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Sample records for fxr accelerator optimization

  1. FLASH X-RAY (FXR) LINEAR INDUCTION ACCELERATOR (LIA) OPTIMIZATION Upgrade of the OTR Emittance Diagnostic

    SciTech Connect

    Houck, T L; Wargo, P E

    2006-12-01

    Knowing the electron beam parameters at the exit of an accelerator is critical for several reasons. Foremost is to optimize the application of the beam, which is flash radiography in the case of the FXR accelerator. The beam parameters not only determine the theoretical dose, x-ray spectrum, and radiograph resolution (spot size), they are required to calculate the final transport magnetic fields that focus the beam on the bremsstrahlung converter to achieve the theoretical limits. Equally important is the comparison of beam parameters to the design specifications. This comparison indicates the ''health'' of the accelerator, warning the operator when systems are deteriorating or failing. For an accelerator of the size and complexity of FXR, a large suite of diagnostics is normally employed to measure and/or infer beam parameters. These diagnostics are distributed throughout the accelerator and can require a large number of ''shots'' (measurements) to calculate a specific beam parameter. The OTR Emittance Diagnostic, however, has the potential to measure all but one of the beam parameters simultaneous at a specific location. Using measurements from a scan of a few shots, this final parameter can also be determined. Since first deployment, the OTR Emittance Diagnostic has been limited to measuring only one of the seven desired parameters, the beam's divergence. This report describes recent upgrades to the diagnostic that permit full realization of its potential.

  2. FLASH X-RAY (FXR) LINEAR INDUCTION ACCELERATOR (LIA) OPTIMIZATION Sensor Delay Correction

    SciTech Connect

    Ong, M M; Houck, T L; Kreitzer, B R; Paris, R D; Vogtlin, G E; Zentler, J M

    2006-05-01

    The radiographic goal of the FXR Optimization Project is to generate an x-ray pulse with peak energy of 19 MeV, spot-size of 1.5 mm, a dose of 500 rad, and duration of 60 ns. The electrical objectives are to generate a 3 kA electron-beam and refine our 16 MV accelerator so that the voltage does not vary more than 1%-rms. In a multi-cell linear induction accelerator, like FXR, the timing of the acceleration pulses relative to the beam is critical. The pulses must be timed optimally so that a cell is at full voltage before the beam arrives and does not drop until the beam passes. In order to stay within the energy-variation budget, the synchronization between the cells and beam arrival must be controlled to a couple of nanoseconds. Therefore, temporal measurements must be accurate to a fraction of a nanosecond. FXR Optimization Project developed a one-giga-sample per second (gs/s) data acquisition system to record beam sensor data. Signal processing algorithms were written to determine cell timing with an uncertainty of a fraction of a nanosecond. However, the uncertainty in the sensor delay was still a few nanoseconds. This error had to be reduced if we are to improve the quality of the electron beam. Two types of sensors are used to align the cell voltage pulse against the beam current. The beam current is measured with resistive-wall sensors. The cell voltages are read with capacitive voltage monitors. Sensor delays can be traced to two mechanisms: (1) the sensors are not co-located at the beam and cell interaction points, and (2) the sensors have different length jumper cables and other components that connect them to the standard-length coaxial cables of the data acquisition system. Using the physical locations and dimensions of the sensor components, and the dielectric constant of the materials, delay times were computed. Relative to the cell voltage, the beam current was theoretically reporting late by 7.7 ns. Two experiments were performed to verify and

  3. FXR accelerator cavity impedance experiments

    SciTech Connect

    Avalle, C.A.

    1998-01-05

    One of the goals of the present Flash X-Ray (FXR) accelerator upgrade effort [1][2] at Lawrence Livermore National Laboratory (LLNL) is to reduce the cavity transverse impedance, since it has been shown that beam stability is significantly affected by this parameter [3]. Recently, we have evaluated various techniques and cell modifications to accomplish that, both through lab measurements and computer models. A spare cell, identical in every way to cells in the accelerator, was specially modified for the experiments. The impedance measurements were done without the beam, by applying twin-wire techniques. This report describes the results of these experiments and suggests possible cell modifications to improve their performance. The techniques and modifications which are suggested might also be applicable to AHF and DARHT-2 long-pulse accelerator development.

  4. Flash X-Ray (FXR) Accelerator Optimization Electronic Time-Resolved Measurement of X-Ray Source Size

    SciTech Connect

    Jacob, J; Ong, M; Wargo, P

    2005-07-21

    Lawrence Livermore National Laboratory (LLNL) is currently investigating various approaches to minimize the x-ray source size on the Flash X-Ray (FXR) linear induction accelerator in order to improve x-ray flux and increase resolution for hydrodynamic radiography experiments. In order to effectively gauge improvements to final x-ray source size, a fast, robust, and accurate system for measuring the spot size is required. Timely feedback on x-ray source size allows new and improved accelerator tunes to be deployed and optimized within the limited run-time constraints of a production facility with a busy experimental schedule; in addition, time-resolved measurement capability allows the investigation of not only the time-averaged source size, but also the evolution of the source size, centroid position, and x-ray dose throughout the 70 ns beam pulse. Combined with time-resolved measurements of electron beam parameters such as emittance, energy, and current, key limiting factors can be identified, modeled, and optimized for the best possible spot size. Roll-bar techniques are a widely used method for x-ray source size measurement, and have been the method of choice at FXR for many years. A thick bar of tungsten or other dense metal with a sharp edge is inserted into the path of the x-ray beam so as to heavily attenuate the lower half of the beam, resulting in a half-light, half-dark image as seen downstream of the roll-bar; by measuring the width of the transition from light to dark across the edge of the roll-bar, the source size can be deduced. For many years, film has been the imaging medium of choice for roll-bar measurements thanks to its high resolution, linear response, and excellent contrast ratio. Film measurements, however, are fairly cumbersome and require considerable setup and analysis time; moreover, with the continuing trend towards all-electronic measurement systems, film is becoming increasingly difficult and expensive to procure. Here, we shall

  5. FXR LIA Optimization - Time-resolved OTR Emittance Measurement

    SciTech Connect

    Jacob, J; Ong, M; Wargo, P; LeSage, G

    2005-07-21

    The Flash X-Ray Radiography (FXR) facility at Lawrence Livermore National Laboratory utilizes a high current, long pulse linear induction accelerator to produce high doses of x-ray radiation. Accurate characterization of the transverse beam emittance is required in order to facilitate accelerator modeling and tuning efforts and, ultimately, to optimize the final focus spot size, yielding higher resolution radiographs. In addition to conventional magnet scan, pepper-pot, and multiple screen techniques, optical transition radiation (OTR) has been proven as a useful emittance measurement diagnostic and is particularly well suited to the FXR accelerator. We shall discuss the time-resolved emittance characterization of an induction linac electron beam using OTR, and we will present our experimental apparatus and analysis software. We shall also develop the theoretical background of beam emittance and transition radiation.

  6. The LLNL flash x-ray induction linear accelerator (FXR)

    NASA Astrophysics Data System (ADS)

    Multhauf, Lloyd G.; Back, Norman L.; Simmons, Larry F.; Zentler, Jan-Mark; Scarpetti, Raymond D.

    2003-07-01

    The FXR is an induction linear accelerator used for high-speed radiography at the Lawrence Livermore National Laboratory's Experimental Test Site. It was designed specifically for the radiography of very thick explosive objects. Since its completion in 1982, it has been very actively used for a large variety of explosives tests, and has been periodically upgraded to achieve higher performance. Upgrades have addressed machine reliability, radiographic sensitivity and resolution, two-frame imaging by double pulsing -- improvements that are described in detail in the paper. At the same time, the facility in which it was installed has also been extensively upgraded, first by adding space for optical and interferometric diagnostics, and more recently by adding a containment chamber to prevent the environmental dispersal of hazardous and radioactive materials. The containment addition also further expands space for new non-radiographic diagnostics. The new Contained Firing Facility is still in the process of activation. At the same time, FXR is continuing to undergo modifications aimed primarily at further increasing radiographic resolution and sensitivity, and at improving double-pulsed performance.

  7. The LLNL Flash X-Ray Induction Linear Accelerator (FXR)

    SciTech Connect

    Multhauf, L G

    2002-09-19

    The FXR is an induction linear accelerator used for high-speed radiography at the Lawrence Livermore National Laboratory's Experimental Test Site. It was designed specifically for the radiography of very thick explosive objects. Since its completion in 1982, it has been very actively used for a large variety of explosives tests, and has been periodically upgraded to achieve higher performance. Upgrades have addressed machine reliability, radiographic sensitivity and resolution, two-frame imaging by double pulsing improvements that are described in detail in the paper. At the same time, the facility in which it was installed has also been extensively upgraded, first by adding space for optical and interferometric diagnostics, and more recently by adding a containment chamber to prevent the environmental dispersal of hazardous and radioactive materials. The containment addition also further expands space for new non-radiographic diagnostics. The new Contained Firing Facility is still in the process of activation. At the same time, FXR is continuing to undergo modifications aimed primarily at further increasing radiographic resolution and sensitivity, and at improving double-pulsed performance.

  8. Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice.

    PubMed

    Zhang, Yanqiao; Ge, Xuemei; Heemstra, Lydia A; Chen, Wei-Dong; Xu, Jiesi; Smith, Joseph L; Ma, Huiyan; Kasim, Neda; Edwards, Peter A; Novak, Colleen M

    2012-02-01

    Farnesoid X receptor (FXR) is known to play important regulatory roles in bile acid, lipid, and carbohydrate metabolism. Aged (>12 months old) Fxr(-/-) mice also develop spontaneous liver carcinomas. In this report, we used three mouse models to investigate the role of FXR deficiency in obesity. As compared with low-density lipoprotein receptor (Ldlr) knockout (Ldlr(-/-)) mice, the Ldlr(-/-)Fxr(-/-) double-knockout mice were highly resistant to diet-induced obesity, which was associated with increased expression of genes involved in energy metabolism in the skeletal muscle and brown adipose tissue. Such a striking effect of FXR deficiency on obesity on an Ldlr(-/-) background led us to investigate whether FXR deficiency alone is sufficient to affect obesity. As compared with wild-type mice, Fxr(-/-) mice showed resistance to diet-induced weight gain. Interestingly, only female Fxr(-/-) mice showed significant resistance to diet-induced obesity, which was accompanied by increased energy expenditure in these mice. Finally, we determined the effect of FXR deficiency on obesity in a genetically obese and diabetic mouse model. We generated ob(-/-)Fxr(-/-) mice that were deficient in both Leptin and Fxr. On a chow diet, ob(-/-)Fxr(-/-) mice gained less body weight and had reduced body fat mass as compared with ob/ob mice. In addition, we observed liver carcinomas in 43% of young (<11 months old) Ob(-/-)Fxr(-/-) mice. Together these data indicate that loss of FXR prevents diet-induced or genetic obesity and accelerates liver carcinogenesis under diabetic conditions. PMID:22261820

  9. Loss of FXR Protects against Diet-Induced Obesity and Accelerates Liver Carcinogenesis in ob/ob Mice

    PubMed Central

    Ge, Xuemei; Heemstra, Lydia A.; Chen, Wei-Dong; Xu, Jiesi; Smith, Joseph L.; Ma, Huiyan; Kasim, Neda; Edwards, Peter A.; Novak, Colleen M.

    2012-01-01

    Farnesoid X receptor (FXR) is known to play important regulatory roles in bile acid, lipid, and carbohydrate metabolism. Aged (>12 months old) Fxr−/− mice also develop spontaneous liver carcinomas. In this report, we used three mouse models to investigate the role of FXR deficiency in obesity. As compared with low-density lipoprotein receptor (Ldlr) knockout (Ldlr−/−) mice, the Ldlr−/−Fxr−/− double-knockout mice were highly resistant to diet-induced obesity, which was associated with increased expression of genes involved in energy metabolism in the skeletal muscle and brown adipose tissue. Such a striking effect of FXR deficiency on obesity on an Ldlr−/− background led us to investigate whether FXR deficiency alone is sufficient to affect obesity. As compared with wild-type mice, Fxr−/− mice showed resistance to diet-induced weight gain. Interestingly, only female Fxr−/− mice showed significant resistance to diet-induced obesity, which was accompanied by increased energy expenditure in these mice. Finally, we determined the effect of FXR deficiency on obesity in a genetically obese and diabetic mouse model. We generated ob−/−Fxr−/− mice that were deficient in both Leptin and Fxr. On a chow diet, ob−/−Fxr−/− mice gained less body weight and had reduced body fat mass as compared with ob/ob mice. In addition, we observed liver carcinomas in 43% of young (<11 months old) Ob−/−Fxr−/− mice. Together these data indicate that loss of FXR prevents diet-induced or genetic obesity and accelerates liver carcinogenesis under diabetic conditions. PMID:22261820

  10. Structural Investigation for Optimization of Anthranilic Acid Derivatives as Partial FXR Agonists by in Silico Approaches.

    PubMed

    Chen, Meimei; Yang, Xuemei; Lai, Xinmei; Kang, Jie; Gan, Huijuan; Gao, Yuxing

    2016-01-01

    In this paper, a three level in silico approach was applied to investigate some important structural and physicochemical aspects of a series of anthranilic acid derivatives (AAD) newly identified as potent partial farnesoid X receptor (FXR) agonists. Initially, both two and three-dimensional quantitative structure activity relationship (2D- and 3D-QSAR) studies were performed based on such AAD by a stepwise technology combined with multiple linear regression and comparative molecular field analysis. The obtained 2D-QSAR model gave a high predictive ability (R²train = 0.935, R²test = 0.902, Q²LOO = 0.899). It also uncovered that number of rotatable single bonds (b_rotN), relative negative partial charges (RPC(-)), oprea's lead-like (opr_leadlike), subdivided van der Waal's surface area (SlogP_VSA2) and accessible surface area (ASA) were important features in defining activity. Additionally, the derived3D-QSAR model presented a higher predictive ability (R²train = 0.944, R²test = 0.892, Q²LOO = 0.802). Meanwhile, the derived contour maps from the 3D-QSAR model revealed the significant structural features (steric and electronic effects) required for improving FXR agonist activity. Finally, nine newly designed AAD with higher predicted EC50 values than the known template compound were docked into the FXR active site. The excellent molecular binding patterns of these molecules also suggested that they can be robust and potent partial FXR agonists in agreement with the QSAR results. Overall, these derived models may help to identify and design novel AAD with better FXR agonist activity. PMID:27070594

  11. Structural Investigation for Optimization of Anthranilic Acid Derivatives as Partial FXR Agonists by in Silico Approaches

    PubMed Central

    Chen, Meimei; Yang, Xuemei; Lai, Xinmei; Kang, Jie; Gan, Huijuan; Gao, Yuxing

    2016-01-01

    In this paper, a three level in silico approach was applied to investigate some important structural and physicochemical aspects of a series of anthranilic acid derivatives (AAD) newly identified as potent partial farnesoid X receptor (FXR) agonists. Initially, both two and three-dimensional quantitative structure activity relationship (2D- and 3D-QSAR) studies were performed based on such AAD by a stepwise technology combined with multiple linear regression and comparative molecular field analysis. The obtained 2D-QSAR model gave a high predictive ability (R2train = 0.935, R2test = 0.902, Q2LOO = 0.899). It also uncovered that number of rotatable single bonds (b_rotN), relative negative partial charges (RPC−), oprea's lead-like (opr_leadlike), subdivided van der Waal’s surface area (SlogP_VSA2) and accessible surface area (ASA) were important features in defining activity. Additionally, the derived3D-QSAR model presented a higher predictive ability (R2train = 0.944, R2test = 0.892, Q2LOO = 0.802). Meanwhile, the derived contour maps from the 3D-QSAR model revealed the significant structural features (steric and electronic effects) required for improving FXR agonist activity. Finally, nine newly designed AAD with higher predicted EC50 values than the known template compound were docked into the FXR active site. The excellent molecular binding patterns of these molecules also suggested that they can be robust and potent partial FXR agonists in agreement with the QSAR results. Overall, these derived models may help to identify and design novel AAD with better FXR agonist activity. PMID:27070594

  12. Design of a High Field Stress, Velvet Cathode for the Flash X-Ray (FXR) Induction Accelerator

    SciTech Connect

    Houck, T; Brown, C; Fleming, D; Kreitzer, B; Lewis, K; Ong, M; Zentler, J

    2007-06-08

    A new cathode design has been proposed for the Flash X-Ray (FXR) induction linear accelerator with the goal of lowering the beam emittance. The original design uses a conventional Pierce geometry and applies a peak field of 134 kV/cm (no beam) to the velvet emission surface. Voltage/current measurements indicate that the velvet begins emitting near this peak field value and images of the cathode show a very non-uniform distribution of plasma light. The new design has a flat cathode/shroud profile that allows for a peak field stress of 230 kV/cm on the velvet. The emission area is reduced by about a factor of four to generate the same total current due to the greater field stress. The relatively fast acceleration of the beam, approximately 2.5 MeV in 10 cm, reduces space charge forces that tend to hollow the beam for a flat, non-Pierce geometry. The higher field stress achieved with the same rise time is expected to lead to an earlier and more uniform plasma formation over the velvet surface. Simulations and initial testing are presented.

  13. FXR and liver carcinogenesis

    PubMed Central

    Huang, Xiong-fei; Zhao, Wei-yu; Huang, Wen-dong

    2015-01-01

    Farnesoid X receptor (FXR) is a member of the nuclear receptor family and a ligand-modulated transcription factor. In the liver, FXR has been considered a multi-functional cell protector and a tumor suppressor. FXR can suppress liver carcinogenesis via different mechanisms: 1) FXR maintains the normal liver metabolism of bile acids, glucose and lipids; 2) FXR promotes liver regeneration and repair after injury; 3) FXR protects liver cells from death and enhances cell survival; 4) FXR suppresses hepatic inflammation, thereby preventing inflammatory damage; and 5) FXR can directly increase the expression of some tumor-suppressor genes and repress the transcription of several oncogenes. However, inflammation and epigenetic silencing are known to decrease FXR expression during tumorigenesis. The reactivation of FXR function in the liver may be a potential therapeutic approach for patients with liver cancer. PMID:25500874

  14. Bile acid nuclear receptor FXR and digestive system diseases

    PubMed Central

    Ding, Lili; Yang, Li; Wang, Zhengtao; Huang, Wendong

    2015-01-01

    Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases. PMID:26579439

  15. Bile acid nuclear receptor FXR and digestive system diseases.

    PubMed

    Ding, Lili; Yang, Li; Wang, Zhengtao; Huang, Wendong

    2015-03-01

    Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases. PMID:26579439

  16. Accelerating optimization by tracing valley

    NASA Astrophysics Data System (ADS)

    Li, Qing-Xiao; He, Rong-Qiang; Lu, Zhong-Yi

    2016-06-01

    We propose an algorithm to accelerate optimization when an objective function locally resembles a long narrow valley. In such a case, a conventional optimization algorithm usually wanders with too many tiny steps in the valley. The new algorithm approximates the valley bottom locally by a parabola that is obtained by fitting a set of successive points generated recently by a conventional optimization method. Then large steps are taken along the parabola, accompanied by fine adjustment to trace the valley bottom. The effectiveness of the new algorithm has been demonstrated by accelerating the Newton trust-region minimization method and the Levenberg-Marquardt method on the nonlinear fitting problem in exact diagonalization dynamical mean-field theory and on the classic minimization problem of the Rosenbrock's function. Many times speedup has been achieved for both problems, showing the high efficiency of the new algorithm.

  17. Recent performance improvements on FXR

    SciTech Connect

    Kulke, B.; Kihara, R.

    1983-01-01

    The FXR machine is a nominal 4-kA, 20-MeV, linear-induction, electron accelerator for flash radiography at LLNL. The machine met its baseline requirements in March 1982. Since then, the performance has been greatly improved. We have achieved stable and repeatable beam acceleration and transport, with over 80% transmission to the tungsten bremsstrahlung target located some 35 m downstream. For best stability, external-beam steering has been eliminated almost entirely. We regularly produce over 500 Roentgen at 1 m from the target (TLD measurement), with a radiographic spot size of 3 to 5 mm. Present efforts are directed towards the development of a 4-kA tune, working interactively with particle-field and beam transport code models. A remaining uncertainty is the possible onset of RF instabilities at the higher current levels.

  18. An Improved SF6 System for the FXR Induction Linac Blumlein Switches

    SciTech Connect

    DeHope, W; Kihara, R; Griffin, K L; Ong, M; Ross, T

    2007-06-16

    The now-mature FXR (Flash X-Ray) radiographic facility at Lawrence Livermore National Laboratory will be briefly described with emphasis on its pulsed power system. The heart of each accelerating cell's pulse forming Blumlein is it's sulfur hexafluoride-based triggered closing switch. FXR's recent upgrade to a recirculating SF{sub 6} gas reclamation system will be described and the resulting accelerator performance and reliability improvements documented. This was accompanied by a detailed switch breakdown study on FXR's Test Stand and the recent analysis of the resulting statistics will be shown.

  19. Reconstruction of FXR Beam Conditions

    SciTech Connect

    Nexen, W E; Scarpetti, R D; Zentler, J

    2001-05-31

    Beam-envelope radius, envelope angle, and beam emittance can be derived from measurements of beam radius for at least three different transport conditions. We have used this technique to reconstruct exit parameters from the FXR injector and accelerator. We use a diamagnetic loop (DML) to measure the magnetic moment of the high current beam. With no assumptions about radial profile, we can derive the beam mean squire radius from the moment under certain easily met conditions. Since it is this parameter which is required for the reconstruction, it is evident that the DML is the ideal diagnostic for this technique. The simplest application of this technique requires at least three shots for a reconstruction but in reality requires averaging over many more shots because of shot to shot variation. Since DML measurements do not interfere with the beam, single shot time resolved measurements of the beam parameters appear feasible if one uses an array of at least three DMLs separated by known transport conditions.

  20. Pulsed Inductive Plasma Acceleration: Performance Optimization Criteria

    NASA Technical Reports Server (NTRS)

    Polzin, Kurt A.

    2014-01-01

    Optimization criteria for pulsed inductive plasma acceleration are developed using an acceleration model consisting of a set of coupled circuit equations describing the time-varying current in the thruster and a one-dimensional momentum equation. The model is nondimensionalized, resulting in the identification of several scaling parameters that are varied to optimize the performance of the thruster. The analysis reveals the benefits of underdamped current waveforms and leads to a performance optimization criterion that requires the matching of the natural period of the discharge and the acceleration timescale imposed by the inertia of the working gas. In addition, the performance increases when a greater fraction of the propellant is initially located nearer to the inductive acceleration coil. While the dimensionless model uses a constant temperature formulation in calculating performance, the scaling parameters that yield the optimum performance are shown to be relatively invariant if a self-consistent description of energy in the plasma is instead used.

  1. Gradient Optimization for SC CW Accelerators

    SciTech Connect

    Schneider, William; Kneisel, Peter; Rode, Claus

    2003-05-01

    The proposed rare isotope accelerator (RIA) design consists of a normally conducting radio frequency quadruple (RFQ) section, a superconducting (SC) drift tube cavity section, a SC elliptical multi-cell cavity section and two charge strippers with associated charge state selection and beam matching optics. The SC elliptical section uses two or three multi-cell beta cavity types installed into cryomodules to span the energy region of about 84.5 MeV/nucleon up to 400 MeV/nucleon. This paper focuses on the gradient optimization of these SC elliptical cavities that provide a significant portion of the total acceleration to the beam. The choice of gradient coupled with the cavity quality factor has a strong affect on the overall cost of the accelerator. The paper describes the optimization of the capital and operating cost associated with the RIA elliptical cavity cryomodules.

  2. Optimization of laser wakefield accelerator parameters

    SciTech Connect

    Pogorelsky, I.V.

