation with the fatigue lifetime of the samples.

Vessel V-7 and V-8 repair and characterization of insert material. Final report

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

Domian, H.A.

1984-05-01

Pieces of Type SA508-2 steel, specially tempered to produce a high-impact-transition temperature, were welded in the side walls of Intermediate Test Vessels V-7 and V-8. These vessels are to be tested by the Oak Ridge National Laboratory (ORNL) in the Pressurized-Thermal-Shock (PTS) Project of the Heavy-Section Steel Technology (HSST) Program. A comparable piece of forging taken from the same source and heat treated with the vessels was characterized for its mechanical properties to provide data for use in the PTS tests.

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

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.

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.

[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.

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, 20.5%), followed by finance and economics (74/508, 14.4%), and then electronic engineering or computer science (67/508, 13.2%). Among the 443 non-medical professionals, 122 have children who are attending university or have graduated, 12 (9.8%, 12/122) of them are pursuing a career in medicine. For the 100 non-medical professional parents whose children did not study medicine and if a choice could be given to them to start again, 60 parents (54.5%) replied they would support their children to study medicine. Our results consistently show medicine remained an attractive profession in China. PMID:26981459

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 by finance and economics (74/508, 14.4%), and then electronic engineering or computer science (67/508, 13.2%). Among the 443 non-medical professionals, 122 have children who are attending university or have graduated, 12 (9.8%, 12/122) of them are pursuing a career in medicine. For the 100 non-medical professional parents whose children did not study medicine and if a choice could be given to them to start again, 60 parents (54.5%) replied they would support their children to study medicine. Our results consistently show medicine remained an attractive profession in China.

Corrosion fatigue characterization of reactor pressure vessel steels. [PWR; BWR

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

Van Der Sluys, W.A.

1982-12-01

During routine operation, light water reactor (LWR) pressure vessels are subjected to a variety of transients that result in time-varying stresses. Consequently, fatigue and environmentally-assisted fatigue are mechanisms of growth relevant to flaws in these pressure vessels. To provide a better understanding of the resistance of nuclear pressure vessel steels to these flaw growth processes, fracture mechanics data were generated on the rates of fatigue crack growth for SA508-2 and SA533B-1 steels in both room temperature air and 288/sup 0/C water. Areas investigated were: the relationship of crack growth rate to prior loading history; the effects of loading frequency andmore » R ratio (K/sub min//K/sub max/) on crack growth rate as a function of the stress intensity factor range (..delta..K); transient aspects of the fatigue crack growth behavior; the effect of material chemistry (sulphur content) on fatigue crack; and growth rate; water chemistry effects (high-purity water versus simulated pressurized water reactotr (PWR) primary coolant).« less

Suicidal ideation and suicide attempts in children and adolescents with bipolar disorder: a systematic review of prevalence and incidence rates, risk factors, and targeted interventions

PubMed Central

Hauser, Marta; Galling, Britta; Correll, Christoph U

2013-01-01

Objective Pediatric bipolar disorder (PBD) is associated with poor outcomes, including suicidal ideation (SI) and suicide attempt (SA). However, frequencies and risk factors of SI/SA and targeted intervention trials for SI/SA in PBD have not been reviewed systematically. Methods We conducted a systematic PubMed review, searching for articles reporting on prevalences/incidences, correlates and intervention studies targeting SI/SA in PBD. Weighted means were calculated, followed by an exploratory meta-regression of SI and SA correlates. Results Fourteen studies (n = 1,595) with 52.1% males aged 14.4 years reported data on SI/SA prevalence (N = 13, n = 1,508) and/or correlates (N = 10, n = 1,348) in PBD. Weighted mean prevalences were: past SI = 57.4%, past SA = 21.3%, current SI = 50.4%, and current SA = 25.5%; incidences (mean: 42 months follow-up were: SI = 14.6% and SA = 14.7%. Regarding significant correlates, SI (N = 3) was associated with a higher percentage of Caucasian race, narrow (as opposed to broad) PBD phenotype, younger age, and higher quality of life than SA. Significant correlates of SA (N = 10) included female gender, older age, earlier illness onset, more severe/episodic PBD, mixed episodes, comorbid disorders, past self-injurious behavior/SI/SA, physical/sexual abuse, parental depression, family history of suicidality, and poor family functioning. Race, socioeconomic status, living situation, and life events were not clearly associated with SA. In a meta-regression analysis, bipolar I disorder and comorbid attention-deficit hyperactivity disorder were significantly associated with SA. Only one open label study targeting the reduction of SI/SA in PBD was identified. Conclusions SI and SA are highly common but under-investigated in PBD. Exploration of predictors and protective factors is imperative for the establishment of effective preventive and intervention strategies, which are urgently needed. PMID:23829436

Conditioning monitoring by microstructural evaluation of cumulative fatigue damage

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

Fukuoka, C.; Nakagawa, Y.G.; Lance, J.J.

1996-12-01

The objective of this work is to evaluate the damage induced below and above the fatigue limit ({Delta}{sigma}{sub t} = 360 MPa) in pressure vessel steels, such as SA508. Fatigue damage was induced in samples taken from an SA508 steel plate by various loading histories in order to examine the influence of prior cyclic loading below the fatigue limit. Cell-to-cell misorientation differences were measured by the selected area diffraction (SAD) method. Surface cracking was also studied by the replication method. Small cracks were observed after precycling both below and above the fatigue limit. It was, however, found that fatigue testmore » bars had a longer lifetime after precycling below the fatigue limit, while precycling above the fatigue limit caused other specimens to fail even when subsequently cycled below the fatigue limit. Cell-to-cell misorientation usually increases with accumulation of fatigue damage, but it was found that the misorientations measured after precycling below the fatigue limit decreased again at the beginning of the subsequent cycling above the fatigue limit. It should be noted that the misorientation at failure was always about 4 to 5 deg, regardless of loading histories. Misorientation showed good correlation with the fatigue lifetime of the samples.« less

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

Fatigue crack growth behavior of pressure vessel steels and submerged arc weldments in a high-temperature pressurized water environment

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

Liaw, P.K.; Logsdon, W.A.; Begley, J.A.

1989-10-01

The fatigue crack growth rate (FCGR) properties of SA508 Cl 2a and SA533 Gr A Cl 2 pressure vessel steels and the corresponding automatic submerged arc weldments were developed in a high-temperature pressurized water (HPW) environment at 288{degrees} C (550{degrees} F) and 7.2 MPa (1044 psi) at load ratios of 0.20 and 0.50. The properties were generally conservative compared to American Society of Mechanical Engineers Section XI water environment reference curve. The growth rate of fatigue cracks in the base materials, however, was faster in the HPW environment than in a 288{degrees} C (550{degrees} F) base line air environment. Themore » growth rate of fatigue cracks in the two submerged arc weldments was also accelerated in the HPW environment but to a lesser degree than that demonstrated by the base materials. In the air environment, fatigue striations were observed, independent of material and load ratio, while in the HPW environment, some intergranular facets were present. The greater environmental effect on crack growth rates displayed by the base materials compared the weldments attributed to a different sulfide composition and morphology.« less

Quantification of the Barkhausen noise method for the evaluation of time-dependent degradation

NASA Astrophysics Data System (ADS)

Kim, Dong-Won; Kwon, Dongil

2003-02-01

The Barkhausen noise (BN) method has long been applied to measure the bulk magnetic properties of magnetic materials. Recently, this important nondestructive testing (NDT) method has been applied to evaluate microstructure, stress distribution analysis, fatigue, creep and fracture characteristics. Until now the BN method has been used only qualitatively in evaluating the variation of BN with variations in material properties. For this reason, few NDT methods have been applied in industrial plants and laboratories. The present investigation studied the coercive force and BN while varying the microstructure of ultrafine-grained steels and SA508 cl.3 steels. This variation was carried out according to the second heat-treatment condition with rolling of ultrafine-grained steels and the simulated time-dependent degradation of SA 508 cl.3 steels. An attempt was also made to quantify BN from the relationship between the velocity of magnetic domain walls and the retarding force, using the coercive force of the domain wall movement. The microstructure variation was analyzed according to time-dependent degradation. Fracture toughness was evaluated quantitatively by measuring the BN from two intermediary parameters; grain size and distribution of nonmagnetic particles. From these measurements, the variation of microstructure and fracture toughness can be directly evaluated by the BN method as an accurate in situ NDT method.

Complex sleep apnoea in congestive heart failure.

PubMed

Bitter, Thomas; Westerheide, Nina; Hossain, Mohammed Sajid; Lehmann, Roman; Prinz, Christian; Kleemeyer, Astrid; Horstkotte, Dieter; Oldenburg, Olaf

2011-05-01

Sleep disordered breathing is common and of prognostic significance in patients with congestive heart failure (CHF). Complex sleep apnoea (complexSA) is defined as the emergence of central sleep apnoea during continuous positive airway pressure (CPAP) treatment in patients with obstructive sleep apnoea (OSA). This study aims to determine the prevalence and predictors for complexSA in patients with CHF with OSA, and to assess the effects of treatment with adaptive servoventilation. 192 patients with CHF (left ventricular ejection fraction (LVEF) ≤45%, New York Heart Association (NYHA) class ≥2) and OSA (apnoea-hypopnoea index (AHI) ≥15) were investigated using echocardiography, cardiopulmonary exercise testing, measurement of hyperoxic, hypercapnic ventilatory response, 6 min walk test and measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) prior to CPAP introduction. If patients demonstrated complexSA (AHI >15/h with <10% obstructive events) during CPAP titration, adaptive servoventilation was introduced and the investigations were repeated at 3 monthly follow-up visits. ComplexSA developed in 34 patients (18%) during CPAP titration. After adjustment for demographic and cardiac parameters, measures of CO(2) sensitivity (higher hyperoxic, hypercapnic ventilatory response) were independently associated with complexSA. Patients using adaptive servoventilation had improved AHI, NYHA class, NT-proBNP concentration, LVEF, hyperoxic, hypercapnic ventilatory response, oxygen uptake during cardiopulmonary exercise testing and the relationship between minute ventilation and the rate of CO(2) elimination (VE/Vco(2) slope) at last individual follow-up (14±4 months). There is a high prevalence of complexSA in patients with OSA and CHF, and those who develop complexSA have evidence of higher respiratory controller gain before application of CPAP. Treatment with adaptive servoventilation effectively suppressed complexSA and had positive effects on cardiac function and respiratory stability.

Occurrence and molecular characteristics of antimicrobial resistance of Escherichia coli from broilers, pigs and meat products in Thailand and Cambodia provinces.

PubMed

Trongjit, Suthathip; Angkittitrakul, Sunpetch; Chuanchuen, Rungtip

2016-09-01

Nine hundred and forty-one samples were collected in Sa Keao, Thailand (n = 554) and Banteay Meanchey, Cambodia (n = 387) from July 2014 to January 2015. A total of 667 Escherichia coli isolates (381 isolates from Sa Keao and 286 isolates from Banteay Meanchey) were obtained and examined for antimicrobial susceptibility, class 1 integrons, ESBL genes and horizontal transfer of resistance determinants. Prevalence of E. coli in pig and broiler carcass samples from slaughterhouses and fresh markets was 36-85% in Sa Keao and 11-69% in Banteay Meanchey. The majority of these isolates were multidrug resistant (75.3%). Class 1 integrons were common in both Thai (47%) and Cambodian (62%) isolates, of which four resistance gene cassette arrays including aadA1, dfrA1-aadA1, dfrA12-aadA2 and aadA2-linF were identified. Class 1 integrons in two broiler isolates from Sa Keao (dfrA12-aadA2) and one broiler isolate from Banteay Meanchey (dfrA1-aadA1) were horizontally transferable. Sixteen isolates were confirmed to be ESBL-producing strains with ESBL gene blaCTX-M-15 , broad spectrum β-lactamase gene blaTEM-1 and the AmpC gene blaCMY-2 being detected. The blaTEM-1 gene was most prevalent and located on a conjugative plasmid. © 2016 The Societies and John Wiley & Sons Australia, Ltd.

Stress-anneal-induced magnetic anisotropy in highly textured Fe-Ga and Fe-Al magnetostrictive strips for bending-mode vibrational energy harvesters

NASA Astrophysics Data System (ADS)

Park, Jung Jin; Na, Suok-Min; Raghunath, Ganesh; Flatau, Alison B.

2016-05-01

Magnetostrictive Fe-Ga and Fe-Al alloys are promising materials for use in bending-mode vibrational energy harvesters. For this study, 50.8 mm × 5.0 mm × 0.5 mm strips of Fe-Ga and Fe-Al were cut from 0.50-mm thick rolled sheet. An atmospheric anneal was used to develop a Goss texture through an abnormal grain growth process. The anneal lead to large (011) grains that covered over 90% of sample surface area. The resulting highly-textured Fe-Ga and Fe-Al strips exhibited saturation magnetostriction values (λsat = λ∥ - λ⊥) of ˜280 ppm and ˜130 ppm, respectively. To maximize 90° rotation of magnetic moments during bending of the strips, we employed compressive stress annealing (SA). Samples were heated to 500°C, and a 100-150 MPa compressive stress was applied while at 500°C for 30 minutes and while being cooled. The effectiveness of the SA on magnetic moment rotation was inferred by comparing post-SA magnetostriction with the maximum possible yield of rotated magnetic moments, which is achieved when λ∥ = λsat and λ⊥ = 0. The uniformity of the SA along the sample length and the impact of the SA on sensing/energy harvesting performance were then assessed by comparing pre- and post-SA bending-stress-induced changes in magnetization at five different locations along the samples. The SA process with a 150 MPa compressive load improved Fe-Ga actuation along the sample length from 170 to 225 ppm (from ˜60% to within ˜80% of λsat). The corresponding sensing/energy harvesting performance improved by as much as a factor of eight in the best sample, however the improvement was not at all uniform along the sample length. The SA process with a 100 MPa compressive load improved Fe-Al actuation along the sample length from 60 to 73 ppm (from ˜46% to ˜56% of λsat, indicating only a marginally effective SA and suggesting the need for modification of the SA protocol. In spite of this, the SA was effective at improving the sensing/energy harvesting performance by a factor of ˜2.5 in the best sample. As with the Fe-Ga strip, improvement in performance was quite varied along the strip length.

Exogenous salicylic acid protects phospholipids against cadmium stress in flax (Linum usitatissimum L.).

PubMed

Belkadhi, Aïcha; De Haro, Antonio; Obregon, Sara; Chaïbi, Wided; Djebali, Wahbi

2015-10-01

Salicylic acid (SA) promotes plant defense responses against toxic metal stresses. The present study addressed the hypothesis that 8-h SA pretreatment, would alter membrane lipids in a way that would protect against Cd toxicity. Flax seeds were pre-soaked for 8h in SA (0, 250 and 1000µM) and then subjected, at seedling stage, to cadmium (Cd) stress. At 100µM CdCl2, significant decreases in the percentages of phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylethanolamine (PE) and monogalactosyldiacylglycerol (MGDG) and changes in their relative fatty acid composition were observed in Cd-treated roots in comparison with controls. However, in roots of 8-h SA pretreated plantlets, results showed that the amounts of PC and PE were significantly higher as compared to non-pretreated plantlets. Additionally, in both lipid classes, the proportion of linolenic acid (18:3) increased upon the pretreatment with SA. This resulted in a significant increase in the fatty acid unsaturation ratio of the root PC and PE classes. As the exogenous application of SA was found to be protective of flax lipid metabolism, the possible mechanisms of protection against Cd stress in flax roots were discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

Results of crack-arrest tests on irradiated a 508 class 3 steel

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

Iskander, S.K.; Milella, P.P.; Pini, M.A.

1998-02-01

Ten crack-arrest toughness values for irradiated specimens of A 508 class 3 forging steel have been obtained. The tests were performed according to the American Society for Testing and Materials (ASTM) Standard Test Method for Determining Plane-Strain Crack-Arrest Fracture Toughness, K{sub la} of Ferritic Steels, E 1221-88. None of these values are strictly valid in all five ASTM E 1221-88 validity criteria. However, they are useful when compared to unirradiated crack-arrest specimen toughness values since they show the small (averaging approximately 10{degrees}C) shifts in the mean and lower-bound crack-arrest toughness curves. This confirms that a low copper content in ASTMmore » A 508 class 3 forging material can be expected to result in small shifts of the transition toughness curve. The shifts due to neutron irradiation of the lower bound and mean toughness curves are approximately the same as the Charpy V-notch (CVN) 41-J temperature shift. The nine crack-arrest specimens were irradiated at temperatures varying from 243 to 280{degrees}C, and to a fluence varying from 1.7 to 2.7 x 10{sup 19} neutrons/cm{sup 2} (> 1 MeV). The test results were normalized to reference values that correspond to those of CVN specimens irradiated at 284{degrees}C to a fluence of 3.2 x 10{sup 19} neutrons/cm{sup 2} (> 1 MeV) in the same capsule as the crack-arrest specimens. This adjustment resulted in a shift to lower temperatures of all the data, and in particular moved two data points that appeared to lie close to or lower than the American Society of Mechanical Engineers K{sub la} curve to positions that seemed more reasonable with respect to the remaining data. A special fixture was designed, fabricated, and successfully used in the testing. For reasons explained in the text, special blocks to receive the Oak Ridge National Laboratory clip gage were designed, and greater-than-standard crack-mouth opening displacements measured were accounted for. 24 refs., 13 figs., 12 tabs.« less

Measurement of irradiation effects in a RPV steel by ball indentation technique and magnetic Barkhausen noise

NASA Astrophysics Data System (ADS)

Kim, In-Sup; Park, Duck-Gun; Byun, Thak-Sang; Hong, Jun-Hwa

1999-12-01

Effects of neutron dose on the mechanical and magnetic properties of a SA508-3 nuclear pressure vessel steel were investigated by using ball indentation test technique and magnetic Barkhausen noise (BN) measurements. The samples were irradiated in a research reactor up to 1018n/cm2 (E>1 MeV) at 70 °C. The yield strength and flow curve were evaluated from the indentation load-depth curves. The change of mechanical properties showed characteristic trend with respect to neutron dose, namely near plateau, rapid increase and slow increase. On the other hand, the BN varied in a reverse manner, a slow decrease up to a neutron dose of 1016n/cm2, followed by a rapid decrease up to a dose of 1018n/cm2.

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

Reactor vessels: weld cladding - base metal interaction

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

Mager, T.R.; Landerman, E.; Kubit, C.J.

1971-07-01

An underclad anomaly first observed during magnetic particle inspection of a European steam generator and subsequently discovered during inspection of certain reactor vessels manufactured in both the United States and in Europe is shown to be inconsequential for the intended application because of its small size and insignificant expected growth. Metallurgical investigation identifies the anomaly as grain boundary separations in the base metal, restricted in extent to the grain coarsened part of the weld heat-affected zone beneath the weld bead overlap. In all cases the depth of the separations was less than the maximum depth (0.125 inches) of the grainmore » coarsened area. The occurrence of the anomaly depends on the specific weld overlay process. It has been found generally after post-weld stress relief in forging and plate material (SA508 Class 2 composition). Fracture mechanics evaluation of the affected materials shows that the expected growth of the grain boundary separations during the lifetime of the plant is insignificant, being only 0.004 inches maximum as calculated based on conservative assumptions verified by the metallurgical investigation. Since the original size of the grain boundary separations is negligible and its growth is insignificant during the 40-year plant life, the structural integrity of the vessels has not been compromised and the affected vessels are suitable for the use intended.« less

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...

Prevalence and antimicrobial resistance in Salmonella enterica isolated from broiler chickens, pigs and meat products in Thailand-Cambodia border provinces.

PubMed

Trongjit, Suthathip; Angkititrakul, Sunpetch; Tuttle, R Emerson; Poungseree, Jiratchaya; Padungtod, Pawin; Chuanchuen, Rungtip

2017-01-01

This study aimed to examine the prevalence and antimicrobial resistance (AMR) of Salmonella isolates from broiler chickens, pigs and their associated meat products in the Thailand-Cambodia border provinces. A total of 941 samples were collected from pigs and broiler chickens at slaughter houses and from carcasses at local fresh markets in Sa Kaeo, Thailand (n = 554) and Banteay Meanchey, Cambodia (n = 387) in 2014 and 2015. From these samples, 345 Salmonella isolates were collected from Sa Keao (n = 145; 23%) and Banteay Meanchey (n = 200; 47%) and assayed for antimicrobial susceptibility, class 1 integrons and extended-spectrum β-lactamase (ESBL) genes. Serovars Typhimurium (29%) and Rissen (29%) were the most common serotypes found in Thai and Cambodian isolates, respectively. Multidrug resistance was detected in 34% and 52% of isolates from Sa Keao and Banteay Meanchey, respectively. The majority of the Thai isolates were resistant to ampicillin (72.4%), whereas most Cambodian isolates were resistant to sulfamethoxazole (71%). Eleven isolates from Sa Keao and 44 from Banteay Meanchey carried class 1 integrons comprising resistance gene cassettes. The most common gene cassette array was dfrA12-aadA2 (61.1%). Six isolates were ESBL producers. The β-lactamase genes found included bla TEM-1 , bla CTX-M-55 and bla CMY-2 . Some of these class 1 integrons and ESBL genes were located on conjugative plasmid. In conclusion, multidrug-resistant Salmonella are common in pigs, chickens and their products in the Thailand-Cambodia border provinces. Our findings indicate that class 1 integrons play a role in spread of AMR in the strains in this study. © 2017 The Societies and John Wiley & Sons Australia, Ltd.

CFTR Genotype and Maximal Exercise Capacity in Cystic Fibrosis: A Cross-sectional Study.

PubMed

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

2018-02-01

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

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...

Fatigue crack growth behavior of pressure vessel steels and submerged arc weldments in a high-temperature pressurized water environment

NASA Astrophysics Data System (ADS)

Liaw, P. K.; Logsdon, W. A.; Begley, J. A.

1989-10-01

The fatigue crack growth rate (FCGR) properties of SA508 C1 2a and SA533 Gr A C1 2 pressure vessel steels and the corresponding automatic submerged are weldments were developed in a high-temperature pressurized water (HPW) environment at 288 °C (550°F) and 7.2 MPa (1044 psi) at load ratios of 0.02 and 0.50. The HPW enviromment FCGR properties of these pressure vessel steels and submerged arc weldments were generally conservative, compared with the approrpriate American Society of Mechanical Engineers (ASME) Section XI water environmental reference curve. The growth rate of fatigue cracks in the base materials, however, was considerably faster in the HPW environment than in a corresponding 288°C (550°F) base line air environment. The growth rate of fatigue cracks in the two submerged are weldments was also accelerated in the HPW environment but to a significantly lesser degree than that demonstrated by the corresponding base materials. In the air environment, fatigue striations were observed, independent of material and load ratio, while in the HPW environment, some intergranular facets were present. The greater environmental effect on crack growth rates displayed by the base materials, as compared with the weldments, was attributed to a different sulfide composition and morphology.

Superiority of stapled side-to-side gastrojejunostomy over conventional hand-sewn end-to-side gastrojejunostomy for reducing the risk of primary delayed gastric emptying after subtotal stomach-preserving pancreaticoduodenectomy.

PubMed

Murata, Yasuhiro; Tanemura, Akihiro; Kato, Hiroyuki; Kuriyama, Naohisa; Azumi, Yoshinori; Kishiwada, Masashi; Mizuno, Shugo; Usui, Masanobu; Sakurai, Hiroyuki; Isaji, Shuji

2017-08-01

Delayed gastric emptying (DGE) is the most common complication following pancreaticoduodenectomy (PD). The clinical efficacy of stapled side-to-side anastomosis using a laparoscopic stapling device during alimentary reconstruction in PD is not well understood and its superiority over conventional hand-sewn end-to-side anastomosis remains controversial. The objective of this study was to evaluate the effectiveness of the stapled side-to-side anastomosis in preventing the development of DGE after PD. The subjects of this retrospective study were 137 patients who underwent pancreaticoduodenectomy, as subtotal stomach-preserving pancreaticoduodenectomy (SSPPD; n = 130), or conventional whipple procedure (n = 7) with Child reconstruction, between January 2010 and May 2014. The patients were divided into two groups according to whether they had had a stapled side-to-side anastomosis (SA group; n = 57) or a conventional hand-sewn end-to-side anastomosis (HA group; n = 80). SA reduced the operative time (SA vs. HA: 508 vs. 557 min, p = 0.028) and the incidence of delayed gastric emptying (SA vs. HA: 21.1 vs. 46.3%, p = 0.003) and was associated with shorter hospitalization (SA vs. HA: 33 vs. 39.5 days, p = 0.007). In this cohort, SA was the only significant factor contributing to a reduction in the incidence of DGE (p = 0.002). Stapled side-to-side gastrojejunostomy reduced the operative time and the incidence of DGE following PD with Child reconstruction, thereby also reducing the length of hospitalization.

Aging and health: Self-efficacy for Self-direction in Health Scale.

PubMed

Oliveira, Albertina L; Silva, José T; Lima, Margarida P

2016-07-04

To validate the Escala de Autoeficácia para a Autodireção na Saúde (EAAS - Self-efficacy for Self-direction in Health Scale). Non-experimental quantitative study of EAAS validation, by confirmatory factorial analyses, evaluating a sample of 508 older adults from the north and the center of Portugal with mean age of 71.67 (from 51 to 96 years), to whom the Self-efficacy for Self-direction in Health Scale, the Rosenberg Self-esteem Scale, the Positive and Negative Affect Schedule, the Satisfaction with Life Scale, and the Instrumental Activities of Daily Living Scale were applied. The EAAS was developed from the theoretical constructs of self-efficacy and from self-directed learning within the PALADIN European project framework, aiming to develop an instrument able to assess the extent to which older adults take good care of their health. The internal consistency was 0.87 (Cronbach's alpha) and confirmatory factorial analyses enabled to find a model near the one theoretically proposed, indicating a structure consisting of four dimensions: physical exercise, healthy diet, engaging in health-related learning, and visits to health professionals. From the psychometric point of view, the model in four factors showed quite satisfactory fit indicators. The Self-efficacy for Self-direction in Health Scale, with 16 items, is adequate to evaluate to what extent older adults have confidence in their ability to take care of their own health, with high degree of autonomy. Validar a Escala de Autoeficácia para a Autodireção no domínio da Saúde (EAAS). Estudo quantitativo não experimental de validação da EAAS, por meio de análises fatoriais confirmatórias, avaliando amostra de 508 seniores e idosos provenientes das regiões Norte e Centro de Portugal com média etária de 71.67 (51 a 96 anos), a quem foram aplicadas a Escala de Autoeficácia para a Autodireção na Saúde, a Escala de Autoestima de Rosenberg, a Escala de Afeto Positivo e Afeto Negativo, a Escala de Satisfação Com a Vida e a escala de Atividades Instrumentais da Vida Diária. A EAAS foi desenvolvida a partir dos construtos teóricos da autoeficácia e da aprendizagem autodirigida no âmbito do projeto europeu PALADIN, visando constituir um instrumento apto a avaliar até que ponto os seniores cuidam bem da sua saúde. A consistência interna encontrada foi de 0.87 (alfa de Cronbach) e as análises fatoriais confirmatórias permitiram encontrar um modelo próximo ao proposto teoricamente, indicando uma estrutura constituída por quatro dimensões: exercício físico, alimentação saudável, envolvimento em aprendizagens relativas à saúde e visitas a profissionais de saúde. Do ponto de vista psicométrico, o modelo em quatro fatores mostrou indicadores de ajustamento bastante satisfatórios. A Escala de Autoeficácia para a Autodireção na Saúde, com 16 itens, é adequada para avaliar em que medida os seniores têm confiança na sua capacidade para tomar conta da própria saúde, com elevado grau de autonomia.

Patterns of Adolescent Bullying Behaviors: Physical, Verbal, Exclusion, Rumor, and Cyber

ERIC Educational Resources Information Center

Wang, Jing; Iannotti, Ronald J.; Luk, Jeremy W.

2012-01-01

Patterns of engagement in cyber bullying and four types of traditional bullying were examined using latent class analysis (LCA). Demographic differences and externalizing problems were evaluated across latent class membership. Data were obtained from the 2005-2006 Health Behavior in School-aged Survey and the analytic sample included 7,508 U.S.…

Protein disulphide isomerase is required for signal peptide peptidase-mediated protein degradation

PubMed Central

Lee, Seong-Ok; Cho, Kwangmin; Cho, Sunglim; Kim, Ilkwon; Oh, Changhoon; Ahn, Kwangseog

2010-01-01

The human cytomegalovirus glycoprotein US2 induces dislocation of MHC class I heavy chains from the endoplasmic reticulum (ER) into the cytosol and targets them for proteasomal degradation. Signal peptide peptidase (SPP) has been shown to be integral for US2-induced dislocation of MHC class I heavy chains although its mechanism of action remains poorly understood. Here, we show that knockdown of protein disulphide isomerase (PDI) by RNA-mediated interference inhibited the degradation of MHC class I molecules catalysed by US2 but not by its functional homolog US11. Overexpression of the substrate-binding mutant of PDI, but not the catalytically inactive mutant, dominant-negatively inhibited US2-mediated dislocation of MHC class I molecules by preventing their release from US2. Furthermore, PDI associated with SPP independently of US2 and knockdown of PDI inhibited SPP-mediated degradation of CD3δ but not Derlin-1-dependent degradation of CFTR DeltaF508. Together, our data suggest that PDI is a component of the SPP-mediated ER-associated degradation machinery. PMID:19942855

Protein disulphide isomerase is required for signal peptide peptidase-mediated protein degradation.

PubMed

Lee, Seong-Ok; Cho, Kwangmin; Cho, Sunglim; Kim, Ilkwon; Oh, Changhoon; Ahn, Kwangseog

2010-01-20

The human cytomegalovirus glycoprotein US2 induces dislocation of MHC class I heavy chains from the endoplasmic reticulum (ER) into the cytosol and targets them for proteasomal degradation. Signal peptide peptidase (SPP) has been shown to be integral for US2-induced dislocation of MHC class I heavy chains although its mechanism of action remains poorly understood. Here, we show that knockdown of protein disulphide isomerase (PDI) by RNA-mediated interference inhibited the degradation of MHC class I molecules catalysed by US2 but not by its functional homolog US11. Overexpression of the substrate-binding mutant of PDI, but not the catalytically inactive mutant, dominant-negatively inhibited US2-mediated dislocation of MHC class I molecules by preventing their release from US2. Furthermore, PDI associated with SPP independently of US2 and knockdown of PDI inhibited SPP-mediated degradation of CD3delta but not Derlin-1-dependent degradation of CFTR DeltaF508. Together, our data suggest that PDI is a component of the SPP-mediated ER-associated degradation machinery.

Residual stress determination in an overlay dissimilar welded pipe by neutron diffraction

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

Woo, Wan Chuck; Em, Vyacheslav; Hubbard, Camden R

2011-01-01

Residual stresses were determined through the thickness of a dissimilar weld overlay pipe using neutron diffraction. The specimen has a complex joining structure consisting of a ferritic steel (SA508), austenitic steel (F316L), Ni-based consumable (Alloy 182), and overlay of Ni-base superalloy (Alloy 52M). It simulates pressurized nozzle components, which have been a critical issue under the severe crack condition of nuclear power reactors. Two neutron diffractometers with different spatial resolutions have been utilized on the identical specimen for comparison. The macroscopic 'stress-free' lattice spacing (d{sub o}) was also obtained from both using a 2-mm width comb-like coupon. The results showmore » significant changes in residual stresses from tension (300-400 MPa) to compression (-600 MPa) through the thickness of the dissimilar weld overlay pipe specimen.« less

Atom probe tomography characterizations of high nickel, low copper surveillance RPV welds irradiated to high fluences

NASA Astrophysics Data System (ADS)

Miller, M. K.; Powers, K. A.; Nanstad, R. K.; Efsing, P.

2013-06-01

The Ringhals Units 3 and 4 reactors in Sweden are pressurized water reactors (PWRs) designed and supplied by Westinghouse Electric Company, with commercial operation in 1981 and 1983, respectively. The reactor pressure vessels (RPVs) for both reactors were fabricated with ring forgings of SA 508 class 2 steel. Surveillance blocks for both units were fabricated using the same weld wire heat, welding procedures, and base metals used for the RPVs. The primary interest in these weld metals is because they have very high nickel contents, with 1.58 and 1.66 wt.% for Unit 3 and Unit 4, respectively. The nickel content in Unit 4 is the highest reported nickel content for any Westinghouse PWR. Although both welds contain less than 0.10 wt.% copper, the weld metals have exhibited high irradiation-induced Charpy 41-J transition temperature shifts in surveillance testing. The Charpy impact 41-J shifts and corresponding fluences are 192 °C at 5.0 × 1023 n/m2 (>1 MeV) for Unit 3 and 162 °C at 6.0 × 1023 n/m2 (>1 MeV) for Unit 4. These relatively low-copper, high-nickel, radiation-sensitive welds relate to the issue of so-called late-blooming nickel-manganese-silicon phases. Atom probe tomography measurements have revealed ˜2 nm-diameter irradiation-induced precipitates containing manganese, nickel, and silicon, with phosphorus evident in some of the precipitates. However, only a relatively few number of copper atoms are contained within the precipitates. The larger increase in the transition temperature shift in the higher copper weld metal from the Ringhals R3 Unit is associated with copper-enriched regions within the manganese-nickel-silicon-enriched precipitates rather than changes in their size or number density.

Underclad cracking of pressure vessel steels for light-water reactors

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

Lopez, H.F.

1987-06-01

Although fracture mechanics analyses have shown that underclad cracks have no detrimental effect on the integrity of thick walled pressure vessels (40 year service), in order to avoid unexpected failures the US Nuclear Regulatory Commission has issued Regulatory Guide 1.43 which sets limits on the extent of fissures permitted and describes acceptable means of controlling the weld cladding processes. Cavitation and intergranular fissuring in SA508-2 and 22NiMoCr37 steels can occur in the presence or absence of intergranular particles. The observations of intergranular fissuring and cavitation in those HAZ free from overlapping effects are attributed to grain boundary segregation. Other probablemore » void nucleation sites are the grain boundary-lath interface intersections which facilitate the formation of grain boundary discontinuities.« less

Comparison of short-term effects between face mask and skeletal anchorage therapy with intermaxillary elastics in patients with maxillary retrognathia.

PubMed

Ağlarcı, Cahide; Esenlik, Elçin; Fındık, Yavuz

2016-06-01

The aim of this study was to compare the short-term dental and skeletal effects of a face mask (FM) with those of skeletal anchorage (SA) therapy with intermaxillary elastics in prepubertal patients with skeletal Class III malocclusion. Fifty patients with skeletal Class III malocclusion and maxillary deficiency were divided into two groups. In the FM group, an FM was applied by a bite plate with a force of 400g for each side. In the SA group, mini-plates were placed between mandibular lateral incisors and canines, and mini-implants were inserted between maxillary second premolars and first molars. A bite plate was inserted into the upper arch, and Class III elastics were applied with a force of 200g between each mini-plate and mini-implant. Mean treatment durations were 0.52±0.09 years for FM and 0.76±0.09 years for SA. After the treatment, statistically significant increases in SNA°, ANB°, A-y, 1-NA, SnGoGn°, Co-A, Co-Gn, and A-Nperp, and reductions in SNB° and FH┴N-Pg were observed in both groups, and these changes were similar in both groups. In the FM group, 1-NB decreased significantly, and in the SA group, it increased significantly (P < 0.05). The undesired dentoalveolar effects of the FM treatment were eliminated with SA treatment, except with regard to lower incisor inclination. Favourable skeletal outcomes can be achieved by SA therapies, which could be an alternative to the extraoral appliances frequently applied to treat skeletal Class III patients with maxillary deficiency. © The Author 2015. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Environmentally Friendly Replacement of Mature 200 MW Coal-Fired Power Blocks with 2 Boilers Working on One 500 MW Class Steam Turbine Generator (2on1 Unit Concept)

NASA Astrophysics Data System (ADS)

Grzeszczak, Jan; Grela, Łukasz; Achter, Thomas

2017-12-01

The paper covers problems of the owners of a fleet of long-operated conventional power plants that are going to be decommissioned soon in result of failing to achieve new admissible emissions levels or exceeding pressure elements design lifetime. Energoprojekt-Katowice SA, Siemens AG and Rafako SA presents their joint concept of the solution which is a 2on1 concept - replacing two unit by two ultra-supercritical boilers feeding one turbine. Polish market has been taken as an example.

45 CFR 164.508 - Uses and disclosures for which an authorization is required.

Code of Federal Regulations, 2011 CFR

2011-10-01

... is in the form of: (A) A face-to-face communication made by a covered entity to an individual; or (B... meaningful fashion. (ii) The name or other specific identification of the person(s), or class of persons...

45 CFR 164.508 - Uses and disclosures for which an authorization is required.

Code of Federal Regulations, 2010 CFR

2010-10-01

... is in the form of: (A) A face-to-face communication made by a covered entity to an individual; or (B... meaningful fashion. (ii) The name or other specific identification of the person(s), or class of persons...

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...

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.

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.

A study on the radiation damage and recovery of neutron irradiated vessel steel using magnetic Barkhausen noise

NASA Astrophysics Data System (ADS)

Park, Duck-Gun; Jeong, Hee-Tae; Hong, Jun-Hwa

1999-04-01

The radiation damage and thermal recovery characteristic of neutron irradiated SA508-3 reactor pressure vessel steel specimens have been investigated. Two recovery stages were identified from the results of hardness measurements during isochronal annealing and the mechanism responsible for the two stages was explained by using the results of Barkhausen noise measurement on the basis of the interaction between radiation induced defects and the magnetic domain wall. The coercivity was not changed by neutron irradiation, whereas the maximum magnetic induction increased. Barkhausen noise parameters associated with the domain wall motion were decreased by neutron irradiation and recovered with subsequent heat treatments.

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

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.

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...

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.

Method to determine the optimal constitutive model from spherical indentation tests

NASA Astrophysics Data System (ADS)

Zhang, Tairui; Wang, Shang; Wang, Weiqiang

2018-03-01

The limitation of current indentation theories was investigated and a method to determine the optimal constitutive model through spherical indentation tests was proposed. Two constitutive models, the Power-law and the Linear-law, were used in Finite Element (FE) calculations, and then a set of indentation governing equations was established for each model. The load-depth data from the normal indentation depth was used to fit the best parameters in each constitutive model while the data from the further loading part was compared with those from FE calculations, and the model that better predicted the further deformation was considered the optimal one. Moreover, a Yang's modulus calculation model which took the previous plastic deformation and the phenomenon of pile-up (or sink-in) into consideration was also proposed to revise the original Sneddon-Pharr-Oliver model. The indentation results on six materials, 304, 321, SA508, SA533, 15CrMoR, and Fv520B, were compared with tensile ones, which validated the reliability of the revised E calculation model and the optimal constitutive model determination method in this study.

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.

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...

Microstructural evaluation of cumulative fatigue damage below the fatigue limit

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

Fukuoka, C.; Nakagawa, Y.G.

1996-05-01

The objective of this work is to evaluate the microstructural changes induced near and below the fatigue limit in a pressure vessel steel plate, SA508. Dislocation cell to cell misorientation differences, {theta}, which increase with fatigue damage accumulation, are measured by the Selected Area Diffraction (SAD) method. The misorientation difference, {theta}, of the sample failed just above the fatigue limit is about 4.0 degrees on the average, which is about the same as that for the failure conditions of low cycle fatigue at higher stresses. The {theta} value increases even below the fatigue limit, but it does not increase atmore » stresses which are lower than 50% of the fatigue limit.« less

Re-Evaluating Student Evaluation of Teaching: The Teaching Evaluation Form.

ERIC Educational Resources Information Center

Wolfer, Terry A.; Johnson, Miriam McNown

2003-01-01

Reports on the aggregate analysis of scores generated by a standardized instrument, the Teaching Evaluation Form (TEF; Hudson, 1982), at the College of Social Work, University of South Carolina. Data included more than 11,000 completions of the instrument in 508 class sections offered during a 4-year period. Analysis revealed a severely negatively…

Design and Optimization of Renin Inhibitors: Orally Bioavailable Alkyl Amines

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

Tice, C.; Xu, Z; Yuan, J

2009-01-01

Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC{sub 50} of 0.47 nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.

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

PubMed

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

2016-01-22

A newly identified pathway for selective degradation of the common mutant of the cystic fibrosis transmembrane conductance regulator (CFTR), F508del, is initiated by binding of the small heat shock protein, Hsp27. Hsp27 collaborates with Ubc9, the E2 enzyme for protein SUMOylation, to selectively degrade F508del CFTR via the SUMO-targeted ubiquitin E3 ligase, RNF4 (RING finger protein 4) (1). Here, we ask what properties of CFTR are sensed by the Hsp27-Ubc9 pathway by examining the ability of NBD1 (locus of the F508del mutation) to mimic the disposal of full-length (FL) CFTR. Similar to FL CFTR, F508del NBD1 expression was reduced 50-60% by Hsp27; it interacted preferentially with the mutant and was modified primarily by SUMO-2. Mutation of the consensus SUMOylation site, Lys(447), obviated Hsp27-mediated F508del NBD1 SUMOylation and degradation. As for FL CFTR and NBD1 in vivo, SUMO modification using purified components in vitro was greater for F508del NBD1 versus WT and for the SUMO-2 paralog. Several findings indicated that Hsp27-Ubc9 targets the SUMOylation of a transitional, non-native conformation of F508del NBD1: (a) its modification decreased as [ATP] increased, reflecting stabilization of the nucleotide-binding domain by ligand binding; (b) a temperature-induced increase in intrinsic fluorescence, which reflects formation of a transitional NBD1 conformation, was followed by its SUMO modification; and (c) introduction of solubilizing or revertant mutations to stabilize F508del NBD1 reduced its SUMO modification. These findings indicate that the Hsp27-Ubc9 pathway recognizes a non-native conformation of mutant NBD1, which leads to its SUMO-2 conjugation and degradation by the ubiquitin-proteasome system. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

The effect of genetic bottlenecks and inbreeding on the incidence of two major autoimmune diseases in standard poodles, sebaceous adenitis and Addison's disease.

PubMed

Pedersen, Niels C; Brucker, Lynn; Tessier, Natalie Green; Liu, Hongwei; Penedo, Maria Cecilia T; Hughes, Shayne; Oberbauer, Anita; Sacks, Ben

2015-01-01

Sebaceous adenitis (SA) and Addison's disease (AD) increased rapidly in incidence among Standard Poodles after the mid-twentieth century. Previous attempts to identify specific genetic causes using genome wide association studies and interrogation of the dog leukocyte antigen (DLA) region have been non-productive. However, such studies led us to hypothesize that positive selection for desired phenotypic traits that arose in the mid-twentieth century led to intense inbreeding and the inadvertent amplification of AD and SA associated traits. This hypothesis was tested with genetic studies of 761 Standard, Miniature, and Miniature/Standard Poodle crosses from the USA, Canada and Europe, coupled with extensive pedigree analysis of thousands more dogs. Genome-wide diversity across the world-wide population was measured using a panel of 33 short tandem repeat (STR) loci. Allele frequency data were also used to determine the internal relatedness of individual dogs within the population as a whole. Assays based on linkage between STR genomic loci and DLA genes were used to identify class I and II haplotypes and disease associations. Genetic diversity statistics based on genomic STR markers indicated that Standard Poodles from North America and Europe were closely related and reasonably diverse across the breed. However, genetic diversity statistics, internal relatedness, principal coordinate analysis, and DLA haplotype frequencies showed a marked imbalance with 30 % of the diversity in 70 % of the dogs. Standard Poodles with SA and AD were strongly linked to this inbred population, with dogs suffering with SA being the most inbred. No single strong association was found between STR defined DLA class I or II haplotypes and SA or AD in the breed as a whole, although certain haplotypes present in a minority of the population appeared to confer moderate degrees of risk or protection against either or both diseases. Dogs possessing minor DLA class I haplotypes were half as likely to develop SA or AD as dogs with common haplotypes. Miniature/Standard Poodle crosses being used for outcrossing were more genetically diverse than Standard Poodles and genetically distinguishable across the genome and in the DLA class I and II region. Ancestral genetic polymorphisms responsible for SA and AD entered Standard Poodles through separate lineages, AD earlier and SA later, and were increasingly fixed by a period of close linebreeding that was related to popular bloodlines from the mid-twentieth century. This event has become known as the midcentury bottleneck or MCB. Sustained positive selection resulted in a marked imbalance in genetic diversity across the genome and in the DLA class I and II region. Both SA and AD were concentrated among the most inbred dogs, with genetic outliers being relatively disease free. No specific genetic markers other than those reflecting the degree of inbreeding were consistently associated with either disease. Standard Poodles as a whole remain genetically diverse, but steps should be taken to rebalance diversity using genetic outliers and if necessary, outcrosses to phenotypically similar but genetically distinct breeds.

In Situ Measurements of Spectral Emissivity of Materials for Very High Temperature Reactors

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

G. Cao; S. J. Weber; S. O. Martin

2011-08-01

An experimental facility for in situ measurements of high-temperature spectral emissivity of materials in environments of interest to the gas-cooled very high temperature reactor (VHTR) has been developed. The facility is capable of measuring emissivities of seven materials in a single experiment, thereby enhancing the accuracy in measurements due to even minor systemic variations in temperatures and environments. The system consists of a cylindrical silicon carbide (SiC) block with seven sample cavities and a deep blackbody cavity, a detailed optical system, and a Fourier transform infrared spectrometer. The reliability of the facility has been confirmed by comparing measured spectral emissivitiesmore » of SiC, boron nitride, and alumina (Al2O3) at 600 C against those reported in literature. The spectral emissivities of two candidate alloys for VHTR, INCONEL{reg_sign} alloy 617 (INCONEL is a registered trademark of the Special Metals Corporation group of companies) and SA508 steel, in air environment at 700 C were measured.« less

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

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

Lewis, H.A.; Wang, C.; Zhao, X.

2012-04-30

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

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

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 molecule corrector. Our combined results indicate that increasing the levels of ER-localized CFTR available for repair provides a novel route to correct F508del CFTR.

Re-evolution of the 2-phenylquinolines: ligand-based design, synthesis, and biological evaluation of a potent new class of Staphylococcus aureus NorA efflux pump inhibitors to combat antimicrobial resistance.

PubMed

Sabatini, Stefano; Gosetto, Francesca; Iraci, Nunzio; Barreca, Maria Letizia; Massari, Serena; Sancineto, Luca; Manfroni, Giuseppe; Tabarrini, Oriana; Dimovska, Mirjana; Kaatz, Glenn W; Cecchetti, Violetta

2013-06-27

Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of antimicrobial agents that are substrates. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, biocides, and dyes, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 2-phenylquinoline derivatives was designed by means of ligand-based pharmacophore modeling in an attempt to identify improved S. aureus NorA efflux pump inhibitors (EPIs). Most of the 2-phenylquinoline derivatives displayed potent EPI activity against the norA overexpressing strain SA-1199B. The antibacterial activity of ciprofloxacin, when used in combination with some of the synthesized compounds, was completely restored in SA-1199B and SA-K2378, a strain overexpressing norA from a multicopy plasmid. Compounds 3m and 3q also showed potent synergistic activity with the ethidium bromide dye in a strain overexpressing the MepA MDR efflux pump.

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.

Quantitative evaluation of essential medicines lists: the South African case study.

PubMed

Perumal-Pillay, Velisha Ann; Suleman, Fatima

2016-12-12

The South African (SA) health system has employed an Essential Medicines List (EML) with Standard Treatment Guidelines (STGs) since 1996. To date no studies have reported the changes in SA STG/EMLs. This study describes these changes over time (1996-2013) and compares latest SA STG/EMLs with the latest World Health Organization (WHO) Model EMLs to assess alignment of these lists. A quantitative evaluation of SA STGs/EMLs at 2 levels of healthcare was performed to assess changes in the number and ratio of molecules, dosage forms, and additions and deletions of medicines. The most recent WHO EMLs (18th list, 4th list for children) and 2012 priority life-saving medicines for women and children (PMWC) list were compared to the most recent available SA STG/EMLs (Primary Health Care (PHC 2008), Adult Hospital 2012, and Paediatric Hospital 2013) at the time of the research. The number of molecules over the years increased for PHC STG/EMLs but decreased slightly for Adult and Paediatric hospital STG/EMLs. The most additions and deletions over time occurred in the Adult hospital level STG/EML (27 in 2006 and 44 in 2012). A comparison between the most recent SA STG/EMLs and WHO Model EML (18th list) showed that a total of 112 medicines were absent on all SA STG/EMLs. A comparison of medicines for children between the 2013 SA Paediatric Hospital level STG/EML and PMWC indicated that these lists were somewhat aligned for most conditions as only 3 of 14 medicines and 11 of 20 vaccines were absent from SA STG/EMLs. This is the first study in SA to investigate changes in National EMLs over time in relation to molecules, dosage forms and therapeutic classes. It is also the first to compare the latest SA STG/EMLs to the WHO Model lists. The results therefore provide insight into the trends and SA STG/EML processes over time.

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...

Black phosphorus: a two-dimension saturable absorption material for mid-infrared Q-switched and mode-locked fiber lasers

PubMed Central

Li, Jianfeng; Luo, Hongyu; Zhai, Bo; Lu, Rongguo; Guo, Zhinan; Zhang, Han; Liu, Yong

2016-01-01

Black phosphorus (BP) as a novel class of two-dimension (2D) materials has recently attracted enormous attention as a result of its unique physical and chemical features. The remarkably strong light-matter interaction and tunable direct band-gap at a wide range make it an ideal candidate especially in the mid-infrared wavelength region as the saturable absorber (SA). In this paper, the simple and effective liquid phase exfoliation (LPE) method was used to fabricate BP. By introducing the same BP SA into two specifically designed rare earth ions doped fluoride fiber lasers at mid-infrared wavebands, Q-switching with the pulse energy of 4.93 μJ and mode-locking with the pulse duration of 8.6 ps were obtained, respectively. The operation wavelength of ~2970 nm for generated pulse is the reported longest wavelength for BP SA based fiber lasers. PMID:27457338

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

PubMed Central

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

2013-01-01

Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR. PMID:23924900

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

PubMed

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

2013-10-01

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

Measurement of fatigue accumulation in high-strength steels by microstructural examination

NASA Astrophysics Data System (ADS)

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

1990-07-01

Fatigue test bars fabricated from an SA508 class 3 low-carbon steel plate were cyclically deformed at 300 °C (constant low-cycle fatigue, total strain range Δɛ = 0.78 pct and 0.48 pct) to crack initiation (100 pct cumulative damage, CD) and to the factors 75, 50, and 25 pct CD. The test bars were cut perpendicular to the stress axis at the center of the gage length. The X-ray diffraction line-broadening (XRD) was performed on the cross sections created by the cuts. Thin foils (˜0.1-μm thick) were prepared from each cross section and used for the transmission electron microscope (TEM) and selected area diffraction (SAD) study. The half-value line breadth change measured by the XRD increased with the CD increase up to 50 pct, beyond which a significant reduction was observed for the 75 and 100 pct CD sample regardless of the incident X-ray beam angle. By the TEM, the undamaged material (0 pct CD) was characterized by high-angle boundaries, small carbide precipitates, and dislocation cell networks in grains. These characteristics did not show any appreciable changes in all of the samples with fatigue damage of the respective levels. Micro-orientation changes of the dislocation cells studied by the SAD of the foils and a statistical data analysis clearly demonstrated that the mean orientation difference in the cells and its standard deviation increased gradually as the CD increased.

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 study suggest that inhibition of endocannabinoid degradative enzymes represents a promising therapeutic approach to decrease effective doses of opioids needed for clinical pain control, and may also possess therapeutic potential to reduce opioid abuse. Copyright © 2016 Elsevier Ltd. All rights reserved.

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 study suggest that inhibition of endocannabinoid degradative enzymes represents a promising therapeutic approach to decrease effective doses of opioids needed for clinical pain control, and may also possess therapeutic potential to reduce opioid abuse. PMID:27890602

Correctors of the Major Cystic Fibrosis Mutant Interact through Membrane-Spanning Domains.

PubMed

Laselva, Onofrio; Molinski, Steven; Casavola, Valeria; Bear, Christine E

2018-06-01

The most common cystic fibrosis causing mutation is deletion of phenylalanine at position 508 (F508del), a mutation that leads to protein misassembly with defective processing. Small molecule corrector compounds: VX-809 or Corr-4a (C4) partially restores processing of the major mutant. These two prototypical corrector compounds cause an additive effect on F508del/cystic fibrosis transmembrane conductance regulator (CFTR) processing, and hence were proposed to act through distinct mechanisms: VX-809 stabilizing the first membrane-spanning domain (MSD) 1, and C4 acting on the second half of the molecule [consisting of MSD2 and/or nucleotide binding domain (NBD) 2]. We confirmed the effect of VX-809 in enhancing the stability of MSD1 and showed that it also allosterically modulates MSD2 when coexpressed with MSD1. We showed for the first time that C4 stabilizes the second half of the CFTR protein through its action on MSD2. Given the allosteric effect of VX-809 on MSD2, we were prompted to test the hypothesis that the two correctors interact in the full-length mutant protein. We did see evidence supporting their interaction in the full-length F508del-CFTR protein bearing secondary mutations targeting domain:domain interfaces. Disruption of the MSD1:F508del-NBD1 interaction (R170G) prevented correction by both compounds, pointing to the importance of this interface in processing. On the other hand, stabilization of the MSD2:F508del-NBD1 interface (by introducing R1070W) led to a synergistic effect of the compound combination on the total abundance of both the immature and mature forms of the protein. Together, these findings suggest that the two correctors interact in stabilizing the complex of MSDs in F508del-CFTR. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Analysis of the SA-N-1 GOA. The Most Common Missile on Soviet Ships (Analisi dell’ SA-N-1 GOA. Il piu’ Diffuso Missile Imbarcato della Marina Sovietica),

DTIC Science & Technology

1983-12-02

range system. Western observers /84 were surprised when a KOTLIN -Clas𔄁 destroyer, the BRAVYY, made a June 1962 deployment to the Baltic displaying a...experimental version, which was only confirmed five years later, when missiles began appearing on several KOTLIN -Class ships with similar modifications...most notable characteristic. On theseldestroyers the SA-N-I became a fully operational system of undisputed capability. In 1967 the remaining KOTLIN

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

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.

A Short Review on the Synthetic Strategies of Duocarmycin Analogs that are Powerful DNA Alkylating Agents.

PubMed

Patil, Pravin C; Satam, Vijay; Lee, Moses

2015-01-01

The duocarmycins and CC-1065 are members of a class of DNA minor groove, AT-sequence selective, and adenine-N3 alkylating agents, isolated from Streptomyces sp. that exhibit extremely potent cytotoxicity against the growth of cancer cells grown in culture. Initial synthesis and structural modification of the cyclopropa[c] pyrrolo[3,2-e]indole (CPI) DNA-alkylating motif as well as the indole non-covalent binding region in the 1980s have led to several compounds that entered clinical trials as potential anticancer drugs. However, due to significant systemic toxicity none of the analogs have passed clinical evaluation. As a result, the intensity in the design, synthesis, and development of novel analogs of the duocarmycins has continued. Accordingly, in this review, which covers a period from the 1990s through the present time, the design and synthesis of duocarmycin SA are described along with the synthesis of novel and highly cytotoxic analogs that lack the chiral center. Examples of achiral analogs of duocarmycin SA described in this review include seco-DUMSA (39 and 40), seco-amino-CBI-TMI (13, Centanamycin), and seco-hydroxy-CBI-TMI (14). In addition, another novel class of biologically active duocarmycin SA analogs that contained the seco-iso-cyclopropylfurano[2,3-e]indoline (seco-iso-CFI) and seco-cyclopropyltetrahydrofurano[2,3-f]quinoline (seco-CFQ) DNA alkylating submit was also designed and synthesized. The synthesis of seco-iso-CFI-TMI (10, Tafuramycin A) and seco-CFQ-TMI (11, Tafuramycin B) is included in this review.

The effect of multimorbidity on sickness absence by specific diagnoses.

PubMed

Ubalde-Lopez, M; Delclos, G L; Benavides, F G; Calvo-Bonacho, E; Gimeno, D

2017-03-01

As the world's population ages, the prevalence of multiple chronic and non-chronic health-related conditions is increasing. Research on multimorbidity, the co-occurrence of two or more health-related conditions, has mainly involved patient and older populations. Its effect in working populations, presumably younger and healthier, is not well known but could conceivably affect sickness absence (SA) and ability to return to work. To examine the effect of multimorbidity on the incidence and duration of SA episodes by frequent diagnostic groups. A prospective study (in 2006-2008) of workers in Spain. Information on health-related conditions was gathered with a standardized questionnaire and used to construct a sex-specific multidimensional multimorbidity score (MDMS). In order to estimate the effect of MDMS on incidence and duration of SA episodes due to cardiovascular diseases (CVD), musculoskeletal disorders (MSD) and mental health disorders (MHD), we fitted Cox models adjusted by age, occupational social class and number of prior SA episodes for both sexes. The study population was 372370. Men with high MDMS showed a trend towards higher incidence risk for SA due to CVD and MSD [adjusted hazard ratio (aHR) = 2.03; 95% confidence interval (CI) 1.48-2.78 and aHR = 1.20; 95% CI 1.01-1.43, respectively]. Women showed a similar trend for MSD, but MHD had the strongest association (aHR = 4.78; 95% CI 1.97-11.62) for high MDMS. In both sexes, the effect of MDMS was strongest among those without a prior SA. No consistent associations with SA duration were observed. Multimorbidity increased the risk of incident musculoskeletal, mental and cardiovascular SA episodes but not their duration. © The Author 2016. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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.

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

PubMed Central

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

2016-01-01

The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to deletion of the phenylalanine at position 508 (ΔF508) in the CFTR protein and causes multiple folding and functional defects. Contrary to large-scale efforts by industry and academia, no significant therapeutic benefit has been achieved with a single “corrector”. Therefore, investigations concentrate on drug combinations. Orkambi (Vertex Pharmaceuticals), the first FDA-approved drug for treatment of cystic fibrosis (CF) caused by this mutation, is a combination of a corrector (VX-809) that facilitates ΔF508 CFTR biogenesis and a potentiator (VX-770), which improves its function. Yet, clinical trials utilizing this combination showed only modest therapeutic benefit. The low efficacy Orkambi has been attributed to VX-770-mediated destabilization of VX-809-rescued ΔF508 CFTR. Here we report that the negative effects of VX-770 can be reversed by increasing the half-life of the endoplasmic reticulum (ER) form (band B) of ΔF508 CFTR with another corrector (Corr-4a.) Although Corr-4a alone has only minimal effects on ΔF508 CFTR rescue, it increases the half-life of ΔF508 CFTR band B when it is present during half-life measurements. Our data shows that stabilization of band B ΔF508 CFTR with Corr-4a and simultaneous rescue with VX-809, leads to a >2-fold increase in cAMP-activated, CFTRinh-172-inhibited currents compared to VX-809 alone, or VX-809+VX-770. The negative effects of VX-770 and the Corr-4a protection are specific to the native I507-ATT ΔF508 CFTR without affecting the inherently more stable, synonymous variant I507-ATC ΔF508 CFTR. Our studies emphasize that stabilization of ΔF508 CFTR band B in the ER might improve its functional rescue by Orkambi. PMID:27214033

Significance of reheat cracks to the integrity of pressure vessels for light-water reactors

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

Canonico, D.A.

1979-05-01

Reheat cracks manifest themselves as macroscopic defects detectable by nondestructive testing (NDT) procedures or as microscopic grain boundary decohesions (GBD) that are beyond the limit of detection by NDT. The significance of the microscopic cracks that may go undetected are discussed. The probability that GBD exist in the heat-affected zones (HAZ) of weldments of pressure vessel steels is high; particularly in SA508 Class 2 weldments. GBD reside in the coarse-grained region of the HAZ. The microstructure of this region tends to be a tempered martensite or lower bainite, a structure whose fracture toughness is superior to that of a highermore » temperature transformation product. This region should be less sensitive to irradiation embrittlement. Toughness data for this region in either the unirradiated or irradiated condition are sparse; however, those data that are available indicate that this area is superior in toughness to the base metal. A sample of the HAZ from the prolongation-weldment from the Heavy Section Steel Technology program Intermediate Test Vessel (ITV) No. 4 was examined by the Staatliche Materialpruefungsanstalt (MPA). They reported GBD 5 mm (0.2 in.) long. This prompted an examination of the HAZ from the ITV vessel that had been tested to failure at 24 C (75 F). During testing, the region of the weld which contained the flaw that initiated the failure was strained up to 0.5%. A metallographic examination of this region of the weldment revealed GBD, but none of the size reported by the MPA. Further, there was no evidence that the GBD had extended as a consequence of the tests. Fracture toughness tests were made of the HAZ of welds from ITV-4. The electron-beam welding procedure, which permits more accurate siting of the crack, was used. Fracture toughness values in excess of 220 MPa/m (200 ksi/in.) were obtained at -18 C (O F).« less

Saturable Absorption in 2D Ti3 C2 MXene Thin Films for Passive Photonic Diodes.

PubMed

Dong, Yongchang; Chertopalov, Sergii; Maleski, Kathleen; Anasori, Babak; Hu, Longyu; Bhattacharya, Sriparna; Rao, Apparao M; Gogotsi, Yury; Mochalin, Vadym N; Podila, Ramakrishna

2018-03-01

MXenes comprise a new class of 2D transition metal carbides, nitrides, and carbonitrides that exhibit unique light-matter interactions. Recently, 2D Ti 3 CNT x (T x represents functional groups such as OH and F) was found to exhibit nonlinear saturable absorption (SA) or increased transmittance at higher light fluences, which is useful for mode locking in fiber-based femtosecond lasers. However, the fundamental origin and thickness dependence of SA behavior in MXenes remain to be understood. 2D Ti 3 C 2 T x thin films of different thicknesses are fabricated using an interfacial film formation technique to systematically study their nonlinear optical properties. Using the open aperture Z-scan method, it is found that the SA behavior in Ti 3 C 2 T x MXene arises from plasmon-induced increase in the ground state absorption at photon energies above the threshold for free carrier oscillations. The saturation fluence and modulation depth of Ti 3 C 2 T x MXene is observed to be dependent on the film thickness. Unlike other 2D materials, Ti 3 C 2 T x is found to show higher threshold for light-induced damage with up to 50% increase in nonlinear transmittance. Lastly, building on the SA behavior of Ti 3 C 2 T x MXenes, a Ti 3 C 2 T x MXene-based photonic diode that breaks time-reversal symmetry to achieve nonreciprocal transmission of nanosecond laser pulses is demonstrated. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

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

Macrosegregation and Microstructural Evolution in a Pressure-Vessel Steel

NASA Astrophysics Data System (ADS)

Pickering, E. J.; Bhadeshia, H. K. D. H.

2014-06-01

This work assesses the consequences of macrosegregation on microstructural evolution during solid-state transformations in a continuously cooled pressure-vessel steel (SA508 Grade 3). Stark spatial variations in microstructure are observed following a simulated quench from the austenitization temperature, which are found to deliver significant variations in hardness. Partial-transformation experiments are used to show the development of microstructure in segregated material. Evidence is presented which indicates the bulk microstructure is not one of upper bainite, as it has been described in the past, but one comprised of Widmanstätten ferrite and pockets of lower bainite. Segregation is observed on three different length scales, and the origins of each type are proposed. Suggestions are put forward for how the segregation might be minimized, and its detrimental effects suppressed by heat treatments.

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.

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.

Ligand-Dependent Disorder of Loop Observed in Extended-Spectrum SHV-Type beta-Lactamase

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

J Sampson; W Ke; C Bethel

2011-12-31

Among Gram-negative bacteria, resistance to {beta}-lactams is mediated primarily by {beta}-lactamases (EC 3.2.6.5), periplasmic enzymes that inactivate {beta}-lactam antibiotics. Substitutions at critical amino acid positions in the class A {beta}-lactamase families result in enzymes that can hydrolyze extended-spectrum cephalosporins, thus demonstrating an 'extended-spectrum' {beta}-lactamase (ESBL) phenotype. Using SHV ESBLs with substitutions in the {Omega} loop (R164H and R164S) as target enzymes to understand this enhanced biochemical capability and to serve as a basis for novel {beta}-lactamase inhibitor development, we determined the spectra of activity and crystal structures of these variants. We also studied the inactivation of the R164H and R164Smore » mutants with tazobactam and SA2-13, a unique {beta}-lactamase inhibitor that undergoes a distinctive reaction chemistry in the active site. We noted that the reduced K{sub i} values for the R164H and R164S mutants with SA2-13 are comparable to those with tazobactam (submicromolar). The apo enzyme crystal structures of the R164H and R164S SHV variants revealed an ordered {Omega} loop architecture that became disordered when SA2-13 was bound. Important structural alterations that result from the binding of SA2-13 explain the enhanced susceptibility of these ESBL enzymes to this inhibitor and highlight ligand-dependent {Omega} loop flexibility as a mechanism for accommodating and hydrolyzing {beta}-lactam substrates.« less

Biocatalytic desulfurization of thiophenic compounds and crude oil by newly isolated bacteria

PubMed Central

Mohamed, Magdy El-Said; Al-Yacoub, Zakariya H.; Vedakumar, John V.

2015-01-01

Microorganisms possess enormous highly specific metabolic activities, which enable them to utilize and transform nearly every known chemical class present in crude oil. In this context, one of the most studied biocatalytic processes is the biodesulfurization (BDS) of thiophenic sulfur-containing compounds such as benzothiophene (BT) and dibenzothiophene (DBT) in crude oils and refinery streams. Three newly isolated bacterial strains, which were affiliated as Rhodococcus sp. strain SA11, Stenotrophomonas sp. strain SA21, and Rhodococcus sp. strain SA31, were enriched from oil contaminated soil in the presence of DBT as the sole S source. GC-FID analysis of DBT-grown cultures showed consumption of DBT, transient formation of DBT sulfone (DBTO2) and accumulation of 2-hydroxybiphenyl (2-HBP). Molecular detection of the plasmid-borne dsz operon, which codes for the DBT desulfurization activity, revealed the presence of dszA, dszB, and dszC genes. These results point to the operation of the known 4S pathway in the BDS of DBT. The maximum consumption rate of DBT was 11 μmol/g dry cell weight (DCW)/h and the maximum formation rate of 2-HBP formation was 4 μmol/g DCW/h. Inhibition of both cell growth and DBT consumption by 2-HBP was observed for all isolates but SA11 isolate was the least affected. The isolated biocatalysts desulfurized other model DBT alkylated homologs. SA11 isolate was capable of desulfurizing BT as well. Resting cells of SA11 exhibited 10% reduction in total sulfur present in heavy crude oil and 18% reduction in total sulfur present in the hexane-soluble fraction of the heavy crude oil. The capabilities of the isolated bacteria to survive and desulfurize a wide range of S compounds present in crude oil are desirable traits for the development of a robust BDS biocatalyst to upgrade crude oils and refinery streams. PMID:25762990

Attitudes of Elementary Schools Pupils to the Physical and Sport Education

ERIC Educational Resources Information Center

Kolofík, Tomáš

2015-01-01

The aim of the research was to find out the attitudes of the pupils of the seventh, eighth and ninth year-classes of the elementary schools in Banská Bystrica to the physical and sport education. The research sample comprised 1092 pupils, out of which 584 were boys and 508 were girls. A standardised questionnaire according to Sivák et al. (2000)…

Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis.