    1998-02-01

    The author reveals the dependencies of the laser wakefield accelerator (LWFA) performance upon such basic parameters as laser wavelength, power, and pulse duration and apply them for optimization of the plasma-channeled standard LWFA operating in a linear regime. The maximum energy gain over the dephasing distance scales proportionally to the laser peak power, while the allowed minimum laser pulse duration is proportional to the square root of the energy gain. Electron beam energy spread, emittance and luminosity tend to improve with the laser wavelength increase. These considerations, supported by quantitative examples for the S GeV LWFA stage, favor picosecond CO{sub 2} laser as the optimum choice for future advanced accelerator projects.

  3. Initial performance parameters on FXR

    SciTech Connect

    Kulke, B.; Innes, T.G.; Kihara, R.; Scarpetti, R.D.

    1982-06-11

    Construction of the new flash x-ray induction LINAC (FXR) at Lawrence Livermore National Laboratory has been completed. Initial tuning of the machine has produced stable current pulses in excess of 2 kA at the design energy of 20 MeV, with an 80 ns FWHM pulse width, producing single-pulse radiation doses near 500 Roentgen at one meter from the target. The electronic spot size on the bremsstrahlung target is estimated at 3 to 5 mm. In this paper we will discuss the basic FXR design; running-in and tuning of the machine; emittance measurements; beam stability; switch gap synchronization; and measurements of the radiation dose and angular distribution.

  4. Statins and transcriptional regulation: The FXR connection

    SciTech Connect

    Habeos, Ioannis; Ziros, Panos G.; Psyrogiannis, Agathoklis; Vagenakis, Apostolos G.; Papavassiliou, Athanasios G. . E-mail: papavas@med.upatras.gr

    2005-08-26

    Farnesoid X receptor (FXR) is a nuclear receptor involved in lipoprotein as well as glucose metabolism. Statins are widely used hypolipidemic agents with many pleiotropic actions. It is known that statins affect other nuclear hormone receptors, but no reports are available on the effect of these drugs on FXR. Employing an animal model (Syrian hamsters), we hereby present evidence to demonstrate that Simvastatin, a broadly prescribed statin, decreases the expression of FXR at both the RNA and protein levels and down-regulates its DNA-binding activity. This novel property may have important implications on the mode statins influence on lipoprotein and carbohydrate homeostasis in the organism.

  5. FXR signaling in the enterohepatic system

    PubMed Central

    Matsubara, Tsutomu; Li, Fei; Gonzalez, Frank J.

    2012-01-01

    Enterohepatic circulation serves to capture bile acids and other steroid metabolites produced in the liver and secreted to the intestine, for reabsorption back into the circulation and reuptake to the liver. This process is under tight regulation by nuclear receptor signaling. Bile acids, produced from cholesterol, can alter gene expression in the liver and small intestine via activating the nuclear receptors farnesoid X receptor (FXR; NR1H4), pregnane X receptor (PXR; NR1I2), vitamin D receptor (VDR; NR1I1), G protein coupled receptor TGR5, and other cell signaling pathways (JNK1/2, AKT and ERK1/2). Among these controls, FXR is known to be a major bile acid-responsive ligand-activated transcription factor and a crucial control element for maintaining bile acid homeostasis. FXR has a high affinity for several major endogenous bile acids, notably cholic acid, deoxycholic acid, chenodeoxycholic acid, and lithocholic acid. By responding to excess bile acids, FXR is a bridge between the liver and small intestine to control bile acid levels and regulate bile acid synthesis and enterohepatic flow. FXR is highly expressed in the liver and gut, relative to other tissues, and contributes to the maintenance of cholesterol/bile acid homeostasis by regulating a variety of metabolic enzymes and transporters. FXR activation also affects lipid and glucose metabolism, and can influence drug metabolism. PMID:22609541

  6. Anthranilic acid derivatives as nuclear receptor modulators--development of novel PPAR selective and dual PPAR/FXR ligands.

    PubMed

    Merk, Daniel; Lamers, Christina; Weber, Julia; Flesch, Daniel; Gabler, Matthias; Proschak, Ewgenij; Schubert-Zsilavecz, Manfred

    2015-02-01

    Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of anthranilic acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism. PMID:25583100

  7. Torque-based optimal acceleration control for electric vehicle

    NASA Astrophysics Data System (ADS)

    Lu, Dongbin; Ouyang, Minggao

    2014-03-01

    The existing research of the acceleration control mainly focuses on an optimization of the velocity trajectory with respect to a criterion formulation that weights acceleration time and fuel consumption. The minimum-fuel acceleration problem in conventional vehicle has been solved by Pontryagin's maximum principle and dynamic programming algorithm, respectively. The acceleration control with minimum energy consumption for battery electric vehicle(EV) has not been reported. In this paper, the permanent magnet synchronous motor(PMSM) is controlled by the field oriented control(FOC) method and the electric drive system for the EV(including the PMSM, the inverter and the battery) is modeled to favor over a detailed consumption map. The analytical algorithm is proposed to analyze the optimal acceleration control and the optimal torque versus speed curve in the acceleration process is obtained. Considering the acceleration time, a penalty function is introduced to realize a fast vehicle speed tracking. The optimal acceleration control is also addressed with dynamic programming(DP). This method can solve the optimal acceleration problem with precise time constraint, but it consumes a large amount of computation time. The EV used in simulation and experiment is a four-wheel hub motor drive electric vehicle. The simulation and experimental results show that the required battery energy has little difference between the acceleration control solved by analytical algorithm and that solved by DP, and is greatly reduced comparing with the constant pedal opening acceleration. The proposed analytical and DP algorithms can minimize the energy consumption in EV's acceleration process and the analytical algorithm is easy to be implemented in real-time control.

  8. Navigation in bile acid chemical space: discovery of novel FXR and GPBAR1 ligands.

    PubMed

    Finamore, Claudia; Festa, Carmen; Renga, Barbara; Sepe, Valentina; Carino, Adriana; Masullo, Dario; Biagioli, Michele; Marchianò, Silvia; Capolupo, Angela; Monti, Maria Chiara; Fiorucci, Stefano; Zampella, Angela

    2016-01-01

    Bile acids are signaling molecules interacting with nuclear receptors and membrane G-protein-coupled receptors. Among these receptors, the farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) have gained increasing consideration as druggable receptors and their exogenous dual regulation represents an attractive strategy in the treatment of enterohepatic and metabolic disorders. However, the therapeutic use of dual modulators could be associated to severe side effects and therefore the discovery of selective GPBAR1 and FXR agonists is an essential step in the medicinal chemistry optimization of bile acid scaffold. In this study, a new series of 6-ethylcholane derivatives modified on the tetracyclic core and on the side chain has been designed and synthesized and their in vitro activities on FXR and GPBAR1 were assayed. This speculation resulted in the identification of compound 7 as a potent and selective GPBAR1 agonist and of several derivatives showing potent dual agonistic activity. PMID:27381677

  9. Navigation in bile acid chemical space: discovery of novel FXR and GPBAR1 ligands

    PubMed Central

    Finamore, Claudia; Festa, Carmen; Renga, Barbara; Sepe, Valentina; Carino, Adriana; Masullo, Dario; Biagioli, Michele; Marchianò, Silvia; Capolupo, Angela; Monti, Maria Chiara; Fiorucci, Stefano; Zampella, Angela

    2016-01-01

    Bile acids are signaling molecules interacting with nuclear receptors and membrane G-protein-coupled receptors. Among these receptors, the farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) have gained increasing consideration as druggable receptors and their exogenous dual regulation represents an attractive strategy in the treatment of enterohepatic and metabolic disorders. However, the therapeutic use of dual modulators could be associated to severe side effects and therefore the discovery of selective GPBAR1 and FXR agonists is an essential step in the medicinal chemistry optimization of bile acid scaffold. In this study, a new series of 6-ethylcholane derivatives modified on the tetracyclic core and on the side chain has been designed and synthesized and their in vitro activities on FXR and GPBAR1 were assayed. This speculation resulted in the identification of compound 7 as a potent and selective GPBAR1 agonist and of several derivatives showing potent dual agonistic activity. PMID:27381677

  10. Computational studies and optimization of wakefield accelerators

    SciTech Connect

    Tsung, Frank S.; Bruhwiler, David L.; Cary, John R.; Esarey, Eric H.; Mori, Warren B.; Vay, Jean-Luc; Martins, Samuel F.; Katsouleas, Tom; Cormier-Michel, Estelle; Fawley, William M.; Huang, Chengkun; Wang, Xiadong; Cowan, Ben; Decyk, Victor K.; Fonseca, Ricardo A.; Lu, Wei; Messmer, Peter; Mullowney, Paul; Nakamura, Kei; Paul, Kevin; Plateau, Guillaume R.; Schroeder, Carl B.; Silva, Luis O.; Toth, Csaba; Geddes, C.G.R.; Tzoufras, Michael; Antonsen, Tom; Vieira, Jorge; Leemans, Wim P.

    2008-06-16

    Laser- and particle beam-driven plasma wakefield accelerators produce accelerating fields thousands of times higher than radio-frequency accelerators, offering compactness and ultrafast bunches to extend the frontiers of high energy physics and to enable laboratory-scale radiation sources. Large-scale kinetic simulations provide essential understanding of accelerator physics to advance beam performance and stability and show and predict the physics behind recent demonstration of narrow energy spread bunches. Benchmarking between codes is establishing validity of the models used and, by testing new reduced models, is extending the reach of simulations to cover upcoming meter-scale multi-GeV experiments. This includes new models that exploit Lorentz boosted simulation frames to speed calculations. Simulations of experiments showed that recently demonstrated plasma gradient injection of electrons can be used as an injector to increase beam quality by orders of magnitude. Simulations are now also modeling accelerator stages of tens of GeV, staging of modules, and new positron sources to design next-generation experiments and to use in applications in high energy physics and light sources.

  11. Using Approximations to Accelerate Engineering Design Optimization

    NASA Technical Reports Server (NTRS)

    Torczon, Virginia; Trosset, Michael W.

    1998-01-01

    Optimization problems that arise in engineering design are often characterized by several features that hinder the use of standard nonlinear optimization techniques. Foremost among these features is that the functions used to define the engineering optimization problem often are computationally intensive. Within a standard nonlinear optimization algorithm, the computational expense of evaluating the functions that define the problem would necessarily be incurred for each iteration of the optimization algorithm. Faced with such prohibitive computational costs, an attractive alternative is to make use of surrogates within an optimization context since surrogates can be chosen or constructed so that they are typically much less expensive to compute. For the purposes of this paper, we will focus on the use of algebraic approximations as surrogates for the objective. In this paper we introduce the use of so-called merit functions that explicitly recognize the desirability of improving the current approximation to the objective during the course of the optimization. We define and experiment with the use of merit functions chosen to simultaneously improve both the solution to the optimization problem (the objective) and the quality of the approximation. Our goal is to further improve the effectiveness of our general approach without sacrificing any of its rigor.

  12. Optimal Staging of Acceleration and Cooling in a Neutrino Factory

    NASA Astrophysics Data System (ADS)

    Johnstone, C.; Berz, M.; Makino, K.

    2005-12-01

    Schemes to produce intense sources of high-energy muons, Neutrino Factories, beta beams, and colliders, require collection, rf capture, and transport of particle beams with unprecedented emittances, both longitudinally and transversely. These large initial emittances must be reduced or cooled both in size and in energy spread before the muons can be efficiently accelerated to multi-GeV energies. The acceleration stage becomes critical in formulating and optimizing muon beams; individual stages are strongly interlinked and not independent as is the case in most conventional acceleration systems. Most importantly, the degree of cooling, or cooling channel, depends on the choice of acceleration. This work discusses two basic, but different approaches to a Neutrino Factory and how the optimal strategy depends on beam parameters and method of acceleration.

  13. Support Vector Machine Based on Adaptive Acceleration Particle Swarm Optimization

    PubMed Central

    Abdulameer, Mohammed Hasan; Othman, Zulaiha Ali

    2014-01-01

    Existing face recognition methods utilize particle swarm optimizer (PSO) and opposition based particle swarm optimizer (OPSO) to optimize the parameters of SVM. However, the utilization of random values in the velocity calculation decreases the performance of these techniques; that is, during the velocity computation, we normally use random values for the acceleration coefficients and this creates randomness in the solution. To address this problem, an adaptive acceleration particle swarm optimization (AAPSO) technique is proposed. To evaluate our proposed method, we employ both face and iris recognition based on AAPSO with SVM (AAPSO-SVM). In the face and iris recognition systems, performance is evaluated using two human face databases, YALE and CASIA, and the UBiris dataset. In this method, we initially perform feature extraction and then recognition on the extracted features. In the recognition process, the extracted features are used for SVM training and testing. During the training and testing, the SVM parameters are optimized with the AAPSO technique, and in AAPSO, the acceleration coefficients are computed using the particle fitness values. The parameters in SVM, which are optimized by AAPSO, perform efficiently for both face and iris recognition. A comparative analysis between our proposed AAPSO-SVM and the PSO-SVM technique is presented. PMID:24790584

  14. Support vector machine based on adaptive acceleration particle swarm optimization.

    PubMed

    Abdulameer, Mohammed Hasan; Sheikh Abdullah, Siti Norul Huda; Othman, Zulaiha Ali

    2014-01-01

    Existing face recognition methods utilize particle swarm optimizer (PSO) and opposition based particle swarm optimizer (OPSO) to optimize the parameters of SVM. However, the utilization of random values in the velocity calculation decreases the performance of these techniques; that is, during the velocity computation, we normally use random values for the acceleration coefficients and this creates randomness in the solution. To address this problem, an adaptive acceleration particle swarm optimization (AAPSO) technique is proposed. To evaluate our proposed method, we employ both face and iris recognition based on AAPSO with SVM (AAPSO-SVM). In the face and iris recognition systems, performance is evaluated using two human face databases, YALE and CASIA, and the UBiris dataset. In this method, we initially perform feature extraction and then recognition on the extracted features. In the recognition process, the extracted features are used for SVM training and testing. During the training and testing, the SVM parameters are optimized with the AAPSO technique, and in AAPSO, the acceleration coefficients are computed using the particle fitness values. The parameters in SVM, which are optimized by AAPSO, perform efficiently for both face and iris recognition. A comparative analysis between our proposed AAPSO-SVM and the PSO-SVM technique is presented. PMID:24790584

  15. Optimization of a Small Scale Linear Reluctance Accelerator

    NASA Astrophysics Data System (ADS)

    Barrera, Thor; Beard, Robby

    2011-11-01

    Reluctance accelerators are extremely promising future methods of transportation. Several problems still plague these devices, most prominently low efficiency. Variables to overcoming efficiency problems are many and difficult to correlate how they affect our accelerator. The study examined several differing variables that present potential challenges in optimizing the efficiency of reluctance accelerators. These include coil and projectile design, power supplies, switching, and the elusive gradient inductance problem. Extensive research in these areas has been performed from computational and theoretical to experimental. Findings show that these parameters share significant similarity to transformer design elements, thus general findings show current optimized parameters the research suggests as a baseline for further research and design. Demonstration of these current findings will be offered at the time of presentation.

  16. Control and optimization of a staged laser-wakefield accelerator

    NASA Astrophysics Data System (ADS)

    Golovin, G.; Banerjee, S.; Chen, S.; Powers, N.; Liu, C.; Yan, W.; Zhang, J.; Zhang, P.; Zhao, B.; Umstadter, D.

    2016-09-01

    We report results of an experimental study of laser-wakefield acceleration of electrons, using a staged device based on a double-jet gas target that enables independent injection and acceleration stages. This novel scheme is shown to produce stable, quasi-monoenergetic, and tunable electron beams. We show that optimal accelerator performance is achieved by systematic variation of five critical parameters. For the injection stage, we show that the amount of trapped charge is controlled by the gas density, composition, and laser power. For the acceleration stage, the gas density and the length of the jet are found to determine the final electron energy. This independent control over both the injection and acceleration processes enabled independent control over the charge and energy of the accelerated electron beam while preserving the quasi-monoenergetic character of the beam. We show that the charge and energy can be varied in the ranges of 2-45 pC, and 50-450 MeV, respectively. This robust and versatile electron accelerator will find application in the generation of high-brightness and controllable x-rays, and as the injector stage for more conventional devices.

  17. Is the FXR the fix for cholesterol gallstone disease?

    PubMed

    Juran, Brian D; Lazaridis, Konstantinos N

    2005-07-01

    Cholesterol gallstone disease is characterized by several events, including cholesterol precipitation in bile, increased bile salt hydrophobicity and gallbladder inflammation. Here, we describe the same phenotype in mice lacking the bile acid receptor, FXR. Furthermore, in susceptible wild-type mice that recapitulate human cholesterol gallstone disease, treatment with a synthetic FXR agonist prevented sequelae of the disease. These effects were mediated by FXR-dependent increases in biliary bile salt and phospholipid concentrations, which restored cholesterol solubility and thereby prevented gallstone formation. Taken together, these results indicate that FXR is a promising therapeutic target for treating or preventing cholesterol gallstone disease. PMID:15962294

  18. FXR induces SOCS3 and suppresses hepatocellular carcinoma.

    PubMed

    Guo, Fei; Xu, Zhizhen; Zhang, Yan; Jiang, Peng; Huang, Gang; Chen, Shan; Lyu, Xilin; Zheng, Ping; Zhao, Xin; Zeng, Yijun; Wang, Shuguang; He, Fengtian

    2015-10-27

    Suppressor of cytokine signaling 3 (SOCS3) is regarded as a vital repressor in the liver carcinogenesis mainly by inhibiting signal transducer and activator of transcription 3 (STAT3) activity. Farnesoid X Receptor (FXR), highly expressed in liver, has an important role in protecting against hepatocellular carcinoma (HCC). However, it is unclear whether the tumor suppressive activity of FXR involves the regulation of SOCS3. In the present study, we found that activation of FXR by its specific agonist GW4064 in HCC cells inhibited cell growth, induced cell cycle arrest at G1 phase, elevated p21 expression and repressed STAT3 activity. The above anti-tumor effects of FXR were dramatically alleviated by knockdown of SOCS3 with siRNA. Reporter assay revealed that FXR activation enhanced the transcriptional activity of SOCS3 promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay displayed that FXR directly bound to IR9 DNA motif within SOCS3 promoter region. The in vivo study in nude mice showed that treatment with FXR ligand GW4064 could decelerate the growth of HCC xenografts, up-regulate SOCS3 and p21 expression and inhibit STAT3 phosphorylation in the xenografts. These results suggest that induction of SOCS3 may be a novel mechanism by which FXR exerts its anti-HCC effects, and the FXR-SOCS3 signaling may serve as a new potential target for the prevention/treatment of HCC. PMID:26416445

  19. Plasma jet accelerator optimization with supple membrane model

    NASA Astrophysics Data System (ADS)

    Galkin, S. A.; Bogatu, I. N.; Kim, J. S.

    2006-10-01

    High density (>=3x10^17cm-3) and high Mach number (M>10) plasma jets have important applications such as plasma rotation, refueling and disruption mitigation in tokamaks. The most deleterious blow-by instability occurs in coaxial plasma accelerators; hence electrode shape optimization is required to accelerate plasmas to ˜200 km/s [1]. A full 3D particle simulation takes a huge computational time. We have developed a membrane model to provide a good starting point and further physical insight for a full 3D optimization. Our model approximates the axisymmetrical plasma by a thin supple conducting membrane with a distributed mass, located between the electrodes, and connects them to model dynamics of the blow-by instability and to conduct the optimization. The supple membrane is allowed to slip along the conductors freely or with some friction as affected by Lorenz force, generated by magnetic field inside the chamber and current on membrane. The total mass and the density distribution represent the initial plasma. The density is redistributed adiabatically during the acceleration. An external electrical circuit with capacitance, inductance and resistivity is a part of the model. The membrane model simulation results will be compared to the 2D fluid MACH2 results and then will be used to guide a full 3D optimization by the LSP code. 1. http://hyperv.com/projects/pic/

  20. Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism.

    PubMed

    Huang, Huang; Si, Pei; Wang, Lei; Xu, Yong; Xu, Xin; Zhu, Jin; Jiang, Hualiang; Li, Weihua; Chen, Lili; Li, Jian

    2015-07-01

    Farnesoid X receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4'-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50 =12.2 ± 0.2 μM). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR. PMID:25982493

  1. Optimizing direct intense-field laser acceleration of ions

    SciTech Connect

    Harman, Zoltan; Salamin, Yousef I.; Galow, Benjamin J.; Keitel, Christoph H.

    2011-11-15

    The dynamics of ion acceleration in tightly focused laser beams is investigated in relativistic simulations. Studies are performed to find the optimal parameters which maximize the energy gain, beam quality, and flux. The exit ionic kinetic energy and its uncertainty are improved and the number of accelerated particles is increased by orders of magnitude over our earlier results, especially when working with a longer laser wavelength. Laser beams of powers of 0.1-10 petawatts and focused to subwavelength spot radii are shown to directly accelerate protons and bare nuclei of helium, carbon, and oxygen from a few to several hundred MeV/nucleon. Variation of the volume of the initial ionic ensemble, as well as the introduction of a pulse shape on the laser fields, have been investigated and are shown to influence the exit particle kinetic energies only slightly.

  2. Global search acceleration in the nested optimization scheme

    NASA Astrophysics Data System (ADS)

    Grishagin, Vladimir A.; Israfilov, Ruslan A.

    2016-06-01

    Multidimensional unconstrained global optimization problem with objective function under Lipschitz condition is considered. For solving this problem the dimensionality reduction approach on the base of the nested optimization scheme is used. This scheme reduces initial multidimensional problem to a family of one-dimensional subproblems being Lipschitzian as well and thus allows applying univariate methods for the execution of multidimensional optimization. For two well-known one-dimensional methods of Lipschitz optimization the modifications providing the acceleration of the search process in the situation when the objective function is continuously differentiable in a vicinity of the global minimum are considered and compared. Results of computational experiments on conventional test class of multiextremal functions confirm efficiency of the modified methods.

  3. Advanced metaheuristic algorithms for laser optimization in optical accelerator technologies

    NASA Astrophysics Data System (ADS)

    Tomizawa, Hiromitsu

    2011-10-01

    Lasers are among the most important experimental tools for user facilities, including synchrotron radiation and free electron lasers (FEL). In the synchrotron radiation field, lasers are widely used for experiments with Pump-Probe techniques. Especially for X-ray-FELs, lasers play important roles as seed light sources or photocathode-illuminating light sources to generate a high-brightness electron bunch. For future accelerators, laser-based techonologies such as electro-optic (EO) sampling to measure ultra-short electron bunches and optical-fiber-based femtosecond timing systems have been intensively developed in the last decade. Therefore, controls and optimizations of laser pulse characteristics are strongly required for many kinds of experiments and improvement of accelerator systems. However, people believe that lasers should be tuned and customized for each requirement manually by experts. This makes it difficult for laser systems to be part of the common accelerator infrastructure. Automatic laser tuning requires sophisticated algorithms, and the metaheuristic algorithm is one of the best solutions. The metaheuristic laser tuning system is expected to reduce the human effort and time required for laser preparations. I have shown some successful results on a metaheuristic algorithm based on a genetic algorithm to optimize spatial (transverse) laser profiles, and a hill-climbing method extended with a fuzzy set theory to choose one of the best laser alignments automatically for each machine requirement.

  4. FXR: Big fish or small fry for drug-induced liver injury?

    PubMed

    Ballet, François

    2016-02-01

    By integrating network analysis and molecular modeling, a "system pharmacology" approach identified FXR as a potential off-target protein mediating non-steroidal anti-inflammatory drugs (NSAID)-induced liver injury. In vitro assays showed that NSAID are potent FXR antagonists that inhibit FXR transcriptional activity. Given the role of FXR in bile acid homeostasis, liver inflammation and cell proliferation, the data suggest that FXR antagonism could mediate, at least in part, NSAID-induced liver injury. PMID:26797115

  5. Hybrid photoneutron source optimization for electron accelerator-based BNCT

    NASA Astrophysics Data System (ADS)

    Rahmani, F.; Shahriari, M.

    2010-06-01

    Boron Neutron Capture Therapy (BNCT) is being studied as a possible radiotherapic treatment for some cancer types. Neutron energy for penetrating into tissue should be in the epithermal range. Different methods are used for neutron production. Electron accelerators are an alternative way for producing neutrons in electron-photon-neutron processes. Optimization of electron/photon and photoneutron targets calculations with respect to electron energy, dimension (radius and thickness) and neutron yield were done by MCNPX Monte Carlo code. According to the results, a hybrid photoneutron source including BeD 2 and Tungsten has been introduced.

  6. Elliptical Cavity Shape Optimization for Acceleration and HOM Damping

    SciTech Connect

    Haipeng Wang; Robert Rimmer; Genfa Wu

    2005-05-01

    We report a survey of center cell shapes developed for Superconducting Radio Frequency (SRF) multi-cell cavities for different projects. Using a set of normalized parameters, we compare the designs for different frequencies and particle velocities for the fundamental mode. Using dispersion curves of High Order Modes (HOM) (frequency verse phase advance) calculated by MAFIA for a single cell, we further optimize the cavity shape to avoid a light cone line crossing at the dangerous resonance frequencies determined by the beam bunch structure and eliminate the trapped (or high R/Q) modes with a low group velocity. We developed this formulation to optimize a 5-cell, 750MHz cavity shape, with good real-estate accelerating gradient and a strong HOM damping waveguide structure for the JLab 1MW ERL-FEL project.

  7. Deciphering the nuclear bile acid receptor FXR paradigm

    PubMed Central

    Modica, Salvatore; Gadaleta, Raffaella M.; Moschetta, Antonio

    2010-01-01

    Originally called retinoid X receptor interacting protein 14 (RIP14), the farnesoid X receptor (FXR) was renamed after the ability of its rat form to bind supra-physiological concentrations of farnesol. In 1999 FXR was de-orphanized since primary bile acids were identified as natural ligands. Strongly expressed in the liver and intestine, FXR has been shown to be the master transcriptional regulator of several entero-hepatic metabolic pathways with relevance to the pathophysiology of conditions such as cholestasis, fatty liver disease, cholesterol gallstone disease, intestinal inflammation and tumors. Furthermore, given the importance of FXR in the gut-liver axis feedbacks regulating lipid and glucose homeostasis, FXR modulation appears to have great input in diseases such as metabolic syndrome and diabetes. Exciting results from several cellular and animal models have provided the impetus to develop synthetic FXR ligands as novel pharmacological agents. Fourteen years from its discovery, FXR has gone from bench to bedside; a novel nuclear receptor ligand is going into clinical use. PMID:21383957

  8. Structural Studies of the Tandem Tudor Domains of Fragile X Mental Retardation Related Proteins FXR1 and FXR2

    SciTech Connect

    Adams-Cioaba, Melanie A.; Guo, Yahong; Bian, ChuanBing; Amaya, Maria F.; Lam, Robert; Wasney, Gregory A.; Vedadi, Masoud; Xu, Chao; Min, Jinrong

    2011-11-23

    Expansion of the CGG trinucleotide repeat in the 5'-untranslated region of the FMR1, fragile X mental retardation 1, gene results in suppression of protein expression for this gene and is the underlying cause of Fragile X syndrome. In unaffected individuals, the FMRP protein, together with two additional paralogues (Fragile X Mental Retardation Syndrome-related Protein 1 and 2), associates with mRNA to form a ribonucleoprotein complex in the nucleus that is transported to dendrites and spines of neuronal cells. It is thought that the fragile X family of proteins contributes to the regulation of protein synthesis at sites where mRNAs are locally translated in response to stimuli. Here, we report the X-ray crystal structures of the non-canonical nuclear localization signals of the FXR1 and FXR2 autosomal paralogues of FMRP, which were determined at 2.50 and 1.92 {angstrom}, respectively. The nuclear localization signals of the FXR1 and FXR2 comprise tandem Tudor domain architectures, closely resembling that of UHRF1, which is proposed to bind methylated histone H3K9. The FMRP, FXR1 and FXR2 proteins comprise a small family of highly conserved proteins that appear to be important in translational regulation, particularly in neuronal cells. The crystal structures of the N-terminal tandem Tudor domains of FXR1 and FXR2 revealed a conserved architecture with that of FMRP. Biochemical analysis of the tandem Tudor doamins reveals their ability to preferentially recognize trimethylated peptides in a sequence-specific manner.

  9. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk.

    PubMed

    Lien, Fleur; Berthier, Alexandre; Bouchaert, Emmanuel; Gheeraert, Céline; Alexandre, Jeremy; Porez, Geoffrey; Prawitt, Janne; Dehondt, Hélène; Ploton, Maheul; Colin, Sophie; Lucas, Anthony; Patrice, Alexandre; Pattou, François; Diemer, Hélène; Van Dorsselaer, Alain; Rachez, Christophe; Kamilic, Jelena; Groen, Albert K; Staels, Bart; Lefebvre, Philippe

    2014-03-01

    The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry-based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis. PMID:24531544

  10. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk

    PubMed Central

    Lien, Fleur; Berthier, Alexandre; Bouchaert, Emmanuel; Gheeraert, Céline; Alexandre, Jeremy; Porez, Geoffrey; Prawitt, Janne; Dehondt, Hélène; Ploton, Maheul; Colin, Sophie; Lucas, Anthony; Patrice, Alexandre; Pattou, François; Diemer, Hélène; Van Dorsselaer, Alain; Rachez, Christophe; Kamilic, Jelena; Groen, Albert K.; Staels, Bart; Lefebvre, Philippe

    2014-01-01

    The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry–based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis. PMID:24531544

  11. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

    SciTech Connect

    Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  12. An Accelerated Particle Swarm Optimization Algorithm on Parametric Optimization of WEDM of Die-Steel

    NASA Astrophysics Data System (ADS)

    Muthukumar, V.; Suresh Babu, A.; Venkatasamy, R.; Senthil Kumar, N.

    2015-01-01

    This study employed Accelerated Particle Swarm Optimization (APSO) algorithm to optimize the machining parameters that lead to a maximum Material Removal Rate (MRR), minimum surface roughness and minimum kerf width values for Wire Electrical Discharge Machining (WEDM) of AISI D3 die-steel. Four machining parameters that are optimized using APSO algorithm include Pulse on-time, Pulse off-time, Gap voltage, Wire feed. The machining parameters are evaluated by Taguchi's L9 Orthogonal Array (OA). Experiments are conducted on a CNC WEDM and output responses such as material removal rate, surface roughness and kerf width are determined. The empirical relationship between control factors and output responses are established by using linear regression models using Minitab software. Finally, APSO algorithm, a nature inspired metaheuristic technique, is used to optimize the WEDM machining parameters for higher material removal rate and lower kerf width with surface roughness as constraint. The confirmation experiments carried out with the optimum conditions show that the proposed algorithm was found to be potential in finding numerous optimal input machining parameters which can fulfill wide requirements of a process engineer working in WEDM industry.

  13. DAX1 suppresses FXR transactivity as a novel co-repressor

    SciTech Connect

    Li, Jin; Lu, Yan; Liu, Ruya; Xiong, Xuelian; Zhang, Zhijian; Zhang, Xianfeng; Ning, Guang; Li, Xiaoying

    2011-09-09

    Highlights: {yields} DAX1 is co-localized with FXR and interacts with FXR. {yields} DAX1 acts as a negative regulator of FXR. {yields} Three LXXLL motifs in the N-terminus of DAX1 were required. {yields} DAX1 suppresses FXR transactivation by competing with co-activators. -- Abstract: Bile acid receptor FXR (farnesoid X receptor) is a key regulator of hepatic bile acid, glucose and lipid homeostasis through regulation of numerous genes involved in the process of bile acid, triglyceride and glucose metabolism. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) is an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains and acts primarily as a co-repressor of many nuclear receptors. Here, we demonstrated that DAX1 is co-localized with FXR in the nucleus and acted as a negative regulator of FXR through a physical interaction with FXR. Our study showed that over-expression of DAX1 down-regulated the expression of FXR target genes, whereas knockdown of DAX1 led to their up-regulation. Furthermore, three LXXLL motifs in the N-terminus of DAX1 were required for the full repression of FXR transactivation. In addition, our study characterized that DAX1 suppresses FXR transactivation via competing with co-activators such as SRC-1 and PGC-1{alpha}. In conclusion, DAX1 acts as a co-repressor to negatively modulate FXR transactivity.

  14. Optimization of electrodynamic acceleration regimes for cylindrical conductors

    NASA Astrophysics Data System (ADS)

    Kalikhman, S. A.

    1985-11-01

    At the present time electromagnetic accelerators which use the action of an impulsive electromagnetic field on a current-carrying conductor appear to be promising devices for the study of high-speed collisions. In the regime using separate sources for the accelerating magnetic field and the current in the conductor being accelerated it is possible to bring cylindrical conductors up to velocities exceeding 12 km/sec [1]. Acceleration regimes have been calculated previously [2] assuming independence of the current density in the conductor from the accelerating magnetic field. However, as analysis of transient electromagnetic processes occurring in the interaction of an impulsive electromagnetic field with a cylindrical conductor shows [3], the maximum current density, limited by heating conditions, depends significantly on the induction of the accelerating magnetic field. In the present study we will analyze regimes for electrodynamic acceleration of cylindrical conductors with consideration of diffusion of both the intrinsic and the external impulsive magnetic field within the conductor.

  15. LLNL flash x-ray radiography machine (FXR) double-pulse upgrade diagnostics

    SciTech Connect

    Ong, M.; Avalee, C.; Richardson, R.; Zentler, J.

    1997-06-26

    When the FXR machine was first tuned on the 1980`s, a minimal amount of diagnostics was available and consisted mostly of power monitors. During the recent accelerator upgrade, additional beam diagnostics were added. The sensor upgrades included beam bugs (resistive wall beam motion sensors) and high-frequency B-dot. Even with this suite of measurement tools, tuning was difficult. For the current Double- Pulse Upgrade, beam transport is a more complex problem--the beam characteristics must be measured better. Streak and framing cameras, which measure beam size and motions, are being added. Characterization of the beam along the entire accelerator is expected and other techniques will be evaluated also. Each sensor has limitations and only provides a piece of the puzzle. Besides providing more beam data, the set of diagnostics used should be broad enough so results can be cross validated. Results will also be compared to theoretical calculations and computer models, and successes and difficulties will be reported.

  16. Optimizing laser-driven proton acceleration from overdense targets

    PubMed Central

    Stockem Novo, A.; Kaluza, M. C.; Fonseca, R. A.; Silva, L. O.

    2016-01-01

    We demonstrate how to tune the main ion acceleration mechanism in laser-plasma interactions to collisionless shock acceleration, thus achieving control over the final ion beam properties (e. g. maximum energy, divergence, number of accelerated ions). We investigate this technique with three-dimensional particle-in-cell simulations and illustrate a possible experimental realisation. The setup consists of an isolated solid density target, which is preheated by a first laser pulse to initiate target expansion, and a second one to trigger acceleration. The timing between the two laser pulses allows to access all ion acceleration regimes, ranging from target normal sheath acceleration, to hole boring and collisionless shock acceleration. We further demonstrate that the most energetic ions are produced by collisionless shock acceleration, if the target density is near-critical, ne ≈ 0.5 ncr. A scaling of the laser power shows that 100 MeV protons may be achieved in the PW range. PMID:27435449

  17. Optimizing laser-driven proton acceleration from overdense targets

    NASA Astrophysics Data System (ADS)

    Stockem Novo, A.; Kaluza, M. C.; Fonseca, R. A.; Silva, L. O.

    2016-07-01

    We demonstrate how to tune the main ion acceleration mechanism in laser-plasma interactions to collisionless shock acceleration, thus achieving control over the final ion beam properties (e. g. maximum energy, divergence, number of accelerated ions). We investigate this technique with three-dimensional particle-in-cell simulations and illustrate a possible experimental realisation. The setup consists of an isolated solid density target, which is preheated by a first laser pulse to initiate target expansion, and a second one to trigger acceleration. The timing between the two laser pulses allows to access all ion acceleration regimes, ranging from target normal sheath acceleration, to hole boring and collisionless shock acceleration. We further demonstrate that the most energetic ions are produced by collisionless shock acceleration, if the target density is near-critical, ne ≈ 0.5 ncr. A scaling of the laser power shows that 100 MeV protons may be achieved in the PW range.

  18. Optimizing laser-driven proton acceleration from overdense targets.

    PubMed

    Stockem Novo, A; Kaluza, M C; Fonseca, R A; Silva, L O

    2016-01-01

    We demonstrate how to tune the main ion acceleration mechanism in laser-plasma interactions to collisionless shock acceleration, thus achieving control over the final ion beam properties (e. g. maximum energy, divergence, number of accelerated ions). We investigate this technique with three-dimensional particle-in-cell simulations and illustrate a possible experimental realisation. The setup consists of an isolated solid density target, which is preheated by a first laser pulse to initiate target expansion, and a second one to trigger acceleration. The timing between the two laser pulses allows to access all ion acceleration regimes, ranging from target normal sheath acceleration, to hole boring and collisionless shock acceleration. We further demonstrate that the most energetic ions are produced by collisionless shock acceleration, if the target density is near-critical, ne ≈ 0.5 ncr. A scaling of the laser power shows that 100 MeV protons may be achieved in the PW range. PMID:27435449

  19. Mechanisms of STAT3 activation in the liver of FXR knockout mice.

    PubMed

    Li, Guodong; Zhu, Yan; Tawfik, Ossama; Kong, Bo; Williams, Jessica A; Zhan, Le; Kassel, Karen M; Luyendyk, James P; Wang, Li; Guo, Grace L

    2013-12-01

    Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is essential in maintaining bile acid (BA) homeostasis, and FXR(-/-) mice develop cholestasis, inflammation, and spontaneous liver tumors. The signal transducer and activator of transcription 3 (STAT3) is well known to regulate liver growth, and STAT3 is feedback inhibited by its target gene, the suppressor of cytokine signaling 3 (SOCS3). Strong activation of STAT3 was detected in FXR(-/-) mouse livers. However, the mechanism of STAT3 activation with FXR deficiency remains elusive. Wild-type (WT) and FXR(-/-) mice were used to detect STAT3 pathway activation in the liver. In vivo BA feeding or deprivation was used to determine the role of BAs in STAT3 activation, and in vitro molecular approaches were used to determine the direct transcriptional regulation of SOCS3 by FXR. STAT3 was activated in FXR(-/-) but not WT mice. BA feeding increased, but deprivation by cholestyramine reduced, serum inflammatory markers and STAT3 activation. Furthermore, the Socs3 gene was determined as a direct FXR target gene. The elevated BAs and inflammation, along with reduced SOCS3, collectively contribute to the activation of the STAT3 signaling pathway in the liver of FXR(-/-) mice. This study suggests that the constitutive activation of STAT3 may be a mechanism of liver carcinogenesis in FXR(-/-) mice. PMID:24091600

  20. Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice.

    PubMed

    Zhang, Xiaoyan; Huang, Shizheng; Gao, Min; Liu, Jia; Jia, Xiao; Han, Qifei; Zheng, Senfeng; Miao, Yifei; Li, Shuo; Weng, Haoyu; Xia, Xuan; Du, Shengnan; Wu, Wanfu; Gustafsson, Jan-Åke; Guan, Youfei

    2014-02-11

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is mainly expressed in liver and small intestine, where it plays an important role in bile acid, lipid, and glucose metabolism. The kidney also has a high FXR expression level, with its physiological function unknown. Here we demonstrate that FXR is ubiquitously distributed in renal tubules. FXR agonist treatment significantly lowered urine volume and increased urine osmolality, whereas FXR knockout mice exhibited an impaired urine concentrating ability, which led to a polyuria phenotype. We further found that treatment of C57BL/6 mice with chenodeoxycholic acid, an FXR endogenous ligand, significantly up-regulated renal aquaporin 2 (AQP2) expression, whereas FXR gene deficiency markedly reduced AQP2 expression levels in the kidney. In vitro studies showed that the AQP2 gene promoter contained a putative FXR response element site, which can be bound and activated by FXR, resulting in a significant increase of AQP2 transcription in cultured primary inner medullary collecting duct cells. In conclusion, the present study demonstrates that FXR plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up-regulating its target gene AQP2 expression in the collecting ducts. PMID:24464484

  1. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice

    NASA Astrophysics Data System (ADS)

    Zhang, Yanqiao; Lee, Florence Ying; Barrera, Gabriel; Lee, Hans; Vales, Charisse; Gonzalez, Frank J.; Willson, Timothy M.; Edwards, Peter A.

    2006-01-01

    Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db/db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db/db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus. glucose | GW4064 | farnesoid X receptor-VP16 | triglyceride | cholesterol

  2. Upregulation of decorin by FXR in vascular smooth muscle cells

    SciTech Connect

    He Fengtian; Zhang Qiuhong; Kuruba, Ramalinga; Gao Xiang; Li Jiang; Li Yong; Gong Wei; Jiang, Yu; Xie Wen; Li Song

    2008-08-08

    Decorin is a member of the family of small leucine-rich proteoglycans that are present in blood vessels and synthesized by vascular smooth muscle cells (VSMCs). Decorin plays complex roles in both normal vascular physiology and the pathogenesis of various types of vascular disorders. However, the mechanisms of regulation of decorin expression in vasculature are not clearly understood. Particularly little information is available about a role of nuclear receptors in the regulation of decorin expression. In the present study, we report that activation of vascular FXR by a specific ligand resulted in upregulation of decorin at the levels of both mRNA and protein. FXR appears to induce decorin expression at a transcriptional level because (1) upregulation of decorin mRNA expression was abolished by the treatment of a transcription inhibitor, actinomycin D; and (2) decorin promoter activity was significantly increased by activation of FXR. Functional analysis of human decorin promoter identified an imperfect inverted repeat DNA motif, IR8 (-2313TGGTCAtagtgtcaTGACCT-2294), as a likely FXR-responsive element that is involved in decorin regulation.

  3. Optimization of THz Radiation Generation from a Laser Wakefield Accelerator

    SciTech Connect

    Plateau, G. R.; Matlis, N. H.; Toth, C.; Geddes, C. G. R.; Schroeder, C. B.; Tilborg, J. van; Albert, O.; Esarey, E.; Leemans, W. P.

    2009-01-22

    Ultrashort terahertz pulses with energies in the {mu}J range can be generated with laser wakefield accelerators (LWFA), which are novel, compact accelerators that produce ultrashort electron bunches with energies up to 1 GeV and energy spreads of a few-percent. Laser pulses interacting with a plasma create accelerated electrons which upon exiting the plasma emit terahertz pulses via transition radiation. Because these electron bunches are ultrashort (<50 fs), they can radiate coherently (coherent transition radiation--CTR) in a wide bandwidth ({approx}1-10 THz) yielding high intensity terahertz pulses. In addition to providing a non-invasive bunch-length diagnostic and thus feedback for the LWFA, these high peak power THz pulses are suitable for high field (MV/cm) pump-probe experiments. Here we present energy-based measurements using a Golay cell and an electro-optic technique which were used to characterize these THz pulses.

  4. Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism

    PubMed Central

    Correia, Jorge C.; Massart, Julie; de Boer, Jan Freark; Porsmyr-Palmertz, Margareta; Martínez-Redondo, Vicente; Agudelo, Leandro Z.; Sinha, Indranil; Meierhofer, David; Ribeiro, Vera; Björnholm, Marie; Sauer, Sascha; Dahlman-Wright, Karin; Zierath, Juleen R.; Groen, Albert K.; Ruas, Jorge L.

    2015-01-01

    Objective Farnesoid X receptor (FXR) plays a prominent role in hepatic lipid metabolism. The FXR gene encodes four proteins with structural differences suggestive of discrete biological functions about which little is known. Methods We expressed each FXR variant in primary hepatocytes and evaluated global gene expression, lipid profile, and metabolic fluxes. Gene delivery of FXR variants to Fxr−/− mouse liver was performed to evaluate their role in vivo. The effects of fasting and physical exercise on hepatic Fxr splicing were determined. Results We show that FXR splice isoforms regulate largely different gene sets and have specific effects on hepatic metabolism. FXRα2 (but not α1) activates a broad transcriptional program in hepatocytes conducive to lipolysis, fatty acid oxidation, and ketogenesis. Consequently, FXRα2 decreases cellular lipid accumulation and improves cellular insulin signaling to AKT. FXRα2 expression in Fxr−/− mouse liver activates a similar gene program and robustly decreases hepatic triglyceride levels. On the other hand, FXRα1 reduces hepatic triglyceride content to a lesser extent and does so through regulation of lipogenic gene expression. Bioenergetic cues, such as fasting and exercise, dynamically regulate Fxr splicing in mouse liver to increase Fxrα2 expression. Conclusions Our results show that the main FXR variants in human liver (α1 and α2) reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Taking this novel mechanism into account could greatly improve the pharmacological targeting and therapeutic efficacy of FXR agonists. PMID:26909306

  5. Origami Optimization: Role of Symmetry in Accelerating Design

    NASA Astrophysics Data System (ADS)

    Buskohl, Philip; Fuchi, Kazuko; Bazzan, Giorgio; Durstock, Michael; Reich, Gregory; Joo, James; Vaia, Richard

    Origami structures morph between 2D and 3D conformations along predetermined fold lines that efficiently program the form, function and mobility of the structure. Design optimization tools have recently been developed to predict optimal fold patterns with mechanics-based metrics, such as the maximal energy storage, auxetic response and actuation. Origami actuator design problems possess inherent symmetries associated with the grid, mechanical boundary conditions and the objective function, which are often exploited to reduce the design space and computational cost of optimization. However, enforcing symmetry eliminates the prediction of potentially better performing asymmetric designs, which are more likely to exist given the discrete nature of fold line optimization. To better understand this effect, actuator design problems with different combinations of rotation and reflection symmetries were optimized while varying the number of folds allowed in the final design. In each case, the optimal origami patterns transitioned between symmetric and asymmetric solutions depended on the number of folds available for the design, with fewer symmetries present with more fold lines allowed. This study investigates the interplay of symmetry and discrete vs continuous optimization in origami actuators and provides insight into how the symmetries of the reference grid regulate the performance landscape. This work was supported by the Air Force Office of Scientific Research.

  6. Optimization of accelerator-driven technology for LWR waste transmutation

    SciTech Connect

    Bowman, C.D.

    1996-12-31

    The role of accelerator-driven transmutation technology is examined in the context of the destruction of actinide waste from commercial light water reactors. It is pointed out that the commercial plutonium is much easier to use for entry-level nuclear weapons than weapons plutonium. Since commercial plutonium is easier to use, since there is very much more of it already, and since it is growing rapidly, the permanent disposition of commercial plutonium is an issue of greater importance than weapons plutonium. The minor actinides inventory, which may be influenced by transmutation, is compared in terms of nuclear properties with commercial and weapons plutonium and for possible utility as weapons material. Fast and thermal spectrum systems are compared as means for destruction of plutonium and the minor actinides. it is shown that the equilibrium fast spectrum actinide inventory is about 100 times larger than for thermal spectrum systems, and that there is about 100 times more weapons-usable material in the fast spectrum system inventory compared to the thermal spectrum system. Finally it is shown that the accelerator size for transmutation can be substantially reduced by design which uses the accelerator-produced neutrons only to initiate the unsustained fission chains characteristic of the subcritical system. The analysis argues for devoting primary attention to the development of thermal spectrum transmutation technology. A thermal spectrum transmuter operating at a fission power of 750-MWth fission power, which is sufficient to destroy the actinide waste from one 3,000-MWth light water reactor, may be driven by a proton beam of 1 GeV energy and a current of 7 mA. This accelerator is within the range of realizable cyclotron technology and is also near the size contemplated for the next generation spallation neutron source under consideration by the US, Europe, and Japan.