PubMed

Patel, Sanjay; Sinha, Ian P; Dwan, Kerry; Echevarria, Carlos; Schechter, Michael; Southern, Kevin W

2015-03-26

Cystic fibrosis is the most common inherited life-shortening illness in Caucasians and caused by a mutation in the gene that codes for the cystic fibrosis transmembrane regulator protein (CFTR), which functions as a salt transporter. This mutation most notably affects the airways of people with cystic fibrosis. Excess salt absorption by defective CFTR dehydrates the airway lining and leads to defective mucociliary clearance. Consequent accumulation of thick, sticky mucus makes the airway prone to chronic infection and progressive inflammation; respiratory failure often ensues. Additionally, abnormalities with CFTR lead to systemic complications like malnutrition, diabetes and subfertility.Since the discovery of the causative gene, our understanding of the structure and function of CFTR and the impact of different mutations has increased and allowed pharmaceutical companies to design new mutation-specific therapies targeting the underlying molecular defect. Therapies targeting mutation classes III and IV (CFTR potentiators) aim to normalise airway surface liquid and help re-establish mucociliary clearance, which then has a beneficial impact on the chronic infection and inflammation that characterizes lung disease in people with cystic fibrosis. These therapies may also affect other mutations. To evaluate the effects of CFTR potentiators on clinically important outcomes in children and adults with cystic fibrosis. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Last search: 05 March 2015.We searched the EU Clinical Trials Register, clinicaltrials.gov (US Clinical Trials Register) and the International Clinical Trials Registry Platform (ICTRP). Last search of clinical trial registries: 06 February 2014. Randomised controlled trials of parallel design comparing CFTR potentiators to placebo in people with cystic fibrosis. In a post hoc change we excluded trials combining CFTR potentiators with other mutation-specific therapies. These will be considered in a separate review. The authors independently extracted data and assessed the risk of bias in included trials; they contacted trial authors for additional data. Meta-analyses were undertaken on outcomes at a number of time points. We included four randomised controlled trials (n = 378), lasting from 28 days to 48 weeks, comparing the potentiator ivacaftor to placebo. Trials differed in terms of design and participant eligibility criteria, which limited the meta-analyses. The phase 2 trial (n = 19) and two phase 3 trials (adult trial (n = 167), paediatric trial (n = 52)), recruited participants with the G551D mutation (class III). The fourth trial (n = 140) enrolled participants homozygous for the ΔF508 mutation (class II).Risks of bias in the trials were moderate. Random sequence generation, allocation concealment and blinding of trial personnel were well-documented. Participant blinding was less clear throughout all trials; in three trials, some participant data were excluded from the analysis. Selective outcome reporting was apparent in three trials. All trials were sponsored by industry and supported by other non-pharmaceutical funding bodies.No trial reported any deaths. Significantly higher quality of life scores in the respiratory domain were reported by the adult phase 3 G551D trial at 24 weeks, mean difference 8.10 (95% confidence interval (CI) 4.77 to 11.43) and 48 weeks, mean difference 8.60 (95% CI 5.27 to 11.93); but not by the paediatric phase 3 G551D trial. The adult phase 3 G551D trial reported improvements in relative change from baseline in forced expiratory volume at one second at 24 weeks, mean difference 16.90% (95% CI 13.60 to 20.20) and 48 weeks, mean difference 16.80% (95% CI 13.50 to 20.10); as did the paediatric G551D trial at 24 weeks, mean difference 17.4% (P < 0.0001)). No improvements in quality of life or lung function were reported in the ΔF508 participants.Combined data from both phase 3 G551D trials demonstrated increased reporting of cough, odds ratio 0.57 (95% CI 0.33 to 1.00) and increased episodes of decreased pulmonary function, odds ratio 0.29 (95% CI 0.10 to 0.82) in the placebo group. The adult phase 3 G551D trial demonstrated increased reporting of dizziness amongst the ivacaftor group, OR 10.55 (95% CI 1.32 to 84.47). No trial showed a difference between treatment arms in the number of participants interrupting or discontinuing the trial drug.In the phase 3 G551D trials, fewer participants assigned to ivacaftor developed serious pulmonary exacerbations. When considering all data for exacerbations, participants taking ivacaftor in the adult phase 3 G551D study developed fewer exacerbations, odds ratio 0.54 (95% CI 0.29 to 1.01). In the other G551D studies and in the ΔF508 study, there was no difference between groups in the number of participants who developed pulmonary exacerbations.Combined data from both phase 3 G551D trials demonstrated significant improvements in absolute change from baseline in forced expiratory volume at one second (% predicted) at 24 weeks, mean difference 10.80% (95% CI 8.91 to 12.69) and 48 weeks, mean difference 10.44% (95% CI 8.56 to 12.32); also in weight at 24 weeks, mean difference 2.37 kg (95% CI 1.68 to 3.06) and 48 weeks, mean difference 2.75 kg (95% CI 1.74 to 3.75). No improvements in these outcomes were reported in the ΔF508 participants.Significant reductions in sweat chloride concentration were reported in both G551D and ΔF508 participants: in combined data from both phase 3 G551D trials at 24 weeks, mean difference -48.98 mmol/L (95% CI -52.07 to -45.89) and 48 weeks, mean difference -49.03 mmol/L (95% CI -52.11 to -45.94); and from the ΔF508 trial at 16 weeks, mean difference -2.90 mmol/L (95% CI -5.60 to -0.20). Both G551D phase 3 trials (n = 219) demonstrated a clinically relevant impact of the potentiator ivacaftor on outcomes at 24 and 48 weeks, providing evidence for the use of this treatment in adults and children (over six years of age) with cystic fibrosis and the G551D mutation (class III). There is no evidence to support the use of ivacaftor in people with the ΔF508 mutation (class II) (n = 140). Trials on ivacaftor in people with different mutations are ongoing.

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.

Surface density of quasars in two high-latitude fields

NASA Technical Reports Server (NTRS)

Usher, P. D.; Green, R. F.; Huang, K. L.; Warnock, A., III

1983-01-01

Fourty-four objects selected for ultraviolet excess have been identified spectroscopically. The objects lie in two Palomar 1.2 m Schmidt fields in the north galactic polar cap, one of 7.7 sq deg centered on Kapteyn Selected Area 29, the other of 36 sq deg centered on SA 55. The objects are characterized by Color Classes (CC) 1A, 1, 1B, 1C, 2, and 3. Quasars comprise 75 percent of the CC 1A objects and 44 percent of the objects in the SA 29 field. Twelve quasars in the SA 29 field comprise a complete sample to B = 18.5 mag, and given an uncorrected surface density of 1.6 quasars/sq deg. This value is essentially that derived by Sandage (1969). Corrections are applied to account for the lack of high redshift quasars. An empirical correction is derived to account for lack of simultaneity in selection and photometry. A corrected lower limit to the surface density is estimated to be 1.85 quasars/sq deg to B = 18.5 mag.

Self-Recognition Sensitizes Mouse and Human Regulatory T Cells to Low-Dose CD28 Superagonist Stimulation.

PubMed

Langenhorst, Daniela; Tabares, Paula; Gulde, Tobias; Becklund, Bryan R; Berr, Susanne; Surh, Charles D; Beyersdorf, Niklas; Hünig, Thomas

2017-01-01

In rodents, low doses of CD28-specific superagonistic monoclonal antibodies (CD28 superagonists, CD28SA) selectively activate regulatory T cells (Treg). This observation has recently been extended to humans, suggesting an option for the treatment of autoimmune and inflammatory diseases. However, a mechanistic explanation for this phenomenon is still lacking. Given that CD28SA amplify T cell receptor (TCR) signals, we tested the hypothesis that the weak tonic TCR signals received by conventional CD4 + T cells (Tconv) in the absence of cognate antigen require more CD28 signaling input for full activation than the stronger TCR signals received by self-reactive Treg. We report that in vitro , the response of mouse Treg and Tconv to CD28SA strongly depends on MHC class II expression by antigen-presenting cells. To separate the effect of tonic TCR signals from self-peptide recognition, we compared the response of wild-type Treg and Tconv to low and high CD28SA doses upon transfer into wild-type or H-2M knockout mice, which lack a self-peptide repertoire. We found that the superior response of Treg to low CD28SA doses was lost in the absence of self-peptide presentation. We also tested if potentially pathogenic autoreactive Tconv would benefit from self-recognition-induced sensitivity to CD28SA stimulation by transferring TCR transgenic OVA-specific Tconv into OVA-expressing mice and found that low-dose CD28SA application inhibited, rather than supported, their expansion, presumably due to the massive concomitant activation of Treg. Finally, we report that also in the in vitro response of human peripheral blood mononuclear cells to CD28SA, HLA II blockade interferes with the expansion of Treg by low-dose CD28SA stimulation. These results provide a rational basis for the further development of low-dose CD28SA therapy for the improvement of Treg activity.

Novel short chain fatty acids restore chloride secretion in cystic fibrosis

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

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

2006-03-31

Phenylalanine deletion at position 508 of the cystic fibrosis transmembrane conductance regulator ({delta}F508-CFTR), the most common mutation in cystic fibrosis (CF), causes a misfolded protein exhibiting partial chloride conductance and impaired trafficking to the plasma membrane. 4-Phenylbutyrate corrects defective {delta}F508-CFTR trafficking in vitro, but is not clinically efficacious. From a panel of short chain fatty acid derivatives, we showed that 2,2-dimethyl-butyrate (ST20) and {alpha}-methylhydrocinnamic acid (ST7), exhibiting high oral bioavailability and sustained plasma levels, correct the {delta}F508-CFTR defect. Pre-incubation ({>=}6 h) of CF IB3-1 airway cells with {>=}1 mM ST7 or ST20 restored the ability of 100 {mu}M forskolin tomore » stimulate an {sup 125}I{sup -} efflux. This efflux was fully inhibited by NPPB, DPC, or glibenclamide, suggesting mediation through CFTR. Partial inhibition by DIDS suggests possible contribution from an additional Cl{sup -} channel regulated by CFTR. Thus, ST7 and ST20 offer treatment potential for CF caused by the {delta}F508 mutation.« less

CFTR rescue with VX-809 and VX-770 favors the repair of primary airway epithelial cell cultures from patients with class II mutations in the presence of Pseudomonas aeruginosa exoproducts.

PubMed

Adam, Damien; Bilodeau, Claudia; Sognigbé, Laura; Maillé, Émilie; Ruffin, Manon; Brochiero, Emmanuelle

2018-04-13

Progressive airway damage due to bacterial infections, especially with Pseudomonas aeruginosa remains the first cause of morbidity and mortality in CF patients. Our previous work revealed a repair delay in CF airway epithelia compared to non-CF. This delay was partially prevented after CFTR correction (with VRT-325) in the absence of infection. Our goals were now to evaluate the effect of the Orkambi combination (CFTR VX-809 corrector + VX-770 potentiator) on the repair of CF primary airway epithelia, in infectious conditions. Primary airway epithelial cell cultures from patients with class II mutations were mechanically injured and wound healing rates and transepithelial resistances were monitored after CFTR rescue, in the absence and presence of P. aeruginosa exoproducts. Our data revealed that combined treatment with VX-809 and VX-770 elicited a greater beneficial impact on airway epithelial repair than VX-809 alone, in the absence of infection. The treatment with Orkambi was effective not only in airway epithelial cell cultures from patients homozygous for the F508del mutation but also from heterozygous patients carrying F508del and another class II mutation (N1303 K, I507del). The stimulatory effect of the Orkambi treatment was prevented by CFTR inhibition with GlyH101. Finally, Orkambi combination elicited a slight but significant improvement in airway epithelial repair and transepithelial resistance, despite the presence of P. aeruginosa exoproducts. Our findings indicate that Orkambi may favor airway epithelial integrity in CF patients with class II mutations. Complementary approaches would however be needed to further improve CFTR rescue and airway epithelial repair. Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Discovery of Multitarget Agents Active as Broad-Spectrum Antivirals and Correctors of Cystic Fibrosis Transmembrane Conductance Regulator for Associated Pulmonary Diseases.

PubMed

Tassini, Sabrina; Sun, Liang; Lanko, Kristina; Crespan, Emmanuele; Langron, Emily; Falchi, Federico; Kissova, Miroslava; Armijos-Rivera, Jorge I; Delang, Leen; Mirabelli, Carmen; Neyts, Johan; Pieroni, Marco; Cavalli, Andrea; Costantino, Gabriele; Maga, Giovanni; Vergani, Paola; Leyssen, Pieter; Radi, Marco

2017-02-23

Enteroviruses (EVs) are among the most frequent infectious agents in humans worldwide and represent the leading cause of upper respiratory tract infections. No drugs for the treatment of EV infections are currently available. Recent studies have also linked EV infection with pulmonary exacerbations, especially in cystic fibrosis (CF) patients, and the importance of this link is probably underestimated. The aim of this work was to develop a new class of multitarget agents active both as broad-spectrum antivirals and as correctors of the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding defect responsible for >90% of CF cases. We report herein the discovery of the first small molecules able to simultaneously act as correctors of the F508del-CFTR folding defect and as broad-spectrum antivirals against a panel of EVs representative of all major species.

Capturing Labile Sulfenamide and Sulfinamide Serum Albumin Adducts of Carcinogenic Arylamines by Chemical Oxidation

PubMed Central

Peng, Lijuan; Turesky, Robert J.

2013-01-01

Aromatic amines and heterocyclic aromatic amines (HAAs) are a class of structurally related carcinogens that are formed during the combustion of tobacco or during the high temperature cooking of meats. These procarcinogens undergo metabolic activation by N-oxidation of the exocyclic amine group to produce N-hydroxylated metabolites, which are critical intermediates implicated in toxicity and DNA damage. The arylhydroxylamines and their oxidized arylnitroso derivatives can also react with cysteine (Cys) residues of glutathione or proteins to form, respectively, sulfenamide and sulfinamide adducts. However, sulfur-nitrogen linked adducted proteins are often difficult to detect because they are unstable and undergo hydrolysis during proteolytic digestion. Synthetic N-oxidized intermediates of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogenic HAA produced in cooked meats, and 4-aminobiphenyl, a carcinogenic aromatic amine present in tobacco smoke were reacted with human serum albumin (SA) and formed labile sulfenamide or sulfinamide adducts at the Cys34 residue. Oxidation of the carcinogen-modified SA with m-chloroperoxybenzoic acid (m-CPBA) produced the arylsulfonamide adducts, which were stable to heat and the chemical reduction conditions employed to denature SA. The sulfonamide adducts of PhIP and 4-ABP were identified, by liquid chromatography/mass spectrometry, in proteolytic digests of denatured SA. Thus, selective oxidation of arylamine-modified SA produces stable arylsulfonamide-SA adducts, which may serve as biomarkers of these tobacco and dietary carcinogens. PMID:23240913

Cyclic crack growth behavior of reactor pressure vessel steels in light water reactor environments

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

Van Der Sluys, W.A.; Emanuelson, R.H.

1986-01-01

During normal operation light water reactor (LWR) pressure vessels are subjected to a variety of transients resulting in time varying stresses. Consequently, fatigue and environmentally assisted fatigue are growth mechanisms relevant to flaws in these pressure vessels. In order to provide a better understanding of the resistance of nuclear pressure vessel steels to flaw growth process, a series of fracture mechanics experiments were conducted to generate data on the rate of cyclic crack growth in SA508-2 and SA533b-1 steels in simulated 550/sup 0/F boiling water reactor (BWR) and 550/sup 0/F pressurized water reactor (PWR) environments. Areas investigated over the coursemore » of the test program included the effects of loading frequency and r ratio (Kmin-Kmax) on crack growth rate as a function of the stress intensity factor (deltaK) range. In addition, the effect of sulfur content of the test material on the cyclic crack growth rate was studied. Cyclic crack growth rates were found to be controlled by deltaK, R ratio, and loading frequency. The sulfur impurity content of the reactor pressure vessel steels studied had a significant effect on the cyclic crack growth rates. The higher growth rates were always associated with materials of higher sulfur content. For a given level of sulfur, growth rates were in a 550/sup 0/F simulated BWR environment than in a 550/sup 0/F simulated PWR environment. In both environments cyclic crack growth rates were a strong function of the loading frequency.« less

Expression analysis of chitinase upon challenge inoculation to Alternaria wounding and defense inducers in Brassica juncea.

PubMed

Rawat, Sandhya; Ali, Sajad; Mittra, Bhabatosh; Grover, Anita

2017-03-01

Chitinases are the hydrolytic enzymes which belong to the pathogenesis-related (PR) protein family and play an important role not only in plant defense but also in various abiotic stresses. However, only a limited number of chitinase genes have been characterised in B. juncea . In this study, we have characterised B. juncea class IV chitinase gene (accession no EF586206) in response to fungal infection, salicylic acid (SA), jasmonic acid (JA) treatments and wounding. Gene expression studies revealed that the transcript levels of Bjchitinase ( BjChp ) gene increases significantly both in local and distal tissues after Alternaria infection. Bjchitinase gene was also induced by jasmonic acid and wounding but moderately by salicylic acid. A 2.5 kb class IV chitinase promoter of this gene was isolated from B. juncea by Genome walking (accession no KF055403.1). In-silico analysis of this promoter revealed a number of conserved cis -regulatory elements related to defense, wounding and signalling molecules like SA, and JA. For validation, chitinase promoter was fused to the GUS gene, and the resultant construct was then introduced into Arabidopsis plants. Histochemical analysis of T 2 transgenic Arabidopsis plants showed that higher GUS activity in leaves after fungal infection, wounding and JA treatment but weakly by SA. GUS activity was seen in meristematic tissues, young leaves, seeds and siliques. Finally investigation has led to the identification of a pathogen-inducible, developmentally regulated and organ-specific promoter. Present study revealed that Bjchitinase ( BjChp ) promoter is induced during biotic and environmental stress and it can be used in developing finely tuned transgenics.

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.

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.

Year to year change in FEV1 in patients with cystic fibrosis and different mutation classes.

PubMed

De Boeck, K; Zolin, A

2017-03-01

In patients with cystic fibrosis, most treatments addressing the underlying basic defect are mutation or mutation class specific. These treatments are disease modifying if they lower the year to year change in lung function. We therefore calculated the current loss of lung function, measured by year to year change in forced expired volume in 1s in 11,417 patients included in the European Cystic Fibrosis Society Patient Registry. Whereas patients with at least one mutation of class IV or V have on average a lower year to year change, we did not find a difference between patients with a stop codon mutation, homozygous for F508del or at least one class III mutation. These data are useful background information to discuss the impact of different disease modifying treatments. Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

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, aparecendo da maior para a menor frequência, classe social, gênero, raça/etnia e geração. Direitos humanos foi pouco, e apenas recentemente, usado como referencial analítico, conectado mais ao gênero do que à classe social. Embora a Revista de Saúde Pública tenha inscrito o tema em suas publicações, consolidando-o como linha de produção científica, há, ainda, grande rarefação teórica explicativa e pouca interseccionalidade entre violência, desigualdades sociais e direitos humanos.

The use of step aerobics and the stability ball to improve balance and quality of life in community-dwelling older adults - a randomized exploratory study.

PubMed

Dunsky, Ayelet; Yahalom, Tal; Arnon, Michal; Lidor, Ronnie

2017-07-01

To explore the use of step aerobics (SA) and the stability ball (SB) as tools for balance improvement in community-dwelling older adults. Forty-two women (age: 72.2±5.8 years) who attended a community day center volunteered to participate in the study. Following the first assessment session, 28 women were assigned randomly to one of two experimental groups (the use of either SA or SB). The other 14 participants, who were engaged in a ceramic class, served as the control group. The study design was based on four assessment sessions and eight weeks of intervention. Assessment included four balance tests: Timed Up and Go (TUG), One-Leg Stand, Functional Reach, and the Performance-Oriented Assessment of Mobility (POMA). Quality of life was assessed by the use of the Short Form-36 Health Survey questionnaire. The TUG and POMA intervention improved significantly (d=.83 and d=.95, respectively) following the SA. In addition, general health perception following both the SA and SB interventions improved significantly relative to the control condition (d=.62 and d=.22, respectively). The findings of this study may imply that trainers should consider the inclusion of SA and SB as components of physical activity programs for seniors, aimed at improving balance ability and quality of life. Copyright © 2017 Elsevier B.V. All rights reserved.

Minimal Niven Numbers

DTIC Science & Technology

2007-12-26

distribution in residue classes of integers with a fixed digit sum’, The Ramanujan J. 9 (2005), 45–62. [12] C . Mauduit and A. Sárközy, ‘On the arithmetic...28 19a. NAME OF RESPONSIBLE PERSON a. REPORT unclassified b. ABSTRACT unclassified c . THIS PAGE unclassified Standard Form 298 (Rev. 8-98...density zero. For the purpose of this section only, we omit the index and simply write C = {1 ≤ n : 2n+1 − 1 ≡ 2j (mod n) for some j = 1, 2

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 American Society for Pharmacology and Experimental Therapeutics.

Entry, Descent and Landing Systems Analysis Study: Phase 2 Report on Exploration Feed-Forward Systems

NASA Technical Reports Server (NTRS)

Dwyer Ciancolo, Alicia M.; Davis, Jody L.; Engelund, Walter C.; Komar, D. R.; Queen, Eric M.; Samareh, Jamshid A.; Way, David W.; Zang, Thomas A.; Murch, Jeff G.; Krizan, Shawn A.;

Small heat shock proteins target mutant cystic fibrosis transmembrane conductance regulator for degradation via a small ubiquitin-like modifier–dependent pathway

PubMed Central

Ahner, Annette; Gong, Xiaoyan; Schmidt, Bela Z.; Peters, Kathryn W.; Rabeh, Wael M.; Thibodeau, Patrick H.; Lukacs, Gergely L.; Frizzell, Raymond A.

2013-01-01

Small heat shock proteins (sHsps) bind destabilized proteins during cell stress and disease, but their physiological functions are less clear. We evaluated the impact of Hsp27, an sHsp expressed in airway epithelial cells, on the common protein misfolding mutant that is responsible for most cystic fibrosis. F508del cystic fibrosis transmembrane conductance regulator (CFTR), a well-studied protein that is subject to cytosolic quality control, selectively associated with Hsp27, whose overexpression preferentially targeted mutant CFTR to proteasomal degradation. Hsp27 interacted physically with Ubc9, the small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, implying that F508del SUMOylation leads to its sHsp-mediated degradation. Enhancing or disabling the SUMO pathway increased or blocked Hsp27’s ability to degrade mutant CFTR. Hsp27 promoted selective SUMOylation of F508del NBD1 in vitro and of full-length F508del CFTR in vivo, which preferred endogenous SUMO-2/3 paralogues that form poly-chains. The SUMO-targeted ubiquitin ligase (STUbL) RNF4 recognizes poly-SUMO chains to facilitate nuclear protein degradation. RNF4 overexpression elicited F508del degradation, whereas Hsp27 knockdown blocked RNF4’s impact on mutant CFTR. Similarly, the ability of Hsp27 to degrade F508del CFTR was lost during overexpression of dominant-negative RNF4. These findings link sHsp-mediated F508del CFTR degradation to its SUMOylation and to STUbL-mediated targeting to the ubiquitin–proteasome system and thereby implicate this pathway in the disposal of an integral membrane protein. PMID:23155000

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...

Applications of Mobile GIS in Forestry South Australia

NASA Astrophysics Data System (ADS)

Battad, D. T.; Mackenzie, P.

2012-07-01

South Australian Forestry Corporation (ForestrySA) had been actively investigating the applications of mobile GIS in forestry for the past few years. The main objective is to develop an integrated mobile GIS capability that allows staff to collect new spatial information, verify existing data, and remotely access and post data from the field. Two (2) prototype mobile GIS applications have been developed already using the Environmental Systems Research Institute (ESRI) ARCGISR technology as the main spatial component. These prototype systems are the Forest Health Surveillance System and the Mobile GIS for Wetlands System. The Forest Health Surveillance System prototype is used primarily for aerial forest health surveillance. It was developed using a tablet PC with ArcMapR GIS. A customised toolbar was developed using ArcObjectsR in the Visual Basic 6 Integrated Development Environment (IDE). The resulting dynamic linked library provides a suite of custom tools which enables the following: - quickly create spatial features and attribute the data - full utilisation of global positioning system (GPS) technology - excellent screen display navigation tools, i.e. pan, rotate map, capture of flight path - seamless integration of data into GIS as geodatabase (GDB) feature classes - screen entry of text and conversion to annotation feature classes The Mobile GIS for Wetlands System prototype was developed for verifying existing wetland areas within ForestrySA's plantation estate, collect new wetland data, and record wetland conditions. Mapping of actual wetlands within ForestrySA's plantation estate is very critical because of the need to establish protection buffers around these features during the implementation of plantation operations. System development has been focussed on a mobile phone platform (HTC HD2R ) with WindowsR Mobile 6, ESRI's ArcGISR Mobile software development kit (SDK) employing ArcObjectsR written on C#.NET IDE, and ArcGIS ServerR technology. The system is also implemented in the VILIVR X70. The system has undergone testing by ForestrySA staff and the refinements had been incorporated in the latest version of the system. The system has the following functionalities: - display and query strategic data layers - collect and edit spatial and attribute data - full utilisation of global positioning GPS technology - distance and area measurements - display of high resolution imagery - seamless integration of data into GIS as feature classes - screen display and navigation tools, i.e. pan, zoom in/out, rotate map - capture of flight path The next stages in the development of mobile GIS technologies at ForestrySA are to enhance the systems' capabilities as one of the organization main data capture systems. These include incorporating other applications, e.g. roads/tracks mapping, mapping of significant sites, etc., and migration of the system to Windows Phone7.

Effects of 2 size classes of intratracheally administered airborne dust particles on primary and secondary specific antibody responses and body weight gain of broilers: a pilot study on the effects of naturally occurring dust.

PubMed

Lai, H T L; Nieuwland, M G B; Aarnink, A J A; Kemp, B; Parmentier, H K

2012-03-01

We studied the effects of a concurrent challenge on slow-growing broilers with 1) airborne particles of 2 sizes: fine dust (smaller than 2.5 microns) and coarse dust (between 2.5 and 10 microns) that were directly collected from a broiler house and 2) lipopolysaccharide on intratracheal immunizations with the specific antigen human serum albumin (HuSA) and measured primary and secondary systemic (total) antibody responses and (isotype-specific) IgM, IgG, and IgA responses at 3 and 7 wk of age. All treatments affected immune responses at several ages, heart morphology, and BW gain, albeit the latter only temporarily. Dust particles significantly decreased primary antibody (IgT and IgG) responses to HuSA at 3 wk of age but enhanced IgM responses to HuSA at 7 wk of age. Dust particles decreased secondary antibody responses to HuSA, albeit not significantly. All of the birds that were challenged with dust particles showed decreased BW gain after the primary but not after the secondary challenge. Relative heart weight was significantly decreased in birds challenged with coarse dust, fine dust, lipopolysaccharide, and HuSA at 3 wk of age, but not in birds challenged at 7 wk of age. Morphology (weight, width, and length) of hearts were also affected by the dust challenge at 3 wk of age. The present results indicate that airborne dust particles obtained from a broiler house when intratracheally administered at an early age affect specific humoral immune responsiveness and BW gain of broilers to simultaneously administered antigens differently than when administered at a later age. The hygienic status of broiler houses at a young age may be of importance for growth and immune responsiveness, and consequently, for vaccine efficacy and disease resistance in broilers. The consequences of our findings are discussed.

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.

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).

Exploring the limit of accuracy for density functionals based on the generalized gradient approximation: Local, global hybrid, and range-separated hybrid functionals with and without dispersion corrections

DOE PAGES

Mardirossian, Narbe; Head-Gordon, Martin

2014-03-25

The limit of accuracy for semi-empirical generalized gradient approximation (GGA) density functionals is explored in this paper by parameterizing a variety of local, global hybrid, and range-separated hybrid functionals. The training methodology employed differs from conventional approaches in 2 main ways: (1) Instead of uniformly truncating the exchange, same-spin correlation, and opposite-spin correlation functional inhomogeneity correction factors, all possible fits up to fourth order are considered, and (2) Instead of selecting the optimal functionals based solely on their training set performance, the fits are validated on an independent test set and ranked based on their overall performance on the trainingmore » and test sets. The 3 different methods of accounting for exchange are trained both with and without dispersion corrections (DFT-D2 and VV10), resulting in a total of 491 508 candidate functionals. For each of the 9 functional classes considered, the results illustrate the trade-off between improved training set performance and diminished transferability. Since all 491 508 functionals are uniformly trained and tested, this methodology allows the relative strengths of each type of functional to be consistently compared and contrasted. Finally, the range-separated hybrid GGA functional paired with the VV10 nonlocal correlation functional emerges as the most accurate form for the present training and test sets, which span thermochemical energy differences, reaction barriers, and intermolecular interactions involving lighter main group elements.« less

Is Greulich and Pyle standards of skeletal maturation applicable for age estimation in South Indian Andhra children?

PubMed

Mohammed, Rezwana Begum; Rao, Dola Srinivasa; Goud, Alampur Srinivas; Sailaja, S; Thetay, Anshuj Ajay Rao; Gopalakrishnan, Meera

2015-01-01

Now-a-day age determination has gained importance for various forensic and legal reasons. Skeletal age (SA) of a test population can be estimated by comparing with established standards of Greulich and Pyle (G-P). As this atlas has been prepared using data from upper-class children born between 1917 and 1942 in the USA and the applicability of these standards to contemporary populations has yet to be tested on Andhra children living in India. Hence, this study was aimed to assess the reliability of bone age calculated by G-P atlas in estimation of age in selected population. A total of 660 children (330 girls, 330 boys) between ages 9 and 20 years were randomly selected from outpatient Department of Oral Medicine in GITAM Dental College, Andhra Pradesh. Digital hand-wrist radiographs were obtained and assessed for SA using G-P atlas and the difference between estimated SA and chronological age (CA) were compared with paired t-test and Wilcoxon signed rank test. G-P method underestimated the SA by 0.23 ± 1.53 years for boys and overestimated SA by 0.02 ± 2 years in girls and mild underestimation was noted in the total sample of about 0.1 ± 1.78 years. Spearman rank test showed significant correlation between SA and CA (r = 0.86; P < 0.001). This study concluded that G-P standards were reliable in assessing age in South Indian Andhra children of age 9-20 years with unknown CA.

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

PubMed Central

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

2016-01-01

Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients. PMID:27402691

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

PubMed

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

2016-09-01

Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients. Copyright © 2016 the American Physiological Society.

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.

Molecular genetic analysis of some mutations in the cystic fibrosis gene in Moldova: Characterization of molecular markers and their linkage to various mutations

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

Gimbovskaya, S.D.; Kalinin, V.N.; Ivashchenko, T.E.

1994-12-01

Sixty-one patients with cystic fibrosis (CF) from Moldova were tested for mutations {Delta}F508, G551D, and R553X. Frequencies of various alleles of the repeated GATT sequence in intron 6B of the GFTR gene, their linkage to other polymorphic markers, and various mutations were determined. The frequency of occurrence of mutation {Delta}F508 was only 25%. An absolute majority of CF patients (80%) had pancreatic insufficiency. Mutations G551D and R553X were not found in our sample. Each of 31 chromosomes with mutation {Delta}F508 carry the 6-GATT allele. Most {open_quotes}non {Delta}F508{close_quotes} (78%) and normal (80%) chromosomes were marked by the 7-GATT allele. Twenty-seven {Delta}F508more » chromosomes (96.4%) belong to haplotype B6, and only one to D6. Most chromosomes with {open_quotes}non {Delta}F508{close_quotes} mutations are associated with haplotypes D7 (26.3%) and C7 (21%). In addition, a significant portion of chromosomes from this subgroup were associated with haplotypes A7 (23.7%), A6 (10.5%), and C6 (2.7%), which are not yet described for mutant chromosomes. The results obtained demonstrate that CF in Moldova is mainly associated with mutations other than {Delta}F508, G551D, and R553X. Severe forms of the disease, with pancreatic insufficiency, are more frequently caused by these mutations; moreover, our data provides strong evidence for the presence of at least seven additional CF mutations in Moldova, apart from {Delta}F508, G551D, and R553X. Some of these are probably not described.« less

Evaluation of the use of partition coefficients and molecular surface properties as predictors of drug absorption: a provisional biopharmaceutical classification of the list of national essential medicines of Pakistan

PubMed Central

Shawahna, R.; Rahman, NU.

2011-01-01

Background and the purpose of the study Partition coefficients (log D and log P) and molecular surface area (PSA) are potential predictors of the intestinal permeability of drugs. The aim of this investigation was to evaluate and compare these intestinal permeability indicators. Methods Aqueous solubility data were obtained from literature or calculated using ACD/Labs and ALOGPS. Permeability data were predicted based on log P, log D at pH 6.0 (log D6.0), and PSA. Results Metoprolol's log P, log D6.0, and a PSA of <65 Å correctly predicted 55.9%, 50.8% and 54.2% of permeability classes, respectively. Labetalol's log P, log D6.0 and PSA correctly predicted 54.2%, 64.4% and 61% of permeability classes, respectively. Log D6.0 correlated well (81%) with Caco-2 permeability (Papp). Of the list of national essential medicines, 135 orally administered drugs were classified into biopharmaceutical classification system (BCS). Of these, 57 (42.2%), 28 (20.7%), 44 (32.6%), and 6 (4.4%) were class I, II, III and IV respectively. Conclusion Log D6.0 showed better prediction capability than log P. Metoprolol as permeability internal standard was more conservative than labetalol. PMID:22615645

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.

Development of "fragility" in relaxor ferroelectrics

NASA Astrophysics Data System (ADS)

Wang, Yi-zhen; Chen, Lan; Wang, Hai-yan; Frank Zhang, X.; Fu, Jun; Xiong, Xiao-min; Zhang, Jin-xiu

2014-02-01

Relaxor ferroelectrics (RFs), a special class of the disordered crystals or ceramics, exhibit a pronounced slowdown of their dynamics upon cooling as glass-forming liquids, called the "Super-Arrhenius (SA)" relaxation. Despite great progress in glass-forming liquids, the "fragility" property of the SA relaxation in RFs remains unclear so far. By measuring the temperature-dependent dielectric relaxation in the typical relaxor Pb(Mg1/3Nb2/3)O3-x%PbTiO3 (PMN - x%PT) with 0 ≤ x ≤ 20.0, we in-depth study the "fragility" properties of the SA relaxation in PMN - x%PT. Such fascinating issues as the mechanism of the "fragility" at an atomic scale, the roles of the systematic configurational entropy change and interaction among relaxing units (RUs, including polar nanoregions and free dipoles) and the relation between "fragility" and ferroelectric order are investigated. Our results show that both the "fragility" of the temperature-dependent SA relaxation and ferroelectric order in the PMN - x%PT systems investigated arise thermodynamically from the configurational-entropy loss due to the attractive interaction among RUs, and develops as a power law, possibly diverging at the finite critical temperature Tc. A reasonable physical scenario, based on our "configurational-entropy-loss" theory and Nowick's "stress-induced-ordering" theory, was proposed.

Assessment of the effectiveness of physical activity interventions in the Brazilian Unified Health System.

PubMed

Ribeiro, Evelyn Helena Corgosinho; Garcia, Leandro Martin Totaro; Salvador, Emanuel Péricles; Costa, Evelyn Fabiana; Andrade, Douglas Roque; Latorre, Maria do Rosario Dias de Oliveira; Florindo, Alex Antonio

2017-06-26

To assess the effect of interventions on the levels of physical activity of healthy adults, users of the Brazilian Unified Health System and attended by the Family Health Strategy. Non-randomized experimental study with 157 adults allocated in three groups: 1) physical exercise classes (n = 54), 2) health education (n = 54), 3) control (n = 49). The study lasted for18 months, with 12 months of interventions and six months of follow-up after intervention. Assessments took place at the beginning, in the 12 months, and in the 18 months of study. Physical activity has been assessed by questionnaires and accelerometry. For the analyses, we have used the intention-to-treat principle and generalized estimating equations. After 12 months, both intervention groups have increased the minutes of weekly leisure time physical activity and annual scores of physical exercise, leisure and transport-related physical activity. The exercise class group has obtained the highest average annual physical exercises score when compared to the other groups (p < 0.001). In the follow-up period, the exercise class group reduced its annual score (average: -0.3; 95%CI -0.5--0.1), while the health education group increased this score (average: 0.2; 95%CI 0.1-0.4). There have been no differences in the levels of physical activity measured by accelerometry. The interventions have been effective in increasing the practice of physical activity. However, we have observed that the health education intervention was more effective for maintaining the practice of physical activity in the period after intervention. We recommend the use of both interventions to promote physical activity in the Brazilian Unified Health System, according to the local reality of professionals, facilities, and team objectives. Avaliar o efeito de intervenções nos níveis de atividade física de adultos saudáveis, usuários do Sistema Único de Saúde e atendidos pela Estratégia de Saúde da Família. Estudo experimental, não randomizado, com 157 adultos alocados em três grupos: 1) classes de exercícios físicos (n = 54); 2) educação em saúde (n = 54); 3) controle (n = 49). O estudo teve duração de 18 meses, sendo 12 meses de intervenções e seis meses de acompanhamento pós-intervenção. As avaliações ocorreram no início, nos 12 e nos 18 meses de estudo. A atividade física foi avaliada por questionários e por acelerometria. Para as análises, utilizaram-se o princípio de intenção de tratar e equações de estimativas generalizadas. Após 12 meses, ambos os grupos de intervenção aumentaram os minutos semanais de atividade física no lazer e os escores anuais de exercícios físicos, de lazer e de deslocamento. O grupo das classes de exercícios físicos obteve maior média de escore anual de exercícios físicos em comparação com os outros grupos (p < 0,001). No período pós-intervenção, o grupo de classes de exercícios físicos reduziu o escore anual de exercícios físicos (média: -0,3; IC95% -0,5--0,1), enquanto o grupo de educação em saúde aumentou este escore (média: 0,2; IC95% 0,1-0,4). Não houve diferenças nos níveis de atividade física mensurados por acelerometria. As intervenções foram efetivas para aumentar a prática de atividade física. No entanto, observou-se que a intervenção de educação em saúde foi mais efetiva para a manutenção da prática de atividade física no período pós-intervenção. Recomenda-se a utilização de ambas as intervenções para a promoção da atividade física no Sistema Único de Saúde, de acordo com as realidades locais de profissionais, instalações e objetivos das equipes.