  7. FERMI&Elettra Accelerator Technical Optimization Final Report

    SciTech Connect

    Cornacchia, M.; Craievich, P.; Di Mitri, S.; Pogorelov, I.; Qiang, J.; Venturini, M.; Zholents, A.; Wang, D.; Warnock, R.; /SLAC

    2007-04-30

    This chapter describes the accelerator physics aspects, the engineering considerations and the choice of parameters that led to the accelerator design of the FERMI Free-Electron-Laser. The accelerator (also called the ''electron beam delivery system'') covers the region from the exit of the injector to the entrance of the first FEL undulator. The considerations that led to the proposed configuration were made on the basis of a study that explored various options and performance limits. This work follows previous studies of x-ray FEL facilities (SLAC LCLS [1], DESY XFEL [2], PAL XFEL [3], MIT [4], BESSY FEL [5], LBNL LUX [6], Daresbury 4GLS [7]) and integrates many of the ideas that were developed there. Several issues specific to harmonic cascade FELs, and that had not yet been comprehensively studied, were also encountered and tackled. A particularly difficult issue was the need to meet the requirement for high peak current and small slice energy spread, as the specification for the ratio of these two parameters (that defines the peak brightness of the electron beam) is almost a factor of two higher than that of the LCLS's SASE FEL. Another challenging aspect was the demand to produce an electron beam with as uniform as possible peak current and energy distributions along the bunch, a condition that was met by introducing novel beam dynamics techniques. Part of the challenge was due to the fact that there were no readily available computational tools to carry out reliable calculations, and these had to be developed. Most of the information reported in this study is available in the form of scientific publications, and is partly reproduced here for the convenience of the reader.

  8. Optimization of accelerator system performance at the NSLS

    SciTech Connect

    Krinsky, S.

    1994-10-01

    There is an active program of accelerator development at the NSLS aimed at improving reliability, stability and brightness. Work is primarily focused on providing improved performance for the NSLS user community, however, important elements of our work have a generic character and should be of value to other synchrotron radiation facilities. In particular, we have successfully operated a small gap undulator with a full vertical beam aperture of only 3.8 mm, with no degradation of beam lifetime. This provides strong support for the belief that small gap, short period devices will play an important role in the future.

  9. Optimizing a mobile robot control system using GPU acceleration

    NASA Astrophysics Data System (ADS)

    Tuck, Nat; McGuinness, Michael; Martin, Fred

    2012-01-01

    This paper describes our attempt to optimize a robot control program for the Intelligent Ground Vehicle Competition (IGVC) by running computationally intensive portions of the system on a commodity graphics processing unit (GPU). The IGVC Autonomous Challenge requires a control program that performs a number of different computationally intensive tasks ranging from computer vision to path planning. For the 2011 competition our Robot Operating System (ROS) based control system would not run comfortably on the multicore CPU on our custom robot platform. The process of profiling the ROS control program and selecting appropriate modules for porting to run on a GPU is described. A GPU-targeting compiler, Bacon, is used to speed up development and help optimize the ported modules. The impact of the ported modules on overall performance is discussed. We conclude that GPU optimization can free a significant amount of CPU resources with minimal effort for expensive user-written code, but that replacing heavily-optimized library functions is more difficult, and a much less efficient use of time.

  10. Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior

    PubMed Central

    Huang, Fei; Wang, Tingting; Lan, Yunyi; Yang, Li; Pan, Weihong; Zhu, Yonghui; Lv, Boyang; Wei, Yuting; Shi, Hailian; Wu, Hui; Zhang, Beibei; Wang, Jie; Duan, Xiaofeng; Hu, Zhibi; Wu, Xiaojun

    2015-01-01

    Farnesoid X receptor (FXR) is a nuclear hormone receptor involved in bile acid synthesis and homeostasis. Dysfunction of FXR is involved in cholestasis and atherosclerosis. FXR is prevalent in liver, gallbladder, and intestine, but it is not yet clear whether it modulates neurobehavior. In the current study, we tested the hypothesis that mouse FXR deficiency affects a specific subset of neurotransmitters and results in an unique behavioral phenotype. The FXR knockout mice showed less depressive-like and anxiety-related behavior, but increased motor activity. They had impaired memory and reduced motor coordination. There were changes of glutamatergic, GABAergic, serotoninergic, and norepinephrinergic neurotransmission in either hippocampus or cerebellum. FXR deletion decreased the amount of the GABA synthesis enzyme GAD65 in hippocampus but increased GABA transporter GAT1 in cerebral cortex. FXR deletion increased serum concentrations of many bile acids, including taurodehydrocholic acid, taurocholic acid, deoxycholic acid (DCA), glycocholic acid (GCA), tauro-α-muricholic acid, tauro-ω-muricholic acid, and hyodeoxycholic acid (HDCA). There were also changes in brain concentrations of taurocholic acid, taurodehydrocholic acid, tauro-ω-muricholic acid, tauro-β-muricholic acid, deoxycholic acid, and lithocholic acid (LCA). Taken together, the results from studies with FXR knockout mice suggest that FXR contributes to the homeostasis of multiple neurotransmitter systems in different brain regions and modulates neurobehavior. The effect appears to be at least partially mediated by bile acids that are known to cross the blood-brain barrier (BBB) inducing potential neurotoxicity. PMID:25870546

  11. The nuclear bile acid receptor FXR controls the liver derived tumor suppressor histidine-rich glycoprotein.

    PubMed

    Deuschle, Ulrich; Birkel, Manfred; Hambruch, Eva; Hornberger, Martin; Kinzel, Olaf; Perović-Ottstadt, Sanja; Schulz, Andreas; Hahn, Ulrike; Burnet, Michael; Kremoser, Claus

    2015-06-01

    The nuclear bile acid receptor Farnesoid X receptor (FXR) is strongly expressed in liver and intestine, controls bile acid and lipid homeostasis and exerts tumor-protective functions in liver and intestine. Histidine-rich glycoprotein (HRG) is an abundant plasma protein produced by the liver with the proposed function as a pattern recognition molecule involved in the clearance of immune complexes, necrotic cells and pathogens, the modulation of angiogenesis, the normalization of deranged endothelial vessel structure in tumors and tumor suppression. FXR recognition sequences were identified within a human HRG promoter fragment that mediated FXR/FXR-agonist dependent reporter gene activity in vitro. We show that HRG is a novel transcriptional target gene of FXR in human hepatoma cells, human upcyte® primary hepatocytes and 3D human liver microtissues in vitro and in mouse liver in vivo. Prolonged administration of the potent nonsteroidal FXR agonist PX20606 increases HRG levels in mouse plasma. Finally, daily oral administration of this FXR agonist for seven days resulted in a significant increase of HRG levels in the plasma of healthy human male volunteers during a clinical Phase I safety study. HRG might serve as a surrogate marker indicative of liver-specific FXR activation in future human clinical studies. Furthermore, potent FXR agonists might be beneficial in serious health conditions where HRG is reduced, for example, in hepatocellular carcinoma but also other solid cancers, liver failure, sepsis and pre-eclampsia. PMID:25363753

  12. Optimized capture section for a muon accelerator front end

    NASA Astrophysics Data System (ADS)

    Kamal Sayed, Hisham; Berg, J. Scott

    2014-07-01

    In a muon accelerator complex, a target is bombarded by a multi-MW proton beam to produce pions, which decay into the muons which are thereafter bunched, cooled, and accelerated. The front end of the complex captures those pions, then manipulates their phase space, and that of the muons into which they decay, to maximize the number of muons within the acceptance of the downstream systems. The secondary pion beam produced at the target is captured by a high field target solenoid that tapers down to a constant field throughout the rest of the front end. In this study we enhance the useful muon flux by introducing a new design of the longitudinal profile of the solenoid field at, and downstream of, the target. We find that the useful muon flux exiting the front end is larger when the field at the target is higher, the distance over which the field tapers down is shorter, and the field at the end of the taper is higher. We describe how the solenoid field profile impacts the transverse and longitudinal phase space of the beam and thereby leads to these dependencies.

  13. Optimizing chirped laser pulse parameters for electron acceleration in vacuum

    SciTech Connect

    Akhyani, Mina; Jahangiri, Fazel; Niknam, Ali Reza; Massudi, Reza

    2015-11-14

    Electron dynamics in the field of a chirped linearly polarized laser pulse is investigated. Variations of electron energy gain versus chirp parameter, time duration, and initial phase of laser pulse are studied. Based on maximizing laser pulse asymmetry, a numerical optimization procedure is presented, which leads to the elimination of rapid fluctuations of gain versus the chirp parameter. Instead, a smooth variation is observed that considerably reduces the accuracy required for experimentally adjusting the chirp parameter.

  14. A Parallel Particle Swarm Optimization Algorithm Accelerated by Asynchronous Evaluations

    NASA Technical Reports Server (NTRS)

    Venter, Gerhard; Sobieszczanski-Sobieski, Jaroslaw

    2005-01-01

    A parallel Particle Swarm Optimization (PSO) algorithm is presented. Particle swarm optimization is a fairly recent addition to the family of non-gradient based, probabilistic search algorithms that is based on a simplified social model and is closely tied to swarming theory. Although PSO algorithms present several attractive properties to the designer, they are plagued by high computational cost as measured by elapsed time. One approach to reduce the elapsed time is to make use of coarse-grained parallelization to evaluate the design points. Previous parallel PSO algorithms were mostly implemented in a synchronous manner, where all design points within a design iteration are evaluated before the next iteration is started. This approach leads to poor parallel speedup in cases where a heterogeneous parallel environment is used and/or where the analysis time depends on the design point being analyzed. This paper introduces an asynchronous parallel PSO algorithm that greatly improves the parallel e ciency. The asynchronous algorithm is benchmarked on a cluster assembled of Apple Macintosh G5 desktop computers, using the multi-disciplinary optimization of a typical transport aircraft wing as an example.

  15. DETERMINING THE OPTIMAL LOCATIONS FOR SHOCK ACCELERATION IN MAGNETOHYDRODYNAMICAL JETS

    SciTech Connect

    Polko, Peter; Markoff, Sera; Meier, David L.

    2010-11-10

    Observations of relativistic jets from black hole systems suggest that particle acceleration often occurs at fixed locations within the flow. These sites could be associated with critical points that allow the formation of standing shock regions, such as the magnetosonic modified fast point (MFP). Using the self-similar formulation of special relativistic magnetohydrodynamics by Vlahakis and Koenigl, we derive a new class of flow solutions that are both relativistic and cross the MFP at a finite height. Our solutions span a range of Lorentz factors up to at least 10, appropriate for most jets in X-ray binaries and active galactic nuclei, and a range in injected particle internal energy. A broad range of solutions exists, which will allow the eventual matching of these scale-free models to physical boundary conditions in the analysis of observed sources.

  16. FERMI&Elettra Accelerator Technical Optimization FinalReport

    SciTech Connect

    Cornacchia, M.; Craievich, P.; Di Mitri, S.; Pogorelov, I.; Qiang, J.; Venturini, M.; Zholents, A.; Wang, D.; Warnock, R.

    2006-07-01

    This report describes the accelerator physics aspects, theengineering considerations and the choice of parameters that led to theaccelerator design of the FERMI Free-Electron-Laser. The accelerator(also called the "electron beam delivery system") covers the region fromthe exit of the injector to the entrance of the first FEL undulator. Theconsiderations that led to the proposed configuration were made on thebasis of a study that explored various options and performance limits.This work follows previous studies of x-ray FEL facilities (SLAC LCLS[1], DESY XFEL [2], PAL XFEL [3], MIT [4], BESSY FEL[5], LBNL LUX [6],Daresbury 4GLS [7]) and integrates many of the ideas that were developedthere. Several issues specific to harmonic cascade FELs, and that had notyet been comprehensively studied, were also encountered and tackled. Aparticularly difficult issue was the need to meet the requirement forhigh peak current and small slice energy spread, as the specification forthe ratio of these two parameters (that defines the peak brightness ofthe electron beam) is almost a factor of two higher than that of theLCLS's SASE FEL. Another challenging aspect was the demand to produce anelectron beam with as uniform as possible peak current and energydistributions along the bunch, a condition that was met by introducingnovel beam dynamics techniques. Part of the challenge was due to the factthat there were no readily available computational tools to carry outreliable calculations, and these had to be developed. Most of theinformation reported in this study is available in the form of scientificpublications, and is partly reproduced here for the convenience of thereader.

  17. Preferential enhancement of laser-driven carbon ion acceleration from optimized nanostructured surfaces.

    PubMed

    Dalui, Malay; Wang, W-M; Trivikram, T Madhu; Sarkar, Subhrangsu; Sarkar, Subhrangshu; Tata, Sheroy; Jha, J; Ayyub, P; Sheng, Z M; Krishnamurthy, M

    2015-01-01

    High-intensity ultrashort laser pulses focused on metal targets readily generate hot dense plasmas which accelerate ions efficiently and can pave way to compact table-top accelerators. Laser-driven ion acceleration studies predominantly focus on protons, which experience the maximum acceleration owing to their highest charge-to-mass ratio. The possibility of tailoring such schemes for the preferential acceleration of a particular ion species is very much desired but has hardly been explored. Here, we present an experimental demonstration of how the nanostructuring of a copper target can be optimized for enhanced carbon ion acceleration over protons or Cu-ions. Specifically, a thin (≈ 0.25 μm) layer of 25-30 nm diameter Cu nanoparticles, sputter-deposited on a polished Cu-substrate, enhances the carbon ion energy by about 10-fold at a laser intensity of 1.2 × 10(18)  W/cm(2). However, particles smaller than 20 nm have an adverse effect on the ion acceleration. Particle-in-cell simulations provide definite pointers regarding the size of nanoparticles necessary for maximizing the ion acceleration. The inherent contrast of the laser pulse is found to play an important role in the species selective ion acceleration. PMID:26153048

  18. Preferential enhancement of laser-driven carbon ion acceleration from optimized nanostructured surfaces

    PubMed Central

    Dalui, Malay; Wang, W.-M.; Trivikram, T. Madhu; Sarkar, Subhrangshu; Tata, Sheroy; Jha, J.; Ayyub, P.; Sheng, Z. M.; Krishnamurthy, M.

    2015-01-01

    High-intensity ultrashort laser pulses focused on metal targets readily generate hot dense plasmas which accelerate ions efficiently and can pave way to compact table-top accelerators. Laser-driven ion acceleration studies predominantly focus on protons, which experience the maximum acceleration owing to their highest charge-to-mass ratio. The possibility of tailoring such schemes for the preferential acceleration of a particular ion species is very much desired but has hardly been explored. Here, we present an experimental demonstration of how the nanostructuring of a copper target can be optimized for enhanced carbon ion acceleration over protons or Cu-ions. Specifically, a thin (≈0.25 μm) layer of 25–30 nm diameter Cu nanoparticles, sputter-deposited on a polished Cu-substrate, enhances the carbon ion energy by about 10-fold at a laser intensity of 1.2×1018  W/cm2. However, particles smaller than 20 nm have an adverse effect on the ion acceleration. Particle-in-cell simulations provide definite pointers regarding the size of nanoparticles necessary for maximizing the ion acceleration. The inherent contrast of the laser pulse is found to play an important role in the species selective ion acceleration. PMID:26153048

  19. Preferential enhancement of laser-driven carbon ion acceleration from optimized nanostructured surfaces

    NASA Astrophysics Data System (ADS)

    Dalui, Malay; Wang, W.-M.; Trivikram, T. Madhu; Sarkar, Subhrangshu; Tata, Sheroy; Jha, J.; Ayyub, P.; Sheng, Z. M.; Krishnamurthy, M.

    2015-07-01

    High-intensity ultrashort laser pulses focused on metal targets readily generate hot dense plasmas which accelerate ions efficiently and can pave way to compact table-top accelerators. Laser-driven ion acceleration studies predominantly focus on protons, which experience the maximum acceleration owing to their highest charge-to-mass ratio. The possibility of tailoring such schemes for the preferential acceleration of a particular ion species is very much desired but has hardly been explored. Here, we present an experimental demonstration of how the nanostructuring of a copper target can be optimized for enhanced carbon ion acceleration over protons or Cu-ions. Specifically, a thin (≈0.25 μm) layer of 25-30 nm diameter Cu nanoparticles, sputter-deposited on a polished Cu-substrate, enhances the carbon ion energy by about 10-fold at a laser intensity of 1.2×1018  W/cm2. However, particles smaller than 20 nm have an adverse effect on the ion acceleration. Particle-in-cell simulations provide definite pointers regarding the size of nanoparticles necessary for maximizing the ion acceleration. The inherent contrast of the laser pulse is found to play an important role in the species selective ion acceleration.

  20. Optimization of Drive-Bunch Current Profile for Enhanced Transformer Ratio in Beam-Driven Acceleration Techniques

    SciTech Connect

    Lemery, F.; Mihalcea, D.; Prokop, C.R.; Piot, P.; /Northern Illinois U. /Fermilab

    2012-07-08

    In recent years, wakefield acceleration has gained attention due to its high acceleration gradients and cost effectiveness. In beam-driven wakefield acceleration, a critical parameter to optimize is the transformer ratio. It has been shown that current shaping of electron beams allows for enhanced (> 2) transformer ratios. In this paper we present the optimization of the pulse shape of the drive bunch for dielectric-wakefield acceleration.

  1. Optimization and Modeling of the Accelerator for the FERMI @ Elettra FEL

    SciTech Connect

    Di Mitri, S.; Cornacchia, M.; Craievich, P.; Emma, P.; Huang, Z.; Wu, J.; Wang, D.; Zholents, A.; /LBL, Berkeley

    2005-09-30

    Design studies are in progress to use the existing FERMI{at}Elettra linear accelerator for a seeded harmonic cascade free-electron laser (FEL) facility [1]. This accelerator will be upgraded to 1.2 GeV and equipped with a low-emittance RF photocathode gun, laser heater, two bunch compressors, and a beam delivery system. We present an optimization study of all the components downstream of the gun, aimed at achieving the high peak current, low energy spread and low emittance electron beam necessary for the FEL. Various operational scenarios are discussed. Results of accelerator simulations including effects of space charge, coherent synchrotron radiation and wakefields are reported.

  2. Optimization of an accelerator-based epithermal neutron source for neutron capture therapy

    SciTech Connect

    Kononov, O.E.; Kononov, V.N.; Bokhovko, M.V.; Korobeynikov, V.V.; Soloviev, A.N.; Chu, W.T.

    2004-02-20

    A modeling investigation was performed to choose moderator material and size for creating optimal epithermal neutron beams for BNCT based on a proton accelerator and the 7Li(p,n)7Be reaction as a neutrons source. An optimal configuration is suggested for the beam shaping assembly made from polytetrafluoroethylene and magnesium fluorine. Results of calculation were experimentally tested and are in good agreement with measurements.

  3. A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity.

    PubMed

    Kim, Dong-Hyun; Xiao, Zhen; Kwon, Sanghoon; Sun, Xiaoxiao; Ryerson, Daniel; Tkac, David; Ma, Ping; Wu, Shwu-Yuan; Chiang, Cheng-Ming; Zhou, Edward; Xu, H Eric; Palvimo, Jorma J; Chen, Lin-Feng; Kemper, Byron; Kemper, Jongsook Kim

    2015-01-13

    Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and acetylation-defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-κB but blocked that with RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα target genes. A dysregulated acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders. PMID:25425577

  4. Microbunching Instability Effect Studies and Laser Heater Optimization for the SPARX FEL Accelerator

    SciTech Connect

    Vaccarezza, C.; Chiadroni, E.; Ferrario, M.; Giannessi, L.; Quattromini, M.; Ronsivalle, C.; Venturini, C.; Migliorati, M.; Dattoli, G.

    2010-05-23

    The effects of microbunching instability for the SPARX accelerator have been analyzed by means of numerical simulations. The laser heater counteracting action has been addressed in order to optimize the parameters of the compression system, either hybrid RF plus magnetic chicane or only magnetic, and possibly enhance the FEL performance.

  5. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance.

    PubMed

    Fang, Sungsoon; Suh, Jae Myoung; Reilly, Shannon M; Yu, Elizabeth; Osborn, Olivia; Lackey, Denise; Yoshihara, Eiji; Perino, Alessia; Jacinto, Sandra; Lukasheva, Yelizaveta; Atkins, Annette R; Khvat, Alexander; Schnabl, Bernd; Yu, Ruth T; Brenner, David A; Coulter, Sally; Liddle, Christopher; Schoonjans, Kristina; Olefsky, Jerrold M; Saltiel, Alan R; Downes, Michael; Evans, Ronald M

    2015-02-01

    The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome. PMID:25559344

  6. Recent advances in non-steroidal FXR antagonists development for therapeutic applications.

    PubMed

    Huang, Huang; Xu, Yong; Zhu, Jin; Li, Jian

    2014-01-01

    Farnesoid X receptor (FXR, NR1H4), a nuclear receptor (NR) highly expressed in the liver, intestine, kidney, adrenal glands and other cholesterol-rich tissues, functions as the master regulator for bile acid homeostasis. FXR, which regulates the expression of genes encoding proteins involved in cholesterol homeostasis, plays an essential role in regulating cholesterol, lipid, and glucose metabolism. Recently, some FXR agonists are reported to have low selectivity on NRs, which forces the researchers to move their eyes onto the development of FXR antagonists with high selectivity. The development of non-steroidal FXR antagonists with different scaffolds including AGN34, tuberatolides, atractylenolides, andrographolides, GW4064 derivatives and 1,3,4-trisubstitutedpyrazolones, provides us a prospect for the therapy of in ammation, metabolic syndrome, diabetes, cholesterol gallstones, and cancer. PMID:25388534

  7. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance

    PubMed Central

    Fang, Sungsoon; Suh, Jae Myoung; Reilly, Shannon M; Yu, Elizabeth; Osborn, Olivia; Lackey, Denise; Yoshihara, Eiji; Perino, Alessia; Jacinto, Sandra; Lukasheva, Yelizaveta; Atkins, Annette R; Khvat, Alexander; Schnabl, Bernd; Yu, Ruth T; Brenner, David A; Coulter, Sally; Liddle, Christopher; Schoonjans, Kristina; Olefsky, Jerrold M; Saltiel, Alan R; Downes, Michael; Evans, Ronald M

    2015-01-01

    The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome. PMID:25559344

  8. FXR Primes the Liver for Intestinal FGF15 Signaling by Transient Induction of β-Klotho.

    PubMed

    Fu, Ting; Kim, Young-Chae; Byun, Sangwon; Kim, Dong-Hyun; Seok, Sunmi; Suino-Powell, Kelly; Xu, H Eric; Kemper, Byron; Kemper, Jongsook Kim

    2016-01-01

    The bile acid (BA)-sensing nuclear receptor, farnesoid X receptor (FXR), regulates postprandial metabolic responses, including inhibition of BA synthesis, by inducing the intestinal hormone, fibroblast growth factor (FGF)15 (FGF19 in human). In this study, we tested a novel hypothesis that FXR not only induces intestinal FGF15 but also primes the liver for effectively responding to the signal by transcriptional induction of the obligate coreceptor for FGF15, β-Klotho (βKL). Activation of FXR by a synthetic agonist, GW4064, in mice increased occupancy of FXR and its DNA-binding partner, retinoid X receptor-α, at FGF15-signaling component genes, particularly βKL, and induced expression of these genes. Interestingly, mRNA levels of Fgfr4, the FGF15 receptor, were not increased by GW4064, but protein levels increased as a result of βKL-dependent increased protein stability. Both FGF receptor 4 and βKL protein levels were substantially decreased in FXR-knockout (KO) mice, and FGF19 signaling, monitored by phosphorylated ERK, was blunted in FXR-KO mice, FXR-KO mouse hepatocytes, and FXR-down-regulated human hepatocytes. Overexpression of βKL in FXR-lacking hepatocytes partially restored FGF19 signaling and inhibition by FGF19 of Cyp7a1, which encodes the rate-limiting BA biosynthetic enzyme. In mice, transient inductions of intestinal Fgf15 and hepatic βKL were temporally correlated after GW4064 treatment, and pretreatment of hepatocytes with GW4064 before FGF19 treatment enhanced FGF19 signaling, which was abolished by transcriptional inhibition or βKL down-regulation. This study identifies FXR as a gut-liver metabolic coordinator for FGF15/19 action that orchestrates transient induction of hepatic βKL and intestinal Fgf15/19 in a temporally correlated manner. PMID:26505219

  9. Role of FXR in β-cells of lean and obese mice.

    PubMed

    Schittenhelm, Björn; Wagner, Rebecca; Kähny, Verena; Peter, Andreas; Krippeit-Drews, Peter; Düfer, Martina; Drews, Gisela

    2015-04-01

    We have recently shown that the bile acid (BA) taurochenodeoxycholate (TCDC) acutely stimulates insulin secretion via activation of the farnesoid X receptor (FXR). Aims of the current investigation were to discriminate between nongenomic (≤1 h) and genomic effects (24-48 h) of BAs on β-cells and to evaluate whether FXR can modulate the adverse effects of a high-fat diet (HFD). TCDC (500 nM) as well as glycine-conjugated and unconjugated CDC (chenodeoxycholate) increased insulin secretion in acute incubations but did not evoke additional effects after 1-2 days of preincubation. The BAs did not stimulate β-cells of FXR-knockout (KO) mice and activation of the G protein-coupled BA receptor TGR5 was ineffective, suggesting that FXR is the sole BA receptor in β-cells activated by TCDC and its analogues. As opposed to lean mice, obese FXR-KO mice did not show HFD-induced glucose intolerance and increased fasting glucose. The beneficial impact of FXR-KO on glucose metabolism cannot be explained by an adaptive compensation of insulin secretion or β-cell mass. Interestingly, in contrast to its effect on islets from lean mice, the FXR agonist GW4064 was ineffective in stimulating insulin secretion of islets from wild type mice fed a HFD or isolated islets kept in a glucolipotoxic medium. Additional feeding of CDC restored the effect of GW4064. CDC prevented HFD-induced impairment of glucose tolerance and in vitro effects of glucolipotoxicity. The data show that the FXR is the most important BA receptor in β-cells and that FXR signaling in β-cells is impaired by overnutrition, which alters activatability of the FXR. PMID:25599407

  10. Knocking on FXR's door: the "hammerhead"-structure series of FXR agonists - amphiphilic isoxazoles with potent in vitro and in vivo activities.