Modeling of Austenite Grain Growth During Austenitization in a Low Alloy Steel

NASA Astrophysics Data System (ADS)

Dong, Dingqian; Chen, Fei; Cui, Zhenshan

2016-01-01

The main purpose of this work is to develop a pragmatic model to predict austenite grain growth in a nuclear reactor pressure vessel steel. Austenite grain growth kinetics has been investigated under different heating conditions, involving heating temperature, holding time, as well as heating rate. Based on the experimental results, the mathematical model was established by regression analysis. The model predictions present a good agreement with the experimental data. Meanwhile, grain boundary precipitates and pinning effects on grain growth were studied by transmission electron microscopy. It is found that with the increasing of the temperature, the second-phase particles tend to be dissolved and the pinning effects become smaller, which results in a rapid growth of certain large grains with favorable orientation. The results from this study provide the basis for the establishment of large-sized ingot heating specification for SA508-III steel.

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

Wang, Siyan; Ding, Jie; Ming, Hongliang

The interface region of welded A508–Alloy 52 M is characterized by scanning probe microscope (SPM) techniques, scanning electron microscopy (SEM)/energy dispersive spectroscopy (EDS), transmission electron microscopy (TEM)/Energy Dispersive Spectroscopy (EDS) and scanning vibrate electrode technique (SVET). The regions along the welded A508–Alloy 52 M interface can be categorized into two types according to their different microstructures. In the type-I interface region, A508 and Alloy 52 M are separated by the fusion boundary, while in the type-II interface region, A508 and Alloy 52 M are separated by a martensite zone. A508, martensite zone and grain boundaries in Alloy 52 M aremore » ferromagnetic while the Alloy 52 M matrix is paramagnetic. The Volta potentials measured by scanning Kelvin probe force microscopy (SKPFM) of A508, martensite zone and Alloy 52 M follow the order: V{sub 52} {sub M} > V{sub A508} > V{sub martensite}. The corrosion behavior of A508–Alloy 52 M interface region is galvanic corrosion, in which Alloy 52 M is cathode while A508 is anode. The martensite dissolves faster than Alloy 52 M, but slower than A508 in the test solution. - Highlights: • The A508–Alloy 52 M interface regions can be categorized into two types. • The chromium depleted region is observed along the Alloy 52 M grain boundary. • The Alloy 52 M grain boundaries which are close to the interface are ferromagnetic. • Martensite zone has lower Volta potential but higher corrosion resistance than A508.« less

Expert Computer Systems for Missile Maintenance.

DTIC Science & Technology

1983-08-09

ADDRESS(II different from Controlling Office) IS. SECURITY CLASS. (of thl report) Unclassified 1Sa. DECL ASSI FICATION/ DOWNGRADING - SCHEDULE I...circuit, and with the diagnostic methods used by the technicians responsible for maintain- ing it, we decided that we should visit Owego. On October 20...This trip was useful in several respects: 1. Insight was gained into the methods used by the technicians to diagnose a faulty circuit. 2. We learned what

Entry, Descent and Landing Systems Analysis: Exploration Feed Forward Internal Peer Review Slide Package

NASA Technical Reports Server (NTRS)

Dwyer Cianciolo, Alicia M. (Editor)

2011-01-01

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 successfully land large payloads at Mars for both robotic and human-scale missions. Year 1 of the study focused on technologies required for Exploration-class missions to land payloads of 10 to 50 mt. Inflatable decelerators, rigid aeroshell and supersonic retro-propulsion emerged as the top candidate technologies. In Year 2 of the study, low TRL technologies identified in Year 1, inflatables aeroshells and supersonic retropropulsion, were combined to create a demonstration precursor robotic mission. This part of the EDL-SA Year 2 effort, called Exploration Feed Forward (EFF), took much of the systems analysis simulation and component model development from Year 1 to the next level of detail.

Human GAPDH Is a Target of Aspirin’s Primary Metabolite Salicylic Acid and Its Derivatives

PubMed Central

Manohar, Murli; Harraz, Maged M.; Park, Sang-Wook; Schroeder, Frank C.; Snyder, Solomon H.; Klessig, Daniel F.

2015-01-01

The plant hormone salicylic acid (SA) controls several physiological processes and is a key regulator of multiple levels of plant immunity. To decipher the mechanisms through which SA’s multiple physiological effects are mediated, particularly in immunity, two high-throughput screens were developed to identify SA-binding proteins (SABPs). Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) from plants (Arabidopsis thaliana) was identified in these screens. Similar screens and subsequent analyses using SA analogs, in conjunction with either a photoaffinity labeling technique or surface plasmon resonance-based technology, established that human GAPDH (HsGAPDH) also binds SA. In addition to its central role in glycolysis, HsGAPDH participates in several pathological processes, including viral replication and neuronal cell death. The anti-Parkinson’s drug deprenyl has been shown to suppress nuclear translocation of HsGAPDH, an early step in cell death and the resulting cell death induced by the DNA alkylating agent N-methyl-N’-nitro-N-nitrosoguanidine. Here, we demonstrate that SA, which is the primary metabolite of aspirin (acetyl SA) and is likely responsible for many of its pharmacological effects, also suppresses nuclear translocation of HsGAPDH and cell death. Analysis of two synthetic SA derivatives and two classes of compounds from the Chinese medicinal herb Glycyrrhiza foetida (licorice), glycyrrhizin and the SA-derivatives amorfrutins, revealed that they not only appear to bind HsGAPDH more tightly than SA, but also exhibit a greater ability to suppress translocation of HsGAPDH to the nucleus and cell death. PMID:26606248

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...

Characteristics of shock-associated fast-drift kilometric radio bursts

NASA Technical Reports Server (NTRS)

Macdowall, R. J.; Kundu, M. R.; Stone, R. G.

1987-01-01

The existence of a class of fast-drift, shock-associated (SA), kilometric radio bursts which occur at the time of metric type II emission and which are not entirely the kilometric continuation of metric type III bursts has been reported previously (Cane et al., 1981). In this paper unambiguous SA event criteria are established for the purpose of statistically comparing SA events with conventional kilometric type III bursts. Applying these criteria to all long-duration, fast-drift bursts observed by the ISEE-3 spacecraft during a 28-month interval, it is found that more than 70 percent of the events satisfying the criteria are associated with the radio signatures of coronal shocks. If a given event is associated with a metric type II or type IV burst, it is 13 times more likely to satisfy the SA criteria than an event associated only with metric type III activity.

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

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 vivo.

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.

Microstructural dependence of Barkhausen noise and magnetic relaxation in the weld HAZ of an RPV steel

NASA Astrophysics Data System (ADS)

Park, Duck-Gun; Kim, Cheol Gi; Hong, Jun-Hwa

2000-06-01

Magnetic Barkhausen noise and permeability spectra have been measured to characterize different microstructure regions such as coarse-grain region, fine-grain region, intercritical structure (composed of tempered martensite and bainite) within the heat-affected zone (HAZ) of SA508-3 steel weldments using simulated HAZ microstructure sample. The intercritical region and coarse-grained region can be distinguished from the BNE and relaxation frequency. The BNE was decreased in the martensite regions and increased in the bainite regions by the post-weld heat treatment (PWHT). The change of relaxation frequency also showed similar trends, but the rate of change was less than that of BNE. The behavior of BNE and permeability spectra on the corresponding microstructure can be explained in terms of carbide morphology and residual stress related with domain wall motion.

Hypoxia, Monitoring, and Mitigation System

DTIC Science & Technology

2014-05-01

indicators based on measured and predicted data. Given the beat-to-beat method in which oxygen saturation is measured via a pulse oximeter , a certain...saturation sample values are far below what would be trusted on a pulse oximeter . No indication was given after oxygen mask placement on subjective...determined using a pulse oximeter for continuous monitoring of arterial oxygen saturation (SaO2) in 95 ASA class I or II adult patients breathing room

A Class of CFAR Detectors Implemented in the SAR-GMTI Processor gmtipro2: Mathematical Formulation of the Algorithms

DTIC Science & Technology

2015-02-01

Right of Canada as represented by the Minister of National Defence, 2015 c© Sa Majesté la Reine (en droit du Canada), telle que représentée par le...References [1] Chiu, S. (2010), Moving target parameter estimation for RADARSAT-2 Moving Object Detection EXperiment (MODEX), International Journal of...of multiple sinusoids in noise, In Proceedings. (ICASSP ’01). 2001 IEEE International Conference on Acoustics, Speech, and Signal Processing, Vol. 5

Pulmonary function disparities exist and persist in Hispanic patients with cystic fibrosis: A longitudinal analysis.

PubMed

McGarry, Meghan E; Neuhaus, John M; Nielson, Dennis W; Burchard, Esteban; Ly, Ngoc P

2017-12-01

Hispanic patients with cystic fibrosis (CF) have decreased life expectancy compared to non-Hispanic white patients. Pulmonary function is a main predictor of life expectancy in CF. Ethnic differences in pulmonary function in CF have been understudied. The objective was to compare longitudinal pulmonary function between Hispanic and non-Hispanic white patients with CF. This cohort study of 15 018 6-25 years old patients in the CF Foundation Patient Registry from 2008 to 2013 compared FEV 1 percent predicted and longitudinal change in FEV 1 percent predicted in Hispanic to non-Hispanic white patients. We used linear mixed effects models with patient-specific slopes and intercepts, adjusting for 14 demographic and clinical variables. We did sub-analyses by CFTR class, F508del copies, and PERT use. Hispanic patients had lower FEV 1 percent predicted (79.9%) compared with non-Hispanic white patients (85.6%); (-5.8%, 95%CI -6.7% to -4.8%, P < 0.001), however, there was no difference in FEV 1 decline over time. Patients on PERT had a larger difference between Hispanic and non-Hispanic white patients in FEV 1 percent predicted than patients not on PERT (-6.0% vs -4.1%, P = 0.02). The ethnic difference in FEV 1 percent predicted was not statistically significant between CFTR classes (Class I-III: -6.1%, Class IV-V: -5.9%, Unclassified: -5.7%, P > 0.05) or between F508del copies (None: -7.6%, Heterozygotes: -5.6%, Homozygotes: -5.3%, P > 0.05). Disparities in pulmonary function exist in Hispanic patients with CF early in life and then persist without improving or worsening over time. It is valuable to investigate the factors contributing to pulmonary function in Hispanic patients with CF. © 2017 Wiley Periodicals, Inc.

The thermodynamic parameters of sorption and enantioselectivity of the chiral smectic liquid crystal 2-methylbutyl ester of 4-(4-decyloxybenzylideneamino)-cinnamic acid

NASA Astrophysics Data System (ADS)

Onuchak, L. A.; Stepanova, R. F.; Akopova, O. B.; Glebova, O. V.; Chernova, O. M.

2008-06-01

The thermodynamic characteristics of sorption of n-alkanes, arenes, aldehydes, monoatomic alcohols, and optical isomers of camphene and butanediol-2,3 by a chiral smectic liquid crystal, 2-methylbutyl ester of 4-(4-decyloxybenzylideneamino)-cinnamic acid, from the gas phase were studied over the temperature range including the S*C and S*A mesophases and isotropic phase. The standard and excess thermodynamic functions of sorption were determined for 26 sorbates of the classes of substances specified. The S*C and S*A mesophases exhibited selectivity with respect to the separation of para and meta xylenes (α p/m = 1.06 1.07, 90 108°C) and pronounced enantioselectivity (αR/S = 1.05 1.09, 87 108°C). The helically twisted structure of the smectic liquid crystal was shown to play an important role in the mechanism of the chiral recognition of optical isomers of polar and low-polarity compounds under gas-liquid chromatography conditions.

Pattern of disabilities in a residential school for the handicapped in Ilorin, Nigeria.

PubMed

Ologe, F E; Akande, T M

2003-12-01

As part of a wider study aimed at establishing baseline information (for planning purposes), the pattern of disabilities in a Residential School for the handicap was determined. Information on demographic data, nature of handicap, age of enrollment, present class and length of stay in the school were obtained. The study involved 82 pupils (28 females) aged 5-30 years (mean 16.9 + 5.08 years). Seventy nine percent (65) were deaf, 13.6%(11) blind and 6.2% (5) had mental retardation. The mean age of enrollment was 10.6 + 4.12 years. Only two (2.5%) of the pupils/students stayed in the school beyond the regulation time. These findings show that deafness was the commonest disability and strongly suggest that none of the disabilities observed had major impact on learning ability in this school system.

Engineering Investigation of Information Integration Display (IID) Integration with Platform Systems

DTIC Science & Technology

2014-07-01

Chair DRP © Her Majesty the Queen in Right of Canada, as represented by the Minister of National Defence, 2014 © Sa Majesté la Reine (en...Objectives Defence Research and Development Canada (DRDC) Atlantic has conducted a Cognitive Work Analysis (CWA) for key Victoria Class Submarine...tables, were added. The “Virtual Victoria Data Model” (reference [2]), “Assumptions and Specifications Matrix” (reference [3]), and a DRDC Atlantic

Immunogenetic background of patients with autoimmune fatigue syndrome.

PubMed

Itoh, Y; Igarashi, T; Tatsuma, N; Imai, T; Yoshida, J; Tsuchiya, M; Murakami, M; Fukunaga, Y

2000-10-01

We have previously reported that approximately 50% of children with chronic nonspecific complaints were positive for antinuclear antibodies (ANA), and that a novel autoantibody to a 62 kD protein (anti-Sa) was found in 40% of these ANA-positive patients. Therefore, we proposed a distinct disease entity termed autoimmune fatigue syndrome (AIFS). We hypothesized that if autoimmune mechanisms did play an important role in the pathogenesis of AIFS, it is possible that it is immunogenetically regulated as observed in other autoimmune disorders. In order to examine the immunogenetic background of AIFS patients, HLA-A, -B, -C, and -DR loci were analyzed serologically in 61 AIFS patients. AIFS was found to be positively associated with the class I antigen HLA-B61 and with the class II antigen HLA-DR9, with odds ratios of 2.77 (p = 0.015, Pcorr = 0.48) and 2.60 (p= 0.012, Pcorr = 0.17), respectively. A negative association was also found between AIFS and HLA-DR2 with odds ratio of 0.25 (p = 0.029, Pcorr = 0.041). When comparing anti-Sa positive AIFS patients with healthy controls, the odds ratios associated with HLA-B61, DR9, and DR2 were 3.42 (p = 0.021, Pcorr = 0.22), 3.96 (p = 0.0011, Pcorr = 0.015), and 0.16 (p = 0.0022, Porr = 0.031), respectively. Thus, the HLA associations observed in this study suggested that immunogenetic background might play a role in AIFS.

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...

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.

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

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...

Activation of the Cystic Fibrosis Transmembrane Conductance Regulator by the Flavonoid Quercetin

PubMed Central

Pyle, Louise C.; Fulton, Jennifer C.; Sloane, Peter A.; Backer, Kyle; Mazur, Marina; Prasain, Jeevan; Barnes, Stephen; Clancy, J. P.; Rowe, Steven M.

2010-01-01

Therapies to correct the ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) folding defect require sensitive methods to detect channel activity in vivo. The β2 adrenergic receptor agonists, which provide the CFTR stimuli commonly used in nasal potential difference assays, may not overcome the channel gating defects seen in ΔF508 CFTR after plasma membrane localization. In this study, we identify an agent, quercetin, that enhances the detection of surface ΔF508 CFTR, and is suitable for nasal perfusion. A screen of flavonoids in CFBE41o− cells stably transduced with ΔF508 CFTR, corrected to the cell surface with low temperature growth, revealed that quercetin stimulated an increase in the short-circuit current. This increase was dose-dependent in both Fisher rat thyroid and CFBE41o− cells. High concentrations inhibited Cl− conductance. In CFBE41o− airway cells, quercetin (20 μg/ml) activated ΔF508 CFTR, whereas the β2 adrenergic receptor agonist isoproterenol did not. Quercetin had limited effects on cAMP levels, but did not produce detectable phosphorylation of the isolated CFTR R-domain, suggesting an activation independent of channel phosphorylation. When perfused in the nares of Cftr+ mice, quercetin (20 μg/ml) produced a hyperpolarization of the potential difference that was absent in Cftr−/− mice. Finally, quercetin-induced, dose-dependent hyperpolarization of the nasal potential difference was also seen in normal human subjects. Quercetin activates CFTR-mediated anion transport in respiratory epithelia in vitro and in vivo, and may be useful in studies intended to detect the rescue of ΔF508 CFTR by nasal potential difference. PMID:20042712

∆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.

Fabrication and characterization of anisotropic nanofiber scaffolds for advanced drug delivery systems

PubMed Central

Jalani, Ghulam; Jung, Chan Woo; Lee, Jae Sang; Lim, Dong Woo

2014-01-01

Stimuli-responsive, polymer-based nanostructures with anisotropic compartments are of great interest as advanced materials because they are capable of switching their shape via environmentally-triggered conformational changes, while maintaining discrete compartments. In this study, a new class of stimuli-responsive, anisotropic nanofiber scaffolds with physically and chemically distinct compartments was prepared via electrohydrodynamic cojetting with side-by-side needle geometry. These nanofibers have a thermally responsive, physically-crosslinked compartment, and a chemically-crosslinked compartment at the nanoscale. The thermally responsive compartment is composed of physically crosslinkable poly(N-isopropylacrylamide) poly(NIPAM) copolymers, and poly(NIPAM-co-stearyl acrylate) poly(NIPAM-co-SA), while the thermally-unresponsive compartment is composed of polyethylene glycol dimethacrylates. The two distinct compartments were physically crosslinked by the hydrophobic interaction of the stearyl chains of poly(NIPAM-co-SA) or chemically stabilized via ultraviolet irradiation, and were swollen in physiologically relevant buffers due to their hydrophilic polymer networks. Bicompartmental nanofibers with the physically-crosslinked network of the poly(NIPAM-co-SA) compartment showed a thermally-triggered shape change due to thermally-induced aggregation of poly(NIPAM-co-SA). Furthermore, when bovine serum albumin and dexamethasone phosphate were separately loaded into each compartment, the bicompartmental nanofibers with anisotropic actuation exhibited decoupled, controlled release profiles of both drugs in response to a temperature. A new class of multicompartmental nanofibers could be useful for advanced nanofiber scaffolds with two or more drugs released with different kinetics in response to environmental stimuli. PMID:24872702

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...

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...

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...

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...

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...

Classification methods to detect sleep apnea in adults based on respiratory and oximetry signals: a systematic review.

PubMed

Uddin, M B; Chow, C M; Su, S W

2018-03-26

Sleep apnea (SA), a common sleep disorder, can significantly decrease the quality of life, and is closely associated with major health risks such as cardiovascular disease, sudden death, depression, and hypertension. The normal diagnostic process of SA using polysomnography is costly and time consuming. In addition, the accuracy of different classification methods to detect SA varies with the use of different physiological signals. If an effective, reliable, and accurate classification method is developed, then the diagnosis of SA and its associated treatment will be time-efficient and economical. This study aims to systematically review the literature and present an overview of classification methods to detect SA using respiratory and oximetry signals and address the automated detection approach. Sixty-two included studies revealed the application of single and multiple signals (respiratory and oximetry) for the diagnosis of SA. Both airflow and oxygen saturation signals alone were effective in detecting SA in the case of binary decision-making, whereas multiple signals were good for multi-class detection. In addition, some machine learning methods were superior to the other classification methods for SA detection using respiratory and oximetry signals. To deal with the respiratory and oximetry signals, a good choice of classification method as well as the consideration of associated factors would result in high accuracy in the detection of SA. An accurate classification method should provide a high detection rate with an automated (independent of human action) analysis of respiratory and oximetry signals. Future high-quality automated studies using large samples of data from multiple patient groups or record batches are recommended.

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.

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...

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 508.8 - 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...

Capturing the Diversity of Successful Aging: An Operational Definition Based on 16-Year Trajectories of Functioning.

PubMed

Kok, Almar A L; Aartsen, Marja J; Deeg, Dorly J H; Huisman, Martijn

2017-04-01

To determine the prevalence and extent of successful aging (SA) when various suggestions proposed in the previous literature for improving models of SA are incorporated into one holistic operational definition. These suggestions include defining and measuring SA as a developmental process, including subjective indicators alongside more objective ones, and expressing SA on a continuum. Data were used from 2,241 respondents in the Longitudinal Aging Study Amsterdam, a multidisciplinary study in a nationally representative sample of older adults in the Netherlands. Latent class growth analysis was used to identify successful 16-year trajectories within nine indicators of physical, cognitive, emotional, and social functioning. SA was quantified as the number of indicators in which individual respondents showed successful trajectories (range 0-9). Successful trajectories were characterized by stability, limited decline, or even improvement of functioning over time. Of the respondents, 39.6% of men and 29.3% of women were successful in at least seven indicators; 7% of men and 11% of women were successful in less than three indicators. Proportions of successful respondents were largest in life satisfaction (>85%) and smallest in social activity (<25%). Correlations of success between separate indicators were low to moderate (range r = .02-.37). Many older adults age relatively successfully, but the character of successful functioning over time varies between indicators, and the combinations of successful indicators vary between individuals. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Clinical outcomes in heart failure: report from a community hospital-based registry.

PubMed

Philbin, E F; Rocco, T A; Lindenmuth, N W; Ulrich, K; Jenkins, P L

1999-12-01

Most of the recent information on the prognosis of patients with heart failure has come from large clinical trials or tertiary care centers. This study reports current information from a community hospital-based heart failure registry. We compiled data from 2,906 unselected consecutive patients with heart failure who were admitted to 10 acute care community hospitals in New York State between 1995 and 1997. Patients were followed prospectively for 6 months after hospital discharge or until their death. The mean (+/- SI)) age of the sample was 76 +/- 11 years. The majority of the patients were women (56%) and most were white (95%). Hospital length of stay averaged 7.4 +/- 7.6 days; hospital charges averaged $7,460 +/- $6,114. Mortality during the index admission was 5%. Among the 2,508 patients for whom mortality or follow-up data were available, an additional 411 died during follow-up, for a cumulative 6-month mortality of 23%. Progressive pump failure was the predominant cause of death in the hospital and after discharge. Although mean functional class (on a 1 to 4 scale) improved from 3.4 +/- 0.7 at hospital admission to 2.3 +/- 0.9 at 1 month after discharge, 43% of patients had at least one hospital readmission during follow-up and 25% had at least one recurrent admission for heart failure. The mean time from index discharge to first rehospitalization was 60 +/- 56 days. In all, 55% of patients (1,370 of 2,508) were rehospitalized or died during the study period. Despite advances in the management of heart failure, patients recently hospitalized for this disorder remain at high risk of death, hospital readmission, and poor clinical outcome. Discovery or implementation of new or existing methods of prevention and treatment remain a high priority.

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

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...

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 508.7 - 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 508.9 - 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...

Respiratory syncytial virus infection disrupts monolayer integrity and function in cystic fibrosis airway cells.

PubMed

Kong, Michele; Maeng, Patrick; Hong, Jeong; Szczesniak, Rhonda; Sorscher, Eric; Sullender, Wayne; Clancy, John Paul

2013-09-19

Respiratory Syncytial Virus (RSV) infection is a common contributor to pulmonary symptoms in children with cystic fibrosis (CF). Here we examined RSV infection in immortalized bronchial epithelial cells (CFBE41o-) expressing wild-type (wt) or F508del cystic fibrosis transmembrane conductance regulator (CFTR), for monolayer integrity and RSV replication. CFBE41o- monolayers expressing wt or F508del CFTR were grown on permeable supports and inoculated with RSV A2 strain. Control experiments utilized UV-inactivated RSV and heat-killed RSV. Monolayer resistance and RSV production was monitored for up to six days post-infection. Within 24 h, a progressive decrease in monolayer resistance was observed in RSV infected F508del CFBE41o- cells, while the monolayer integrity of RSV infected wt CFTR CFBE41o- cells remained stable. RSV replication was necessary to disrupt F508del CFBE41o- monolayers as UV-irradiated and heat killed RSV had no effect on monolayer integrity, with an earlier and much more pronounced peak in RSV titer noted in F508del relative to wt CFTR-expressing cells. RSV infection of wt CFBE41o- monolayers also resulted in blunting of CFTR response. These findings identify an enhanced sensitivity of CFBE41o- cells expressing F508del CFTR to RSV infection, replication and monolayer disruption independent of the cellular immune response, and provide a novel mechanism by which cystic fibrosis airway epithelia are susceptible to RSV-dependent injury.

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...

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

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

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...

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...

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...

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...

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...

MASTICATORY FUNCTION OF OBESE CANDIDATES TO BARIATRIC SURGERY FROM DISTINCT SOCIOECONOMIC CLASSES.

PubMed

Passeri, Celso Roberto; Andrade, Jacira Alves Caracik de Camargo; Tomal, Karla Thaíza; Pracucho, Eduardo Marcucci; Campos, Livia Paschoalino de; Sales-Peres, Silvia Helena de Carvalho

Obesity and metabolic syndrome can be labeled as worldwide outbreak; thus, both have led to serious public health problem. Oral health can be worsened by both, obesity and metabolic syndrome. Tooth loss harms masticatory function, essential status to whom will be submitted to bariatric surgery. Assess masticatory function of obese candidates to bariatric surgery, who belong to distinct socioeconomic class range, in order to recognize hazard factors and the bias of socioeconomic factor in this context. Observational cross-section study, with samples comprised by two groups of patients, with distinct socioeconomic class range, one of them belonging to public health system (SUSG) and the other to private clinic (CPG), candidates to bariatric surgery. Were assessed anthropometric data, comorbidities and medicines usage, blood tests, habits and the number of dental functional units. The groups SUSG and CPG were homogeneous taking into account gender (p=0,890) and age range (p=0,170). The number of dental functional units was higher in the private group (p<0.001). The impaired masticatory function was rather present among public group (p<0.001) and female gender (p<0,001). Regarded as blood tests, fasting glucose was higher in female in SUSG (p<0,001). The following hazard factors have corroborated to have patients rated as impaired masticatory function: belong to public service (OR: 8.420, p=0.003), higher age (OR: 1.186, p<0.001), female gender (OR: 0.153, p=0.029), diabetes mellitus (OR: 2.545, p=0.045) and smokers (OR: 2.951, p=0.043). The general health and masticatory function of female SUSG were worse, highlighting the socioeconomic condition as hazard factor. Obesidade e síndrome metabólica são graves problemas de saúde pública, com características de epidemia mundial. A saúde bucal é agravada por ambas as condições. Perda dentária prejudica função mastigatória, condição essencial para o paciente que será submetido à cirurgia bariátrica. Avaliar a função mastigatória de pacientes obesos candidatos à cirurgia bariátrica pertencentes a dois serviços de saúde com padrões socioeconômicos distintos, afim de identificar fatores de risco e a influência do fator socioeconômico nesta condição. Estudo observacional transversal, com amostra constituída por dois grupos de pacientes obesos, com condições socioeconômicas distintas, um pertencente ao sistema público de saúde (GSUS) e outro à clínica privada (GCP), candidatos à cirurgia bariátrica. Foram analisados dados antropométricos, comorbidades e uso de medicamentos para seu controle, exames laboratoriais, hábitos e o número de unidades funcionais dentárias presentes. Os grupos GSUS e GCP foram homogêneos quanto ao gênero (p=0,890) e faixa etária (p=0,170). A média de unidades funcionais dentárias foi maior no grupo privado (p<0,001). A função mastigatória prejudicada foi mais presente no grupo GSUS e no gênero feminino (p<0,001). Quanto aos exames laboratoriais: glicemia de jejum esteve mais alterada em mulheres do GSUS (p<0,001). Foram fatores de risco independentes para ter função mastigatória prejudicada: ter origem no serviço público de saúde (OR: 8,420 - p=0,003), maior idade (OR: 1,186 - p<0,001), ser do gênero feminino (OR: 0,153 - p=0,029), portador de diabete melito (OR: 2,545 - p=0,045) e tabagista (OR: 2,951 - p=0,043). A saúde geral e função mastigatória de mulheres do GSUS foram piores, ressaltando a condição socioeconômica como fator de risco.

Fatigue curve needs for higher strength 2-1/4Cr-1Mo steel for petroleum process vessels

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

Jaske, C.E.

This paper reviews the data needed to develop fatigue design rules for pressure vessels fabricated from heat-treated 2-1/4Cr-1Mo steel (SA-387, Grade 22, Class 2 plates and SA-336, Grade F22 forgings) that are operated or designed to operate at temperatures greater than 371 C (700F). The available data were reviewed, and the results of that review were used to develop recommendations for needed analytical and experimental work. Extension of the fatigue-curve approach currently used for temperatures up to 371 C (700F) and development of a fracture-mechanics-based, crack-growth approach were addressed. Both of these two approaches must include means for assessing themore » time-dependent effects of oxidation and/or creep when fatigue cycling occurs at low stain rates or includes hold times. The recommendations of this study provide a plan for the development of fatigue design rules for the use of heat-treated 2-1/4Cr-1Mo steel at temperatures in the range of 371 to 482 C (700 to 900 F).« less

Vulnerability assessment of RC frames considering the characteristic of pulse-like ground motions

NASA Astrophysics Data System (ADS)

Xu, Chao; Wen, Zengping

2017-04-01

Pulse-like ground motions are a special class of ground motions that are particularly challenging to characterize for earthquake hazard assessment. These motions are characterized by a "pulse" in the velocity time history of the motion, and they are typically very intense and have been observed to cause severe damage to structures in past earthquakes. So it is particularly important to characterize these ground motions. Previous studies show that the severe response of structure is not entirely accounted for by measuring the intensity of the ground motion using spectral acceleration of the elastic first-mode period of a structure (Sa(T1)). This paper will use several alternative intensity measures to characterize the effect of pulse-like ground motions in vulnerability assessment. The ability of these intensity measures to characterize pulse-like ground motions will be evaluated. Pulse-like ground motions and ordinary ground motions are selected as input to carry out incremental dynamic analysis. Structural response and vulnerability are estimated by using Sa(T1) as the intensity measure. The impact of pulse period on structural response is studied through residual analysis. By comparing the difference between the structural response and vulnerability curves using pulse-like ground motions and ordinary ground motions as the input, the impact of velocity pulse on vulnerability is investigated and the shortcoming of using Sa(T1) to characterize pulse-like ground motion is analyzed. Then, vector-valued ground motion intensity measures(Sa(T1)&RT1,T2, Sa(T1)&RPGV,Sa) and inelastic displacement spectra(Sdi(T1)) are used to characterize the damage potential of pulse-like ground motions, the efficiency and sufficiency of these intensity measures are evaluated. The study shows that: have strong the damage potential of near fault ground motions with velocity pulse is closely related to the pulse period of strong motion as well as first mode period of vibration and nonlinear features of the structure. The above factors should be taken into account when choosing a reasonable ground motion parameter to characterize the damage potential of pulse-like ground motions. Vulnerability curves based on Sa(T1) show obvious differences between using near fault ground motions and ordinary ground motions, as well as pulse-like ground motions with different pulse periods as the input. When using vector-valued intensity measures such as Sa(T1)&RT1,T2, Sa(T1)&RPGV,Sa and inelastic displacement spectra, the results of vulnerability analysis are roughly the same. These ground motion intensity measures are more efficient and sufficient to characterize the damage potential of near fault ground motions with velocity pulse.

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.

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. ...

Transforming common-sense beliefs into Newtonian thinking through Just-In-Time Teaching

NASA Astrophysics Data System (ADS)

Formica, Sarah P.; Easley, Jessica L.; Spraker, Mark C.

2010-07-01

To determine whether teaching an introductory physics course with a traditional lecture style or with Just-in-Time teaching (a student-centered, interactive-engagement style) will help students to better understand Newtonian concepts, such as Newton’s Third Law, 222 students in introductory physics courses taught by traditional lecture styles and Just-in-Time teaching at North Georgia College & State University over the span of five semesters were examined using the Force Concept Inventory as a pretest and a post-test. Overall, the gains favor the Just-in-Time teaching method with a 37.6%±2.0% gain compared to the 17.9%±2.5% seen in traditional lecture classes. When analyzing only those gains pertaining to the Newton’s Third Law questions, the results again favor the Just-in-Time teaching method with a gain of 50.8%±4.1% while the traditional lecture classes only saw a gain of 6.6%±5.2% . We also employed a new method of analysis which was a BIT Coding method created to quickly identify students’ understanding of Newton’s Third Law questions. This study shows that students in courses that are taught using the Just-in-Time teaching strategy better understand Newton’s Third Law after instruction than do students in traditional lecture courses.

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.

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...

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...

Titanium vs. polyetheretherketone (PEEK) interbody fusion: Meta-analysis and review of the literature.

PubMed

Seaman, Scott; Kerezoudis, Panagiotis; Bydon, Mohamad; Torner, James C; Hitchon, Patrick W

2017-10-01

Spinal interbody fusion is a standard and accepted method for spinal fusion. Interbody fusion devices include titanium (Ti) and polyetheretherketone (PEEK) cages with distinct biomechanical properties. Titanium and PEEK cages have been evaluated in the cervical and lumbar spine, with conflicting results in bony fusion and subsidence. Using Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines, we reviewed the available literature evaluating Ti and PEEK cages to assess subsidence and fusion rates. Six studies were included in the analysis, 3 of which were class IV evidence, 2 were class III, and 1 was class II. A total of 410 patients (Ti-228, PEEK-182) and 587 levels (Ti-327, PEEK-260) were studied. Pooled mean age was 50.8years in the Ti group, and 53.1years in the PEEK group. Anterior cervical discectomy was performed in 4 studies (395 levels) and transforaminal interbody fusion in 2 studies (192 levels). No statistically significant difference was found between groups with fusion (OR 1.16, 95% C.I 0.59-2.89, p=0.686, I 2 =49.7%) but there was a statistically significant the rate of subsidence with titanium (OR 3.59, 95% C.I 1.28-10.07, p=0.015, I 2 =56.9%) at last follow-up. Titanium and PEEK cages are associated with a similar rate of fusion, but there is an increased rate of subsidence with titanium cage. Future prospective randomized controlled trials are needed to further evaluate these cages using surgical and patient-reported outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

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...