    PubMed

    Gege, Christian; Kinzel, Olaf; Steeneck, Christoph; Schulz, Andreas; Kremoser, Claus

    2014-01-01

    The Farnesoid X Receptor (FXR) was recently validated in clinical studies using the bile acid analogue Obeticholic Acid (OCA) as an attractive drug target for liver diseases such as Primary Biliary Cirrhosis (PBC) or Non-alcoholic Steatohepatitis (NASH). OCA, however, turned out to induce cholesterol- related side effects upon prolonged treatment and it shows bile acid like pharmacokinetics. The quest for synthetic non-steroidal FXR agonists with general drug likeliness and improved pharmacokinetic and - dynamic properties has started more than a decade ago: The first non-steroidal and selective FXR agonist with decent submicromolar potency, GW4064, was patented in 1998 and published in 2000. Since then, many pharmaceutical companies have taken GW4064 as a structural template for their efforts in identifying novel patentable FXR agonists with the GW-derived trisubstituted isoxazole general structure. However, so far only one compound out of these different series has made it into the early stages of clinical development: The Px-102/Px-104 from Phenex is currently tested in a phase IIa study in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). In this review we try to summarize from the patent and scientific literature the attempts to improve the GW4064 structure into different directions. Furthermore, we suggest directions for further improvements of this special class of synthetic FXR agonists which all display the typical "hammerhead"-conformation in the FXR ligand binding pocket that provides the basis for their impressive in vitro and in vivo potencies. PMID:25388536

  11. Non-linear stochastic optimal control of acceleration parametrically excited systems

    NASA Astrophysics Data System (ADS)

    Wang, Yong; Jin, Xiaoling; Huang, Zhilong

    2016-02-01

    Acceleration parametrical excitations have not been taken into account due to the lack of physical significance in macroscopic structures. The explosive development of microtechnology and nanotechnology, however, motivates the investigation of the acceleration parametrically excited systems. The adsorption and desorption effects dramatically change the mass of nano-sized structures, which significantly reduces the precision of nanoscale sensors or can be reasonably utilised to detect molecular mass. This manuscript proposes a non-linear stochastic optimal control strategy for stochastic systems with acceleration parametric excitation based on stochastic averaging of energy envelope and stochastic dynamic programming principle. System acceleration is approximately expressed as a function of system displacement in a short time range under the conditions of light damping and weak excitations, and the acceleration parametrically excited system is shown to be equivalent to a constructed system with an additional displacement parametric excitation term. Then, the controlled system is converted into a partially averaged Itô equation with respect to the total system energy through stochastic averaging of energy envelope, and the optimal control strategy for the averaged system is derived from solving the associated dynamic programming equation. Numerical results for a controlled Duffing oscillator indicate the efficacy of the proposed control strategy.

  12. Optimization of the combined proton acceleration regime with a target composition scheme

    NASA Astrophysics Data System (ADS)

    Yao, W. P.; Li, B. W.; Zheng, C. Y.; Liu, Z. J.; Yan, X. Q.; Qiao, B.

    2016-01-01

    A target composition scheme to optimize the combined proton acceleration regime is presented and verified by two-dimensional particle-in-cell simulations by using an ultra-intense circularly polarized (CP) laser pulse irradiating an overdense hydrocarbon (CH) target, instead of a pure hydrogen (H) one. The combined acceleration regime is a two-stage proton acceleration scheme combining the radiation pressure dominated acceleration (RPDA) stage and the laser wakefield acceleration (LWFA) stage sequentially together. Protons get pre-accelerated in the first stage when an ultra-intense CP laser pulse irradiating an overdense CH target. The wakefield is driven by the laser pulse after penetrating through the overdense CH target and propagating in the underdense tritium plasma gas. With the pre-accelerate stage, protons can now get trapped in the wakefield and accelerated to much higher energy by LWFA. Finally, protons with higher energies (from about 20 GeV up to about 30 GeV) and lower energy spreads (from about 18% down to about 5% in full-width at half-maximum, or FWHM) are generated, as compared to the use of a pure H target. It is because protons can be more stably pre-accelerated in the first RPDA stage when using CH targets. With the increase of the carbon-to-hydrogen density ratio, the energy spread is lower and the maximum proton energy is higher. It also shows that for the same laser intensity around 1022 W cm-2, using the CH target will lead to a higher proton energy, as compared to the use of a pure H target. Additionally, proton energy can be further increased by employing a longitudinally negative gradient of a background plasma density.

  13. PPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis

    PubMed Central

    Zhou, Xueyan; Cao, Lijuan; Jiang, Changtao; Xie, Yang; Cheng, Xuefang; Krausz, Kristopher W.; Qi, Yunpeng; Sun, Lu; Shah, Yatrik M.; Gonzalez, Frank J.; Wang, Guangji; Hao, Haiping

    2014-01-01

    Bile acids play a pivotal role in the pathological development of inflammatory bowel disease (IBD). However, the mechanism of bile acid dysregulation in IBD remains unanswered. Here we show that intestinal peroxisome proliferator-activated receptor α (PPARα)-UDP-glucuronosyltransferases (UGTs) signalling is an important determinant of bile acid homeostasis. Dextran sulphate sodium (DSS)-induced colitis leads to accumulation of bile acids in inflamed colon tissues via activation of the intestinal peroxisome PPARα-UGTs pathway. UGTs accelerate the metabolic elimination of bile acids, and thereby decrease their intracellular levels in the small intestine. Reduced intracellular bile acids results in repressed farnesoid X receptor (FXR)-FGF15 signalling, leading to upregulation of hepatic CYP7A1, thus promoting the de novo bile acid synthesis. Both knockout of PPARα and treatment with recombinant FGF19 markedly attenuate DSS-induced colitis. Thus, we propose that intestinal PPARα-UGTs and downstream FXR-FGF15 signalling play vital roles in control of bile acid homeostasis and the pathological development of colitis. PMID:25183423

  14. Novel FXR (farnesoid X receptor) modulators: Potential therapies for cholesterol gallstone disease.

    PubMed

    Yu, Donna D; Andrali, Sreenath S; Li, Hongzhi; Lin, Min; Huang, Wendong; Forman, Barry M

    2016-09-15

    Metabolic disorders such as diabetes are known risk factors for developing cholesterol gallstone disease (CGD). Cholesterol gallstone disease is one of the most prevalent digestive diseases, leading to considerable financial and social burden worldwide. Ursodeoxycholic acid (UDCA) is the only bile acid drug approved by FDA for the non-surgical treatment of gallstones. However, the molecular link between UDCA and CGD is unclear. Previous data suggest that the farnesoid X receptor (FXR), a bile acid nuclear receptor, may protect against the development of CGD. In studies aimed at identifying the role of FXR, we recently identify a novel chemical tool, 6EUDCA (6-αethyl-ursodeoxycholic acid), a synthetic derivative of UDCA, for studying FXR. We found that 6EUDCA binds FXR stronger than UDCA in a TR-FRET binding assay. This result was supported by computational docking models that suggest 6EUDCA forms a more extensive hydrogen bound network with FXR. Interestingly, neither compound could activate FXR target genes in human nor mouse liver cells, suggesting UDCA and 6EUDCA activate non-genomic signals in an FXR-dependent manner. Overall these studies may lead to the identification of a novel mechanism by which bile acids regulate cell function, and 6EUDCA may be an effective targeted CGD therapeutic. PMID:27372840

  15. The nuclear receptor FXR regulates hepatic transport and metabolism of glutamine and glutamate.

    PubMed

    Renga, Barbara; Mencarelli, Andrea; Cipriani, Sabrina; D'Amore, Claudio; Zampella, Angela; Monti, Maria Chiara; Distrutti, Eleonora; Fiorucci, Stefano

    2011-11-01

    Hepatic transport and metabolism of glutamate and glutamine are regulated by intervention of several proteins. Glutamine is taken up by periportal hepatocytes and is the major source of ammonia for urea synthesis and glutamate for N-acetylglutamate (NAG) synthesis, which is catalyzed by the N-acetylglutamate synthase (NAGS). Glutamate is taken up by perivenous hepatocytes and is the main source for the synthesis of glutamine, catalyzed by glutamine synthase (GS). Accumulation of glutamate and ammonia is a common feature of chronic liver failure, but mechanism that leads to failure of the urea cycle in this setting is unknown. The Farnesoid X Receptor (FXR) is a bile acid sensor in hepatocytes. Here, we have investigated its role in the regulation of the metabolism of both glutamine and glutamate. In vitro studies in primary cultures of hepatocytes from wild type and FXR(-/-) mice and HepG2 cells, and in vivo studies, in FXR(-/-) mice as well as in a rodent model of hepatic liver failure induced by carbon tetrachloride (CCl(4)), demonstrate a role for FXR in regulating this metabolism. Further on, promoter analysis studies demonstrate that both human and mouse NAGS promoters contain a putative FXRE, an ER8 sequence. EMSA, ChIP and luciferase experiments carried out to investigate the functionality of this sequence demonstrate that FXR is essential to induce the expression of NAGS. In conclusion, FXR activation regulates glutamine and glutamate metabolism and FXR ligands might have utility in the treatment of hyperammonemia states. PMID:21757002

  16. Splenic dendritic cell involvement in FXR-mediated amelioration of DSS colitis.

    PubMed

    Massafra, Vittoria; Ijssennagger, Noortje; Plantinga, Maud; Milona, Alexandra; Ramos Pittol, José M; Boes, Marianne; van Mil, Saskia W C

    2016-02-01

    Inflammatory Bowel Disease (IBD) is a multifactorial disorder involving dysregulation of the immune response and bacterial translocation through the intestinal mucosal barrier. Previously, we have shown that activation of the bile acid sensor Farnesoid X Receptor (FXR), which belongs to the family of nuclear receptors, improves experimental intestinal inflammation, decreasing expression of pro-inflammatory cytokines and protecting the intestinal barrier. Here, we aimed to investigate the immunological mechanisms that ameliorate colitis when FXR is activated. We analyzed by FACS immune cell populations in mesenteric lymph nodes (MLN) and in the spleen to understand whether FXR activation alters the systemic immune response. We show that FXR activation by obeticholic acid (OCA) has systemic anti-inflammatory effects that include increased levels of plasma IL-10, inhibition of both DSS-colitis associated decrease in splenic dendritic cells (DCs) and increase in Tregs. Impact of OCA on DC relative abundance was seen in spleen but not MLN, possibly related to the increased FXR expression in splenic DCs compared to MLN DCs. Moreover, FXR activation modulates the chemotactic environment in the colonic site of inflammation, as Madcam1 expression is decreased, while Ccl25 is upregulated. Together, our data suggest that OCA treatment elicits an anti-inflammatory immune status including retention of DCs in the spleen, which is associated with decreased colonic inflammation. Pharmacological FXR activation is therefore an attractive new drug target for treatment of IBD. PMID:26554605

  17. Suppression of interleukin-6-induced C-reactive protein expression by FXR agonists

    SciTech Connect

    Zhang Songwen Liu Qiangyuan; Wang Juan; Harnish, Douglas C.

    2009-02-06

    C-reactive protein (CRP), a human acute-phase protein, is a risk factor for future cardiovascular events and exerts direct pro-inflammatory and pro-atherogenic properties. The farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily, plays an essential role in the regulation of enterohepatic circulation and lipid homeostasis. In this study, we report that two synthetic FXR agonists, WAY-362450 and GW4064, suppressed interleukin-6-induced CRP expression in human Hep3B hepatoma cells. Knockdown of FXR by short interfering RNA attenuated the inhibitory effect of the FXR agonists and also increased the ability of interleukin-6 to induce CRP production. Furthermore, treatment of wild type C57BL/6 mice with the FXR agonist, WAY-362450, attenuated lipopolysaccharide-induced serum amyloid P component and serum amyloid A3 mRNA levels in the liver, whereas no effect was observed in FXR knockout mice. These data provide new evidence for direct anti-inflammatory properties of FXR.

  18. Investigation of the dominant positive effect of porcine farnesoid X receptor (FXR) splice variant 1.

    PubMed

    Gray, Matthew A; James Squires, E

    2015-04-10

    Pigs are well recognized as a model for humans in research studies due to similarities in metabolism and physiology between the two species. The potential for pigs to model humans in studying metabolic diseases is highly dependent on similarities in hepatic metabolism between the two species, including similarities in the farnesoid X receptor (FXR; NR1H4) which regulate bile acid homeostasis. During initial cloning of porcine FXR (pFXR), an alternative splice variant (pFXR-SV1) was isolated which contained a four amino acid (MYTG) insert that exerted a dominant positive effect on the wild type receptor (pFXR-WT). The current study investigated the role of this insert in the dominant positive effect. Individual point mutations were made to the first three amino acids of the MYTG insert. Mutations of the methionine (M) or threonine (T) to alanine (A) reduced the dominant positive effect, while mutation of the tyrosine (Y) to either A or phenylalanine (F) completely abolished the dominant positive effect. Treatment with the tyrosine phosphatase inhibitor sodium orthovanadate (Na3VO4) increased the dominant positive effect of pFXR-SV1 by about 30%. These results suggest that the dominant positive effect may be dependent on the phosphorylation status of the tyrosine in the MYTG insert. The human variant hFXRα+ has the same MYTG insert as pFXR-SV1, but did not cause a dominant positive effect on hFXR-WT and significantly reduced the activity of hFXR-WT. Thus, although the MYTG insert is conserved in both human and pig, the effects of this insert are different in the two species. PMID:25623328

  19. Modern Simulation and Optimization Tools for Non-Scaling FFAGs and Related Accelerators

    SciTech Connect

    C. Johnstone; M. Berz; K. Makino

    2010-11-04

    With the U.S. experimental effort in HEP largely located at laboratories supporting the operations of large, highly specialized accelerators, the understanding and prediction of high energy particle accelerators becomes critical to the overall success of the DOE HEP program. One area in which small businesses can contribute to the ongoing success of the U.S. program in HEP is through innovations in computer techniques and sophistication in the modeling of high-energy accelerators. A specific newly identified problem lies in the simulation and optimization of FFAGs and related devices, for which currently available tools originally developed for other purposes provide only approximate and inefficient simulation. We propose to develop a set of tools for this purpose based on modern techniques and simulation approaches.

  20. Optimization of parameters for the inline-injection system at Brookhaven Accelerator Test Facility

    SciTech Connect

    Parsa, Z.; Ko, S.K.

    1995-10-01

    We present some of our parameter optimization results utilizing code PARMLEA, for the ATF Inline-Injection System. The new solenoid-Gun-Solenoid -- Drift-Linac Scheme would improve the beam quality needed for FEL and other experiments at ATF as compared to the beam quality of the original design injection system. To optimize the gain in the beam quality we have considered various parameters including the accelerating field gradient on the photoathode, the Solenoid field strengths, separation between the gun and entrance to the linac as well as the (type size) initial charge distributions. The effect of the changes in the parameters on the beam emittance is also given.

  1. Automated ARGET ATRP Accelerates Catalyst Optimization for the Synthesis of Thiol-Functionalized Polymers

    PubMed Central

    Siegwart, Daniel J.; Leiendecker, Matthias; Langer, Robert; Anderson, Daniel G.

    2013-01-01

    Conventional synthesis of polymers by ATRP is relatively low throughput, involving iterative optimization of conditions in an inert atmosphere. Automated, high-throughput controlled radical polymerization was developed to accelerate catalyst optimization and production of disulfide-functionalized polymers without the need of an inert gas. Using ARGET ATRP, polymerization conditions were rapidly identified for eight different monomers, including the first ARGET ATRP of 2-(diethylamino)ethyl methacrylate and di(ethylene glycol) methyl ether methacrylate. In addition, butyl acrylate, oligo(ethylene glycol) methacrylate 300 and 475, 2-(dimethylamino)ethyl methacrylate, styrene, and methyl methacrylate were polymerized using bis(2-hydroxyethyl) disulfide bis(2-bromo-2-methylpropionate) as the initiator, tris(2-pyridylmethyl)amine as the ligand, and tin(II) 2-ethylhexanoate as the reducing agent. The catalyst and reducing agent concentration was optimized specifically for each monomer, and then a library of polymers was synthesized systematically using the optimized conditions. The disulfide-functionalized chains could be cleaved to two thiol-terminated chains upon exposure to dithiothreitol, which may have utility for the synthesis of polymer bioconjugates. Finally, we demonstrated that these new conditions translated perfectly to conventional batch polymerization. We believe the methods developed here may prove generally useful to accelerate the systematic optimization of a variety of chemical reactions and polymerizations. PMID:23599541

  2. Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis.

    PubMed

    Kong, Bo; Zhu, Yan; Li, Guodong; Williams, Jessica A; Buckley, Kyle; Tawfik, Ossama; Luyendyk, James P; Guo, Grace L

    2016-03-01

    Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily with its endogenous ligands bile acids. Mice with whole body FXR deficiency develop liver tumors spontaneously, but the underlying mechanism is unclear. Moreover, it is unknown whether FXR deficiency in liver alone serves as a tumor initiator or promoter during liver carcinogenesis. This study aims to evaluate the effects of hepatocyte-specific FXR deficiency (FXR(hep-/-)) in liver tumor formation. The results showed that FXR(hep-/-) mice did not show spontaneous liver tumorigenesis with aging (up to 24 mo of age). Therefore FXR(hep-/-) mice were fed a bile acid (cholic acid)-containing diet alone or along with a liver tumor initiator, diethylnitrosamine (DEN). Thirty weeks later, no tumors were found in wild-type or FXR(hep-/-) mice without any treatment or with DEN only. However, with cholic acid, while only some wild-type mice developed tumors, all FXR(hep-/-) mice presented with severe liver injury and tumors. Interestingly, FXR(hep-/-) mouse livers increased basal expression of tumor suppressor p53 protein, apoptosis, and decreased basal cyclin D1 expression, which may prevent tumor development in FXR(hep-/-) mice. However, cholic acid feeding reversed these effects in FXR(hep-/-) mice, which is associated with an increased cyclin D1 and decreased cell cycle inhibitors. More in-depth analysis indicates that the increased in cell growth might result from disturbance of the MAPK and JAK/Stat3 signaling pathways. In conclusion, this study shows that hepatic FXR deficiency may only serve as a tumor initiator, and increased bile acids is required for tumor formation likely by promoting cell proliferation. PMID:26744468

  3. Three-dimensional magnetic optimization of accelerator magnets using an analytic strip model

    SciTech Connect

    Rochepault, Etienne Aubert, Guy; Vedrine, Pierre

    2014-07-14

    The end design is a critical step in the design of superconducting accelerator magnets. First, the strain energy of the conductors must be minimized, which can be achieved using differential geometry. The end design also requires an optimization of the magnetic field homogeneity. A mechanical and magnetic model for the conductors, using developable strips, is described in this paper. This model can be applied to superconducting Rutherford cables, and it is particularly suitable for High Temperature Superconducting tapes. The great advantage of this approach is analytic simplifications in the field computation, allowing for very fast and accurate computations, which save a considerable computational time during the optimization process. Some 3D designs for dipoles are finally proposed, and it is shown that the harmonic integrals can be easily optimized using this model.

  4. Three-dimensional magnetic optimization of accelerator magnets using an analytic strip model

    NASA Astrophysics Data System (ADS)

    Rochepault, Etienne; Aubert, Guy; Vedrine, Pierre

    2014-07-01

    The end design is a critical step in the design of superconducting accelerator magnets. First, the strain energy of the conductors must be minimized, which can be achieved using differential geometry. The end design also requires an optimization of the magnetic field homogeneity. A mechanical and magnetic model for the conductors, using developable strips, is described in this paper. This model can be applied to superconducting Rutherford cables, and it is particularly suitable for High Temperature Superconducting tapes. The great advantage of this approach is analytic simplifications in the field computation, allowing for very fast and accurate computations, which save a considerable computational time during the optimization process. Some 3D designs for dipoles are finally proposed, and it is shown that the harmonic integrals can be easily optimized using this model.

  5. FXR1P is a GSK3β substrate regulating mood and emotion processing

    PubMed Central

    Del’Guidice, Thomas; Latapy, Camille; Rampino, Antonio; Khlghatyan, Jivan; Lemasson, Morgane; Gelao, Barbara; Quarto, Tiziana; Rizzo, Giuseppe; Barbeau, Annie; Lamarre, Claude; Bertolino, Alessandro; Blasi, Giuseppe; Beaulieu, Jean-Martin

    2015-01-01

    Inhibition of glycogen synthase kinase 3β (GSK3β) is a shared action believed to be involved in the regulation of behavior by psychoactive drugs such as antipsychotics and mood stabilizers. However, little is known about the identity of the substrates through which GSK3β affects behavior. We identified fragile X mental retardation-related protein 1 (FXR1P), a RNA binding protein associated to genetic risk for schizophrenia, as a substrate for GSK3β. Phosphorylation of FXR1P by GSK3β is facilitated by prior phosphorylation by ERK2 and leads to its down-regulation. In contrast, behaviorally effective chronic mood stabilizer treatments in mice inhibit GSK3β and increase FXR1P levels. In line with this, overexpression of FXR1P in the mouse prefrontal cortex also leads to comparable mood-related responses. Furthermore, functional genetic polymorphisms affecting either FXR1P or GSK3β gene expression interact to regulate emotional brain responsiveness and stability in humans. These observations uncovered a GSK3β/FXR1P signaling pathway that contributes to regulating mood and emotion processing. Regulation of FXR1P by GSK3β also provides a mechanistic framework that may explain how inhibition of GSK3β can contribute to the regulation of mood by psychoactive drugs in mental illnesses such as bipolar disorder. Moreover, this pathway could potentially be implicated in other biological functions, such as inflammation and cell proliferation, in which FXR1P and GSK3 are known to play a role. PMID:26240334

  6. Bile Acids, FXR, and Metabolic Effects of Bariatric Surgery

    PubMed Central

    Noel, Olivier F.; Still, Christopher D.; Argyropoulos, George; Edwards, Michael; Gerhard, Glenn S.

    2016-01-01

    Overweight and obesity represent major risk factors for diabetes and related metabolic diseases. Obesity is associated with a chronic and progressive inflammatory response leading to the development of insulin resistance and type 2 diabetes (T2D) mellitus, although the precise mechanism mediating this inflammatory process remains poorly understood. The most effective intervention for the treatment of obesity, bariatric surgery, leads to glucose normalization and remission of T2D. Recent work in both clinical studies and animal models supports bile acids (BAs) as key mediators of these effects. BAs are involved in lipid and glucose homeostasis primarily via the farnesoid X receptor (FXR) transcription factor. BAs are also involved in regulating genes involved in inflammation, obesity, and lipid metabolism. Here, we review the novel role of BAs in bariatric surgery and the intersection between BAs and immune, obesity, weight loss, and lipid metabolism genes. PMID:27006824

  7. Optimization and beam control in large-emittance accelerators: Neutrino factories;

    SciTech Connect

    Carol Johnstone

    2004-08-23

    Schemes for intense sources of high-energy muons require collection, rf capture, and transport of particle beams with unprecedented emittances, both longitudinally and transversely. These large emittances must be reduced or ''cooled'' both in size and in energy spread before the muons can be efficiently accelerated. Therefore, formation of muon beams sufficiently intense to drive a Neutrino Factory or Muon Collider requires multi-stage preparation. Further, because of the large beam phase space which must be successfully controlled, accelerated, and transported, the major stages that comprise such a facility: proton driver, production, capture, phase rotation, cooling, acceleration, and storage are complex and strongly interlinked. Each of the stages must be consecutively matched and simultaneously optimized with upstream and downstream systems, meeting challenges not only technically in the optics and component design, but also in the modeling of both new and extended components. One design for transverse cooling, for example, employs meter-diameter solenoids to maintain strong focusing--300-500 mr beam divergences--across ultra-large momentum ranges, {ge} {+-}20% {delta}p/p, defying conventional approximations to the dynamics and field representation. To now, the interplay of the different systems and staging strategies has not been formally addressed. This work discusses two basic, but different approaches to a Neutrino Factory and how the staging strategy depends on beam parameters and method of acceleration.

  8. Design and Optimization of Large Accelerator Systems through High-Fidelity Electromagnetic Simulations

    SciTech Connect

    Ng, Cho; Akcelik, Volkan; Candel, Arno; Chen, Sheng; Ge, Lixin; Kabel, Andreas; Lee, Lie-Quan; Li, Zenghai; Prudencio, Ernesto; Schussman, Greg; Uplenchwar1, Ravi; Xiao1, Liling; Ko1, Kwok; Austin, T.; Cary, J.R.; Ovtchinnikov, S.; Smith, D.N.; Werner, G.R.; Bellantoni, L.; /SLAC /TechX Corp. /Fermilab

    2008-08-01

    SciDAC1, with its support for the 'Advanced Computing for 21st Century Accelerator Science and Technology' (AST) project, witnessed dramatic advances in electromagnetic (EM) simulations for the design and optimization of important accelerators across the Office of Science. In SciDAC2, EM simulations continue to play an important role in the 'Community Petascale Project for Accelerator Science and Simulation' (ComPASS), through close collaborations with SciDAC CETs/Institutes in computational science. Existing codes will be improved and new multi-physics tools will be developed to model large accelerator systems with unprecedented realism and high accuracy using computing resources at petascale. These tools aim at targeting the most challenging problems facing the ComPASS project. Supported by advances in computational science research, they have been successfully applied to the International Linear Collider (ILC) and the Large Hadron Collider (LHC) in High Energy Physics (HEP), the JLab 12-GeV Upgrade in Nuclear Physics (NP), as well as the Spallation Neutron Source (SNS) and the Linac Coherent Light Source (LCLS) in Basic Energy Sciences (BES).

  9. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.

    PubMed

    Verbeke, Len; Farre, Ricard; Verbinnen, Bert; Covens, Kris; Vanuytsel, Tim; Verhaegen, Jan; Komuta, Mina; Roskams, Tania; Chatterjee, Sagnik; Annaert, Pieter; Vander Elst, Ingrid; Windmolders, Petra; Trebicka, Jonel; Nevens, Frederik; Laleman, Wim

    2015-02-01

    Bacterial translocation (BTL) drives pathogenesis and complications of cirrhosis. Farnesoid X-activated receptor (FXR) is a key transcription regulator in hepatic and intestinal bile metabolism. We studied potential intestinal FXR dysfunction in a rat model of cholestatic liver injury and evaluated effects of obeticholic acid (INT-747), an FXR agonist, on gut permeability, inflammation, and BTL. Rats were gavaged with INT-747 or vehicle during 10 days after bile-duct ligation and then were assessed for changes in gut permeability, BTL, and tight-junction protein expression, immune cell recruitment, and cytokine expression in ileum, mesenteric lymph nodes, and spleen. Auxiliary in vitro BTL-mimicking experiments were performed with Transwell supports. Vehicle-treated bile duct-ligated rats exhibited decreased FXR pathway expression in both jejunum and ileum, in association with increased gut permeability through increased claudin-2 expression and related to local and systemic recruitment of natural killer cells resulting in increased interferon-γ expression and BTL. After INT-747 treatment, natural killer cells and interferon-γ expression markedly decreased, in association with normalized permeability selectively in ileum (up-regulated claudin-1 and occludin) and a significant reduction in BTL. In vitro, interferon-γ induced increased Escherichia coli translocation, which remained unaffected by INT-747. In experimental cholestasis, FXR agonism improved ileal barrier function by attenuating intestinal inflammation, leading to reduced BTL and thus demonstrating a crucial protective role for FXR in the gut-liver axis. PMID:25592258

  10. Data on the optimization of behavioral tasks for senescence-accelerated mouse prone 8 (SAMP8).

    PubMed

    Yanai, Shuichi; Endo, Shogo

    2016-09-01

    This data article contains the supporting information for the research article entitled "Early onset of behavioral alterations in senescence-accelerated mouse prone 8 (SAMP8)" [1]. Senescence-accelerated mouse prone 8 (SAMP8), which originally developed from AKR/J mice, shows learning and memory impairments at the age of 8-12 months. However, little information is still available on phenotypical characteristics of younger SAMP8. To fully understand the phenotype of younger SAMP8, we optimized two behavioral tasks for SAMP8. In the object recognition task, 4-month-old SAMP8 made significantly more contacts with the familiar objects compared to age-matched SAMR1, however, distance traveled for both strains of mice were comparable. In the fear conditioning task, conventionally-used CS-US combination failed to induce robust conditioned fear in both strains of mice. PMID:27331099

  11. Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease

    PubMed Central

    Jin, Lihua; Wang, Rui; Zhu, Yanlin; Zheng, Weili; Han, Yaping; Guo, Fusheng; Ye, Frank Bin; Li, Yong

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. Farnesoid X receptor (FXR) is an ideal target for NAFLD drug development due to its crucial roles in lipid metabolism. The aim of this work is to examine the molecular mechanisms and functional roles of FXR modulation by avermectin analogues in regulating metabolic syndromes like NAFLD. We found that among avermectin analogues studied, the analogues that can bind and activate FXR are effective in regulating metabolic parameters tested, including reducing hepatic lipid accumulation, lowering serum cholesterol and glucose levels, and improving insulin sensitivity, in a FXR dependent manner. Mechanistically, the avermectin analogues that interact with FXR exhibited features as partial agonists, with distinctive properties in modulating coregulator recruitment. Structural features critical for avermectin analogues to selectively bind to FXR were also revealed. This study indicated that in addition to antiparasitic activity, avermectin analogues are promising drug candidates to treat metabolism syndrome including NAFLD by directly targeting FXR. Additionally, the structural features that discriminate the selective binding of FXR by avermectin analogues may provide a unique safe approach to design drugs targeting FXR signaling. PMID:26620317

  12. FXR blocks the growth of liver cancer cells through inhibiting mTOR-s6K pathway.

    PubMed

    Huang, Xiongfei; Zeng, Yeting; Wang, Xinrui; Ma, Xiaoxiao; Li, Qianqian; Li, Ningbo; Su, Hongying; Huang, Wendong

    2016-05-27

    The nuclear receptor Farnesoid X Receptor (FXR) is likely a tumor suppressor in liver tissue but its molecular mechanism of suppression is not well understood. In this study, the gene expression profile of human liver cancer cells was investigated by microarray. Bioinformatics analysis of these data revealed that FXR might regulate the mTOR/S6K signaling pathway. This was confirmed by altering the expression level of FXR in liver cancer cells. Overexpression of FXR prevented the growth of cells and induced cell cycle arrest, which was enhanced by the mTOR/S6K inhibitor rapamycin. FXR upregulation also intensified the inhibition of cell growth by rapamycin. Downregulation of FXR produced the opposite effect. Finally, we found that ectopic expression of FXR in SK-Hep-1 xenografts inhibits tumor growth and reduces expression of the phosphorylated protein S6K. Taken together, our data provide the first evidence that FXR suppresses proliferation of human liver cancer cells via the inhibition of the mTOR/S6K signaling pathway. FXR expression can be used as a biomarker of personalized mTOR inhibitor treatment assessment for liver cancer patients. PMID:27109477

  13. Optimization and control of two-component radially self-accelerating beams

    SciTech Connect

    Vetter, Christian; Eichelkraut, Toni; Ornigotti, Marco; Szameit, Alexander

    2015-11-23

    We report on the properties of radially self-accelerating intensity distributions consisting of two components in the angular frequency domain. We show how this subset of solutions, in literature also known as helicon beams, possesses peculiar characteristics that enable a better control over its properties. In this work, we present a step-by-step optimization procedure to achieve the best possible intensity contrast, a distinct rotation rate and long propagation lengths. All points are discussed on a theoretical basis and are experimentally verified.

  14. Optimal convolution SOR acceleration of waveform relaxation with application to semiconductor device simulation

    NASA Technical Reports Server (NTRS)

    Reichelt, Mark

    1993-01-01

    In this paper we describe a novel generalized SOR (successive overrelaxation) algorithm for accelerating the convergence of the dynamic iteration method known as waveform relaxation. A new convolution SOR algorithm is presented, along with a theorem for determining the optimal convolution SOR parameter. Both analytic and experimental results are given to demonstrate that the convergence of the convolution SOR algorithm is substantially faster than that of the more obvious frequency-independent waveform SOR algorithm. Finally, to demonstrate the general applicability of this new method, it is used to solve the differential-algebraic system generated by spatial discretization of the time-dependent semiconductor device equations.

  15. The buncher optimization for the biperiodic accelerating structure with the high-frequency focusing

    NASA Astrophysics Data System (ADS)

    Fadin, A. I.

    2006-03-01

    The bunching part optimization results of an on-axis-coupled biperiodic accelerating structure for electron linac with high-frequency focusing are presented. System is intended for operation in the continuous regime at operating frequency of 2856 MHz and input power 5.5 MW. The basic development challenge for such installations on average input currents is the effective beam transfer through the structure. Some variants of the bunching sections distinguished by number of bunching cells were considered. The optimum capture ratio and an acceptable spectrum are provided by structure with five bunching cells. Optimization was carried out by means of dynamics simulation code PARMELA and a package of applied programs for the axial symmetric structures calculation SUPERFISH. Taking into account, space-charge limitation, the maximum capture ratio is 55%.

  16. Optimized ion acceleration using high repetition rate, variable thickness liquid crystal targets

    NASA Astrophysics Data System (ADS)

    Poole, Patrick; Willis, Christopher; Cochran, Ginevra; Andereck, C. David; Schumacher, Douglass

    2015-11-01

    Laser-based ion acceleration is a widely studied plasma physics topic for its applications to secondary radiation sources, advanced imaging, and cancer therapy. Recent work has centered on investigating new acceleration mechanisms that promise improved ion energy and spectrum. While the physics of these mechanisms is not yet fully understood, it has been observed to dominate for certain ranges of target thickness, where the optimum thickness depends on laser conditions including energy, pulse width, and contrast. The study of these phenomena is uniquely facilitated by the use of variable-thickness liquid crystal films, first introduced in P. L. Poole et al. PoP21, 063109 (2014). Control of the formation parameters of these freely suspended films such as volume, temperature, and draw speed allows on-demand thickness variability between 10 nanometers and several 10s of microns, fully encompassing the currently studied thickness regimes with a single target material. The low vapor pressure of liquid crystal enables in-situ film formation and unlimited vacuum use of these targets. Details on the selection and optimization of ion acceleration mechanism with target thickness will be presented, including recent experiments on the Scarlet laser facility and others. This work was performed with support from the DARPA PULSE program through a grant from AMRDEC and by the NNSA under contract DE-NA0001976.

  17. SIRT1 controls liver regeneration by regulating BA metabolism through FXR and mTOR signaling

    PubMed Central

    García-Rodríguez, Juan L.; Barbier-Torres, Lucía; Fernández-Álvarez, Sara; Juan, Virginia Gutiérrez-de; Monte, María J.; Halilbasic, Emina; Herranz, Daniel; Álvarez, Luis; Aspichueta, Patricia; Marín, Jose J. G.; Trauner, Michael; Mato, Jose M.; Serrano, Manuel; Beraza, Naiara; Martínez-Chantar, María Luz

    2014-01-01

    Sirtuin1 (SIRT1) regulates central metabolic functions such as lipogenesis, protein synthesis, gluconeogenesis and bile acid (BA) homeostasis through deacetylation. Here, we describe that SIRT1 tightly controls the regenerative response of the liver. We performed partial hepatectomy (PH) to transgenic mice that overexpress SIRT1 (SIRT). SIRT mice showed increased mortality, impaired hepatocyte proliferation, BA accumulation and profuse liver injury after surgery. The damaging phenotype in SIRT mice correlated with impaired FXR activity due to persistent deacetylation and lower protein expression that led to decreased FXR-target gene expression; SHP, BSEP and increased Cyp7A1. Next, we convincingly show that 24-norUrsodeoxycholic acid (NorUDCA) attenuates SIRT protein expression, increases the acetylation of FXR and neighboring histones, restores trimethylation of H3K4 and H3K9 and increases miR34a expression, thus re-establishing BA homeostasis. Consequently, NorUDCA restored liver regeneration in SIRT mice, which showed increased survival and hepatocyte proliferation. Furthermore, a Leucine-enriched diet restored mTOR activation, acetylation of FXR and histones, leading to an overall lower BA production through SHP-inhibition of Cyp7A1 and higher transport (BSEP) and detoxification (Sult2a1) leading to an improved liver regeneration. Finally, we found that human HCC samples have increased presence of SIRT1, which correlated with absence of FXR suggesting its oncogenic potential. Conclusions Overall, we define SIRT1 as a key regulator of the regenerative response in the liver through post-transcriptional modifications that regulate the activity of FXR, histones and mTOR. Moreover, our data suggest that SIRT1 contributes to liver tumorigenesis through dysregulation of BA homeostasis by persistent FXR deacetylation. PMID:24338587

  18. Molecule-optimized basis sets and Hamiltonians for accelerated electronic structure calculations of atoms and molecules.

    PubMed

    Gidofalvi, Gergely; Mazziotti, David A

    2014-01-16

    Molecule-optimized basis sets, based on approximate natural orbitals, are developed for accelerating the convergence of quantum calculations with strongly correlated (multireferenced) electrons. We use a low-cost approximate solution of the anti-Hermitian contracted Schrödinger equation (ACSE) for the one- and two-electron reduced density matrices (RDMs) to generate an approximate set of natural orbitals for strongly correlated quantum systems. The natural-orbital basis set is truncated to generate a molecule-optimized basis set whose rank matches that of a standard correlation-consistent basis set optimized for the atoms. We show that basis-set truncation by approximate natural orbitals can be viewed as a one-electron unitary transformation of the Hamiltonian operator and suggest an extension of approximate natural-orbital truncations through two-electron unitary transformations of the Hamiltonian operator, such as those employed in the solution of the ACSE. The molecule-optimized basis set from the ACSE improves the accuracy of the equivalent standard atom-optimized basis set at little additional computational cost. We illustrate the method with the potential energy curves of hydrogen fluoride and diatomic nitrogen. Relative to the hydrogen fluoride potential energy curve from the ACSE in a polarized triple-ζ basis set, the ACSE curve in a molecule-optimized basis set, equivalent in size to a polarized double-ζ basis, has a nonparallelity error of 0.0154 au, which is significantly better than the nonparallelity error of 0.0252 au from the polarized double-ζ basis set. PMID:24387056

  19. Comparative effects of 1α-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on transporters and enzymes in fxr(+/+) and fxr(-/-) mice.

    PubMed

    Chow, Edwin C Y; Durk, Matthew R; Maeng, Han-Joo; Pang, K Sandy

    2013-10-01

    Previous studies have shown that 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] treatment in mice resulted in induction of intestinal and renal Cyp24a1 and Trpv6 expression, increased hepatic Cyp7a1 expression and activity, as well as higher renal Mdr1/P-gp expression. The present study compared the equimolar efficacies of 1α-hydroxyvitamin D3 [1α(OH)D3 ] (6 nmol/kg i.p. q2d × 4), a lipophilic precursor with a longer plasma half-life that is converted to 1,25(OH)2 D3 , and 1,25(OH)2 D3 on vitamin D receptor (VDR) target genes. To clarify whether changes in VDR genes was due to VDR and not secondary, farnesoid X receptor (FXR)-directed effects, namely, lower Cyp7a1 expression in rat liver due to increased bile acid absorption, wildtype [fxr(+/+)] and FXR knockout [fxr(-/-)] mice were used to distinguish between VDR and FXR effects. With the exception that hepatic Sult2a1 mRNA was increased equally well by 1α(OH)D3 and 1,25(OH)2 D3 , 1α(OH)D3 treatment led to higher increases in hepatic Cyp7a1, renal Cyp24a1, VDR, Mdr1 and Mrp4, and intestinal Cyp24a1 and Trpv6 mRNA expression in both fxr(+/+) and fxr(-/-) mice compared to 1,25(OH)2 D3 treatment. A similar induction in protein expression and microsomal activity of hepatic Cyp7a1 and renal P-gp and Mrp4 protein expression was noted for both compounds. A higher intestinal induction of Trpv6 was observed, resulting in greater hypercalcemic effect following 1α(OH)D3 treatment. The higher activity of 1α(OH)D3 was explained by its rapid conversion to 1,25(OH)2 D3 in tissue sites, furnishing higher plasma and tissue 1,25(OH)2 D3 levels compared to following 1,25(OH)2 D3 -treatment. In conclusion, 1α(OH)D3 exerts a greater effect on VDR gene induction than equimolar doses of 1,25(OH)2 D3 in mice. PMID:23897575

  20. Mechanisms of STAT3 activation in the liver of FXR knockout mice

    PubMed Central

    Li, Guodong; Zhu, Yan; Tawfik, Ossama; Kong, Bo; Williams, Jessica A.; Zhan, Le; Kassel, Karen M.; Luyendyk, James P.; Wang, Li

    2013-01-01

    Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is essential in maintaining bile acid (BA) homeostasis, and FXR−/− mice develop cholestasis, inflammation, and spontaneous liver tumors. The signal transducer and activator of transcription 3 (STAT3) is well known to regulate liver growth, and STAT3 is feedback inhibited by its target gene, the suppressor of cytokine signaling 3 (SOCS3). Strong activation of STAT3 was detected in FXR−/− mouse livers. However, the mechanism of STAT3 activation with FXR deficiency remains elusive. Wild-type (WT) and FXR−/− mice were used to detect STAT3 pathway activation in the liver. In vivo BA feeding or deprivation was used to determine the role of BAs in STAT3 activation, and in vitro molecular approaches were used to determine the direct transcriptional regulation of SOCS3 by FXR. STAT3 was activated in FXR−/− but not WT mice. BA feeding increased, but deprivation by cholestyramine reduced, serum inflammatory markers and STAT3 activation. Furthermore, the Socs3 gene was determined as a direct FXR target gene. The elevated BAs and inflammation, along with reduced SOCS3, collectively contribute to the activation of the STAT3 signaling pathway in the liver of FXR−/− mice. This study suggests that the constitutive activation of STAT3 may be a mechanism of liver carcinogenesis in FXR−/− mice. PMID:24091600

  1. Analytic characterization of linear accelerator radiosurgery dose distributions for fast optimization

    NASA Astrophysics Data System (ADS)

    Meeks, Sanford L.; Bova, Frank J.; Buatti, John M.; Friedman, William A.; Eyster, Brian; Kendrick, Lance A.

    1999-11-01

    Linear accelerator (linac) radiosurgery utilizes non-coplanar arc therapy delivered through circular collimators. Generally, spherically symmetric arc sets are used, resulting in nominally spherical dose distributions. Various treatment planning parameters may be manipulated to provide dose conformation to irregular lesions. Iterative manipulation of these variables can be a difficult and time-consuming task, because (a) understanding the effect of these parameters is complicated and (b) three-dimensional (3D) dose calculations are computationally expensive. This manipulation can be simplified, however, because the prescription isodose surface for all single isocentre distributions can be approximated by conic sections. In this study, the effects of treatment planning parameter manipulation on the dimensions of the treatment isodose surface were determined empirically. These dimensions were then fitted to analytic functions, assuming that the dose distributions were characterized as conic sections. These analytic functions allowed real-time approximation of the 3D isodose surface. Iterative plan optimization, either manual or automated, is achieved more efficiently using this real time approximation of the dose matrix. Subsequent to iterative plan optimization, the analytic function is related back to the appropriate plan parameters, and the dose distribution is determined using conventional dosimetry calculations. This provides a pseudo-inverse approach to radiosurgery optimization, based solely on geometric considerations.

  2. Determining optimization of the initial parameters in Monte Carlo simulation for linear accelerator radiotherapy

    NASA Astrophysics Data System (ADS)

    Chang, Kwo-Ping; Wang, Zhi-Wei; Shiau, An-Cheng

    2014-02-01

    Monte Carlo (MC) method is a well known calculation algorithm which can accurately assess the dose distribution for radiotherapy. The present study investigated all the possible regions of the depth-dose or lateral profiles which may affect the fitting of the initial parameters (mean energy and the radial intensity (full width at half maximum, FWHM) of the incident electron). EGSnrc-based BEAMnrc codes were used to generate the phase space files (SSD=100 cm, FS=40×40 cm2) for the linac (linear accelerator, Varian 21EX, 6 MV photon mode) and EGSnrc-based DOSXYZnrc code was used to calculate the dose in the region of interest. Interpolation of depth dose curves of pre-set energies was proposed as a preliminary step for optimal energy fit. A good approach for determination of the optimal mean energy is the difference comparison of the PDD curves excluding buildup region, and using D(10) as a normalization method. For FWHM fitting, due to electron disequilibrium and the larger statistical uncertainty, using horn or/and penumbra regions will give inconsistent outcomes at various depths. Difference comparisons should be performed in the flat regions of the off-axis dose profiles at various depths to optimize the FWHM parameter.