Salicylic acid 3-hydroxylase regulates Arabidopsis leaf longevity by mediating salicylic acid catabolism

PubMed Central

Zhang, Kewei; Halitschke, Rayko; Yin, Changxi; Liu, Chang-Jun; Gan, Su-Sheng

2013-01-01

The plant hormone salicylic acid (SA) plays critical roles in plant defense, stress responses, and senescence. Although SA biosynthesis is well understood, the pathways by which SA is catabolized remain elusive. Here we report the identification and characterization of an SA 3-hydroxylase (S3H) involved in SA catabolism during leaf senescence. S3H is associated with senescence and is inducible by SA and is thus a key part of a negative feedback regulation system of SA levels during senescence. The enzyme converts SA (with a Km of 58.29 µM) to both 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-DHBA in vitro but only 2,3-DHBA in vivo. The s3h knockout mutants fail to produce 2,3-DHBA sugar conjugates, accumulate very high levels of SA and its sugar conjugates, and exhibit a precocious senescence phenotype. Conversely, the gain-of-function lines contain high levels of 2,3-DHBA sugar conjugates and extremely low levels of SA and its sugar conjugates and display a significantly extended leaf longevity. This research reveals an elegant SA catabolic mechanism by which plants regulate SA levels by converting it to 2,3-DHBA to prevent SA overaccumulation. The research also provides strong molecular genetic evidence for an important role of SA in regulating the onset and rate of leaf senescence. PMID:23959884

Segmentation of pulmonary nodules in computed tomography using a regression neural network approach and its application to the Lung Image Database Consortium and Image Database Resource Initiative dataset.

PubMed

Messay, Temesguen; Hardie, Russell C; Tuinstra, Timothy R

2015-05-01

We present new pulmonary nodule segmentation algorithms for computed tomography (CT). These include a fully-automated (FA) system, a semi-automated (SA) system, and a hybrid system. Like most traditional systems, the new FA system requires only a single user-supplied cue point. On the other hand, the SA system represents a new algorithm class requiring 8 user-supplied control points. This does increase the burden on the user, but we show that the resulting system is highly robust and can handle a variety of challenging cases. The proposed hybrid system starts with the FA system. If improved segmentation results are needed, the SA system is then deployed. The FA segmentation engine has 2 free parameters, and the SA system has 3. These parameters are adaptively determined for each nodule in a search process guided by a regression neural network (RNN). The RNN uses a number of features computed for each candidate segmentation. We train and test our systems using the new Lung Image Database Consortium and Image Database Resource Initiative (LIDC-IDRI) data. To the best of our knowledge, this is one of the first nodule-specific performance benchmarks using the new LIDC-IDRI dataset. We also compare the performance of the proposed methods with several previously reported results on the same data used by those other methods. Our results suggest that the proposed FA system improves upon the state-of-the-art, and the SA system offers a considerable boost over the FA system. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Salicylic acid alleviates aluminum toxicity in soybean roots through modulation of reactive oxygen species metabolism

NASA Astrophysics Data System (ADS)

Liu, Ning; Song, Fengbin; Zhu, Xiancan; You, Jiangfeng; Yang, Zhenming; Li, Xiangnan

2017-11-01

As an important signal molecule, salicylic acid (SA) improves plant tolerance to aluminum (Al) stress. The objective of this study was to investigate the effects of exogenous SA application on the dynamics of endogenous SA and reactive oxygen species in soybean (Glycine max L.) exposed to Al stress. The roots of soybean seedlings were exposed to a combination of AlCl3 (30 μM) and SA (10 μM)/PAC (100 μM, paclobutrazol, SA biosynthesis inhibitor) for 3, 6, 9 and 12 h. Al stress induced an increase in endogenous SA concentration in a time-dependent manner, also verified by the up-regulated expression of GmNPR1, an SA-responsive gene. Al stress increased the activities of phenylalanine ammonia-lyase (PAL) and benzoic acid 2-hydroxylase (BA2H), and the contents of SA, O2- and malondialdehyde (MDA) in the root apex. The application of exogenous SA increased PAL and BA2H, and reduced O2- and MDA contents in soybean roots under Al stress. PAC inhibited the SA induced increase in BA2H activity. In addition, the SA application resulted in a rapid increase in hydrogen peroxide (H2O2) concentration under Al stress, followed by a sharp decrease. Compared with the plants exposed to Al alone, Al+SA plants possessed higher activities of superoxide dismutase, peroxidase and ascorbate peroxidase, and lower catalase activity, indicating that SA alleviated Al-induced oxidative damage. These results suggested that PAL and BA2H were involved in Al-induced SA production and showed that SA alleviated the adverse effects of Al toxicity by modulating the cellular H2O2 level and the antioxidant enzyme activities in the soybean root apex.

77 FR 56612 - New England Fishery Management Council; Public Meeting; Correction

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-13

... Harbor, 180 Water Street, Plymouth, MA 02360; telephone: (508) 747- 4900; fax: (508) 747-8937. Council Address: New England Fishery Management Council, 50 Water Street, Mill 2, Newburyport, MA 01950. FOR... Sustainable Fisheries, National Marine Fisheries Service. [FR Doc. 2012-22506 Filed 9-12-12; 8:45 am] BILLING...

A feasibility study of a culturally and gender-specific dance to promote physical activity for South Asian immigrant women in the greater Toronto area.

PubMed

Vahabi, Mandana; Damba, Cynthia

2015-01-01

Despite ample evidence demonstrating the protective effect of physical activity, the uptake of regular physical activity among South Asian (SA) women remains relatively low. The purpose of this study was to explore the feasibility and health impacts of implementing a culture- and gender-specific physical activity among SA immigrant women residing in Greater Toronto Area (GTA) in Ontario, Canada. A community-based mixed methods approach combining cohort pretest and posttest design and qualitative methods employing in depth interviews was used. Twenty-seven SA women from the GTA participated in a 6-week, 2 days per week, Bollywood Dance exercise program led by a female SA instructor. The participation rate was considerably high (85%) and approximately 82% of the participants attended 10 or more of the classes offered. The participants' physical measurements (weight, waist and hip, and body mass index) decreased, although not significantly, over the 6-week period and there was an improvement in their physical, mental, and social health. During the face-to-face interviews, participants reported feeling less stressed and tired, being more mentally and physically robust, and having a sense of fulfillment and self-satisfaction. The only common criticism expressed was that the 6-week duration of the intervention was too short. The results showed that the Bollywood Dance was a feasible strategy in engaging SA immigrant women in physical activity. The key aspects when designing culture- and gender-specific dance interventions include community participation and active engagement in planning and implementation of the program, a supportive environment, same gender and culturally attuned dance instructor, easy access, and minimal to no cost. Copyright © 2015 Jacobs Institute of Women's Health. Published by Elsevier Inc. All rights reserved.

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...

Linking Thermodynamics to Pollutant Reduction Kinetics by Fe2+ Bound to Iron Oxides.

PubMed

Stewart, Sydney M; Hofstetter, Thomas B; Joshi, Prachi; Gorski, Christopher A

2018-05-15

Numerous studies have reported that pollutant reduction rates by ferrous iron (Fe 2+ ) are substantially enhanced in the presence of an iron (oxyhydr)oxide mineral. Developing a thermodynamic framework to explain this phenomenon has been historically difficult due to challenges in quantifying reduction potential ( E H ) values for oxide-bound Fe 2+ species. Recently, our group demonstrated that E H values for hematite- and goethite-bound Fe 2+ can be accurately calculated using Gibbs free energy of formation values. Here, we tested if calculated E H values for oxide-bound Fe 2+ could be used to develop a free energy relationship capable of describing variations in reduction rate constants of substituted nitrobenzenes, a class of model pollutants that contain reducible aromatic nitro groups, using data collected here and compiled from the literature. All the data could be described by a single linear relationship between the logarithms of the surface-area-normalized rate constant ( k SA ) values and E H and pH values [log( k SA ) = - E H /0.059 V - pH + 3.42]. This framework provides mechanistic insights into how the thermodynamic favorability of electron transfer from oxide-bound Fe 2+ relates to redox reaction kinetics.

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...

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

Treatment burden in patients with at least one class IV or V CFTR mutation.

PubMed

Dewulf, Jonas; Vermeulen, François; Wanyama, Simeon; Thomas, Muriel; Proesmans, Marijke; Dupont, Lieven; De Boeck, Kris

2015-12-01

CFTR mutations are grouped according to disease-causing mechanism. Several studies demonstrated that patients having at least one mutation of class IV/V, present with a milder phenotype, but little is known about their relative treatment burden. We compared treatment burden between patients with two class I, II, or III mutations and patients with at least one mutation of class IV/V in the 2010 database of the Belgian CF Registry. We calculated a "Treatment Burden Index" (TBI) by assigning long term therapies to categories low, medium and high intensity, for differential weighing in the total score. There were 779 patients with two known class I/II/III mutations and 94 patients with at least one class IV/V mutation. Compared to class I/II/III, class IV/V patients had a lower median number of clinic visits (4 vs. 5; P < 0.001), a lower risk of hospitalization (24.7% vs. 50.8%; P < 0.001) and intravenous antibiotic treatment (23.5% vs. 46.0%; P < 0.001) and a lower median TBI (6 vs. 9; P < 0.001). These differences remained significant when only class IV/V patients with pancreatic insufficiency (n = 31) were considered. This study clearly demonstrates the significantly lower treatment burden in patients with CF and at least one class IV/V mutation compared to patients with two class I/II/III mutations and contributes to providing better individual counseling at time of diagnosis. © 2015 Wiley Periodicals, Inc.

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.

Photochromic properties of the N-Salicylideneaniline in Polyvinyl Butyral matrix: Experimental and theoretical investigations

NASA Astrophysics Data System (ADS)

Shahab, Siyamak; Filippovich, Liudmila; Aharodnikova, M.; Almodarresiyeh, Hora A.; Hajikolaee, Fatemeh Haji; Kumar, Rakesh; Mashayekhi, Mahsa

2017-04-01

In the present work, isomerization, photophysical properties, thermal conductivity (λ) and spectral study of the N-Salicylideneaniline: 2-[(E)-(phenylimino)methyl]phenol (SA) under the action of UV radiation in the Polyvinyl Butyral (PVB) matrix were studied using the Indicator method and Density Functional Theory (DFT). The electronic absorption spectra of SA and its isomers (SA1 and SA2) in dimethylformamide (DMF) solutions were also calculated. The nature of absorption bands of SA, SA1 and SA2 in the visible and near ultraviolet spectral regions was interpreted. The excitation energies, electronic transitions and oscillator strengths for SA, SA1 and SA2 have also been calculated. Thermal Conductivity of PVB-films containing SA before and after UV radiation was also measured. A Photochromic PVB - film on the basis of SA for application in optical devices and display technologies was made.

Two sensory channels mediate perception of fingertip force.

PubMed

Brothers, Trevor; Hollins, Mark

2014-01-01

In two experiments we examined the ability of humans to exert forces accurately with the fingertips, and to perceive those forces. In experiment 1 participants used visual feedback to apply a range of fingertip forces with the distal pad of the thumb. Participants made magnitude discriminations regarding these forces, and their just noticeable differences were calculated at a series of standards by means of a two-interval, forced-choice tracking paradigm. As the standard increased, participants demonstrated a relative improvement in force discrimination; and the presence of a possible inflection point, at approximately 400 g, suggested that two sensory channels may contribute to performance. If this is the case, the operative channel at low forces is almost certainly the slowly adapting type I (SA-I) channel, while another mechanoreceptor class, the SA-II nail unit, is a plausible mediator of the more accurate performance seen at high force levels. To test this two-channel hypothesis in experiment 2, we hydrated participants' thumbnails in order to reduce nail rigidity and thus prevent stimulation of underlying SA-II mechanoreceptors. This technique was found to reduce sensory accuracy in a force-matching task at high forces (1000 g) while leaving low force matching (100 g) unimpaired. Taken together, these results suggest that two sensory channels mediate the perception of fingertip forces in humans: one channel predominating at low forces (below approximately 400 g) and another responsible for perceiving high forces which is likely mediated by the SA-II nail unit.

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...

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. ...

[Outbreak of skin infections due to Staphylococcus aureus carrying Panton-Valentine leukocidin genes in pupils and their relatives].

PubMed

Carré, N; Herbreteau, N; Askeur, N; Dabas, J-P; Sillam, F; Pinchon, C; Bes, M; Tristan, A; Vandenesch, F

2011-07-01

The study objectives were to describe an outbreak of skin infections in school settings, caused by Staphylococcus aureus carrying Panton-Valentine leukocidin genes (Sa PVL(+)), over a 2-year period. Nasal colonization prevalence was assessed in families where new skin infections occurred, despite a prevention and control strategy. A retrospective investigation of skin infections likely to be related to Sa and prospective monitoring and treatment of new infections occurring in pupils and their family members were implemented in October 2006, following the reporting of Sa PVL(+) abscesses and furuncles in a primary school. Additional nasal screening was performed in families where new skin infections occurred, after an initial systematic screening of Sa PVL(+) nasal carriers. On October 31, 2008, 53 patients, accounting for 30 households, had developed 69 skin infections, in four decreasing outbreaks. The cumulative incidence of a first skin infection was 34.6% in primary classes, 21.3% in nursery schools, and 6.5% in the pupils' family households. Several skin infections were reported in 13 households, and in one of them, all of the seven family members had developed at least one skin infection during follow-up. The estimated frequency of nasal colonization ranged from 14.1% to 19.5% according to successive nasal screenings. Early reporting of skin infection clusters is necessary to reinforce the effectiveness of hygiene and prevention measures, and thus limit the risk of a long-lasting outbreak. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Expression of proteinase inhibitor II proteins during floral development in Solanum americanum.

PubMed

Sin, Suk-Fong; Chye, Mee-Len

2004-10-01

The heterologous expression of serine proteinase inhibitor II (PIN2) proteins confers insect resistance in transgenic plants, but little is known of their endogenous roles. We have cloned two cDNAs encoding Solanum americanum PIN2 proteins, SaPIN2a and SaPIN2b. SaPIN2a is highly expressed in stem, particularly in the phloem, suggesting it could possibly regulate proteolysis in the sieve elements. When SaPIN2a was expressed in transgenic lettuce, we observed an inhibition of endogenous trypsin- and chymotrypsin-like activities. Here, we demonstrate that both SaPIN2a and SaPIN2b are expressed in floral tissues that are destined to undergo developmental programmed cell death (PCD), suggesting possible endogenous roles in inhibiting trypsin- and chymotrypsin-like activities during flower development. Northern and western blot analyses revealed that SaPIN2a and SaPIN2b mRNAs and proteins show highest expression early in floral development. In situ hybridization analysis and immunolocalization on floral sections, localized SaPIN2a and SaPIN2b mRNAs and their proteins to tissues that would apparently undergo PCD: the ovules, the stylar transmitting tissue, the stigma and the vascular bundles. Detection of PCD in floral sections was achieved using terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) analysis. Examination of the mid-style before, and 1 day after, pollination revealed that high expression of SaPIN2a and SaPIN2b in the style was inversely correlated with PCD.

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

Observations of ’Economical’ Fixed Prosthodontic Alloys,

DTIC Science & Technology

1982-01-01

Office) 15. SECURITY CLASS. (of this ,.portj Ia. OS7RI~fl3 ~TATM~T1of5sA. DECLASSIFICATION/OO44GRAUTIV S Unlimited 17. 0137 PI3UT10ON STATEMENT (of the...however, the silver-palladium and silver-indium materials require ~DA~3 47 EOfl4O tO’/SfOBOLTE UNCLASSIFIED 8 2’ 02 R -/ SECURITY CLASSIFICATION OF...ous grain boundary netowrk , whereas those of Salivan revealed large grains, discontinuous grain boundaries and prominent subgrains. Microstructures

Trimeric transmembrane domain interactions in paramyxovirus fusion proteins: roles in protein folding, stability, and function.

PubMed

Smith, Everett Clinton; Smith, Stacy E; Carter, James R; Webb, Stacy R; Gibson, Kathleen M; Hellman, Lance M; Fried, Michael G; Dutch, Rebecca Ellis

2013-12-13

Paramyxovirus fusion (F) proteins promote membrane fusion between the viral envelope and host cell membranes, a critical early step in viral infection. Although mutational analyses have indicated that transmembrane (TM) domain residues can affect folding or function of viral fusion proteins, direct analysis of TM-TM interactions has proved challenging. To directly assess TM interactions, the oligomeric state of purified chimeric proteins containing the Staphylococcal nuclease (SN) protein linked to the TM segments from three paramyxovirus F proteins was analyzed by sedimentation equilibrium analysis in detergent and buffer conditions that allowed density matching. A monomer-trimer equilibrium best fit was found for all three SN-TM constructs tested, and similar fits were obtained with peptides corresponding to just the TM region of two different paramyxovirus F proteins. These findings demonstrate for the first time that class I viral fusion protein TM domains can self-associate as trimeric complexes in the absence of the rest of the protein. Glycine residues have been implicated in TM helix interactions, so the effect of mutations at Hendra F Gly-508 was assessed in the context of the whole F protein. Mutations G508I or G508L resulted in decreased cell surface expression of the fusogenic form, consistent with decreased stability of the prefusion form of the protein. Sedimentation equilibrium analysis of TM domains containing these mutations gave higher relative association constants, suggesting altered TM-TM interactions. Overall, these results suggest that trimeric TM interactions are important driving forces for protein folding, stability and membrane fusion promotion.

Trimeric Transmembrane Domain Interactions in Paramyxovirus Fusion Proteins

PubMed Central

Smith, Everett Clinton; Smith, Stacy E.; Carter, James R.; Webb, Stacy R.; Gibson, Kathleen M.; Hellman, Lance M.; Fried, Michael G.; Dutch, Rebecca Ellis

2013-01-01

Paramyxovirus fusion (F) proteins promote membrane fusion between the viral envelope and host cell membranes, a critical early step in viral infection. Although mutational analyses have indicated that transmembrane (TM) domain residues can affect folding or function of viral fusion proteins, direct analysis of TM-TM interactions has proved challenging. To directly assess TM interactions, the oligomeric state of purified chimeric proteins containing the Staphylococcal nuclease (SN) protein linked to the TM segments from three paramyxovirus F proteins was analyzed by sedimentation equilibrium analysis in detergent and buffer conditions that allowed density matching. A monomer-trimer equilibrium best fit was found for all three SN-TM constructs tested, and similar fits were obtained with peptides corresponding to just the TM region of two different paramyxovirus F proteins. These findings demonstrate for the first time that class I viral fusion protein TM domains can self-associate as trimeric complexes in the absence of the rest of the protein. Glycine residues have been implicated in TM helix interactions, so the effect of mutations at Hendra F Gly-508 was assessed in the context of the whole F protein. Mutations G508I or G508L resulted in decreased cell surface expression of the fusogenic form, consistent with decreased stability of the prefusion form of the protein. Sedimentation equilibrium analysis of TM domains containing these mutations gave higher relative association constants, suggesting altered TM-TM interactions. Overall, these results suggest that trimeric TM interactions are important driving forces for protein folding, stability and membrane fusion promotion. PMID:24178297

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

PubMed

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

2017-03-03

Cystic fibrosis (CF) is caused by mutations that disrupt the plasma membrane expression, stability, and function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl - channel. Two small molecules, the CFTR corrector lumacaftor and the potentiator ivacaftor, are now used clinically to treat CF, although some studies suggest that they have counteracting effects on CFTR stability. Here, we investigated the impact of these compounds on the instability of F508del-CFTR, the most common CF mutation. To study individual CFTR Cl - channels, we performed single-channel recording, whereas to assess entire CFTR populations, we used purified CFTR proteins and macroscopic CFTR Cl - currents. At 37 °C, low temperature-rescued F508del-CFTR more rapidly lost function in cell-free membrane patches and showed altered channel gating and current flow through open channels. Compared with purified wild-type CFTR, the full-length F508del-CFTR was about 10 °C less thermostable. Lumacaftor partially stabilized purified full-length F508del-CFTR and slightly delayed deactivation of individual F508del-CFTR Cl - channels. By contrast, ivacaftor further destabilized full-length F508del-CFTR and accelerated channel deactivation. Chronic (prolonged) co-incubation of F508del-CFTR-expressing cells with lumacaftor and ivacaftor deactivated macroscopic F508del-CFTR Cl - currents. However, at the single-channel level, chronic co-incubation greatly increased F508del-CFTR channel activity and temporal stability in most, but not all, cell-free membrane patches. We conclude that chronic lumacaftor and ivacaftor co-treatment restores stability in a small subpopulation of F508del-CFTR Cl - channels but that the majority remain destabilized. A fuller understanding of these effects and the characterization of the small F508del-CFTR subpopulation might be crucial for CF therapy development. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Comparative processing and function of human and ferret cystic fibrosis transmembrane conductance regulator.

PubMed

Fisher, John T; Liu, Xiaoming; Yan, Ziying; Luo, Meihui; Zhang, Yulong; Zhou, Weihong; Lee, Ben J; Song, Yi; Guo, Chenhong; Wang, Yujiong; Lukacs, Gergely L; Engelhardt, John F

2012-06-22

The most common cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation is ΔF508, and this causes cystic fibrosis (CF). New CF models in the pig and ferret have been generated that develop lung, pancreatic, liver, and intestinal pathologies that reflect disease in CF patients. Species-specific biology in the processing of CFTR has demonstrated that pig and mouse ΔF508-CFTR proteins are more effectively processed to the apical membrane of airway epithelia than human ΔF508-CFTR. The processing behavior of ferret WT- and ΔF508-CFTR proteins remains unknown, and such information is important to predicting the utility of a ΔF508-CFTR ferret. To this end, we sought to compare processing, membrane stability, and function of human and ferret WT- and ΔF508-CFTR proteins in a heterologous expression system using HT1080, HEK293T, BHK21, and Cos7 cells as well as human and ferret CF polarized airway epithelia. Analysis of the protein processing and stability by metabolic pulse-chase and surface On-Cell Western blots revealed that WT-fCFTR half-life and membrane stability were increased relative to WT-hCFTR. Furthermore, in BHK21, Cos7, and CuFi cells, human and ferret ΔF508-CFTR processing was negligible, whereas low levels of processing of ΔF508-fCFTR could be seen in HT1080 and HEK293T cells. Only the WT-fCFTR, but not ΔF508-fCFTR, produced functional cAMP-inducible chloride currents in both CF human and ferret airway epithelia. Further elucidation of the mechanism responsible for elevated fCFTR protein stability may lead to new therapeutic approaches to augment CFTR function. These findings also suggest that generation of a ferret CFTR(ΔF508/ΔF508) animal model may be useful.

Comparative Processing and Function of Human and Ferret Cystic Fibrosis Transmembrane Conductance Regulator*

PubMed Central

Fisher, John T.; Liu, Xiaoming; Yan, Ziying; Luo, Meihui; Zhang, Yulong; Zhou, Weihong; Lee, Ben J.; Song, Yi; Guo, Chenhong; Wang, Yujiong; Lukacs, Gergely L.; Engelhardt, John F.

2012-01-01

The most common cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation is ΔF508, and this causes cystic fibrosis (CF). New CF models in the pig and ferret have been generated that develop lung, pancreatic, liver, and intestinal pathologies that reflect disease in CF patients. Species-specific biology in the processing of CFTR has demonstrated that pig and mouse ΔF508-CFTR proteins are more effectively processed to the apical membrane of airway epithelia than human ΔF508-CFTR. The processing behavior of ferret WT- and ΔF508-CFTR proteins remains unknown, and such information is important to predicting the utility of a ΔF508-CFTR ferret. To this end, we sought to compare processing, membrane stability, and function of human and ferret WT- and ΔF508-CFTR proteins in a heterologous expression system using HT1080, HEK293T, BHK21, and Cos7 cells as well as human and ferret CF polarized airway epithelia. Analysis of the protein processing and stability by metabolic pulse-chase and surface On-Cell Western blots revealed that WT-fCFTR half-life and membrane stability were increased relative to WT-hCFTR. Furthermore, in BHK21, Cos7, and CuFi cells, human and ferret ΔF508-CFTR processing was negligible, whereas low levels of processing of ΔF508-fCFTR could be seen in HT1080 and HEK293T cells. Only the WT-fCFTR, but not ΔF508-fCFTR, produced functional cAMP-inducible chloride currents in both CF human and ferret airway epithelia. Further elucidation of the mechanism responsible for elevated fCFTR protein stability may lead to new therapeutic approaches to augment CFTR function. These findings also suggest that generation of a ferret CFTRΔF508/ΔF508 animal model may be useful. PMID:22570484

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

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.

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 3045.508-3 - 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...

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...

Erectile Dysfunction in Patients with Sleep Apnea--A Nationwide Population-Based Study.

PubMed

Chen, Chia-Min; Tsai, Ming-Ju; Wei, Po-Ju; Su, Yu-Chung; Yang, Chih-Jen; Wu, Meng-Ni; Hsu, Chung-Yao; Hwang, Shang-Jyh; Chong, Inn-Wen; Huang, Ming-Shyan

2015-01-01

Increased incidence of erectile dysfunction (ED) has been reported among patients with sleep apnea (SA). However, this association has not been confirmed in a large-scale study. We therefore performed a population-based cohort study using Taiwan National Health Insurance (NHI) database to investigate the association of SA and ED. From the database of one million representative subjects randomly sampled from individuals enrolled in the NHI system in 2010, we identified adult patients having SA and excluded those having a diagnosis of ED prior to SA. From these suspected SA patients, those having SA diagnosis after polysomnography were defined as probable SA patients. The dates of their first SA diagnosis were defined as their index dates. Each SA patient was matched to 30 randomly-selected, age-matched control subjects without any SA diagnosis. The control subjects were assigned index dates as their corresponding SA patients, and were ensured having no ED diagnosis prior to their index dates. Totally, 4,835 male patients with suspected SA (including 1,946 probable SA patients) were matched to 145,050 control subjects (including 58,380 subjects matched to probable SA patients). The incidence rate of ED was significantly higher in probable SA patients as compared with the corresponding control subjects (5.7 vs. 2.3 per 1000 patient-year; adjusted incidence rate ratio = 2.0 [95% CI: 1.8-2.2], p<0.0001). The cumulative incidence was also significantly higher in the probable SA patients (p<0.0001). In multivariable Cox regression analysis, probable SA remained a significant risk factor for the development of ED after adjusting for age, residency, income level and comorbidities (hazard ratio = 2.0 [95%CI: 1.5-2.7], p<0.0001). In line with previous studies, this population-based large-scale study confirmed an increased ED incidence in SA patients in Chinese population. Physicians need to pay attention to the possible underlying SA while treating ED patients.

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

PubMed Central

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

2016-01-01

ABSTRACT 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. PMID:27849291

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...

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...

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...

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...

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...

Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population

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

Abeliovich, D.; Lavon, I.P.; Lerer, I.

1992-11-01

To determine the distribution and frequency of cystic fibrosis (CF) mutations in the Israeli population, the authors have screened 96 patients for 11 relatively common mutations. Five mutations - [Delta]F508, G542X, W1282X, N1303K, and 3849 + 10kb C[yields]T-were found to account for 97% of the CF alleles in the Ashkenazi Jews. In contrast, of the 11 mutations tested, only [Delta]F508 was detected in Jewish patients of Sephardic or Oriental origin, accounting for 43% of the CF alleles. Four mutations - [Delta]F508, G542X, W1282X, and N1303K- accounted for 55% of the CF alleles in Arab patients. In a pilot screening study,more » a random sample of 424 Ashkenazi individuals was analyzed for three mutations - [Delta]F508, W128X, and G542X. Thirteen individuals were detected as heterozygotes (six for [Delta]F508 and seven for W1282X), predicting a heterozygote frequency of 1:29. This is similar to the frequency of carriers in the Caucasian population of northern European ancestry. On the basis of these data, the Ashkenazi populations is considered to be a candidate for CF heterozygote screening. 32 refs., 2 tabs.« less

Age-Related DNA Methylation Changes and Neoplastic Transformation of the Human Prostate

DTIC Science & Technology

2009-07-01

transcriptional silencing by aberrant CpG m ethylation of C pG-rich promoter regions. 5, 6 Aberrant promoter methylation of GSTP1 , e ncoding the π-class...during prostate cancer developm ent.7 Since the recogni tion that the GSTP1 Cp G was frequently hypermethylated in prostate cancer, more than 40 genes...8 genes; SPARC, RARb2, AR, TIMP3, GSTP1 , NKX2 .5, RASSF1 A and CYP27B1 in DNA sa mples fro m African American (AA) and Caucasian (C au) m en as a

Patterns of Adolescent Bullying Behaviors: Physical, Verbal, Exclusion, Rumor, and Cyber

PubMed Central

Wang, Jing; Iannotti, Ronald J.; Luk, Jeremy W.

2012-01-01

Patterns of engagement in cyber bullying and four types of traditional bullying were examined using latent class analysis (LCA). Demographic differences and externalizing problems were evaluated across latent class membership. Data were obtained from the 2005–2006 Health Behavior in School-aged Survey and the analytic sample included 7,508 U.S. adolescents in grades 6 through 10. LCA models were tested on physical bullying, verbal bullying, social exclusion, spreading rumors, and cyber bullying behaviors. Three latent classes were identified for each gender: All-Types Bullies (10.5% for boys and 4.0% for girls), Verbal/Social Bullies (29.3% for boys and 29.4% for girls), and a Non-Involved class (60.2% for boys and 66.6% for girls). Boys were more likely to be All-Types Bullies than girls. The prevalence rates of All-Types and Verbal/Social Bullies peaked during grades 6 to 8 and grades 7 & 8, respectively. Pairwise comparisons across the three latent classes on externalizing problems were conducted. Overall, the All-Types Bullies were at highest risk of using substances and carrying weapons, the Non-Involved were at lowest risk, and the Verbal/Social Bullies were in the middle. Results also suggest that most cyber bullies belong to a group of highly aggressive adolescents who conduct all types of bullying. This finding does not only improve our understanding of the relation between cyber bullying and traditional bullying, but it also suggests that prevention and intervention efforts could target cyber bullies as a high-risk group for elevated externalizing problems. PMID:22710019

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.

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...

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...

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...

A spectroscopic study of phenylbutazone and aspirin bound to serum albumin in rheumatoid diseases

NASA Astrophysics Data System (ADS)

Maciążek-Jurczyk, M.; Sułkowska, A.; Bojko, B.; Równicka-Zubik, J.; Sułkowski, W. W.

2011-11-01

Interaction of phenylbutazone (PBZ) and aspirin (ASA), two drugs recommended in rheumatoid diseases (RDs), when binding to human (HSA) and bovine (BSA) serum albumins, has been studied by quenching of fluorescence and proton nuclear magnetic resonance ( 1HNMR) techniques. On the basis of spectrofluorescence measurements high affinity binding sites of PBZ and ASA on albumin as well as their interaction within the binding sites were described. A low affinity binding site has been studied by proton nuclear magnetic resonance spectroscopy. Using fluorescence spectroscopy the location of binding site in serum albumin (SA) for PBZ and ASA was found. Association constants Ka were determined for binary (i.e. PBZ-SA and ASA-SA) and ternary complexes (i.e. PBZ-[ASA]-SA and ASA-[PBZ]-SA). PBZ and ASA change the affinity of each other to the binding site in serum albumin (SA). The presence of ASA causes the increase of association constants KaI of PBZ-SA complex. Similarly, PBZ influences KaI of ASA-SA complex. This phenomenon shows that the strength of binding and the stability of the complexes increase in the presence of the second drug. The decrease of KaII values suggests that the competition between PBZ and ASA in binding to serum albumin in the second class of binding sites occurs. The analysis of 1HNMR spectral parameters i.e. changes of chemical shifts and relaxation times of the drug indicate that the presence of ASA weakens the interaction of PBZ with albumin. Similarly PBZ weakens the interaction of ASA with albumin. This conclusion points to the necessity of using a monitoring therapy owning to the possible increase of uncontrolled toxic effects.

Comparing U.S. Army Systems with Foreign Counterparts: Identifying Possible Capability Gaps and Insights from Other Armies

DTIC Science & Technology

2015-01-01

C O R P O R A T I O N Research Report Comparing U.S. Army Systems with Foreign Counterparts Identifying Possible Capability Gaps and Insights from...Couffer; photo by E. Heidtmann, CC BY 3.0; photo by Black Mammmba, CC BY 3.0; and photo by Vitaly V. Kuzmin, CC BY 3.0. M1A2 Abrams Leopard 2A6 Merkava...photo by Mass Communication Specialist 1st Class Daniel N . Woods; photo by Daniel Steger, CC BY-SA 2.5; “MIL_Finlândia-Army_Demo Day 2005 Rovajärvellä

Spiral Arm Morphology of Nearby Galaxies

NASA Astrophysics Data System (ADS)

Ann, Hong Bae; Lee, Hyun-Rok

2013-06-01

We analyze the spiral structure of 1725 nearby spiral galaxies with redshift less than 0.02. We use the color images provided by the Sloan Digital Sky Survey. We determine the arm classes (grand design, multiple-arm, flocculent) and the broad Hubble types (early, intermediate, late) as well as the bar types (SA, SAB, SB) by visual inspection. We find that flocculent galaxies are mostly of late Hubble type while multiple-arm galaxies are likely to be of early Hubble type. The fractional distribution of grand design galaxies is nearly constant along the Hubble type. The dependence of arm class on bar type is not as strong as that of the Hubble type. However, there is about a three times larger fraction of grand design spirals in SB galaxies than in SA galaxies, with nearly constant fractions of multiple-arm galaxies. However, if we consider the Hubble type and bar type together, grand design spirals are more frequent in early types than in late types for SA and SAB galaxies, while they are almost constant along the Hubble type for SB galaxies. There are clear correlations between spiral structures and the local background density: strongly barred, early-type, grand design spirals favor high-density regions, while non-barred, late-type, flocculent galaxies are likely to be found in low-density regions.

Animal Welfare Groups Press for Limits on High School Research.

ERIC Educational Resources Information Center

BioScience, 1979

1979-01-01

Discussions from the conference on "The Use of Animals in High School Biology Classes" are highlighted in this article. The list of science fair rules, which resulted from the conference, is included. (SA)

Comparison of actual oxygen delivery kinetics to those predicted by mathematical modeling following stage 1 palliation just prior to superior cavopulmonary anastomosis.

PubMed

Yuki, Koichi; DiNardo, James A

2015-02-01

Optimizing systemic oxygen delivery (DO2) and hemodynamics in children with hypoplastic left heart syndrome (HLHS) is a clinical challenge. Mathematical modeling of the HLHS circulation has been used to determine the relationship between oxygen kinetic parameters and DO2 and to determine how DO2 might be optimized. The model demonstrates that neither arterial oxygen saturation (SaO2) nor mixed venous oxygen saturation (SvO2) alone accurately predicts DO2. Oxygen delivery kinetics predicted by previously described mathematical modeling were compared with actual patients' hemodynamic data. We sought to determine which patient derived parameters correlated best with DO2. Patients with HLHS who underwent cardiac catheterization prior to surgery to create a superior cavopulmonary anastomosis from 2007 to 2011 were identified. Hemodynamic data obtained were compared with the data derived from the mathematical model. Correlations between SaO2, SvO2, SaO2-SvO2, SaO2/(SaO2-SvO2), pulmonary-to-systemic blood flow ratio (Qp/Qs), and DO2 were evaluated using both linear and nonlinear analyses, and R(2) was calculated. Patients' data fit most aspects of the mathematical model. DO2 had the best correlation with SaO2/(SaO2-SvO2; R(2) = 0.8755) followed by SaO2 -SvO2 (R(2) = 0.8063), while SaO2 or SvO2 alone did not demonstrate a significant correlation as predicated by the mathematical model (R(2) = 0.09564 and 0.4831, respectively). SaO2/(SaO2 -SvO2) would be useful clinically to track changes in DO2 that occur with changes in patient condition or with interventions. © 2014 John Wiley & Sons Ltd.

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

Cirrhosis could be associated with severe mutations of the cystic fibrosis gene

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

Lenaerts, C.; Piussan, C.; Soto, B.

1994-09-01

Previous studies failed to demonstrate a genetic predisposition to liver disease in cystic fibrosis. In order to characterize patients with cirrhosis defined on the basis of either hepatosplenomegaly, portal hypertension or liver biopsy, we analyzed a total number of 110 cirrhotic CF patients from different CF centers in France. Of them, 71 are males, which is not different from the overall CF french population. All but 2 are pancreatic insufficient. A history of meconium ileus {plus_minus} meconium ileus equivalent seems to be a risk factor for cirrhosis since these complications are present in 29% of the cirrhotic patients vs. 19%more » in the non-cirrhotic population (p = 0.03). This confirms our previous data in a postmortem study. Genotype analysis was performed in all the patients. {Delta}F508 represents 70% of the identified mutations with a higher proportion of {Delta}F508 +/+ in the cirrhotic than in the non-cirrhotic population (52% vs. 42%, p=0.003), 35% {Delta}F508 +/- vs. 42% and 13% {Delta}F508 -/- vs. 16%. Sixty percent of the other mutations associated with cirrhosis are identified, usually in {Delta}F508 +/- and include 1303 N-K, 542 G-X, 1078 del T, 1282 W-X, 1313 Q-X, 827 E-X, 1061 G-R, 1301 N-H, 14 K-X, 1717-1 G-A, 1918 delGC, 2183 A-G, 2184 delA, 405+1 G-A, 507 {Delta}l, 574 delA, 621+1 G-T, 85 G-E and 1303 N-K/other, 227 L-R/other. None of the cirrhotic patients bear one of the dominant missense mutations regarded as mild with respect to pancreatic function (117 R-H, 334 R-W, 347 R-P, 455 A-E, 574 P-H) or both the {Delta}F508 and the 5512 G-A mutations associated with a decreased risk of meconium ileus. Cirrhosis could thus be linked to the presence of 2 of the severe mutations of the CF gene associated with pancreatic insufficiency.« less

The DELLA Protein SLR1 Integrates and Amplifies Salicylic Acid- and Jasmonic Acid-Dependent Innate Immunity in Rice1

PubMed Central

De Vleesschauwer, David; Seifi, Hamed Soren; Haeck, Ashley; Huu, Son Nguyen; Demeestere, Kristof

2016-01-01

Gibberellins are a class of tetracyclic plant hormones that are well known to promote plant growth by inducing the degradation of a class of nuclear growth-repressing proteins, called DELLAs. In recent years, GA and DELLAs are also increasingly implicated in plant responses to pathogen attack, although our understanding of the underlying mechanisms is still limited, especially in monocotyledonous crop plants. Aiming to further decipher the molecular underpinnings of GA- and DELLA-modulated plant immunity, we studied the dynamics and impact of GA and DELLA during infection of the model crop rice (Oryza sativa) with four different pathogens exhibiting distinct lifestyles and infection strategies. Opposite to previous findings in Arabidopsis (Arabidopsis thaliana), our findings reveal a prominent role of the DELLA protein Slender Rice1 (SLR1) in the resistance toward (hemi)biotrophic but not necrotrophic rice pathogens. Moreover, contrary to the differential effect of DELLA on the archetypal defense hormones salicylic acid (SA) and jasmonic acid (JA) in Arabidopsis, we demonstrate that the resistance-promoting effect of SLR1 is due at least in part to its ability to boost both SA- and JA-mediated rice defenses. In a reciprocal manner, we found JA and SA treatment to interfere with GA metabolism and stabilize SLR1. Together, these findings favor a model whereby SLR1 acts as a positive regulator of hemibiotroph resistance in rice by integrating and amplifying SA- and JA-dependent defense signaling. Our results highlight the differences in hormone defense networking between rice and Arabidopsis and underscore the importance of GA and DELLA in molding disease outcomes. PMID:26829979

The DELLA Protein SLR1 Integrates and Amplifies Salicylic Acid- and Jasmonic Acid-Dependent Innate Immunity in Rice.

PubMed

De Vleesschauwer, David; Seifi, Hamed Soren; Filipe, Osvaldo; Haeck, Ashley; Huu, Son Nguyen; Demeestere, Kristof; Höfte, Monica

2016-03-01

Gibberellins are a class of tetracyclic plant hormones that are well known to promote plant growth by inducing the degradation of a class of nuclear growth-repressing proteins, called DELLAs. In recent years, GA and DELLAs are also increasingly implicated in plant responses to pathogen attack, although our understanding of the underlying mechanisms is still limited, especially in monocotyledonous crop plants. Aiming to further decipher the molecular underpinnings of GA- and DELLA-modulated plant immunity, we studied the dynamics and impact of GA and DELLA during infection of the model crop rice (Oryza sativa) with four different pathogens exhibiting distinct lifestyles and infection strategies. Opposite to previous findings in Arabidopsis (Arabidopsis thaliana), our findings reveal a prominent role of the DELLA protein Slender Rice1 (SLR1) in the resistance toward (hemi)biotrophic but not necrotrophic rice pathogens. Moreover, contrary to the differential effect of DELLA on the archetypal defense hormones salicylic acid (SA) and jasmonic acid (JA) in Arabidopsis, we demonstrate that the resistance-promoting effect of SLR1 is due at least in part to its ability to boost both SA- and JA-mediated rice defenses. In a reciprocal manner, we found JA and SA treatment to interfere with GA metabolism and stabilize SLR1. Together, these findings favor a model whereby SLR1 acts as a positive regulator of hemibiotroph resistance in rice by integrating and amplifying SA- and JA-dependent defense signaling. Our results highlight the differences in hormone defense networking between rice and Arabidopsis and underscore the importance of GA and DELLA in molding disease outcomes. © 2016 American Society of Plant Biologists. All Rights Reserved.

Breed of cow and herd productivity affect milk nutrient recovery in curd, and cheese yield, efficiency and daily production.

PubMed

Stocco, G; Cipolat-Gotet, C; Gasparotto, V; Cecchinato, A; Bittante, G

2018-02-01

Little is known about cheese-making efficiency at the individual cow level, so our objective was to study the effects of herd productivity, individual herd within productivity class and breed of cow within herd by producing, then analyzing, 508 model cheeses from the milk of 508 cows of six different breeds reared in 41 multi-breed herds classified into two productivity classes (high v. low). For each cow we obtained six milk composition traits; four milk nutrient (fat, protein, solids and energy) recovery traits (REC) in curd; three actual % cheese yield traits (%CY); two theoretical %CYs (fresh cheese and cheese solids) calculated from milk composition; two overall cheese-making efficiencies (% ratio of actual to theoretical %CYs); daily milk yield (dMY); and three actual daily cheese yield traits (dCY). The aforementioned phenotypes were analyzed using a mixed model which included the fixed effects of herd productivity, parity, days in milk (DIM) and breed; the random effects were the water bath, vat, herd and residual. Cows reared in high-productivity herds yielded more milk with higher nutrient contents and more cheese per day, had greater theoretical %CY, and lower cheese-making efficiency than low-productivity herds, but there were no differences between them in terms of REC traits. Individual herd within productivity class was an intermediate source of total variation in REC, %CY and efficiency traits (10.0% to 17.2%), and a major source of variation in milk yield and dCY traits (43.1% to 46.3%). Parity of cows was an important source of variation for productivity traits, whereas DIM affected almost all traits. Breed within herd greatly affected all traits. Holsteins produced more milk, but Brown Swiss cows produced milk with higher actual and theoretical %CYs and cheese-making efficiency, so that the two large-framed breeds had the same dCY. Compared with the two large-framed breeds, the small Jersey cows produced much less milk, but with greater actual and theoretical %CYs, similar efficiencies and a slightly lower dCY. Compared with the average of the specialized dairy breeds, the three dual-purpose breeds (Simmental and the local Rendena and Alpine Grey) had, on average, similar dMY, lower actual and theoretical %CY, similar fat and protein REC, and slightly greater cheese-making efficiency.

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...

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...

Changing Incidence of Cystic Fibrosis in Wisconsin, USA

PubMed Central

Bersie, Rachel; Hoffman, Gary; Rock, Michael; Baker, Mei; Farrell, Philip M.; Simpson, Pippa; Levy, Hara

2015-01-01

Summary Rationale Previous investigations of cystic fibrosis (CF) incidence in Massachusetts, Colorado, and Minnesota (USA) yielded contradictory results, particularly regarding allele p.Phe508del; the racial compositions of the cohorts were not reported. Objectives To clarify discrepancies in reported incidence with the ultimate goal of improving screening and quality of care, we assessed CF incidence, stratified by race and mutations in cystic fibrosis transmembrane conductance regulator (CFTR), in Wisconsin (USA) from 1994 to 2011. Methods Data on patients diagnosed with CF (N=283), CFTR genotypes, CF carriers, and birth rate were collected. All data were categorized by racial background of the birth mother and the incidence of CF births was accordingly adjusted. Spearman’s nonparametric rank correlation and Fisher’s exact test were performed for continuous and categorical variables, respectively. Trends over time were fitted with a cubic spline. Results We detected a trending increase in CF cases (range within all data 1.67–2.98 per 10,000 births per year), homozygous p.Phe508del cases (0.57–1.79 per 10,000), heterozygous p.Phe508del cases (0.29–1.55 per 10,000), and cases lacking p. Phe508del (0–0.45 per 10,000). Both the number of cases lacking the p.Phe508del mutation per year and the number of cases lacking p.Phe508del per 10,000 births significantly increased (P=0.05) from 1994 to 2011; the increase in overall incidence was not significant. The number of carriers identified through newborn screening significantly increased within the non-Hispanic Black (P=0.0.021) and Hispanic (P=0.003) populations. Conclusion The racial composition of the CF cohort is changing in Wisconsin, possibly influencing disease detection, care, and outcome. PMID:26258862

Changing incidence of cystic fibrosis in Wisconsin, USA.

PubMed

Parker-McGill, Katelyn; Nugent, Melodee; Bersie, Rachel; Hoffman, Gary; Rock, Michael; Baker, Mei; Farrell, Philip M; Simpson, Pippa; Levy, Hara

2015-11-01

Previous investigations of cystic fibrosis (CF) incidence in Massachusetts, Colorado, and Minnesota (USA) yielded contradictory results, particularly regarding allele p.Phe508del; the racial compositions of the cohorts were not reported. To clarify discrepancies in reported incidence with the ultimate goal of improving screening and quality of care, we assessed CF incidence, stratified by race and mutations in cystic fibrosis transmembrane conductance regulator (CFTR), in Wisconsin (USA) from 1994 to 2011. Data on patients diagnosed with CF (N = 283), CFTR genotypes, CF carriers, and birth rate were collected. All data were categorized by racial background of the birth mother and the incidence of CF births was accordingly adjusted. Spearman's nonparametric rank correlation and Fisher's exact test were performed for continuous and categorical variables, respectively. Trends over time were fitted with a cubic spline. We detected a trending increase in CF cases (range within all data 1.67-2.98 per 10,000 births per year), homozygous p.Phe508del cases (0.57-1.79 per 10,000), heterozygous p.Phe508del cases (0.29-1.55 per 10,000), and cases lacking p.Phe508del (0-0.45 per 10,000). Both the number of cases lacking the p.Phe508del mutation per year and the number of cases lacking p.Phe508del per 10,000 births significantly increased (P = 0.05) from 1994 to 2011; the increase in overall incidence was not significant. The number of carriers identified through newborn screening significantly increased within the non-Hispanic Black (P = 0.0.021) and Hispanic (P = 0.003) populations. The racial composition of the CF cohort is changing in Wisconsin, possibly influencing disease detection, care, and outcome. © 2015 Wiley Periodicals, Inc.

Remarks on a Sequence of Minimal Niven Numbers

DTIC Science & Technology

2007-01-01

On the distribution in residue classes of integers with a fixed digit sum’, The Ramanujan J. 9 (2005), 45–62. 8. C . Mauduit and A. Sárközy, ‘On the...PAGES 8 19a. NAME OF RESPONSIBLE PERSON a. REPORT unclassified b. ABSTRACT unclassified c . THIS PAGE unclassified Standard Form 298 (Rev. 8-98...118–120. 2. C . N. Cooper and R. E. Kennedy, ‘On consecutive Niven numbers’, Fibonacci Quart. 21 (1993), 146–151. 3. J. M. De Koninck and N. Doyon, ‘On

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.

Complete Genome Sequence of Pseudomonas chlororaphis subsp. aurantiaca Reveals a Triplicate Quorum-Sensing Mechanism for Regulation of Phenazine Production

PubMed Central

Morohoshi, Tomohiro; Yamaguchi, Takahito; Xie, Xiaonan; Wang, Wen-zhao; Takeuchi, Kasumi; Someya, Nobutaka

2017-01-01

Pseudomonas chlororaphis subsp. aurantiaca StFRB508 regulates phenazine production through N-acyl-l-homoserine lactone (AHL)-mediated quorum sensing. Two sets of AHL-synthase and AHL-receptor genes, phzI/phzR and aurI/aurR, have been identified from the incomplete draft genome of StFRB508. In the present study, the complete genome of StFRB508, comprising a single chromosome of 6,997,933 bp, was sequenced. The complete genome sequence revealed the presence of a third quorum-sensing gene set, designated as csaI/csaR. An LC-MS/MS analysis revealed that StFRB508 produced six types of AHLs, with the most important AHL being N-(3-hydroxyhexanoyl)-l-homoserine lactone (3-OH-C6-HSL). PhzI mainly catalyzed the biosynthesis of 3-OH-C6-HSL, while AurI and CsaI catalyzed that of N-hexanoyl-l-homoserine lactone and N-(3-oxohexanoyl)-l-homoserine lactone, respectively. A mutation in phzI decreased phenazine production, whereas that in aurI or csaI did not. A phzI aurI csaI triple mutant (508ΔPACI) did not produce phenazine. Phenazine production by 508ΔPACI was stimulated by exogenous AHLs and 3-OH-C6-HSL exerted the strongest effects on phenazine production at the lowest concentration tested (0.1 μM). The plant protection efficacy of 508ΔPACI against an oomycete pathogen was lower than that of wild-type StFRB508. These results demonstrate that the triplicate quorum-sensing system plays an important role in phenazine production by and the biocontrol activity of StFRB508. PMID:28239068

HLA similarities indicate shared genetic risk in 21-hydroxylase autoantibody positive South African and United States Addison's disease.

PubMed

Ross, I L; Babu, S; Armstrong, T; Zhang, L; Schatz, D; Pugliese, A; Eisenbarth, G; Baker Ii, P

2014-10-01

Genetic similarities between patients from the United States and South African (SA) Addison's Disease (AD) strengthen evidence for genetic association. SA-AD (n = 73), SA healthy controls (N = 78), and US-AD patients (N = 83) were genotyped for DQA1, DQB1, DRB1, and HLA-B alleles. Serum was tested for the quantity of 21OH-AA and IFNα-AA at the Barbara Davis Center. Although not as profound as in US-AD, in SA-AD 21OH-AA + subjects the predominantly associated risk haplotypes were DRB1*0301-DQB1*0201 (DR3), DRB1*04xx-DQB1*0302 (DR4), and the combined DR3/4 genotype. DQB1*0302 associated DRB1*04xx haplotypes conferred higher risk than those DRB1*04xx haplotypes associated with other DQB1 alleles. We found negative association in 21OH-AA + SA-AD for DQA1*0201-DQB1*0202 and DQA1*0101-DQB1*0501 vs SA controls, and positive association for DQA1*0401-DQB1*0402 vs US-AD. Apart from the class II DR3 haplotype, HLA-B8 did not have an independent effect; however together DR3 and HLA-B8 conferred the highest risk vs 21OH-AA negative SA-AD and SA-controls. HLA-B7 (often with DR4) conferred novel risk in 21OH-AA + SA-AD vs controls. This study represents the first comparison between South African and United States AD populations utilizing genotyping and serology performed at the same center. SA-AD and US-AD 21OH-AA + patients share common HLA risk haplotypes including DR4 (with HLA-B7) and DR3 (with HLA-B8), strengthening previously described HLA associations and implicating similar genetic etiology. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Geography of Mental Health and General Wellness in Galveston Bay After Hurricane Ike: A Spatial Epidemiologic Study With Longitudinal Data.

PubMed

Gruebner, Oliver; Lowe, Sarah R; Tracy, Melissa; Cerdá, Magdalena; Joshi, Spruha; Norris, Fran H; Galea, Sandro

2016-04-01

To demonstrate a spatial epidemiologic approach that could be used in the aftermath of disasters to (1) detect spatial clusters and (2) explore geographic heterogeneity in predictors for mental health and general wellness. We used a cohort study of Hurricane Ike survivors (n=508) to assess the spatial distribution of postdisaster mental health wellness (most likely resilience trajectory for posttraumatic stress symptoms [PTSS] and depression) and general wellness (most likely resilience trajectory for PTSS, depression, functional impairment, and days of poor health) in Galveston, Texas. We applied the spatial scan statistic (SaTScan) and geographically weighted regression. We found spatial clusters of high likelihood wellness in areas north of Texas City and spatial concentrations of low likelihood wellness in Galveston Island. Geographic variation was found in predictors of wellness, showing increasing associations with both forms of wellness the closer respondents were located to Galveston City in Galveston Island. Predictors for postdisaster wellness may manifest differently across geographic space with concentrations of lower likelihood wellness and increased associations with predictors in areas of higher exposure. Our approach could be used to inform geographically targeted interventions to promote mental health and general wellness in disaster-affected communities.

RICOR's new development of a highly reliable integral rotary cooler: engineering and reliability aspects

NASA Astrophysics Data System (ADS)

Filis, Avishai; Pundak, Nachman; Barak, Moshe; Porat, Ze'ev; Jaeger, Mordechai

2011-06-01

The growing demand for EO applications that work around the clock 24hr/7days a week, such as in border surveillance systems, emphasizes the need for a highly reliable cryocooler having increased operational availability and decreased integrated system Life Cycle (ILS) cost. In order to meet this need RICOR has developed a new rotary Stirling cryocooler, model K508N, intended to double the K508's operating MTTF achieving 20,000 operating MTTF hours. The K508N employs RICOR's latest mechanical design technologies such as optimized bearings and greases, bearings preloading, advanced seals, laser welded cold finger and robust design structure with increased natural frequency compared to the K508 model. The cooler enhanced MTTF was demonstrated by a Validation and Verification (V&V) plan comprising analytical means and a comparative accelerated life test between the standard K508 and the K508N models. Particularly, point estimate and confidence interval for the MTTF improvement factor where calculated periodically during and after the test. The (V&V) effort revealed that the K508N meets its MTTF design goal. The paper will focus on the technical and engineering aspects of the new design. In addition it will discuss the market needs and expectations, investigate the reliability data of the present reference K508 model; and report the accelerate life test data and the statistical analysis methodology as well as its underlying assumptions and results.

Genetic deletion of keratin 8 corrects the altered bone formation and osteopenia in a mouse model of cystic fibrosis.

PubMed

Le Henaff, Carole; Faria Da Cunha, Mélanie; Hatton, Aurélie; Tondelier, Danielle; Marty, Caroline; Collet, Corinne; Zarka, Mylène; Geoffroy, Valérie; Zatloukal, Kurt; Laplantine, Emmanuel; Edelman, Aleksander; Sermet-Gaudelus, Isabelle; Marie, Pierre J

2016-04-01

Patients with cystic fibrosis (CF) display low bone mass and alterations in bone formation. Mice carrying the F508del genetic mutation in the cystic fibrosis conductance regulator (Cftr) gene display reduced bone formation and decreased bone mass. However, the underlying molecular mechanisms leading to these skeletal defects are unknown, which precludes the development of an efficient anti-osteoporotic therapeutic strategy. Here we report a key role for the intermediate filament protein keratin 8 (Krt8), in the osteoblast dysfunctions in F508del-Cftr mice. We found that murine and human osteoblasts express Cftr and Krt8 at low levels. Genetic studies showed that Krt8 deletion (Krt8(-/-)) in F508del-Cftr mice increased the levels of circulating markers of bone formation, corrected the expression of osteoblast phenotypic genes, promoted trabecular bone formation and improved bone mass and microarchitecture. Mechanistically, Krt8 deletion in F508del-Cftr mice corrected overactive NF-κB signaling and decreased Wnt-β-catenin signaling induced by the F508del-Cftr mutation in osteoblasts. In vitro, treatment with compound 407, which specifically disrupts the Krt8-F508del-Cftr interaction in epithelial cells, corrected the abnormal NF-κB and Wnt-β-catenin signaling and the altered phenotypic gene expression in F508del-Cftr osteoblasts. In vivo, short-term treatment with 407 corrected the altered Wnt-β-catenin signaling and bone formation in F508del-Cftr mice. Collectively, the results show that genetic or pharmacologic targeting of Krt8 leads to correction of osteoblast dysfunctions, altered bone formation and osteopenia in F508del-Cftr mice, providing a therapeutic strategy targeting the Krt8-F508del-CFTR interaction to correct the abnormal bone formation and bone loss in cystic fibrosis. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

In vitro microtensile bond strength of four adhesives tested at the gingival and pulpal walls of class II restorations

PubMed Central

Purk, John H.; Healy, Matthew; Dusevich, Vladimir; Glaros, Alan; Eick, J. David

2007-01-01

Background The authors compared the microtensile bond strength of teeth restored with four adhesives at the gingival and pulpal cavity walls of Class II resin-based composite restorations. Methods Five pairs of extracted third molars received two Class II preparations/restorations in each tooth. The authors randomly assigned each preparation to one of four adhesive groups: Adper Scotchbond Multipurpose Dental Adhesive (SBMP) (3M ESPE, St. Paul, Minn.), Clearfil SE Bond (CFSE) (Kuraray America, New York City), Prime & Bond NT (PBNT) (Dentsply Caulk, Milford, Del.) and PQ1 (Ultradent, South Jordan, Utah). They restored the teeth and obtained microtensile specimens from each cavity wall. Specimens were tested on a testing machine until they failed. Results The mean (± standard deviation) bond strengths (in megapascals) were as follows: SBMP (pulpal), 36.4 (17.2); SBMP (gingival), 29.7 (15.3); CFSE (pulpal), 50.8 (13.6); CFSE (gingival), 50.2 (14.0); PBNT (pulpal), 38.3 (19.2); PBNT (gingival), 38.9 (17.7); PQ1 (pulpal), 58.7 (8.7); and PQ1 (gingival), 54.5 (18.5). A two-way analysis of variance found an adhesive effect (P < .001) but no location effect (P > .05). Conclusions PQ1 and CFSE performed the best. The results showed no significant difference in microtensile bond strength at the gingival wall versus the pulpal wall. Clinical Implications Under in vitro conditions, a total-etch ethanol-based adhesive (PQ1) failed cohesively more often than did the other adhesives tested. PMID:17012721

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.

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.

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...

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...

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...

Fatigue crack growth rates in a pressure vessel steel under various conditions of loading and the environment

NASA Astrophysics Data System (ADS)

Hicks, P. D.; Robinson, F. P. A.

1986-10-01

Corrosion fatigue (CF) tests have been carried out on SA508 Cl 3 pressure vessel steel, in simulated P.W.R. environments. The test variables investigated included air and P.W.R. water environments, frequency variation over the range 1 Hz to 10 Hz, transverse and longitudinal crack growth directions, temperatures of 20 °C and 50 °C, and R-ratios of 0.2 and 0.7. It was found that decreasing the test frequency increased fatigue crack growth rates (FCGR) in P.W.R. environments, P.W.R. environment testing gave enhanced crack growth (vs air tests), FCGRs were greater for cracks growing in the longitudinal direction, slight increases in temperature gave noticeable accelerations in FCGR, and several air tests gave FCGR greater than those predicted by the existing ASME codes. Fractographic evidence indicates that FCGRs were accelerated by a hydrogen embrittlement mechanism. The presence of elongated MnS inclusions aided both mechanical fatigue and hydrogen embrittlement processes, thus producing synergistically fast FCGRs. Both anodic dissolution and hydrogen embrittlement mechanisms have been proposed for the environmental enhancement of crack growth rates. Electrochemical potential measurements and potentiostatic tests have shown that sample isolation of the test specimens from the clevises in the apparatus is not essential during low temperature corrosion fatigue testing.

Hydrogen Peroxide Is a Second Messenger in the Salicylic Acid-Triggered Adventitious Rooting Process in Mung Bean Seedlings

PubMed Central

Yang, Wei; Zhu, Changhua; Ma, Xiaoling; Li, Guijun; Gan, Lijun; Ng, Denny; Xia, Kai

2013-01-01

In plants, salicylic acid (SA) is a signaling molecule that regulates disease resistance responses, such as systemic acquired resistance (SAR) and hypertensive response (HR). SA has been implicated as participating in various biotic and abiotic stresses. This study was conducted to investigate the role of SA in adventitious root formation (ARF) in mung bean (Phaseolus radiatus L) hypocotyl cuttings. We observed that hypocotyl treatment with SA could significantly promote the adventitious root formation, and its effects were dose and time dependent. Explants treated with SA displayed a 130% increase in adventitious root number compared with control seedlings. The role of SA in mung bean hypocotyl ARF as well as its interaction with hydrogen peroxide (H2O2) were also elucidated. Pretreatment of mung bean explants with N, N’-dimethylthiourea (DMTU), a scavenger for H2O2, resulted in a significant reduction of SA-induced ARF. Diphenyleneiodonium (DPI), a specific inhibitor of membrane-linked NADPH oxidase, also inhibited the effect of adventitious rooting triggered by SA treatment. The determination of the endogenous H2O2 level indicated that the seedlings treated with SA could induce H2O2 accumulation compared with the control treatment. Our results revealed a distinctive role of SA in the promotion of adventitious rooting via the process of H2O2 accumulation. This conclusion was further supported by antioxidant enzyme activity assays. Based on these results, we conclude that the accumulation of free H2O2 might be a downstream event in response to SA-triggered adventitious root formation in mung bean seedlings. PMID:24386397

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

PubMed

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

2015-07-17

The prevalent human ΔF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is associated with reduced bone formation and bone loss in mice. The molecular mechanisms by which the ΔF508-CFTR mutation causes alterations in bone formation are poorly known. In this study, we analyzed the osteoblast phenotype in ΔF508-CFTR mice and characterized the signaling mechanisms underlying this phenotype. Ex vivo studies showed that the ΔF508-CFTR mutation negatively impacted the differentiation of bone marrow stromal cells into osteoblasts and the activity of osteoblasts, demonstrating that the ΔF508-CFTR mutation alters both osteoblast differentiation and function. Treatment with a CFTR corrector rescued the abnormal collagen gene expression in ΔF508-CFTR osteoblasts. Mechanistic analysis revealed that NF-κB signaling and transcriptional activity were increased in mutant osteoblasts. Functional studies showed that the activation of NF-κB transcriptional activity in mutant osteoblasts resulted in increased β-catenin phosphorylation, reduced osteoblast β-catenin expression, and altered expression of Wnt/β-catenin target genes. Pharmacological inhibition of NF-κB activity or activation of canonical Wnt signaling rescued Wnt target gene expression and corrected osteoblast differentiation and function in bone marrow stromal cells and osteoblasts from ΔF508-CFTR mice. Overall, the results show that the ΔF508-CFTR mutation impairs osteoblast differentiation and function as a result of overactive NF-κB and reduced Wnt/β-catenin signaling. Moreover, the data indicate that pharmacological inhibition of NF-κB or activation of Wnt/β-catenin signaling can rescue the abnormal osteoblast differentiation and function induced by the prevalent ΔF508-CFTR mutation, suggesting novel therapeutic strategies to correct the osteoblast dysfunctions in cystic fibrosis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

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

PubMed Central

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

2015-01-01

The prevalent human ΔF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is associated with reduced bone formation and bone loss in mice. The molecular mechanisms by which the ΔF508-CFTR mutation causes alterations in bone formation are poorly known. In this study, we analyzed the osteoblast phenotype in ΔF508-CFTR mice and characterized the signaling mechanisms underlying this phenotype. Ex vivo studies showed that the ΔF508-CFTR mutation negatively impacted the differentiation of bone marrow stromal cells into osteoblasts and the activity of osteoblasts, demonstrating that the ΔF508-CFTR mutation alters both osteoblast differentiation and function. Treatment with a CFTR corrector rescued the abnormal collagen gene expression in ΔF508-CFTR osteoblasts. Mechanistic analysis revealed that NF-κB signaling and transcriptional activity were increased in mutant osteoblasts. Functional studies showed that the activation of NF-κB transcriptional activity in mutant osteoblasts resulted in increased β-catenin phosphorylation, reduced osteoblast β-catenin expression, and altered expression of Wnt/β-catenin target genes. Pharmacological inhibition of NF-κB activity or activation of canonical Wnt signaling rescued Wnt target gene expression and corrected osteoblast differentiation and function in bone marrow stromal cells and osteoblasts from ΔF508-CFTR mice. Overall, the results show that the ΔF508-CFTR mutation impairs osteoblast differentiation and function as a result of overactive NF-κB and reduced Wnt/β-catenin signaling. Moreover, the data indicate that pharmacological inhibition of NF-κB or activation of Wnt/β-catenin signaling can rescue the abnormal osteoblast differentiation and function induced by the prevalent ΔF508-CFTR mutation, suggesting novel therapeutic strategies to correct the osteoblast dysfunctions in cystic fibrosis. PMID:26060255

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...

A parallel metaheuristic for large mixed-integer dynamic optimization problems, with applications in computational biology

PubMed Central

Henriques, David; González, Patricia; Doallo, Ramón; Saez-Rodriguez, Julio; Banga, Julio R.

2017-01-01

Background We consider a general class of global optimization problems dealing with nonlinear dynamic models. Although this class is relevant to many areas of science and engineering, here we are interested in applying this framework to the reverse engineering problem in computational systems biology, which yields very large mixed-integer dynamic optimization (MIDO) problems. In particular, we consider the framework of logic-based ordinary differential equations (ODEs). Methods We present saCeSS2, a parallel method for the solution of this class of problems. This method is based on an parallel cooperative scatter search metaheuristic, with new mechanisms of self-adaptation and specific extensions to handle large mixed-integer problems. We have paid special attention to the avoidance of convergence stagnation using adaptive cooperation strategies tailored to this class of problems. Results We illustrate its performance with a set of three very challenging case studies from the domain of dynamic modelling of cell signaling. The simpler case study considers a synthetic signaling pathway and has 84 continuous and 34 binary decision variables. A second case study considers the dynamic modeling of signaling in liver cancer using high-throughput data, and has 135 continuous and 109 binaries decision variables. The third case study is an extremely difficult problem related with breast cancer, involving 690 continuous and 138 binary decision variables. We report computational results obtained in different infrastructures, including a local cluster, a large supercomputer and a public cloud platform. Interestingly, the results show how the cooperation of individual parallel searches modifies the systemic properties of the sequential algorithm, achieving superlinear speedups compared to an individual search (e.g. speedups of 15 with 10 cores), and significantly improving (above a 60%) the performance with respect to a non-cooperative parallel scheme. The scalability of the method is also good (tests were performed using up to 300 cores). Conclusions These results demonstrate that saCeSS2 can be used to successfully reverse engineer large dynamic models of complex biological pathways. Further, these results open up new possibilities for other MIDO-based large-scale applications in the life sciences such as metabolic engineering, synthetic biology, drug scheduling. PMID:28813442

A parallel metaheuristic for large mixed-integer dynamic optimization problems, with applications in computational biology.

PubMed

Penas, David R; Henriques, David; González, Patricia; Doallo, Ramón; Saez-Rodriguez, Julio; Banga, Julio R

2017-01-01

We consider a general class of global optimization problems dealing with nonlinear dynamic models. Although this class is relevant to many areas of science and engineering, here we are interested in applying this framework to the reverse engineering problem in computational systems biology, which yields very large mixed-integer dynamic optimization (MIDO) problems. In particular, we consider the framework of logic-based ordinary differential equations (ODEs). We present saCeSS2, a parallel method for the solution of this class of problems. This method is based on an parallel cooperative scatter search metaheuristic, with new mechanisms of self-adaptation and specific extensions to handle large mixed-integer problems. We have paid special attention to the avoidance of convergence stagnation using adaptive cooperation strategies tailored to this class of problems. We illustrate its performance with a set of three very challenging case studies from the domain of dynamic modelling of cell signaling. The simpler case study considers a synthetic signaling pathway and has 84 continuous and 34 binary decision variables. A second case study considers the dynamic modeling of signaling in liver cancer using high-throughput data, and has 135 continuous and 109 binaries decision variables. The third case study is an extremely difficult problem related with breast cancer, involving 690 continuous and 138 binary decision variables. We report computational results obtained in different infrastructures, including a local cluster, a large supercomputer and a public cloud platform. Interestingly, the results show how the cooperation of individual parallel searches modifies the systemic properties of the sequential algorithm, achieving superlinear speedups compared to an individual search (e.g. speedups of 15 with 10 cores), and significantly improving (above a 60%) the performance with respect to a non-cooperative parallel scheme. The scalability of the method is also good (tests were performed using up to 300 cores). These results demonstrate that saCeSS2 can be used to successfully reverse engineer large dynamic models of complex biological pathways. Further, these results open up new possibilities for other MIDO-based large-scale applications in the life sciences such as metabolic engineering, synthetic biology, drug scheduling.

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...

"Successful aging," gerontological theory and neoliberalism: a qualitative critique.