  3. Pipe degradation investigations for optimization of flow-accelerated corrosion inspection location selection

    SciTech Connect

    Chandra, S.; Habicht, P.; Chexal, B.; Mahini, R.; McBrine, W.; Esselman, T.; Horowitz, J.

    1995-12-01

    A large amount of piping in a typical nuclear power plant is susceptible to Flow-Accelerated Corrosion (FAC) wall thinning to varying degrees. A typical PAC monitoring program includes the wall thickness measurement of a select number of components in order to judge the structural integrity of entire systems. In order to appropriately allocate resources and maintain an adequate FAC program, it is necessary to optimize the selection of components for inspection by focusing on those components which provide the best indication of system susceptibility to FAC. A better understanding of system FAC predictability and the types of FAC damage encountered can provide some of the insight needed to better focus and optimize the inspection plan for an upcoming refueling outage. Laboratory examination of FAC damaged components removed from service at Northeast Utilities` (NU) nuclear power plants provides a better understanding of the damage mechanisms involved and contributing causes. Selected results of this ongoing study are presented with specific conclusions which will help NU to better focus inspections and thus optimize the ongoing FAC inspection program.

  4. A novel optimized parallelization strategy to accelerate microwave tomography for breast cancer screening.

    PubMed

    Shahzad, A; O'Halloran, M; Glavin, M; Jones, E

    2014-01-01

    Microwave tomography has been proven to successfully reconstruct the dielectric profile of a human breast when used in breast imaging applications, thereby providing an alternative to other imaging modalities. However, the method suffers from high computational requirements which restrict its use in practical imaging systems. This paper presents a novel parallelization strategy to accelerate microwave tomography for reconstruction of the dielectric properties of the human breast. A Time Domain algorithm using this parallelization strategy has been validated and benchmarked against an optimized sequential implementation on a conventional high-end desktop Central Processing Unit (CPU), and a comparison of throughput is presented in this paper. The gain in computational throughput is shown to be significantly higher compared with the sequential implementation, ranging from a factor of 26 to 58, on imaging grid sizes of up to 25 cm square at 1 mm resolution. PMID:25570487

  5. Detailed design optimization of the MITICA negative ion accelerator in view of the ITER NBI

    NASA Astrophysics Data System (ADS)

    Agostinetti, P.; Aprile, D.; Antoni, V.; Cavenago, M.; Chitarin, G.; de Esch, H. P. L.; De Lorenzi, A.; Fonnesu, N.; Gambetta, G.; Hemsworth, R. S.; Kashiwagi, M.; Marconato, N.; Marcuzzi, D.; Pilan, N.; Sartori, E.; Serianni, G.; Singh, M.; Sonato, P.; Spada, E.; Toigo, V.; Veltri, P.; Zaccaria, P.

    2016-01-01

    The ITER Neutral Beam Test Facility (PRIMA) is presently under construction at Consorzio RFX (Padova, Italy). PRIMA includes two experimental devices: an ITER-size ion source with low voltage extraction, called SPIDER, and the full prototype of the whole ITER Heating Neutral Beams (HNBs), called MITICA. The purpose of MITICA is to demonstrate that all operational parameters of the ITER HNB accelerator can be experimentally achieved, thus establishing a large step forward in the performances of neutral beam injectors in comparison with the present experimental devices. The design of the MITICA extractor and accelerator grids, here described in detail, was developed using an integrated approach, taking into consideration at the same time all the relevant physics and engineering aspects. Particular care was taken also to support and validate the design on the basis of the expertise and experimental data made available by the collaborating neutral beam laboratories of CEA, IPP, CCFE, NIFS and JAEA. Considering the operational requirements and the other physics constraints of the ITER HNBs, the whole design has been thoroughly optimized and improved. Furthermore, specific innovative concepts have been introduced.

  6. Optimization of accelerator target and detector for portal imaging using Monte Carlo simulation and experiment

    NASA Astrophysics Data System (ADS)

    Flampouri, S.; Evans, P. M.; Verhaegen, F.; Nahum, A. E.; Spezi, E.; Partridge, M.

    2002-09-01

    Megavoltage portal images suffer from poor quality compared to those produced with kilovoltage x-rays. Several authors have shown that the image quality can be improved by modifying the linear accelerator to generate more low-energy photons. This work addresses the problem of using Monte Carlo simulation and experiment to optimize the beam and detector combination to maximize image quality for a given patient thickness. A simple model of the whole imaging chain was developed for investigation of the effect of the target parameters on the quality of the image. The optimum targets (6 mm thick aluminium and 1.6 mm copper) were installed in an Elekta SL25 accelerator. The first beam will be referred to as Al6 and the second as Cu1.6. A tissue-equivalent contrast phantom was imaged with the 6 MV standard photon beam and the experimental beams with standard radiotherapy and mammography film/screen systems. The arrangement with a thin Al target/mammography system improved the contrast from 1.4 cm bone in 5 cm water to 19% compared with 2% for the standard arrangement of a thick, high-Z target/radiotherapy verification system. The linac/phantom/detector system was simulated with the BEAM/EGS4 Monte Carlo code. Contrast calculated from the predicted images was in good agreement with the experiment (to within 2.5%). The use of MC techniques to predict images accurately, taking into account the whole imaging system, is a powerful new method for portal imaging system design optimization.

  7. Optimization of accelerator parameters using normal form methods on high-order transfer maps

    SciTech Connect

    Snopok, Pavel; /Michigan State U.

    2007-05-01

    Methods of analysis of the dynamics of ensembles of charged particles in collider rings are developed. The following problems are posed and solved using normal form transformations and other methods of perturbative nonlinear dynamics: (1) Optimization of the Tevatron dynamics: (a) Skew quadrupole correction of the dynamics of particles in the Tevatron in the presence of the systematic skew quadrupole errors in dipoles; (b) Calculation of the nonlinear tune shift with amplitude based on the results of measurements and the linear lattice information; (2) Optimization of the Muon Collider storage ring: (a) Computation and optimization of the dynamic aperture of the Muon Collider 50 x 50 GeV storage ring using higher order correctors; (b) 750 x 750 GeV Muon Collider storage ring lattice design matching the Tevatron footprint. The normal form coordinates have a very important advantage over the particle optical coordinates: if the transformation can be carried out successfully (general restrictions for that are not much stronger than the typical restrictions imposed on the behavior of the particles in the accelerator) then the motion in the new coordinates has a very clean representation allowing to extract more information about the dynamics of particles, and they are very convenient for the purposes of visualization. All the problem formulations include the derivation of the objective functions, which are later used in the optimization process using various optimization algorithms. Algorithms used to solve the problems are specific to collider rings, and applicable to similar problems arising on other machines of the same type. The details of the long-term behavior of the systems are studied to ensure the their stability for the desired number of turns. The algorithm of the normal form transformation is of great value for such problems as it gives much extra information about the disturbing factors. In addition to the fact that the dynamics of particles is represented

  8. Chronic activation of FXR in transgenic mice caused perinatal toxicity and sensitized mice to cholesterol toxicity.

    PubMed

    Cheng, Qiuqiong; Inaba, Yuka; Lu, Peipei; Xu, Meishu; He, Jinhan; Zhao, Yueshui; Guo, Grace L; Kuruba, Ramalinga; de la Vega, Rona; Evans, Rhobert W; Li, Song; Xie, Wen

    2015-04-01

    The nuclear receptor farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4, or NR1H4) is highly expressed in the liver and intestine. Previous reports have suggested beneficial functions of FXR in the homeostasis of bile acids, lipids, and glucose, as well as in promoting liver regeneration and inhibiting carcinogenesis. To investigate the effect of chronic FXR activation in vivo, we generated transgenic mice that conditionally and tissue specifically express the activated form of FXR in the liver and intestine. Unexpectedly, the transgenic mice showed several intriguing phenotypes, including partial neonatal lethality, growth retardation, and spontaneous liver toxicity. The transgenic mice also displayed heightened sensitivity to a high-cholesterol diet-induced hepatotoxicity but resistance to the gallstone formation. The phenotypes were transgene specific, because they were abolished upon treatment with doxycycline to silence the transgene expression. The perinatal toxicity, which can be rescued by a maternal vitamin supplement, may have resulted from vitamin deficiency due to low biliary bile acid output as a consequence of inhibition of bile acid formation. Our results also suggested that the fibroblast growth factor-inducible immediate-early response protein 14 (Fn14), a member of the proinflammatory TNF family, is a FXR-responsive gene. However, the contribution of Fn14 induction in the perinatal toxic phenotype of the transgenic mice remains to be defined. Because FXR is being explored as a therapeutic target, our results suggested that a chronic activation of this nuclear receptor may have an unintended side effect especially during the perinatal stage. PMID:25719402

  9. Synthetic FXR agonist GW4064 is a modulator of multiple G protein-coupled receptors.

    PubMed

    Singh, Nidhi; Yadav, Manisha; Singh, Abhishek Kumar; Kumar, Harish; Dwivedi, Shailendra Kumar Dhar; Mishra, Jay Sharan; Gurjar, Anagha; Manhas, Amit; Chandra, Sharat; Yadav, Prem Narayan; Jagavelu, Kumaravelu; Siddiqi, Mohammad Imran; Trivedi, Arun Kumar; Chattopadhyay, Naibedya; Sanyal, Sabyasachi

    2014-05-01

    The synthetic nuclear bile acid receptor (farnesoid X receptor [FXR]) agonist GW4064 is extensively used as a specific pharmacological tool to illustrate FXR functions. We noticed that GW4064 activated empty luciferase reporters in FXR-deficient HEK-293T cells. We postulated that this activity of GW4064 might be routed through as yet unknown cellular targets and undertook an unbiased exploratory approach to identify these targets. Investigations revealed that GW4064 activated cAMP and nuclear factor for activated T-cell response elements (CRE and NFAT-RE, respectively) present on these empty reporters. Whereas GW4064-induced NFAT-RE activation involved rapid intracellular Ca(2+) accumulation and NFAT nuclear translocation, CRE activation involved soluble adenylyl cyclase-dependent cAMP accumulation and Ca(2+)-calcineurin-dependent nuclear translocation of transducers of regulated CRE-binding protein 2. Use of dominant negative heterotrimeric G-protein minigenes revealed that GW4064 caused activation of Gαi/o and Gq/11 G proteins. Sequential pharmacological inhibitor-based screening and radioligand-binding studies revealed that GW4064 interacted with multiple G protein-coupled receptors. Functional studies demonstrated that GW4064 robustly activated H1 and H4 and inhibited H2 histamine receptor signaling events. We also found that MCF-7 breast cancer cells, reported to undergo GW4064-induced apoptosis in an FXR-dependent manner, did not express FXR, and the GW4064-mediated apoptosis, also apparent in HEK-293T cells, could be blocked by selective histamine receptor regulators. Taken together, our results demonstrate identification of histamine receptors as alternate targets for GW4064, which not only necessitates cautious interpretation of the biological functions attributed to FXR using GW4064 as a pharmacological tool but also provides a basis for the rational designing of new pharmacophores for histamine receptor modulation. PMID:24597548

  10. Chronic Activation of FXR in Transgenic Mice Caused Perinatal Toxicity and Sensitized Mice to Cholesterol Toxicity

    PubMed Central

    Cheng, Qiuqiong; Inaba, Yuka; Lu, Peipei; Xu, Meishu; He, Jinhan; Zhao, Yueshui; Guo, Grace L.; Kuruba, Ramalinga; de la Vega, Rona; Evans, Rhobert W.; Li, Song

    2015-01-01

    The nuclear receptor farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4, or NR1H4) is highly expressed in the liver and intestine. Previous reports have suggested beneficial functions of FXR in the homeostasis of bile acids, lipids, and glucose, as well as in promoting liver regeneration and inhibiting carcinogenesis. To investigate the effect of chronic FXR activation in vivo, we generated transgenic mice that conditionally and tissue specifically express the activated form of FXR in the liver and intestine. Unexpectedly, the transgenic mice showed several intriguing phenotypes, including partial neonatal lethality, growth retardation, and spontaneous liver toxicity. The transgenic mice also displayed heightened sensitivity to a high-cholesterol diet-induced hepatotoxicity but resistance to the gallstone formation. The phenotypes were transgene specific, because they were abolished upon treatment with doxycycline to silence the transgene expression. The perinatal toxicity, which can be rescued by a maternal vitamin supplement, may have resulted from vitamin deficiency due to low biliary bile acid output as a consequence of inhibition of bile acid formation. Our results also suggested that the fibroblast growth factor-inducible immediate-early response protein 14 (Fn14), a member of the proinflammatory TNF family, is a FXR-responsive gene. However, the contribution of Fn14 induction in the perinatal toxic phenotype of the transgenic mice remains to be defined. Because FXR is being explored as a therapeutic target, our results suggested that a chronic activation of this nuclear receptor may have an unintended side effect especially during the perinatal stage. PMID:25719402

  11. Accelerated Simplified Swarm Optimization with Exploitation Search Scheme for Data Clustering

    PubMed Central

    Yeh, Wei-Chang; Lai, Chyh-Ming

    2015-01-01

    Data clustering is commonly employed in many disciplines. The aim of clustering is to partition a set of data into clusters, in which objects within the same cluster are similar and dissimilar to other objects that belong to different clusters. Over the past decade, the evolutionary algorithm has been commonly used to solve clustering problems. This study presents a novel algorithm based on simplified swarm optimization, an emerging population-based stochastic optimization approach with the advantages of simplicity, efficiency, and flexibility. This approach combines variable vibrating search (VVS) and rapid centralized strategy (RCS) in dealing with clustering problem. VVS is an exploitation search scheme that can refine the quality of solutions by searching the extreme points nearby the global best position. RCS is developed to accelerate the convergence rate of the algorithm by using the arithmetic average. To empirically evaluate the performance of the proposed algorithm, experiments are examined using 12 benchmark datasets, and corresponding results are compared with recent works. Results of statistical analysis indicate that the proposed algorithm is competitive in terms of the quality of solutions. PMID:26348483

  12. Optimization by response surface methodology of lutein recovery from paprika leaves using accelerated solvent extraction.

    PubMed

    Kang, Jae-Hyun; Kim, Suna; Moon, BoKyung

    2016-08-15

    In this study, we used response surface methodology (RSM) to optimize the extraction conditions for recovering lutein from paprika leaves using accelerated solvent extraction (ASE). The lutein content was quantitatively analyzed using a UPLC equipped with a BEH C18 column. A central composite design (CCD) was employed for experimental design to obtain the optimized combination of extraction temperature (°C), static time (min), and solvent (EtOH, %). The experimental data obtained from a twenty sample set were fitted to a second-order polynomial equation using multiple regression analysis. The adjusted coefficient of determination (R(2)) for the lutein extraction model was 0.9518, and the probability value (p=0.0000) demonstrated a high significance for the regression model. The optimum extraction conditions for lutein were temperature: 93.26°C, static time: 5 min, and solvent: 79.63% EtOH. Under these conditions, the predicted extraction yield of lutein was 232.60 μg/g. PMID:27006224

  13. Accelerated barrier optimization compressed sensing (ABOCS) reconstruction for cone-beam CT: Phantom studies

    PubMed Central

    Niu, Tianye; Zhu, Lei

    2012-01-01

    Purpose: Recent advances in compressed sensing (CS) enable accurate CT image reconstruction from highly undersampled and noisy projection measurements, due to the sparsifiable feature of most CT images using total variation (TV). These novel reconstruction methods have demonstrated advantages in clinical applications where radiation dose reduction is critical, such as onboard cone-beam CT (CBCT) imaging in radiation therapy. The image reconstruction using CS is formulated as either a constrained problem to minimize the TV objective within a small and fixed data fidelity error, or an unconstrained problem to minimize the data fidelity error with TV regularization. However, the conventional solutions to the above two formulations are either computationally inefficient or involved with inconsistent regularization parameter tuning, which significantly limit the clinical use of CS-based iterative reconstruction. In this paper, we propose an optimization algorithm for CS reconstruction which overcomes the above two drawbacks. Methods: The data fidelity tolerance of CS reconstruction can be well estimated based on the measured data, as most of the projection errors are from Poisson noise after effective data correction for scatter and beam-hardening effects. We therefore adopt the TV optimization framework with a data fidelity constraint. To accelerate the convergence, we first convert such a constrained optimization using a logarithmic barrier method into a form similar to that of the conventional TV regularization based reconstruction but with an automatically adjusted penalty weight. The problem is then solved efficiently by gradient projection with an adaptive Barzilai–Borwein step-size selection scheme. The proposed algorithm is referred to as accelerated barrier optimization for CS (ABOCS), and evaluated using both digital and physical phantom studies. Results: ABOCS directly estimates the data fidelity tolerance from the raw projection data. Therefore, as

  14. Accelerated testing of an optimized closing system for automotive fuel tank

    NASA Astrophysics Data System (ADS)

    Gligor, A.; Ilie, S.; Nicolae, V.; Mitran, G.

    2015-11-01

    Taking into account the legal prescriptions which are in force and the new regulatory requirements that will be mandatory to implement in the near future regarding testing characteristics of automotive fuel tanks, resulted the necessity to develop a new testing methodology which allows to estimate the behaviour of the closing system of automotive fuel tank over a long period of time (10-15 years). Thus, were designed and conducted accelerated tests under extreme assembling and testing conditions (high values for initial tightening torques, extreme values of temperature and pressure). In this paper are presented two of durability tests which were performed on an optimized closing system of fuel tank: (i) the test of exposure to temperature with cyclical variation and (ii) the test of continuous exposure to elevated temperature. In these experimental tests have been used main components of the closing system manufactured of two materials variants, both based on the polyoxymethylene, material that provides higher mechanical stiffness and strength in a wide temperature range, as well as showing increased resistance to the action of chemical agents and fuels. The tested sample included a total of 16 optimized locking systems, 8 of each of 2 versions of material. Over deploying the experiments were determined various parameters such as: the initial tightening torque, the tightening torque at different time points during measurements, the residual tightening torque, defects occurred in the system components (fissures, cracks, ruptures), the sealing conditions of system at the beginning and at the end of test. Based on obtained data were plotted the time evolution diagrams of considered parameter (the residual tightening torque of the system consisting of locking nut and threaded ring), in different temperature conditions, becoming possible to make pertinent assessments on the choice between the two types of materials. By conducting these tests and interpreting the

  15. Advanced Simulation and Optimization Tools for Dynamic Aperture of Non-scaling FFAGs and Accelerators including Modern User Interfaces

    SciTech Connect

    Mills, F.; Makino, Kyoko; Berz, Martin; Johnstone, C.

    2010-09-01

    With the U.S. experimental effort in HEP largely located at laboratories supporting the operations of large, highly specialized accelerators, colliding beam facilities, and detector facilities, the understanding and prediction of high energy particle accelerators becomes critical to the success, overall, of the DOE HEP program. One area in which small businesses can contribute to the ongoing success of the U.S. program in HEP is through innovations in computer techniques and sophistication in the modeling of high-energy accelerators. Accelerator modeling at these facilities is performed by experts with the product generally highly specific and representative only of in-house accelerators or special-interest accelerator problems. Development of new types of accelerators like FFAGs with their wide choices of parameter modifications, complicated fields, and the simultaneous need to efficiently handle very large emittance beams requires the availability of new simulation environments to assure predictability in operation. In this, ease of use and interfaces are critical to realizing a successful model, or optimization of a new design or working parameters of machines. In Phase I, various core modules for the design and analysis of FFAGs were developed and Graphical User Interfaces (GUI) have been investigated instead of the more general yet less easily manageable console-type output COSY provides.

  16. Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling.

    PubMed

    Dossa, Avafia Y; Escobar, Oswaldo; Golden, Jamie; Frey, Mark R; Ford, Henri R; Gayer, Christopher P

    2016-01-15

    Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation. PMID:26608185

  17. Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene

    SciTech Connect

    Bass, Jonathan Y.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Mills, Wendy Y.; Navas, III, Frank; Parks, Derek J.; Smalley, Jr., Terrence L.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2014-08-13

    To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.

  18. Comparative study of ion acceleration by linearly polarized laser pulses from optimized targets of solid and near-critical density

    NASA Astrophysics Data System (ADS)

    Bychenkov, V. Yu; Brantov, A. V.; Govras, E. A.

    2016-03-01

    The results of a 3D optimization study of ion acceleration from ultrathin solid density foils (Brantov et al 2015 Phys. Rev. Spec. Top. Accel. Beams 18 021301) are complemented with an improved analytic model of the directed Coulomb explosion. Similarly to optimizing overdense targets, we also optimize low-density targets to obtain maximum ion energy, motivated by progress in producing a new generation of low-density slab targets whose density can be very homogeneous and as low as the relativistic critical density. Using 3D simulations, we show that for the same laser pulse, the ion energy can be significantly increased with low-density targets. A new acceleration mechanism is responsible for such an increase. This mechanism is described qualitatively, and it explains an advantage of low-density targets for high-energy ion production by lasers.

  19. Genome-wide profiling to analyze the effects of FXR activation on mouse renal proximal tubular cells.

    PubMed

    Gui, Ting; Gai, Zhibo

    2015-12-01

    To assess the effect of farnesoid X receptor (FXR), a bile acid nuclear receptor, on renal proximal tubular cells, primary cultured mouse kidney proximal tubular cells were treated with GW4064 (a FXR agonist) or DMSO (as controls) overnight. Analysis of gene expression in the proximal tubular cells by whole genome microarrays indicated that FXR activation induced genes involved in fatty acid degradation and oxidation reduction. Among them, genes involved in glutathione metabolism were mostly induced. Here we describe in details the contents and quality controls for the gene expression and related results associated with the data uploaded to Gene Expression Omnibus (accession number GSE70296). PMID:26697325

  20. Genome-wide profiling to analyze the effects of FXR activation on mouse renal proximal tubular cells

    PubMed Central

    Gui, Ting; Gai, Zhibo

    2015-01-01

    To assess the effect of farnesoid X receptor (FXR), a bile acid nuclear receptor, on renal proximal tubular cells, primary cultured mouse kidney proximal tubular cells were treated with GW4064 (a FXR agonist) or DMSO (as controls) overnight. Analysis of gene expression in the proximal tubular cells by whole genome microarrays indicated that FXR activation induced genes involved in fatty acid degradation and oxidation reduction. Among them, genes involved in glutathione metabolism were mostly induced. Here we describe in details the contents and quality controls for the gene expression and related results associated with the data uploaded to Gene Expression Omnibus (accession number GSE70296). PMID:26697325

  1. Optimization of Beam Injection Into the First Accelerating Module at TTF With Cavity Dipole Mode Signals

    SciTech Connect

    Baboi, N.; Kreps, G.; Schlarb, H.; Wendt, M.; Frisch, J.; McCormick, D.; Ross, M.; Smith, T.; Napoly, O.; Paparella, R.G.; /DSM, DAPNIA, Saclay

    2006-04-10

    The TESLA Test Facility (TTF) is a user facility for intense VUV-FEL light. The facility is densely equipped with diagnostics, essential in obtaining the necessary beam parameters, in particular the low emittance. However there is no dedicated component for alignment of the beam in the accelerating modules, each containing eight superconducting cavities. Large beam offsets can lead to an increase of the beam emittance. The centering of the beam in these modules is therefore important, mostly at the low energy end. A misalignment of the first TTF module with respect to the gun axis has already been observed using cavity dipole modes. This paper presents the experimental results of the optimization of the beam injection into the first module, based on the monitoring of dipole modes through the couplers installed for wakefield damping. For this we use a spectrum analyzer together with a multiplexer. By scanning the beam position and tilt with two pairs of steerers, we can find the trajectory which minimizes the dipole modes amplitude. The impact of the beam steering in the module on the beam is discussed. A time domain setup is also being presented.