PubMed

Rubinstein, Robert L; de Medeiros, Kate

2015-02-01

This article is a critique of the successful aging (SA) paradigm as described in the Rowe and Kahn book, Successful Aging (1998). The major point of this article is that two key ideas in the book may be understood as consonant with neoliberalism, a social perspective that came into international prominence at the same time the SA paradigm was initially promoted. These two key ideas are (a) the emphasis on individual social action applied to the nature of the aging experience and (b) the failure to provide a detailed policy agenda for the social and cultural change being promoted and, particularly, for older adults who may be left behind by the approach to change the book suggests. The article provides no evidence for a direct connection between SA and neoliberalism, but rather shows how similarities in their approaches to social change characterize both of them. In sum, the article shows (a) how the implicit social theory developed in the book, in a manner similar to neoliberalism, elevates the individual as the main source of any changes that must accompany the SA paradigm and (b) the focus on SA as individual action does not provide for those older adults who do not or will not age "successfully." This, we conclude, implicitly sets up a two-class system of older adults, which may not be an optimal means of addressing the needs of all older adults. The article also reviews a number of studies about SA and shows how these, too, may emphasize its similarities to neoliberalism and other issues that the SA paradigm does not adequately address. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Predicting forested catchment evapotranspiration and streamflow from stand sapwood area and Aridity Index

NASA Astrophysics Data System (ADS)

Lane, Patrick

2016-04-01

Estimating the water balance of ungauged catchments has been the subject of decades of research. An extension of the fundamental problem of estimating the hydrology is then understanding how do changes in catchment attributes affect the water balance component? This is a particular issue in forest hydrology where vegetation exerts such a strong influence on evapotranspiration (ET), and consequent streamflow (Q). Given the primacy of trees in the water balance, and the potential for change to species and density through logging, fire, pests and diseases and drought, methods that directly relate ET/Q to vegetation structure, species, and stand density are very powerful. Plot studies on tree water use routinely use sapwood area (SA) to calculate transpiration and upscale to the stand/catchment scale. Recent work in south eastern Australian forests have found stand-wide SA to be linearly correlated (R2 = 0.89) with long term mean annual loss (P-Q), and hence, long term mean annual catchment streamflow. Robust relationships can be built between basal area (BA), tree density and stand SA. BA and density are common forest inventory measurements. Until now, no research has related the fundamental stand attribute of SA to streamflow. The data sets include catchments that have been thinned and with varying age classes. Thus far these analyses have been for energy limited systems in wetter forest types. SA has proven to be a more robust biometric than leaf area index which varies seasonally. That long term ET/Q is correlated with vegetation conforms to the Budyko framework. Use of a downscaled (20 m) Aridity Index (AI) has shown distinct correlations with stand SA, and therefore T. Structural patterns at a the hillslope scale not only correlate with SA and T, but also with interception (I) and forest floor evaporation (Es). These correlations between AI and I and Es have given R2 > 0.8. The result of these studies suggest an ability to estimate mean annual ET fluxes at sub hillslope scale using mappable attributes (AI, forest inventory data). Advances in forest inventory techniques, including LiDAR, mean stand attributes can increasingly be mapped over large areas. If combined with process measurements, these mapped attributes provide a powerful platform for simple but robust modelling at the sub-hillslope scale, including exploring hinge points of stand vulnerability to the drier, hotter climate predicted for SE Australia where energy limited systems may face water limitation.

Hydrogen sulfide acts as a downstream signal molecule in salicylic acid-induced heat tolerance in maize (Zea mays L.) seedlings.

PubMed

Li, Zhong-Guang; Xie, Lin-Run; Li, Xiao-Juan

2015-04-01

Salicylic acid (SA), 2-hydroxy benzoic acid, is a small phenolic compound with multifunction that is involved in plant growth, development, and the acquisition of stress tolerance. In recent years, hydrogen sulfide (H2S) has been found to have similar functions, but cross talk between SA and H2S in the acquisition of heat tolerance is not clear. In this study, pretreatment of maize seedlings with SA improved the survival percentage of seedlings under heat stress, indicating that SA pretreatment could improve the heat tolerance of maize seedlings. In addition, treatment with SA enhanced the activity of L-cysteine desulfhydrase (L-DES), a key enzyme in H2S biosynthesis, which in turn induced accumulation of endogenous H2S. Interestingly, SA-induced heat tolerance was enhanced by addition of NaHS, a H2S donor, but weakened by specific inhibitors of H2S biosynthesis DL-propargylglycine (PAG) and its scavenger hydroxylamine (HT). Furthermore, pretreatment with paclobutrazol (PAC) and 2-aminoindan-2-phosphonic acid (AIP), inhibitors of SA biosynthesis, had no significant effect on NaHS-induced heat tolerance of maize seedlings. Similarly, significant change in the activities of phenylalanine ammonia lyase (PAL) and benzoic-acid-2-hydroxylase (BA2H), the key enzymes in SA biosynthesis, and the content of endogenous SA, was not observed in maize seedlings by NaHS treatment. All of the above-mentioned results suggest that SA pretreatment could improve the heat tolerance of maize seedlings, and H2S might be a novel downstream signal molecule in SA-induced heat tolerance. Copyright © 2015 Elsevier GmbH. All rights reserved.

Integrating nitric oxide into salicylic acid and jasmonic acid/ ethylene plant defense pathways.

PubMed

Mur, Luis A J; Prats, Elena; Pierre, Sandra; Hall, Michael A; Hebelstrup, Kim H

2013-01-01

Plant defense against pests and pathogens is known to be conferred by either salicylic acid (SA) or jasmonic acid (JA)/ethylene (ET) pathways, depending on infection or herbivore-grazing strategy. It is well attested that SA and JA/ET pathways are mutually antagonistic allowing defense responses to be tailored to particular biotic stresses. Nitric oxide (NO) has emerged as a major signal influencing resistance mediated by both signaling pathways but no attempt has been made to integrate NO into established SA/JA/ET interactions. NO has been shown to act as an inducer or suppressor of signaling along each pathway. NO will initiate SA biosynthesis and nitrosylate key cysteines on TGA-class transcription factors to aid in the initiation of SA-dependent gene expression. Against this, S-nitrosylation of NONEXPRESSOR OF PATHOGENESIS-RELATED PROTEINS1 (NPR1) will promote the NPR1 oligomerization within the cytoplasm to reduce TGA activation. In JA biosynthesis, NO will initiate the expression of JA biosynthetic enzymes, presumably to over-come any antagonistic effects of SA on JA-mediated transcription. NO will also initiate the expression of ET biosynthetic genes but a suppressive role is also observed in the S-nitrosylation and inhibition of S-adenosylmethionine transferases which provides methyl groups for ET production. Based on these data a model for NO action is proposed but we have also highlighted the need to understand when and how inductive and suppressive steps are used.

Integrating nitric oxide into salicylic acid and jasmonic acid/ ethylene plant defense pathways

PubMed Central

Mur, Luis A. J.; Prats, Elena; Pierre, Sandra; Hall, Michael A.; Hebelstrup, Kim H.

2013-01-01

Plant defense against pests and pathogens is known to be conferred by either salicylic acid (SA) or jasmonic acid (JA)/ethylene (ET) pathways, depending on infection or herbivore-grazing strategy. It is well attested that SA and JA/ET pathways are mutually antagonistic allowing defense responses to be tailored to particular biotic stresses. Nitric oxide (NO) has emerged as a major signal influencing resistance mediated by both signaling pathways but no attempt has been made to integrate NO into established SA/JA/ET interactions. NO has been shown to act as an inducer or suppressor of signaling along each pathway. NO will initiate SA biosynthesis and nitrosylate key cysteines on TGA-class transcription factors to aid in the initiation of SA-dependent gene expression. Against this, S-nitrosylation of NONEXPRESSOR OF PATHOGENESIS-RELATED PROTEINS1 (NPR1) will promote the NPR1 oligomerization within the cytoplasm to reduce TGA activation. In JA biosynthesis, NO will initiate the expression of JA biosynthetic enzymes, presumably to over-come any antagonistic effects of SA on JA-mediated transcription. NO will also initiate the expression of ET biosynthetic genes but a suppressive role is also observed in the S-nitrosylation and inhibition of S-adenosylmethionine transferases which provides methyl groups for ET production. Based on these data a model for NO action is proposed but we have also highlighted the need to understand when and how inductive and suppressive steps are used. PMID:23818890

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)

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...

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...

Assessing Visual Delays using Pupil Oscillations

NASA Technical Reports Server (NTRS)

Mulligan, Jeffrey B.

2012-01-01

Stark (1962) demonstrated vigorous pupil oscillations by illuminating the retina with a beam of light focussed to a small spot near the edge of the pupil. Small constrictions of the pupil then are sufficient to completely block the beam, amplifying the normal relationship between pupil area and retinal illuminance. In addition to this simple and elegant method, Stark also investigated more complex feedback systems using an electronic "clamping box" which provided arbitrary gain and phase delay between a measurement of pupil area and an electronically controlled light source. We have replicated Stark's results using a video-based pupillometer to control the luminance of a display monitor. Pupil oscillations were induced by imposing a linear relationship between pupil area and display luminance, with a variable delay. Slopes of the period-vs-delay function for 3 subjects are close to the predicted value of 2 (1.96-2.39), and the implied delays range from 254 to 376 508 to 652 milliseconds. Our setup allows us to extend Stark's work by investigating a broader class of stimuli.

A History of the Chemistry Division, Naval Research Laboratory, Washington, D.C., 1927-1982.

DTIC Science & Technology

1983-04-22

APR 83 NRL-MR-5064 UNCLASSIFIED F/G 14/2 NL BEhhhhhhEBEE mhhhhhEEmllI Illsommommommom IImllllllmlllI o /lommommommo - ..... *1 4 , 11111 .08 J&5 iii0...ADDRESS(II differet from Con rollll Office) 15. SECURITY CLASS. (at thi soperl) UNCLASSIFIED(Sa. DECL ASSI FICA TION/DOWNGRADING SCHEDULE 16. DISTRIBUTION...it. DO , o 1473 EDITION OF I NOV 1S IS OBSOLETE S/N 0102-014-6601 SECURITY CLASSIFICATION OF THIS PAGE (When Date &imed) U " 1 ’ " ’ L I L i ’ i

Status and understanding of groundwater quality in the North San Francisco Bay Shallow Aquifer study unit, 2012; California GAMA Priority Basin Project (ver. 1.1, February 2018)

USGS Publications Warehouse

Bennett, George L.

2017-07-20

Groundwater quality in the North San Francisco Bay Shallow Aquifer study unit (NSF-SA) was investigated as part of the Priority Basin Project of the California Groundwater Ambient Monitoring and Assessment (GAMA) Program. The study unit is in Marin, Mendocino, Napa, Solano, and Sonoma Counties and included two physiographic study areas: the Valleys and Plains area and the surrounding Highlands area. The NSF-SA focused on groundwater resources used for domestic drinking water supply, which generally correspond to shallower parts of aquifer systems than that of groundwater resources used for public drinking water supply in the same area. The assessments characterized the quality of untreated groundwater, not the quality of drinking water.This study included three components: (1) a status assessment, which characterized the status of the quality of the groundwater resources used for domestic supply for 2012; (2) an understanding assessment, which evaluated the natural and human factors potentially affecting water quality in those resources; and (3) a comparison between the groundwater resources used for domestic supply and those used for public supply.The status assessment was based on data collected from 71 sites sampled by the U.S. Geological Survey for the GAMA Priority Basin Project in 2012. To provide context, concentrations of constituents measured in groundwater were compared to U.S. Environmental Protection Agency (EPA) and California State Water Resources Control Board Division of Drinking Water regulatory and non-regulatory benchmarks for drinking-water quality. The status assessment used a grid-based method to estimate the proportion of the groundwater resources that has concentrations of water-quality constituents approaching or above benchmark concentrations. This method provides statistically unbiased results at the study-area scale and permits comparisons to other GAMA Priority Basin Project study areas.In the NSF-SA study unit as a whole, inorganic constituents with human-health benchmarks were detected at high relative concentrations (RCs) in 27 percent of the shallow aquifer system, and inorganic constituents with secondary maximum contaminant levels (SMCL) were detected at high RCs in 24 percent of the system. The inorganic constituents detected at high RCs were arsenic, boron, fluoride, manganese, nitrate, iron, sulfate, and total dissolved solids (TDS). Organic constituents with human-health benchmarks were detected at high RCs in 1 percent of the shallow aquifer system. Of the 148 organic constituents analyzed, 30 constituents were detected, although only 1, chloroform, had a detection frequency greater than 10 percent.Natural and anthropogenic factors that could affect the groundwater quality were evaluated by using results from statistical testing of associations between constituent concentrations and values of potential explanatory factors. Groundwater age class (modern, mixed, or pre-modern), redox class (oxic or anoxic), aquifer lithology class (metamorphic, sedimentary, or volcanic), and dissolved oxygen concentrations were the explanatory factors that explained distribution patterns of most of the inorganic constituents best. Groundwater classified primarily as pre-modern or mixed in age was associated with higher concentrations of arsenic and fluoride than waters classified as modern. Anoxic or mixed redox conditions were associated with higher concentrations of boron, fluoride, and manganese. Similar patterns of association with explanatory variables were seen for inorganic constituents with aesthetic-based benchmarks detected at high concentrations. Nitrate and perchlorate had higher concentrations in oxic than in the anoxic redox class and were positively correlated with urban land use.The NSF-SA water-quality results were compared to those of the GAMA North San Francisco Bay Public-Supply Aquifer study unit (NSF-PA). The NSF-PA was sampled in 2004 and covers much of the same area as the NSF-SA, but focused on the deeper public-supply aquifer system. The comparison of the NSF-PA to the NSF-SA showed that there were more differences between the Valleys and Plains study areas of the two study units than between the Highlands study areas of the two study units. As expected from the shallower depth of wells, the NSF-SA Valleys and Plains study area had a lesser proportion of pre-modern age groundwater and greater proportion of modern age groundwater than the NSF-PA Valleys and Plains study area. In contrast, well depths and groundwater ages were not significantly different between the two Highlands study areas. Arsenic, manganese, and nitrate were present at high RCs, and perchlorate was detected in greater proportions of the NSF-SA Valleys and Plains study area than the NSF-PA Valleys and Plains study area.

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.

A Latent Class Analysis of Early Adolescent Peer and Dating Violence: Associations With Symptoms of Depression and Anxiety.

PubMed

Garthe, Rachel C; Sullivan, Terri N; Behrhorst, Kathryn L

2018-02-01

Violence within peer and dating contexts is prevalent among early adolescents. Youth may be victims and/or aggressors and be involved in violence across multiple contexts, resulting in negative outcomes. This study identified patterns of perpetration and victimization for peer and dating violence, using a latent class analysis (LCA), and examined how different patterns of engaging in or experiencing violence among early adolescents were associated with symptoms of depression and anxiety. Participants included a sample of 508 racially and ethnically diverse youth (51% male) who had dated in the past 3 months. Youth were in the seventh grade within 37 schools and were primarily from economically disadvantaged communities across four sites in the United States. LCA identified three classes: (a) a low involvement in violence class, (b) a peer aggression and peer victimization class, and (c) a peer and dating violence class. Youth involved with multiple forms of violence displayed significantly higher levels of depressive and anxious symptoms than those with low involvement in violence. Study findings revealed the importance of understanding how peer and dating violence co-occur, and how different patterns of aggression and victimization were related to internalizing symptoms. Prevention efforts should address the intersection of victimization and perpetration in peer and dating contexts in potentially reducing internalizing symptoms among early adolescents.

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...

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…

Functional Characterization of Novel Sesquiterpene Synthases from Indian Sandalwood, Santalum album

PubMed Central

Srivastava, Prabhakar Lal; Daramwar, Pankaj P.; Krithika, Ramakrishnan; Pandreka, Avinash; Shankar, S. Shiva; Thulasiram, Hirekodathakallu V.

2015-01-01

Indian Sandalwood, Santalum album L. is highly valued for its fragrant heartwood oil and is dominated by a blend of sesquiterpenes. Sesquiterpenes are formed through cyclization of farnesyl diphosphate (FPP), catalyzed by metal dependent terpene cyclases. This report describes the cloning and functional characterization of five genes, which encode two sesquisabinene synthases (SaSQS1, SaSQS2), bisabolene synthase (SaBS), santalene synthase (SaSS) and farnesyl diphosphate synthase (SaFDS) using the transcriptome sequencing of S. album. Using Illumina next generation sequencing, 33.32 million high quality raw reads were generated, which were assembled into 84,094 unigenes with an average length of 494.17 bp. Based on the transcriptome sequencing, five sesquiterpene synthases SaFDS, SaSQS1, SaSQS2, SaBS and SaSS involved in the biosynthesis of FPP, sesquisabinene, β-bisabolene and santalenes, respectively, were cloned and functionally characterized. Novel sesquiterpene synthases (SaSQS1 and SaSQS2) were characterized as isoforms of sesquisabinene synthase with varying kinetic parameters and expression levels. Furthermore, the feasibility of microbial production of sesquisabinene from both the unigenes, SaSQS1 and SaSQS2 in non-optimized bacterial cell for the preparative scale production of sesquisabinene has been demonstrated. These results may pave the way for in vivo production of sandalwood sesquiterpenes in genetically tractable heterologous systems. PMID:25976282

Functional Characterization of Novel Sesquiterpene Synthases from Indian Sandalwood, Santalum album.

PubMed

Srivastava, Prabhakar Lal; Daramwar, Pankaj P; Krithika, Ramakrishnan; Pandreka, Avinash; Shankar, S Shiva; Thulasiram, Hirekodathakallu V

2015-05-15

Indian Sandalwood, Santalum album L. is highly valued for its fragrant heartwood oil and is dominated by a blend of sesquiterpenes. Sesquiterpenes are formed through cyclization of farnesyl diphosphate (FPP), catalyzed by metal dependent terpene cyclases. This report describes the cloning and functional characterization of five genes, which encode two sesquisabinene synthases (SaSQS1, SaSQS2), bisabolene synthase (SaBS), santalene synthase (SaSS) and farnesyl diphosphate synthase (SaFDS) using the transcriptome sequencing of S. album. Using Illumina next generation sequencing, 33.32 million high quality raw reads were generated, which were assembled into 84,094 unigenes with an average length of 494.17 bp. Based on the transcriptome sequencing, five sesquiterpene synthases SaFDS, SaSQS1, SaSQS2, SaBS and SaSS involved in the biosynthesis of FPP, sesquisabinene, β-bisabolene and santalenes, respectively, were cloned and functionally characterized. Novel sesquiterpene synthases (SaSQS1 and SaSQS2) were characterized as isoforms of sesquisabinene synthase with varying kinetic parameters and expression levels. Furthermore, the feasibility of microbial production of sesquisabinene from both the unigenes, SaSQS1 and SaSQS2 in non-optimized bacterial cell for the preparative scale production of sesquisabinene has been demonstrated. These results may pave the way for in vivo production of sandalwood sesquiterpenes in genetically tractable heterologous systems.

SSRI and SNRI withdrawal symptoms reported on an internet forum.

PubMed

Stockmann, Tom; Odegbaro, Dolapo; Timimi, Sami; Moncrieff, Joanna

2018-05-09

Antidepressant withdrawal symptoms are well-recognised, but their potential duration remains uncertain. We aimed to describe the characteristics of withdrawal associated with two popular classes of antidepressants, including duration. We analysed the content of a sample of posts on an antidepressant withdrawal website. We compared the characteristics of withdrawal associated with SSRIs and SNRIs, including time of onset, duration and nature of symptoms. 110 posts about SSRI withdrawal, and 63 concerning SNRI withdrawal, were analysed. The mean duration of withdrawal symptoms was significantly longer with SSRIs than SNRIs: 90.5 weeks (standard deviation, SD, 150.0) and 50.8 weeks (SD 76.0) respectively; p = 0.043). Neurological symptoms, such as 'brain zaps,' were more common among SNRI users (p = 0.023). Psychosexual/genitourinary symptoms may be more common among SSRI users (p = 0.054). The website aims to help people with antidepressant withdrawal, and is therefore likely to attract people who have difficulties. Length of prior use of antidepressants was long, with a mean of 252.2 weeks (SD 250.8). People accessing antidepressant withdrawal websites report experiencing protracted withdrawal symptoms. There are some differences in the characteristics of withdrawal associated with different classes of antidepressants.

Gender difference in cycling speed and age of winning performers in ultra-cycling - the 508-mile "Furnace Creek" from 1983 to 2012.

PubMed

Rüst, Christoph Alexander; Rosemann, Thomas; Lepers, Romuald; Knechtle, Beat

2015-01-01

We analysed (i) the gender difference in cycling speed and (ii) the age of winning performers in the 508-mile "Furnace Creek 508". Changes in cycling speeds and gender differences from 1983 to 2012 were analysed using linear, non-linear and hierarchical multi-level regression analyses for the annual three fastest women and men. Cycling speed increased non-linearly in men from 14.6 (s = 0.3) km · h(-1) (1983) to 27.1 (s = 0.7) km · h(-1) (2012) and non-linearly in women from 11.0 (s = 0.3) km · h(-1) (1984) to 24.2 (s = 0.2) km · h(-1) (2012). The gender difference in cycling speed decreased linearly from 26.2 (s = 0.5)% (1984) to 10.7 (s = 1.9)% (2012). The age of winning performers increased from 26 (s = 2) years (1984) to 43 (s = 11) years (2012) in women and from 33 (s = 6) years (1983) to 50 (s = 5) years (2012) in men. To summarise, these results suggest that (i) women will be able to narrow the gender gap in cycling speed in the near future in an ultra-endurance cycling race such as the "Furnace Creek 508" due to the linear decrease in gender difference and (ii) the maturity of these athletes has changed during the last three decades where winning performers become older and faster across years.

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...

The interaction of salicylic acid and Ca(2+) alleviates aluminum toxicity in soybean (Glycine max L.).

PubMed

Lan, Tu; You, Jiangfeng; Kong, Lingnan; Yu, Miao; Liu, Minghui; Yang, Zhenming

2016-01-01

Both calcium ion (Ca(2+)) and salicylic acid (SA) influence various stress responses in plants. In acidic soils, aluminum (Al) toxicity adversely affects crop yield. In this study, we determined the influences of Ca(2+) and SA on root elongation, Al accumulation, and citrate secretion in soybean plant. We also investigated the activity of antioxidative enzymes in Al-exposed soybean roots. Root elongation was severally inhibited when the roots were exposed to 30 μM Al. The Al-induced inhibition of root elongation was ameliorated by Ca(2+) and SA but aggravated by Ca(2+) channel inhibitor (VP), CaM antagonists (TFP), Ca(2+) chelator (EGTA), and SA biosynthesis inhibitor (PAC). Furthermore, 1.0 mM CaCl2 and 10 μM SA reduced the accumulation of Al in roots, but their inhibitors stimulated the accumulation of Al in roots. Citrate secretion from these roots increased with the addition of either 1.0 mM CaCl2 or 10 μM SA but did not increase significantly when treated with higher Ca(2+) concentration. Enzymatic analysis showed that Ca(2+) and SA stimulated the activities of superoxidase (SOD), peroxidase (POD), and ascorbate peroxidase (APX) in Al-treated roots. In addition, SA restored the inhibition of Ca(2+) inhibitors on root elongation and Al content. Thus, both Ca(2+) and SA contribute to Al tolerance in soybean. Furthermore, Ca(2+) supplements rapidly increased Al-induced accumulation of free-SA or conjugated SA (SAG), while Ca(2+) inhibitors delayed the accumulation of SA for more than 8 h. Within 4 h of treatment, SA increased cytosolic Ca(2+) concentration in Al-treated roots, and upregulated the expression of four genes that possibly encode calmodulin-like (CML) proteins. These findings indicate that SA is involved in Ca(2+)-mediated signal transduction pathways in Al tolerance. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Comparisons of sleep apnoea rate and outcomes among patients with resistant and non-resistant hypertension.

PubMed

Bhandari, Simran K; Shi, Jiaxiao; Molnar, Miklos Z; Rasgon, Scott A; Derose, Stephen F; Kovesdy, Csaba P; Calhoun, David A; Kalantar-Zadeh, Kamyar; Jacobsen, Steven J; Sim, John J

2016-11-01

We directly compared sleep apnoea (SA) rates and risk of cardiovascular and mortality outcomes among SA patients with resistant hypertension (RH) and non-RH within a large diverse hypertension population. A retrospective cohort study between 1 January 2006 and 31 December 2010 among hypertensive adults (age ≥ 18 years) was performed within an integrated health system. Rates of SA in RH and non-RH were determined. Multivariable logistic regression analyses were used to calculate OR for SA. Cox proportional hazard modelling was used to estimate hazard ratios (HRs) for cardiovascular and mortality outcomes between SA in RH versus SA in non-RH adjusting for age, gender, race, BMI, chronic kidney disease and other comorbidities. SA was identified in 33 682 (7.2%) from 470 386 hypertensive individuals. SA in RH accounted for 5806 (9.6%) compared to SA in non-RH 27 876 individuals (6.8%). Multivariable OR (95% CI) for SA was 1.16 (1.12, 1.19), 3.57 (3.47, 3.66) and 2.20 (2.15, 2.25) for RH versus non-RH, BMI ≥ 30, and males, respectively. Compared to SA in non-RH individuals, SA in RH had a multivariable adjusted HR (95% CI) of 1.24 (1.13, 1.36), 1.43 (1.28, 1.61), 0.98 (0.85, 1.12) and 1.04 (0.95, 1.14) for ischaemic heart event (IHE), congestive heart failure (CHF), stroke and mortality, respectively. We observed a modest increase in likelihood for SA among RH compared to non-RH patients. Risks for IHE and CHF were higher for SA in RH compared to SA in non-RH patients; however, there were no differences in risk for stroke and mortality. © 2016 Asian Pacific Society of Respirology.

Cerebral Oxygen Saturation in Children With Congenital Heart Disease and Chronic Hypoxemia.

PubMed

Kussman, Barry D; Laussen, Peter C; Benni, Paul B; McGowan, Francis X; McElhinney, Doff B

2017-07-01

Increased hemoglobin (Hb) concentration accompanying hypoxemia is a compensatory response to maintain tissue oxygen delivery. Near infrared spectroscopy (NIRS) is used clinically to detect abnormalities in the balance of cerebral tissue oxygen delivery and consumption, including in children with congenital heart disease (CHD). Although NIRS-measured cerebral tissue O2 saturation (ScO2) correlates with arterial oxygen saturation (SaO2), jugular bulb O2 saturation (SjbO2), and Hb, little data exist on the interplay between these factors and cerebral O2 extraction (COE). This study investigated the associations of ScO2 and ΔSaO2-ScO2 with SaO2 and Hb and verified the normal range of ScO2 in children with CHD. Children undergoing cardiac catheterization for CHD were enrolled in a calibration and validation study of the FORE-SIGHT NIRS monitor. Two pairs of simultaneous arterial and jugular bulb samples were drawn for co-oximetry, calculation of a reference ScO2 (REF CX), and estimation of COE. Pearson correlation and linear regression were used to determine relationships between O2 saturation parameters and Hb. Data were also analyzed according to diagnostic group defined as acyanotic (SaO2 ≥ 90%) and cyanotic (SaO2 < 90%). Of 65 children studied, acceptable jugular bulb samples (SjbO2 absolute difference between samples ≤10%) were obtained in 57 (88%). The ΔSaO2-SjbO2, ΔSaO2-ScO2, and ΔSaO2-REF CX were positively correlated with SaO2 and negatively correlated with Hb (all P < .001). Although by diagnostic group ScO2 differed statistically (P = .002), values in the cyanotic patients were within the range considered normal (69% ± 6%). COE estimated by the difference between arterial and jugular bulb O2 content (ΔCaO2-CjbO2, mL O2/100 mL) was not different for cyanotic and acyanotic patients (P = .10), but estimates using ΔSaO2-SjbO2, ΔSaO2-ScO2, or ΔSaO2-ScO2/SaO2 were significantly different between the cyanotic and acyanotic children (P < .001). Children with adequately compensated chronic hypoxemia appear to have ScO2 values within the normal range. The ΔSaO2-ScO2 is inversely related to Hb, with the implication that in the presence of reduced Hb, particularly if coupled with a decreased cardiac output, the ScO2 can fall to values associated with brain injury in laboratory studies.

Childbirth, hospitalisation and sickness absence: a study of female twins

PubMed Central

Björkenstam, Emma; Alexanderson, Kristina; Narusyte, Jurgita; Kjeldgård, Linnea; Ropponen, Annina; Svedberg, Pia

2015-01-01

Objective To investigate associations of giving birth with morbidity in terms of hospitalisation and social consequences of morbidity in terms of sickness absence (SA), while taking familial (genetics and shared environmental) factors into account. Design Prospective register-based cohort study. Estimates of risk of hospitalisation and SA were calculated as HRs with 95% CIs. Setting All female twins, that is, women with a twin sister, born in Sweden. Participants 5118 Swedish female twins (women with a twin sister), born during 1959–1990, where at least one in the twin pair had their first childbirth (T0) during 1994–2009 and none gave birth before 1994. Main outcome measures Hospitalisation and SA during year 3–5 after first delivery or equivalent. Results Preceding the first childbirth, the mean annual number of SA days increased for mothers, and then decreased again. Hospitalisation after T0 was associated with higher HRs of short-term and long-term SA (HR for short-term SA 3.0; 95% CI 2.5 to 3.6 and for long-term SA 2.3; 95% CI 1.6 to 3.2). Hospitalisation both before and after first childbirth was associated with a higher risk of future SA (HR for long-term SA 4.2; 95% CI 2.7 to 6.4). Familial factors influenced the association between hospitalisation and long-term SA, regardless of childbirth status. Conclusions Women giving birth did not have a higher risk for SA than those not giving birth and results indicate a positive health selection into giving birth. Mothers hospitalised before and/or after giving birth had higher risks for future SA, that is, there was a strong association between morbidity and future SA. PMID:25573523

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

Patterns of adolescent bullying behaviors: physical, verbal, exclusion, rumor, and cyber.

PubMed

Wang, Jing; Iannotti, Ronald J; Luk, Jeremy W

2012-08-01

Patterns of engagement in cyber bullying and four types of traditional bullying were examined using latent class analysis (LCA). Demographic differences and externalizing problems were evaluated across latent class membership. Data were obtained from the 2005-2006 Health Behavior in School-aged Survey and the analytic sample included 7,508 U.S. adolescents in grades 6 through 10. LCA models were tested on physical bullying, verbal bullying, social exclusion, spreading rumors, and cyber bullying behaviors. Three latent classes were identified for each gender: All-Types Bullies (10.5% for boys and 4.0% for girls), Verbal/Social Bullies (29.3% for boys and 29.4% for girls), and a Non-Involved class (60.2% for boys and 66.6% for girls). Boys were more likely to be All-Types Bullies than girls. The prevalence rates of All-Types and Verbal/Social Bullies peaked during grades 6 to 8 and grades 7 and 8, respectively. Pairwise comparisons across the three latent classes on externalizing problems were conducted. Overall, the All-Types Bullies were at highest risk of using substances and carrying weapons, the Non-Involved were at lowest risk, and the Verbal/Social Bullies were in the middle. Results also suggest that most cyber bullies belong to a group of highly aggressive adolescents who conduct all types of bullying. This finding does not only improve our understanding of the relation between cyber bullying and traditional bullying, but it also suggests that prevention and intervention efforts could target cyber bullies as a high-risk group for elevated externalizing problems. Copyright © 2012 Society for the Study of School Psychology. All rights reserved.

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...

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

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...

The importance of preoperative oxygen saturation as a predictor of pulmonary arterial hypertension after surgery of atrial septal defects.

PubMed

Park, Han Ki; Shin, Hong Ju; Park, Young Hwan; Ma, Bo Gyoung

2016-09-01

There is no concrete predictor of the change of pulmonary arterial pressure after surgical closure of an atrial septal defect (ASD) in patients with pulmonary arterial hypertension (PAH). The aim of this study was to investigate the role of preoperative room air arterial oxygen saturation (SaO2) (arterial blood gas data) as a predictor of postoperative PAH. The medical records of 36 patients [>20 years, mean pulmonary arterial pressure (mPAP) ≥25 mmHg] who underwent surgical closure of an ASD between March 2004 and January 2014 were retrospectively reviewed. The median age was 47 years (range, 24.6-65.9 years) and mPAP was 38 ± 14 mmHg. The mean pulmonary vascular resistance (Rp) was 3.9 ± 4.2 Wood units, and fenestration was performed in 12 (33%) patients. Only 1 patient received anti-PAH medication preoperatively. The median follow-up period was 4 years (range, 0-10 years). There were two hospital deaths, one of which was related to PAH. At the last follow-up, PAH (estimated tricuspid regurgitation velocity >3 m/s) existed in 7 patients (19%), and 10 patients (28%) were receiving anti-PAH medications (considered as clinical PAH). Univariate analysis for persistent clinical PAH revealed that mPAP, Qp/Qs, Rp, room air arterial oxygen saturation and postoperative functional class were significant risk factors. Only SaO2 remained a significant risk factor in multivariate analysis (P = 0.03). Preoperative room air SaO2 is a useful predictor of persistent PAH in adult patients undergoing surgical closure of an ASD. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Sanguinarine induces apoptosis of human osteosarcoma cells through the extrinsic and intrinsic pathways

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

Park, Hyunjin; Bergeron, Eric; Senta, Helena

2010-08-27

Research highlights: {yields} We show for the first time the effect of sanguinarine (SA) on MG63 and SaOS-2 cells. {yields} SA altered osteosarcoma cell viability in a concentration and time dependent manner. {yields} SA induced osteosarcoma cell apoptosis and increased caspase-8 and -9 activities. {yields} SA decreased dose dependently the Bcl-2 protein level only in MG63 cells. {yields} SaOS-2 which are osteoblast-derived, seemed more resistant to SA than MG63. -- Abstract: The quaternary benzo[c]phenanthridine alkaloid sanguinarine inhibits the proliferation of cancerous cells from different origins, including lung, breast, pancreatic and colon, but nothing is known of its effects on osteosarcoma,more » a primary malignant bone tumour. We have found that sanguinarine alters the morphology and reduces the viability of MG-63 and SaOS-2 human osteosarcoma cell lines in concentration- and time-dependent manner. Incubation with 1 {mu}mol/L sanguinarine for 4 and 24 h killed more efficiently MG-63 cells than SaOS-2 cells, while incubation with 5 {mu}mol/L sanguinarine killed almost 100% of both cell populations within 24 h. This treatment also changed the mitochondrial membrane potential in both MG-63 and SaOS-2 cells within 1 h, caused chromatin condensation and the formation of apoptotic bodies. It activated multicaspases, and increased the activities of caspase-8 and caspase-9 in both MG-63 and SaOS-2 cells. These data highlight sanguinarine as a novel potential agent for bone cancer therapy.« less

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.

Indirect assessment of stifle angle for improved accuracy of preoperative planning of tibial osteotomy procedures in dogs.

PubMed

Barnes, D C; Owen, M R

2015-07-25

To assess reliability of the mechanical axes stifle angle in dogs positioned for radiography with a neutral stifle (neutral stifle angle (nSA)). To investigate radiographic landmarks for assessment of nSA from a collimated radiographic view. One hundred radiographs were taken of normal stifles belonging to 55 skeletally mature medium and large breed dogs, positioned using a repeatable protocol. Radiographs were widely collimated to include the femoral head and the talus. The angle of Blumensaat's line through the intercondylar fossa relative to the Mechanical Axis of the femur (intercondylar fossa angle, IFA), the angle of inclination of a tibial crest tangent line relative to the Mechanical Axis of the tibia (tibial crest angle, TCA) and the tibial plateau angle (TPA) were recorded. Mean nSA was 133.5°. Mean IFA was 155.5°. TCA had a mean of 6.7°. Estimates for nSA were calculated using mean IFA combined with mean TCA (enSA1), mean TPA (enSA2) and the mechanical axis of the tibia (enSA3). Mean percentage error relative was 2.99 per cent for enSA1, 2.82 per cent for enSA2, 1.67 per cent for enSA3. Blumensaat's line provides a consistent radiological feature for assessment of nSA. Assessment of nSA and correction for values varying from 135° may allow more consistent and accurate measurement of patellar tendon angle for presurgical planning. British Veterinary Association.

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.

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

PubMed Central

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

2011-01-01

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

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

PubMed

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

2011-06-17

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

Effect of Macrosegregation on the Microstructure and Mechanical Properties of a Pressure-Vessel Steel

NASA Astrophysics Data System (ADS)

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

2017-07-01

Macrosegregation refers to the chemical segregation, which occurs quite commonly in the large forgings such as nuclear reactor pressure vessel. This work assesses the effect of macrosegregation and homogenization treatment on the mechanical properties of a pressure-vessel steel (SA508 Gr.3). It was found that the primary reason for the inhomogeneity of the microstructure was the segregation of Mn, Mo, and Ni. Martensite, and coarse upper bainite with M-A (martensite-austenite) islands have been obtained, respectively, in the positive and negative segregation zone during a simulated quenching process. During tempering, the carbon-rich M-A islands decomposed into a mixture of ferrite and numerous carbides which deteriorated the toughness of the material. The segregation has been substantially minimized by a homogenizing treatment. The results indicate that the material homogenized has a higher impact toughness than the material with segregation, due to the reduction in M-A island in the negative segregation zone. It can be concluded that the microstructure and mechanical properties have been improved remarkably by means of homogenization treatment.

Metabolic interactions between cysteamine and epigallocatechin gallate.

PubMed

Izzo, Valentina; Pietrocola, Federico; Sica, Valentina; Durand, Sylvère; Lachkar, Sylvie; Enot, David; Bravo-San Pedro, José Manuel; Chery, Alexis; Esposito, Speranza; Raia, Valeria; Maiuri, Luigi; Maiuri, Maria Chiara; Kroemer, Guido

2017-02-01

Phase II clinical trials indicate that the combination of cysteamine plus epigallocatechin gallate (EGCG) is effective against cystic fibrosis in patients bearing the most frequent etiological mutation (CFTRΔF508). Here, we investigated the interaction between both agents on cultured respiratory epithelia cells from normal and CFTRΔF508-mutated donors. We observed that the combination of both agents affected metabolic circuits (and in particular the tricarboxylic acid cycle) in a unique way and that cysteamine plus EGCG reduced cytoplasmic protein acetylation more than each of the 2 components alone. In a cell-free system, protein cross-linking activity of EGCG was suppressed by cysteamine. Finally, EGCG was able to enhance the conversion of cysteamine into taurine in metabolic flux experiments. Altogether, these results indicate that multiple pharmacological interactions occur between cysteamine and EGCG, suggesting that they contribute to the unique synergy of both agents in restoring the function of mutated CFTRΔF508.

Metabolic interactions between cysteamine and epigallocatechin gallate

PubMed Central

Izzo, Valentina; Pietrocola, Federico; Sica, Valentina; Durand, Sylvère; Lachkar, Sylvie; Enot, David; Bravo-San Pedro, José Manuel; Chery, Alexis; Esposito, Speranza; Raia, Valeria; Maiuri, Luigi; Maiuri, Maria Chiara; Kroemer, Guido

2017-01-01

ABSTRACT Phase II clinical trials indicate that the combination of cysteamine plus epigallocatechin gallate (EGCG) is effective against cystic fibrosis in patients bearing the most frequent etiological mutation (CFTRΔF508). Here, we investigated the interaction between both agents on cultured respiratory epithelia cells from normal and CFTRΔF508-mutated donors. We observed that the combination of both agents affected metabolic circuits (and in particular the tricarboxylic acid cycle) in a unique way and that cysteamine plus EGCG reduced cytoplasmic protein acetylation more than each of the 2 components alone. In a cell-free system, protein cross-linking activity of EGCG was suppressed by cysteamine. Finally, EGCG was able to enhance the conversion of cysteamine into taurine in metabolic flux experiments. Altogether, these results indicate that multiple pharmacological interactions occur between cysteamine and EGCG, suggesting that they contribute to the unique synergy of both agents in restoring the function of mutated CFTRΔF508. PMID:28059601

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.

Galactosylated pullulan-curcumin conjugate micelles for site specific anticancer activity to hepatocarcinoma cells.

PubMed

Sarika, P R; James, Nirmala Rachel; Nishna, N; Anil Kumar, P R; Raj, Deepa K

2015-09-01

Galactosylated pullulan-curcumin conjugate (LANH2-Pu Ald-Cur SA) is developed for target specific delivery of curcumin to hepatocarcinoma cells by five step synthetic strategy, which includes oxidation of pullulan (Pu Ald), introduction of amino group to the targeting ligand (LANH2), grafting of the LANH2 to Pu Ald, modification of curcumin (Cur SA) and conjugation of Cur SA to pullulan. Nongalactosylated pullulan-curcumin conjugate (Pu-Cur SA) is also prepared to compare the enhancement in cytotoxicity offered by the targeting group. Both LANH2-Pu Ald-Cur SA and Pu-Cur SA conjugates could self assemble to micelle in water with hydrodynamic diameters of 355±9nm and 363±10nm, respectively. Both conjugates show spherical morphology and enhance stability of curcumin in physiological pH. Compared to Pu-Cur SA, LANH2-Pu Ald-Cur SA exhibits higher toxicity and internalization towards HepG2 cells. This indicates the enhanced uptake of LANH2-Pu Ald-Cur SA conjugate via ASGPR (asialoglycoprotein receptor) mediated endocytosis into HepG2 cells. Copyright © 2015 Elsevier B.V. All rights reserved.

Comparison of two estimation methods for surface area concentration using number concentration and mass concentration of combustion-related ultrafine particles

NASA Astrophysics Data System (ADS)

Park, Ji Young; Raynor, Peter C.; Maynard, Andrew D.; Eberly, Lynn E.; Ramachandran, Gurumurthy

Recent research has suggested that the adverse health effects caused by nanoparticles are associated with their surface area (SA) concentrations. In this study, SA was estimated in two ways using number and mass concentrations and compared with SA (SA meas) measured using a diffusion charger (DC). Aerosol measurements were made twice: once starting in October 2002 and again starting in December 2002 in Mysore, India in residences that used kerosene or liquefied petroleum gas (LPG) for cooking. Mass, number, and SA concentrations and size distributions by number were measured in each residence. The first estimation method (SA PSD) used the size distribution by number to estimate SA. The second method (SA INV) used a simple inversion scheme that incorporated number and mass concentrations while assuming a lognormal size distribution with a known geometrical standard deviation. SA PSD was, on average, 2.4 times greater (range = 1.6-3.4) than SA meas while SA INV was, on average, 6.0 times greater (range = 4.6-7.7) than SA meas. The logarithms of SA PSD and SA INV were found to be statistically significant predictors of the logarithm of SA meas. The study showed that particle number and mass concentration measurements can be used to estimate SA with a correction factor that ranges between 2 and 6.

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...

Anti-inflammatory effects of sodium alginate/gelatine porous scaffolds merged with fucoidan in murine microglial BV2 cells.

PubMed

Nguyen, Van-Tinh; Ko, Seok-Chun; Oh, Gun-Woo; Heo, Seong-Yeong; Jeon, You-Jin; Park, Won Sun; Choi, Il-Whan; Choi, Sung-Wook; Jung, Won-Kyo

2016-12-01

Microglia are the immune cells of the central nervous system (CNS). Overexpression of inflammatory mediators by microglia can induce several neurological diseases. Thus, the underlying basic requirement for neural tissue engineering is to develop materials that exhibit little or no neuro-inflammatory effects. In this study, we have developed a method to create porous scaffolds by adding fucoidan (Fu) into porous sodium alginate (Sa)/gelatine (G) (SaGFu). For mechanical characterization, in vitro degradation, stress/strain, swelling, and pore size were measured. Furthermore, the biocompatibility was evaluated by assessing the adhesion and proliferation of BV2 microglial cells on the SaGFu porous scaffolds using scanning electron microscopy (SEM) and lactate dehydrogenase (LDH) assay, respectively. Moreover, we studied the neuro-inflammatory effects of SaGFu on BV2 microglial cells. The effect of gelatine and fucoidan content on the various properties of the scaffold was investigated and the results showed that mechanical properties increased porosity and swelling ratio with an increase in the gelatine and fucoidan, while the in vitro biodegradability decreased. The average SaGFu diameter attained by fabrication of SaGFu ranged from 60 to 120μm with high porosity (74.44%-88.30%). Cell culture using gelatine 2.0% (SaG2Fu) and 4.0% (SaG4Fu), showed good cell proliferation; more than 60-80% that with Sa alone. Following stimulation with 0.5μg/mL LPS, microglia cultured in porous SaGFu decreased their expression of nitric oxide (NO), prostaglandin E2 (PGE2), and reactive oxygen species (ROS). SaG2Fu and SaG4Fu also inhibited the activation and translocation of p65 NF-κB protein levels, resulting in reduction of NO, ROS, and PGE2 production. These results provide insights into the diverse biological effects and opens new avenues for the applications of SaGFu in neuroscience. Copyright © 2016 Elsevier B.V. All rights reserved.

A study of photochemical againg of ambient air using Potential Aerosol Mass (PAM) chamber under the different sources and types of emissions

NASA Astrophysics Data System (ADS)

Lee, T.; Son, J.; Kim, J.; Kim, S.; Sung, K.; Park, G.; Link, M.; Park, T.; Kim, K.; Kang, S.; Ban, J.; Kim, D. S.

2016-12-01

Recent research proposed that Secondary Aerosol (SA) is important class of predicting future climate change scenarios, health effect, and a general air quality. However, there has been lack of studies to investigate SA formation all over the world. This study tried to focus on understanding potential secondary aerosol formation and its local impact by the photochemical aging of inorganic and organic aerosols in the ambient air using the Potential Aerosol Mass (PAM) chamber under the different sources and types of emissions. PAM chamber manufactured by Aerodyne make an oxidizing environment that simulates oxidation processes on timescales of 12-15 hrs in the atmosphere. Chemical compositions of ambient aerosol and aerosol that was aged in the PAM chamber were alternately measured every 2-minutes using the High Resolution-Time of Flight-Aerosol Mass Spectrometer (HR-ToF-AMS). HR-ToF-AMS provides non-refractory aerosol mass concentrations including nitrate, sulfate, hydrocarbon-like and oxygenated organic aerosol in real time. This study includes a residence area of mixture of sources, a forest site of dominant source of biogenic VOCs, an underground parking lot of dominant vehicle emission, and laboratory experiment of vehicle emissions under different fuels and speeds using the chassis dynamometer. As a result, it was revealed that gasoline and LPG vehicle relatively made more potential SA than diesel vehicle.

Salicylic acid potentiates an agonist-dependent gain control that amplifies pathogen signals in the activation of defense mechanisms.

PubMed

Shirasu, K; Nakajima, H; Rajasekhar, V K; Dixon, R A; Lamb, C

1997-02-01

The phenylpropanoid-derived natural product salicylic acid (SA) plays a key role in disease resistance. However, SA administered in the absence of a pathogen is a paradoxically weak inductive signal, often requiring concentrations of 0.5 to 5 mM to induce acquired resistance or related defense mechanisms or to precondition signal systems. In contrast, endogenous SA accumulates to concentrations of < 70 microM at the site of attempted infection. Here, we show that although 10 to 100 microM SA had negligible effects when administered to soybean cell suspensions in the absence of a pathogen, physiological concentrations of SA markedly enhanced the induction of defense gene transcripts, H2O2 accumulation, and hypersensitive cell death by an avirulent strain of Pseudomonas syringae pv glycinea, with optimal effects being at approximately 50 microM. SA also synergistically enhanced H2O2 accumulation in response to the protein phosphatase type 2A inhibitor cantharidin in the absence of a pathogen. The synergistic effect of SA was potent, rapid, and insensitive to the protein synthesis inhibitor cycloheximide, and we conclude that SA stimulates an agonist-dependent gain control operating at an early step in the signal pathway for induction of the hypersensitive response. This fine control mechanism differs from previously described time-dependent, inductive coarse control mechanisms for SA action in the absence of a pathogen. Induction of H2O2 accumulation and hypersensitive cell death by avirulent P. s. glycinea was blocked by the phenylpropanoid synthesis inhibitor alpha-aminooxy-beta-phenylpropionic acid, and these responses could be rescued by exogenous SA. Because the agonist-dependent gain control operates at physiological levels of SA, we propose that rapid fine control signal amplification makes an important contribution to SA function in the induction of disease resistance mechanisms.

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...

Assessing the Role of ETHYLENE RESPONSE FACTOR Transcriptional Repressors in Salicylic Acid-Mediated Suppression of Jasmonic Acid-Responsive Genes.

PubMed

Caarls, Lotte; Van der Does, Dieuwertje; Hickman, Richard; Jansen, Wouter; Verk, Marcel C Van; Proietti, Silvia; Lorenzo, Oscar; Solano, Roberto; Pieterse, Corné M J; Van Wees, Saskia C M

2017-02-01

Salicylic acid (SA) and jasmonic acid (JA) cross-communicate in the plant immune signaling network to finely regulate induced defenses. In Arabidopsis, SA antagonizes many JA-responsive genes, partly by targeting the ETHYLENE RESPONSE FACTOR (ERF)-type transcriptional activator ORA59. Members of the ERF transcription factor family typically bind to GCC-box motifs in the promoters of JA- and ethylene-responsive genes, thereby positively or negatively regulating their expression. The GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Here, we investigated whether SA-induced ERF-type transcriptional repressors, which may compete with JA-induced ERF-type activators for binding at the GCC-box, play a role in SA/JA antagonism. We selected ERFs that are transcriptionally induced by SA and/or possess an EAR transcriptional repressor motif. Several of the 16 ERFs tested suppressed JA-dependent gene expression, as revealed by enhanced JA-induced PDF1.2 or VSP2 expression levels in the corresponding erf mutants, while others were involved in activation of these genes. However, SA could antagonize JA-induced PDF1.2 or VSP2 in all erf mutants, suggesting that the tested ERF transcriptional repressors are not required for SA/JA cross-talk. Moreover, a mutant in the co-repressor TOPLESS, that showed reduction in repression of JA signaling, still displayed SA-mediated antagonism of PDF1.2 and VSP2. Collectively, these results suggest that SA-regulated ERF transcriptional repressors are not essential for antagonism of JA-responsive gene expression by SA. We further show that de novo SA-induced protein synthesis is required for suppression of JA-induced PDF1.2, pointing to SA-stimulated production of an as yet unknown protein that suppresses JA-induced transcription. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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...

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...

Quantifying Acoustic Uncertainty Due to Marine Mammals and Fish Near the Shelfbreak Front off Cape Hatteras

DTIC Science & Technology

2014-09-30

and Fish Near the Shelfbreak Front off Cape Hatteras James F. Lynch MS #11, Woods Hole Oceanographic Institution Woods Hole, MA 02543 Phone...508) 289-2230 Fax: (508) 457-2194 e-mail: jlynch@whoi.edu Glen Gawarkiewicz MS#21, Woods Hole Oceanographic Institution Woods Hole, MA 02543...Phone: (508) 289-2913 Fax: (508) 457-2181 e-mail: gleng@whoi.edu Ying-Tsong Lin MS #11, Woods Hole Oceanographic Institution Woods Hole, MA 02543

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

PubMed

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

2017-10-01

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

A Laboratory Exercise on Photoperiodic Changes in the Testes of the Mongolian Gerbil.

ERIC Educational Resources Information Center

Treagust, David F.; And Others

1980-01-01

A laboratory exercise using a gerbil is described for use in the high school biology class and in accordance with the National Science Teachers Association guidelines. The authors cite references that deal with current awareness of the moral status concerning animals. The exercise includes measurement and calculations. (SA)

Science Achievement and Students' Self-Confidence and Interest in Science: A Taiwanese Representative Sample Study

ERIC Educational Resources Information Center

Chang, Chun-Yen; Cheng, Wei-Ying

2008-01-01

The interrelationship between senior high school students' science achievement (SA) and their self-confidence and interest in science (SCIS) was explored with a representative sample of approximately 1,044 11th-grade students from 30 classes attending four high schools throughout Taiwan. Statistical analyses indicated that a statistically…

Permanent draft genome sequence of the gliding predator Saprospira grandis strain Sa g1 (= HR1)

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

Mavromatis, K; Chertkov, Olga; Lapidus, Alla L.

2012-01-01

Saprospira grandis Gross et al. 1911 is a member of the Saprospiraceae, a family in the class 'Sphingobacteria' that remains poorly characterized at the genomic level. The species is known for preying on other marine bacteria via 'ixotrophy'. S. grandis strain Sa g1 was isolated from decaying crab carapace in France and was selected for genome sequencing because of its isolated location in the tree of life. Only one type strain genome has been published so far from the Saprospiraceae, while the sequence of strain Sa g1 represents the second genome to be published from a non-type strain of S.more » grandis. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 4,495,250 bp long Improved-High-Quality draft of the genome with its 3,536 protein-coding and 62 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project.« less

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.

[Heart transplantation for the treatment of isolated left ventricular myocardial noncompaction. First case in Mexico].

PubMed

Zetina-Tun, Hugo Jesús; Careaga-Reyna, Guillermo; Galván-Díaz, José; Sánchez-Uribe, Magdalena

Myocardial noncompaction of the left ventricle is a congenital cardiomyopathy characterised by left ventricular hypertrabeculation and prominent intertrabecular recesses. The incidence ranges from 0.15% to 2.2%. Clinical manifestations include heart failure, arrhythmias, and stroke. Prognosis is fatal in most cases. Heart transplantation is a therapeutic option for this cardiomyopathy, and few had been made worldwide. The case is presented of a 20 year-old male with noncompacted myocardium of the left ventricle, who had clinical signs of heart failure. His functional class was IV on the New York Heart Association scale. He was successfully transplanted. Its survival to 15 months is optimal in class I New York Heart Association, and endomyocardial biopsies have been reported without evidence of acute rejection. It is concluded that heart transplantation modified the natural history and improved survival in patients with this congenital heart disease. Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.

The Impact of Self-Assessment on Language Learners' Writing Skill

ERIC Educational Resources Information Center

Mazloomi, Siamak; Khabiri, Mona

2018-01-01

The present study investigates the impact of self-assessment (SA) training applied as a writing task and a dynamic assessment on English language learners' writing ability and explores the changes in their language proficiency level. This quasi-experimental research on two homogenised essay writing classes of 60 Iranian university students at…

Identification and characterization of a cyclosporin binding cyclophilin from Staphylococcus aureus Newman

PubMed Central

Polley, Soumitra; Seal, Soham; Mahapa, Avisek; Jana, Biswanath; Biswas, Anindya; Mandal, Sukhendu; Sinha, Debabrata; Sau, Keya; Sau, Subrata

2017-01-01

Cyclophilins, a class of peptidyl-prolyl cis-trans isomerase (PPIase) enzymes, are inhibited by cyclosporin A (CsA), an immunosuppressive drug. Staphylococcus aureus Newman, a pathogenic bacterium, carries a gene for encoding a putative cyclophilin (SaCyp). SaCyp shows significant homology with other cyclophilins at the sequence level. A three-dimensional model structure of SaCyp harbors a binding site for CsA. To verify whether SaCyp possesses both the PPIase activity and the CsA binding ability, we have purified and investigated a recombinant SaCyp (rCyp) using various in vitro tools. Our RNase T1 refolding assay indicates that rCyp has a substantial extent of PPIase activity. rCyp that exists as a monomer in the aqueous solution is truly a cyclophilin as its catalytic activity specifically shows sensitivity to CsA. rCyp appears to bind CsA with a reasonably high affinity. Additional investigations reveal that binding of CsA to rCyp alters its structure and shape to some extent. Both rCyp and rCyp-CsA are unfolded via the formation of at least one intermediate in the presence of guanidine hydrochloride. Unfolding study also indicates that there is substantial extent of thermodynamic stabilization of rCyp in the presence of CsA as well. The data suggest that rCyp may be exploited to screen the new antimicrobial agents in the future. PMID:28584448

Scavengers of reactive γ-ketoaldehydes extend Caenorhabditis elegans lifespan and healthspan through protein-level interactions with SIR-2.1 and ETS-7

PubMed Central

Nguyen, Thuy T.; Caito, Samuel W.; Zackert, William E.; West, James D.; Zhu, Shijun

2016-01-01

Isoketals (IsoKs) are highly reactive γ-ketoaldehyde products of lipid peroxidation that covalently adduct lysine side chains in proteins, impairing their function. Using C. elegans as a model organism, we sought to test the hypothesis that IsoKs contribute to molecular aging through adduction and inactivation of specific protein targets, and that this process can be abrogated using salicylamine (SA), a selective IsoK scavenger. Treatment with SA extends adult nematode longevity by nearly 56% and prevents multiple deleterious age-related biochemical and functional changes. Testing of a variety of molecular targets for SA's action revealed the sirtuin SIR-2.1 as the leading candidate. When SA was administered to a SIR-2.1 knockout strain, the effects on lifespan and healthspan extension were abolished. The SIR-2.1-dependent effects of SA were not mediated by large changes in gene expression programs or by significant changes in mitochondrial function. However, expression array analysis did show SA-dependent regulation of the transcription factor ets-7 and associated genes. In ets-7 knockout worms, SA's longevity effects were abolished, similar to sir-2.1 knockouts. However, SA dose-dependently increases ets-7 mRNA levels in non-functional SIR-2.1 mutant, suggesting that both are necessary for SA's complete lifespan and healthspan extension. PMID:27514077

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...

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...

Neuropeptide Receptors NPR-1 and NPR-2 Regulate Caenorhabditis elegans Avoidance Response to the Plant Stress Hormone Methyl Salicylate

PubMed Central

Luo, Jintao; Xu, Zhaofa; Tan, Zhiping; Zhang, Zhuohua; Ma, Long

2015-01-01

Methyl salicylate (MeSa) is a stress hormone released by plants under attack by pathogens or herbivores . MeSa has been shown to attract predatory insects of herbivores and repel pests. The molecules and neurons underlying animal response to MeSa are not known. Here we found that the nematode Caenorhabditis elegans exhibits a strong avoidance response to MeSa, which requires the activities of two closely related neuropeptide receptors NPR-1 and NPR-2. Molecular analyses suggest that NPR-1 expressed in the RMG inter/motor neurons is required for MeSa avoidance. An NPR-1 ligand FLP-18 is also required. Using a rescuing npr-2 promoter to drive a GFP transgene, we identified that NPR-2 is expressed in multiple sensory and interneurons. Genetic rescue experiments suggest that NPR-2 expressed in the AIZ interneurons is required for MeSa avoidance. We also provide evidence that the AWB sensory neurons might act upstream of RMGs and AIZs to detect MeSa. Our results suggest that NPR-2 has an important role in regulating animal behavior and that NPR-1 and NPR-2 act on distinct interneurons to affect C. elegans avoidance response to MeSa. PMID:25527285

Hepatic structure-pharmacokinetic relationships: the hepatic disposition and metabolite kinetics of a homologous series of O-acyl derivatives of salicylic acid.

PubMed

Hung, D Y; Mellick, G D; Anissimov, Y G; Weiss, M; Roberts, M S

1998-08-01

1. The hepatic disposition and metabolite kinetics of a homologous series of O-acyl (acetyl, propionyl, butanoyl, pentanoyl, hexanoyl and octanoyl) esters of salicylic acid (C2SA, C3SA, C4SA, C5SA, C6SA and C8SA, respectively) was determined using a single-pass, in-situ rat liver preparation. 2. The hepatic venous outflow profiles for the parent esters and the generated metabolite, salicylic acid (SA) were analysed by HPLC. Non-parametric moments analysis was used to determine the area under the curve (AUC'), mean transit time (MTT) and normalized variance (CV2) for the parent esters and generated SA. 3. Pregenerated SA ([14C]-salicylic acid) was injected into each liver with the parent ester to determine its distribution characteristics. 4. The overall recovery of ester plus metabolite was 89% of the ester dose injected and independent of the ester carbon number, suggesting that ester extraction was due to hepatic metabolism to salicylic acid. 5. The metabolite AUC' value increased directly with the lipophilicity of the parent ester (from 0.12 for C2SA to 0.95 for C8SA). By contrast, the parent AUC' decreased with the lipophilicity (from 0.85 for C2SA to zero for C8SA). The metabolite MTT value also showed a trend to increase with the lipophilicity of the parent ester (from 15.72 s for C3SA to 61.97 s for C8SA). However, the parent MTT value shows no significant change across the series. 6. The two-compartment dispersion model was used to derive the kinetic parameters for parent ester, pregenerated SA and generated SA. Consequently, these parameters were used to estimate the values of AUC', MTT and CV2 for the parent ester and metabolite. The moments values obtained using the two-compartment dispersion model show similar trends to the corresponding moments values obtained from the outflow profiles using a non-parametric approach. 7. The more lipophilic aspirin analogues are more confined to the portal circulation after oral administration than aspirin due to their more extensive hepatic elimination avoiding systemic prostacyclin inhibition. Given that aspirin's selectivity as an anti-thrombotic agent has been postulated to be due to selective anti-platelet effects in the portal circulation, the more lipophilic and highly extracted analogues are potentially more selective anti-thrombotic agents than aspirin.

Application of SP test to Evaluate Embrittlement of Dual Phase Stainless Steel Caused by Sigma Phase and Neutron Irradiation

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

Lee, J.S.; Institute of Advanced Energy, Kyoto University, Gokasho, Uji, Kyoto 611-0011; Kim, I.S.

2004-07-01

The degradation of mechanical properties in dual phase 309L stainless steel RPV clad caused by the presence of s-phase as well as neutron irradiation was investigated using a small punch (SP) test. Two kinds of overlay-weld clad were fabricated on SA508 cl.3 pressure vessel steel plates with ER309L welding consumable strip by differing in heat input rates. The microstructure of the clad was composed of a main part of fcc austenite, a few percent of bcc d- ferrite and brittle bct s-phase. Area fraction of s-phase was ranging approximately 2 {approx} 8 percent depending on welding conditions. The JMTR wasmore » utilized for neutron irradiation and SP specimens were irradiated up to 1.02 x 10{sup 19} n/cm{sup 2} (E>1 MeV) at 563 K. After irradiation the SP ductile-to-brittle transition behavior moved to higher temperatures, however, it was more strongly affected by the amount of brittle s-phase rather than the irradiation at current doses. The cracking appearances in the SP specimens gradually changed from circumferential to radial cracking as the test temperature became low, content of {sigma}-phase increased and the specimens were irradiated. Those results were accounted for in terms of the inconsistency of fracture stress between the phases as well as the effects of stress-strain portioning combined with the changes of governing stress components for crack initiation. (authors)« less

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

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...

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...

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...

In-situ Thermal Treatment of Trichloroethene at Marshall Space Flight Center

NASA Technical Reports Server (NTRS)

Cole, Jason; McElroy, William J.; Glasgow, Jason; Heron, Gorm; Galligan, Jim; Parker, Ken; Davis, E. F.

2008-01-01

This viewgraph presentation describes the in-situ thermal treatment of trichloroethene at Marshall space Flight Center. The contents include: 1) Background 1 and 2; 2) Source Area-13; 3) In-situ Thermal Treatment; 4) SA-13 Lithology; 5) SA-13 In-Situ Thermal TS; 6) SA-13 ISTD System Components; 7) ISTD Overview; 8) Heaters; 9) SA-13 ISTD Wellfield Layout; 10) SA-13 Well Field; 11) ISTD Process and Instrumentation; 12) Treatment Zone Temperature; 13) SA-13 System Removals; 14) SA-13 DNAPL (typical photos); 15) Treatment Results 1-5; and 16) SA-13 TCE Removal Summary.

Salicylic Acid-Dependent Plant Stress Signaling via Mitochondrial Succinate Dehydrogenase1[OPEN

PubMed Central

Thatcher, Louise F.

2017-01-01

Mitochondria are known for their role in ATP production and generation of reactive oxygen species, but little is known about the mechanism of their early involvement in plant stress signaling. The role of mitochondrial succinate dehydrogenase (SDH) in salicylic acid (SA) signaling was analyzed using two mutants: disrupted in stress response1 (dsr1), which is a point mutation in SDH1 identified in a loss of SA signaling screen, and a knockdown mutant (sdhaf2) for SDH assembly factor 2 that is required for FAD insertion into SDH1. Both mutants showed strongly decreased SA-inducible stress promoter responses and low SDH maximum capacity compared to wild type, while dsr1 also showed low succinate affinity, low catalytic efficiency, and increased resistance to SDH competitive inhibitors. The SA-induced promoter responses could be partially rescued in sdhaf2, but not in dsr1, by supplementing the plant growth media with succinate. Kinetic characterization showed that low concentrations of either SA or ubiquinone binding site inhibitors increased SDH activity and induced mitochondrial H2O2 production. Both dsr1 and sdhaf2 showed lower rates of SA-dependent H2O2 production in vitro in line with their low SA-dependent stress signaling responses in vivo. This provides quantitative and kinetic evidence that SA acts at or near the ubiquinone binding site of SDH to stimulate activity and contributes to plant stress signaling by increased rates of mitochondrial H2O2 production, leading to part of the SA-dependent transcriptional response in plant cells. PMID:28209841

Supplement Analysis for the Site-Wide Environmental Impact Statement for Continued Operation of Los Alamos National Laboratory -- Recovery and Storage of Strontium-90 Fueled Radioisotope Thermal Electric Generators at Los Alamos National Laboratory

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

N /A

2004-01-22

This Supplement Analysis (SA) has been prepared to determine if the Site-Wide Environmental Impact Statement for Continued Operations of Los Alamos National Laboratory (SWEIS) (DOE/EIS-0238) adequately addresses the environmental effects of recovery and storage for disposal of six strontium-90 (Sr-90) fueled radioisotope thermal electric generators (RTGs) at the Los Alamos National Laboratory (LANL) Technical Area (TA)-54, Area G, or if the SWEIS needs to be supplemented. DOE's National Nuclear Security Administration (NNSA) proposed to recover and store six Sr-90 RTGs from the commercial sector as part of its Offsite-Source Recovery Project (OSRP). The OSRP focuses on the proactive recovery andmore » storage of unwanted radioactive sealed sources exceeding the US Nuclear Regulatory Commission (NRC) limits for Class C low-level waste (also known as Greater than Class C waste, or GTCC). In response to the events of September 11, 2001, NRC conducted a risk-based evaluation of potential vulnerabilities to terrorist threats involving NRC-licensed nuclear facilities and materials. NRC's evaluation concluded that possession of unwanted radioactive sealed sources with no disposal outlet presents a potential vulnerability (NRC 2002). In a November 25, 2003 letter to the manager of the NNSA's Los Alamos Site Office, the NRC Office of Nuclear Security and Incident Response identified recovery of several Sr-90 RTGs as the highest priority and requested that DOE take whatever actions necessary to recovery these sources as soon as possible. This SA specifically compares key impact assessment parameters of this proposal to the offsite source recovery program evaluated in the SWEIS and a subsequent SA that evaluated a change to the approach of a portion of the recovery program. It also provides an explanation of any differences between the Proposed Action and activities described in the previous SWEIS and SA analyses.« less

Elevated nuclear sphingoid base-1-phosphates and decreased histone deacetylase activity after fumonisin B1 treatment in mouse embryonic fibroblasts

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

Gardner, Nicole M., E-mail: nicolegardner@creighton.edu; Riley, Ronald T.; Showker, Jency L.

Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of corn. Administration of FB1 to pregnant LM/Bc mice induces exencephaly in embryos, and ingestion of FB1-contaminated food during early pregnancy is associated with increased risk for neural tube defects (NTDs) in humans. FB1 inhibits ceramide synthase enzymes in sphingolipid biosynthesis, causing sphinganine (Sa) and bioactive sphinganine-1-phosphate (Sa1P) accumulation in blood, cells, and tissues. Sphingosine kinases (Sphk) phosphorylate Sa to form Sa1P. Upon activation, Sphk1 associates primarily with the plasma membrane, while Sphk2 is found predominantly in the nucleus. In cells over-expressing Sphk2, accumulation of Sa1P in themore » nuclear compartment inhibits histone deacetylase (HDAC) activity, causing increased acetylation of histone lysine residues. In this study, FB1 treatment in LM/Bc mouse embryonic fibroblasts (MEFs) resulted in significant accumulation of Sa1P in nuclear extracts relative to cytoplasmic extracts. Elevated nuclear Sa1P corresponded to decreased histone deacetylase (HDAC) activity and increased histone acetylation at H2BK12, H3K9, H3K18, and H3K23. Treatment of LM/Bc MEFs with a selective Sphk1 inhibitor, PF-543, or with ABC294640, a selective Sphk2 inhibitor, significantly reduced nuclear Sa1P accumulation after FB1, although Sa1P levels remained significantly increased relative to basal levels. Concurrent treatment with both PF-543 and ABC294640 prevented nuclear accumulation of Sa1P in response to FB1. Other HDAC inhibitors are known to cause NTDs, so these results suggest that FB1-induced disruption of sphingolipid metabolism leading to nuclear Sa1P accumulation, HDAC inhibition, and histone hyperacetylation is a potential mechanism for FB1-induced NTDs. - Highlights: • FB1 treatment results in accumulation of Sa1P primarily in the nucleus of MEFs. • FB1 treatment and elevated nuclear Sa1P are associated with HDAC inhibition. • Sphk2 inhibition alone significantly decreases nuclear Sa1P in response to FB1. • Sphk1 and Sphk2 inhibitors prevent nuclear Sa1P accumulation in response to FB1.« less

[Accuracy of a pulse oximeter during hypoxia].

PubMed

Tachibana, C; Fukada, T; Hasegawa, R; Satoh, K; Furuya, Y; Ohe, Y

1996-04-01

The accuracy of the pulse oximeter was examined in hypoxic patients. We studied 11 cyanotic congenital heart disease patients during surgery, and compared the arterial oxygen saturation determined by both the simultaneous blood gas analysis (CIBA-CORNING 288 BLOOD GAS SYSTEM, SaO2) and by the pulse oximeter (DATEX SATELITE, with finger probe, SpO2). Ninty sets of data on SpO2 and SaO2 were obtained. The bias (SpO2-SaO2) was 1.7 +/- 6.9 (mean +/- SD) %. In cyanotic congenital heart disease patients, SpO2 values were significantly higher than SaO2. Although the reason is unknown, in constantly hypoxic patients, SpO2 values are possibly over-estimated. In particular, pulse oximetry at low levels of saturation (SaO2 below 80%) was not as accurate as at a higher saturation level (SaO2 over 80%). There was a positive correlation between SpO2 and SaO2 (linear regression analysis yields the equation y = 0.68x + 26.0, r = 0.93). In conclusion, the pulse oximeter is useful to monitor oxygen saturation in constantly hypoxic patients, but the values thus obtained should be compared with the values measured directly when hypoxemia is severe.