  2. Dose optimization for the MRI-accelerator: IMRT in the presence of a magnetic field

    NASA Astrophysics Data System (ADS)

    Raaijmakers, A. J. E.; Hårdemark, B.; Raaymakers, B. W.; Raaijmakers, C. P. J.; Lagendijk, J. J. W.

    2007-12-01

    A combined system of a 6 MV linear accelerator and a 1.5 T MRI scanner is currently being developed. In this system, the patient will be irradiated in the presence of a 1.5 T magnetic field. This causes a strong dose increase at tissue-air interfaces. Around air cavities in the patient, these effects may become problematic. Homogeneous dose distributions can be obtained around regularly shaped symmetrical cavities using opposing beams. However, for more irregularly shaped cavities this approach may not be sufficient. This study will investigate whether IMRT can be used to cope with magnetic field dose effects, in particular for target volumes adjacent to irregularly shaped air cavities. Therefore, an inverse treatment planning approach has been designed based on pre-calculated beamlet dose distribution kernels. Using this approach, optimized dose distributions were calculated for B = 1.5 T and for B = 0 T. Investigated target sites include a prostate cancer, a laryngeal cancer and an oropharyngeal cancer. Differences in the dose distribution between B = 0 and 1.5 T were minimal; only the skin dose increased for B = 1.5 T. Homogeneous dose distributions were obtained for target structures adjacent to air cavities without the use of opposing beams. These results show that a 1.5 T magnetic field does not compromise the ability to achieve desired dose distributions with IMRT.

  3. Acceleration of the Geostatistical Software Library (GSLIB) by code optimization and hybrid parallel programming

    NASA Astrophysics Data System (ADS)

    Peredo, Oscar; Ortiz, Julián M.; Herrero, José R.

    2015-12-01

    The Geostatistical Software Library (GSLIB) has been used in the geostatistical community for more than thirty years. It was designed as a bundle of sequential Fortran codes, and today it is still in use by many practitioners and researchers. Despite its widespread use, few attempts have been reported in order to bring this package to the multi-core era. Using all CPU resources, GSLIB algorithms can handle large datasets and grids, where tasks are compute- and memory-intensive applications. In this work, a methodology is presented to accelerate GSLIB applications using code optimization and hybrid parallel processing, specifically for compute-intensive applications. Minimal code modifications are added decreasing as much as possible the elapsed time of execution of the studied routines. If multi-core processing is available, the user can activate OpenMP directives to speed up the execution using all resources of the CPU. If multi-node processing is available, the execution is enhanced using MPI messages between the compute nodes.Four case studies are presented: experimental variogram calculation, kriging estimation, sequential gaussian and indicator simulation. For each application, three scenarios (small, large and extra large) are tested using a desktop environment with 4 CPU-cores and a multi-node server with 128 CPU-nodes. Elapsed times, speedup and efficiency results are shown.

  4. Dihydroartemisinin restricts hepatic stellate cell contraction via an FXR-S1PR2-dependent mechanism.

    PubMed

    Xu, Wenxuan; Lu, Chunfeng; Zhang, Feng; Shao, Jiangjuan; Zheng, Shizhong

    2016-05-01

    Hepatic stellate cells (HSCs) are universally acknowledged to play a stimulative role in the pathogenesis of hepatic fibrosis and portal hypertension. HSCs when activated in response to liver injury are characterized with many changes, with HSC contraction being the most common cause of portal hypertension. Previous studies have shown that dihydroartemisinine (DHA) is a potential antifibrotic natural product by inducing HSC apoptosis, whereas the role of DHA in regulating HSC contraction and the mechanisms involved remain a riddle. Recent studies have emphasized on the importance of farnesoid X receptor (FXR) and sphingosine-1-phosphate receptor 2 (S1PR2) in controlling cell contractility. This study showed that DHA strongly induced the mRNA and protein expression of FXR in LX-2 cells in a dose- and time-dependent manner and inhibited HSC activation, implying a conceivable impact of DHA on HSC contraction. The gel contraction assays and fluorescence staining of actin cytoskeleton verified that DHA dose-dependently limited contraction of collagen lattices and reorganization of actin stress fibers in LX-2 cells. DHA also decreased the phosphorylation of myosin light chain that is responsible for the contractile force of HSCs. Furthermore, gain- or loss-of-function analyses exhibited a FXR- and S1PR2-dependent mechanism of inhibiting HSC contraction by DHA, and DHA decreased S1PR2 expression by modulating FXR activation. Subsequent work revealed that inhibition of both Ca(2+) -dependent and Ca(2+) -sensitization signaling transductions contributed to DHA-induced HSC relaxation. In summary, these findings suggest that DHA could restrict HSC contraction through modulating FXR/S1PR2 pathway-mediated Ca(2+) -dependent and Ca(2+) -sensitization signaling. Our discoveries make DHA a potential candidate for portal hypertension. © 2016 IUBMB Life 68(5):376-387, 2016. PMID:27027402

  5. FXR-dependent reduction of hepatic steatosis in a bile salt deficient mouse model.

    PubMed

    Kunne, Cindy; Acco, Alexandra; Duijst, Suzanne; de Waart, Dirk R; Paulusma, Coen C; Gaemers, Ingrid; Oude Elferink, Ronald P J

    2014-05-01

    It has been established that bile salts play a role in the regulation of hepatic lipid metabolism. Accordingly, overt signs of steatosis have been observed in mice with reduced bile salt synthesis. The aim of this study was to identify the mechanism of hepatic steatosis in mice with bile salt deficiency due to a liver specific disruption of cytochrome P450 reductase. In this study mice lacking hepatic cytochrome P450 reductase (Hrn) or wild type (WT) mice were fed a diet supplemented with or without either 0.1% cholic acid (CA) or 0.025% obeticholic acid, a specific FXR-agonist. Feeding a CA-supplemented diet resulted in a significant decrease of plasma ALT in Hrn mice. Histologically, hepatic steatosis ameliorated after CA feeding and this was confirmed by reduced hepatic triglyceride content (115.5±7.3mg/g liver and 47.9±4.6mg/g liver in control- and CA-fed Hrn mice, respectively). The target genes of FXR-signaling were restored to normal levels in Hrn mice when fed cholic acid. VLDL secretion in both control and CA-fed Hrn mice was reduced by 25% compared to that in WT mice. In order to gain insight in the mechanism behind these bile salt effects, the FXR agonist also was administered for 3weeks. This resulted in a similar decrease in liver triglycerides, indicating that the effect seen in bile salt fed Hrn animals is FXR dependent. In conclusion, steatosis in Hrn mice is ameliorated when mice are fed bile salts. This effect is FXR dependent. Triglyceride accumulation in Hrn liver may partly involve impaired VLDL secretion. PMID:24548803

  6. Energy enhancement of proton acceleration in combinational radiation pressure and bubble by optimizing plasma density

    SciTech Connect

    Bake, Muhammad Ali; Xie Baisong; Shan Zhang; Hong Xueren; Wang Hongyu

    2012-08-15

    The combinational laser radiation pressure and plasma bubble fields to accelerate protons are researched through theoretical analysis and numerical simulations. The dephasing length of the accelerated protons bunch in the front of the bubble and the density gradient effect of background plasma on the accelerating phase are analyzed in detail theoretically. The radiation damping effect on the accelerated protons energy is also considered. And it is demonstrated by two-dimensional particle-in-cell simulations that the protons bunch energy can be increased by using the background plasma with negative density gradient. However, radiation damping makes the maximal energy of the accelerated protons a little reduction.

  7. Optimized laser pulse profile for efficient radiation pressure acceleration of ions

    SciTech Connect

    Bulanov, S. S.; Schroeder, C. B.; Esarey, E.; Leemans, W. P.

    2012-12-21

    The radiation pressure acceleration regime of laser ion acceleration requires high intensity laser pulses to function efficiently. Moreover the foil should be opaque for incident radiation during the interaction to ensure maximum momentum transfer from the pulse to the foil, which requires proper matching of the target to the laser pulse. However, in the ultrarela-tivistic regime, this leads to large acceleration distances, over which the high laser intensity for a Gaussian laser pulse must be maintained. It is shown that proper tailoring of the laser pulse profile can significantly reduce the acceleration distance, leading to a compact laser ion accelerator, requiring less energy to operate.

  8. Optimized laser pulse profile for efficient radiation pressure acceleration of ions

    SciTech Connect

    Bulanov, S. S.; Schroeder, C. B.; Esarey, E.; Leemans, W. P.

    2012-09-15

    The radiation pressure acceleration regime of laser ion acceleration requires high intensity laser pulses to function efficiently. Moreover, the foil should be opaque for incident radiation during the interaction to ensure maximum momentum transfer from the pulse to the foil, which requires proper matching of the target to the laser pulse. However, in the ultrarelativistic regime, this leads to large acceleration distances, over which the high laser intensity for a Gaussian laser pulse must be maintained. It is shown that proper tailoring of the laser pulse profile can significantly reduce the acceleration distance, leading to a compact laser ion accelerator, requiring less energy to operate.

  9. Conformational dynamics of human FXR-LBD ligand interactions studied by hydrogen/deuterium exchange mass spectrometry: insights into the antagonism of the hypolipidemic agent Z-guggulsterone.

    PubMed

    Yang, Liping; Broderick, David; Jiang, Yuan; Hsu, Victor; Maier, Claudia S

    2014-09-01

    Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of transcription factors that plays a key role in the regulation of bile acids, lipid and glucose metabolisms. The regulative function of FXR is governed by conformational changes of the ligand binding domain (LBD) upon ligand binding. Although FXR is a highly researched potential therapeutic target, only a limited number of FXR-agonist complexes have been successfully crystallized and subsequently yielded high resolution structures. There is currently no structural information of any FXR-antagonist complexes publically available. We therefore explored the use of amide hydrogen/deuterium exchange (HDX) coupled with mass spectrometry for characterizing conformational changes in the FXR-LBD upon ligand binding. Ligand-specific deuterium incorporation profiles were obtained for three FXR ligand chemotypes: GW4064, a synthetic non-steroidal high affinity agonist; the bile acid chenodeoxycholic acid (CDCA), the endogenous low affinity agonist of FXR; and Z-guggulsterone (GG), an in vitro antagonist of the steroid chemotype. A comparison of the HDX profiles of their ligand-bound FXR-LBD complexes revealed a unique mode of interaction for GG. The conformational features of the FXR-LBD-antagonist interaction are discussed. PMID:24953769

  10. Optimal technique of linear accelerator-based stereotactic radiosurgery for tumors adjacent to brainstem.

    PubMed

    Chang, Chiou-Shiung; Hwang, Jing-Min; Tai, Po-An; Chang, You-Kang; Wang, Yu-Nong; Shih, Rompin; Chuang, Keh-Shih

    2016-01-01

    either DCA or IMRS plans, at 9.2 ± 7% and 8.2 ± 6%, respectively. Owing to the multiple arc or beam planning designs of IMRS and VMAT, both of these techniques required higher MU delivery than DCA, with the averages being twice as high (p < 0.05). If linear accelerator is only 1 modality can to establish for SRS treatment. Based on statistical evidence retrospectively, we recommend VMAT as the optimal technique for delivering treatment to tumors adjacent to brainstem. PMID:27396940

  11. Monte Carlo study of photon beams from medical linear accelerators: Optimization, benchmark and spectra

    NASA Astrophysics Data System (ADS)

    Sheikh-Bagheri, Daryoush

    1999-12-01

    BEAM is a general purpose EGS4 user code for simulating radiotherapy sources (Rogers et al. Med. Phys. 22, 503-524, 1995). The BEAM code is optimized by first minimizing unnecessary electron transport (a factor of 3 improvement in efficiency). The efficiency of the uniform bremsstrahlung splitting (UBS) technique is assessed and found to be 4 times more efficient. The Russian Roulette technique used in conjunction with UBS is substantially modified to make simulations additionally 2 times more efficient. Finally, a novel and robust technique, called selective bremsstrahlung splitting (SBS), is developed and shown to improve the efficiency of photon beam simulations by an additional factor of 3-4, depending on the end- point considered. The optimized BEAM code is benchmarked by comparing calculated and measured ionization distributions in water from the 10 and 20 MV photon beams of the NRCC linac. Unlike previous calculations, the incident e - energy is known independently to 1%, the entire extra-focal radiation is simulated and e- contamination is accounted for. Both beams use clinical jaws, whose dimensions are accurately measured, and which are set for a 10 x 10 cm2 field at 110 cm. At both energies, the calculated and the measured values of ionization on the central-axis in the buildup region agree within 1% of maximum dose. The agreement is well within statistics elsewhere on the central-axis. Ionization profiles match within 1% of maximum dose, except at the geometrical edges of the field, where the disagreement is up to 5% of dose maximum. Causes for this discrepancy are discussed. The benchmarked BEAM code is then used to simulate beams from the major commercial medical linear accelerators. The off-axis factors are matched within statistical uncertainties, for most of the beams at the 1 σ level and for all at the 2 σ level. The calculated and measured depth-dose data agree within 1% (local dose), at about 1% (1 σ level) statistics, at all depths past

  12. Optimization of magnetically accelerated, ultra-high velocity aluminum flyer plates for use in plate impact, shock wave experiments.

    SciTech Connect

    Cochrane, Kyle Robert; Knudson, Marcus D.; Slutz, Stephen A.; Lemke, Raymond William; Davis, J. P.; Harjes, Henry Charles III; Giunta, Anthony Andrew; Bliss, David Emery

    2005-05-01

    The intense magnetic field produced by the 20 MA Z accelerator is used as an impulsive pressure source to accelerate metal flyer plates to high velocity for the purpose of performing plate impact, shock wave experiments. This capability has been significantly enhanced by the recently developed pulse shaping capability of Z, which enables tailoring the rise time to peak current for a specific material and drive pressure to avoid shock formation within the flyer plate during acceleration. Consequently, full advantage can be taken of the available current to achieve the maximum possible magnetic drive pressure. In this way, peak magnetic drive pressures up to 490 GPa have been produced, which shocklessly accelerated 850 {micro}m aluminum (6061-T6) flyer plates to peak velocities of 34 km/s. We discuss magnetohydrodynamic (MHD) simulations that are used to optimize the magnetic pressure for a given flyer load and to determine the shape of the current rise time that precludes shock formation within the flyer during acceleration to peak velocity. In addition, we present results pertaining to plate impact, shock wave experiments in which the aluminum flyer plates were magnetically accelerated across a vacuum gap and impacted z-cut, {alpha}-quartz targets. Accurate measurements of resulting quartz shock velocities are presented and analyzed through high-fidelity MHD simulations enhanced using optimization techniques. Results show that a fraction of the flyer remains at solid density at impact, that the fraction of material at solid density decreases with increasing magnetic pressure, and that the observed abrupt decrease in the quartz shock velocity is well correlated with the melt transition in the aluminum flyer.

  13. Target design optimization for an electron accelerator driven subcritical facility with circular and square beam profiles.

    SciTech Connect

    Gohar, M. Y. A; Sofu, T.; Zhong, Z.; Belch, H.; Naberezhnev, D.; Nuclear Engineering Division

    2008-10-30

    A subcritical facility driven by an electron accelerator is planned at the Kharkov Institute of Physics and Technology (KIPT) in Ukraine for medical isotope production, materials research, training, and education. The conceptual design of the facility is being pursued through collaborations between ANL and KIPT. As part of the design effort, the high-fidelity analyses of various target options are performed with formulations to reflect the realistic configuration and the three dimensional geometry of each design. This report summarizes the results of target design optimization studies for electron beams with two different beam profiles. The target design optimization is performed via the sequential neutronic, thermal-hydraulic, and structural analyses for a comprehensive assessment of each configuration. First, a target CAD model is developed with proper emphasis on manufacturability to provide a basis for separate but consistent models for subsequent neutronic, thermal-hydraulic, and structural analyses. The optimizations are pursued for maximizing the neutron yield, streamlining the flow field to avoid hotspots, and minimizing the thermal stresses to increase the durability. In addition to general geometric modifications, the inlet/outlet channel configurations, target plate partitioning schemes, flow manipulations and rates, electron beam diameter/width options, and cladding material choices are included in the design optimizations. The electron beam interactions with the target assembly and the neutronic response of the subcritical facility are evaluated using the MCNPX code. the results for the electron beam energy deposition, neutron generation, and utilization in the subcritical pile are then used to characterize the axisymmetric heat generation profiles in the target assembly with explicit simulations of the beam tube, the coolant, the clad, and the target materials. Both tungsten and uranium are considered as target materials. Neutron spectra from tungsten

  14. Numerically optimized structures for dielectric asymmetric dual-grating laser accelerators

    SciTech Connect

    Aimidula, A.; Bake, M. A.; Wan, F.; Xie, B. S.; Welsch, C. P.; Xia, G.; Mete, O.; Uesaka, M.; Matsumura, Y.; Yoshida, M.; Koyama, K.

    2014-02-15

    Optical scale dielectric structures are promising candidates to realize future compact, low cost particle accelerators, since they can sustain high acceleration gradients in the range of GeV/m. Here, we present numerical simulation results for a dielectric asymmetric dual-grating accelerator. It was found that the asymmetric dual-grating structures can efficiently modify the laser field to synchronize it with relativistic electrons, therefore increasing the average acceleration gradient by ∼10% in comparison to symmetric structures. The optimum pillar height which was determined by simulation agrees well with that estimated analytically. The effect of the initial kinetic energy of injected electrons on the acceleration gradient is also discussed. Finally, the required laser parameters were calculated analytically and a suitable laser is proposed as energy source.

  15. Human FXR Regulates SHP Expression through Direct Binding to an LRH-1 Binding Site, Independent of an IR-1 and LRH-1

    PubMed Central

    Hoeke, Martijn O.; Heegsma, Janette; Hoekstra, Mark; Moshage, Han; Faber, Klaas Nico

    2014-01-01

    Background Farnesoid X receptor/retinoid X receptor-alpha (FXR/RXRα) is the master transcriptional regulator of bile salt synthesis and transport in liver and intestine. FXR is activated by bile acids, RXRα by the vitamin A–derivative 9-cis retinoic acid (9cRA). Remarkably, 9cRA inhibits binding of FXR/RXRα to its response element, an inverted repeat-1 (IR-1). Still, most FXR/RXRα target genes are maximally expressed in the presence of both ligands, including the small heterodimer partner (SHP). Here, we revisited the FXR/RXRα-mediated regulation of human SHP. Methods A 579-bp hSHP promoter element was analyzed to locate FXR/chenodeoxycholic acid (CDCA)- and RXRα/9cRA-responsive elements. hSHP promoter constructs were analyzed in FXR/RXRα-transfected DLD-1, HEK293 and HepG2 cells exposed to CDCA, GW4064 (synthetic FXR ligand) and/or 9cRA. FXR-DNA interactions were analyzed by in vitro pull down assays. Results hSHP promoter elements lacking the previously identified IR-1 (−291/−279) largely maintained their activation by FXR/CDCA, but were unresponsive to 9cRA. FXR-mediated activation of the hSHP promoter was primarily dependent on the −122/−69 region. Pull down assays revealed a direct binding of FXR to the −122/−69 sequence, which was abrogated by site-specific mutations in a binding site for the liver receptor homolog-1 (LRH-1) at −78/−70. These mutations strongly impaired the FXR/CDCA-mediated activation, even in the context of a hSHP promoter containing the IR-1. LRH-1 did not increase FXR/RXRα-mediated activation of hSHP promoter activity. Conclusion FXR/CDCA-activated expression of SHP is primarily mediated through direct binding to an LRH-1 binding site, which is not modulated by LRH-1 and unresponsive to 9cRA. 9cRA-induced expression of SHP requires the IR-1 that overlaps with a direct repeat-2 (DR-2) and DR-4. This establishes for the first time a co-stimulatory, but independent, action of FXR and RXRα agonists. PMID:24498423

  16. Beam shaping assembly optimization for (7)Li(p,n)(7)Be accelerator based BNCT.

    PubMed

    Minsky, D M; Kreiner, A J

    2014-06-01

    Within the framework of accelerator-based BNCT, a project to develop a folded Tandem-ElectroStatic-Quadrupole accelerator is under way at the Atomic Energy Commission of Argentina. The proposed accelerator is conceived to deliver a proton beam of 30mA at about 2.5MeV. In this work we explore a Beam Shaping Assembly (BSA) design based on the (7)Li(p,n)(7)Be neutron production reaction to obtain neutron beams to treat deep seated tumors. PMID:24345525

  17. FXR is a molecular target for the effects of vertical sleeve gastrectomy

    PubMed Central

    Ryan, Karen K.; Tremaroli, Valentina; Clemmensen, Christoffer; Kovatcheva-Datchary, Petia; Myronovych, Andriy; Karns, Rebekah; Wilson-Pérez, Hilary E.; Sandoval, Darleen A.; Kohli, Rohit; Bäckhed, Fredrik; Seeley, Randy J.

    2014-01-01

    SUMMARY Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are currently the most effective therapy for the treatment of obesity, and are associated with substantial improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering tremendous potential to reveal new targets for therapeutic intervention. The present study demonstrates that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, we report that VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of nuclear bile acid receptor FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signaling as an important molecular underpinning for the beneficial effects of this weight-loss surgery. PMID:24670636

  18. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis

    PubMed Central

    Gomez-Ospina, Natalia; Potter, Carol J.; Xiao, Rui; Manickam, Kandamurugu; Kim, Mi-Sun; Kim, Kang Ho; Shneider, Benjamin L.; Picarsic, Jennifer L.; Jacobson, Theodora A.; Zhang, Jing; He, Weimin; Liu, Pengfei; Knisely, A. S.; Finegold, Milton J.; Muzny, Donna M.; Boerwinkle, Eric; Lupski, James R.; Plon, Sharon E.; Gibbs, Richard A.; Eng, Christine M.; Yang, Yaping; Washington, Gabriel C.; Porteus, Matthew H.; Berquist, William E.; Kambham, Neeraja; Singh, Ravinder J.; Xia, Fan; Enns, Gregory M.; Moore, David D.

    2016-01-01

    Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection. PMID:26888176

  19. Cysteine Sulfinic Acid Decarboxylase Regulation: A Role for FXR and SHP in Murine Hepatic Taurine Metabolism

    PubMed Central

    Kerr, Thomas A.; Matsumoto, Yuri; Matsumoto, Hitoshi; Xie, Yan; Hirschberger, Lawrence L.; Stipanuk, Martha H.; Anakk, Sayeepriyadarshini; Moore, David D.; Watanabe, Mitsuhiro; Kennedy, Susan

    2014-01-01

    Background Bile acid synthesis is regulated by nuclear receptors including farnesoid X receptor (FXR) and small heterodimer partner (SHP), and by fibroblast growth factor15/19 (FGF15/19). Because bile acid synthesis involves amino acid conjugation, we hypothesized that hepatic cysteine sulfinic acid decarboxylase (CSAD) (a key enzyme in taurine synthesis) is regulated by bile acids. Aims To investigate CSAD regulation by bile acids and CSAD regulatory mechanisms. Methods Mice were fed a control diet or a diet supplemented with either 0.5% cholate or 2% cholestyramine. To gain mechanistic insight into CSAD regulation, we utilized GW4064 (FXR agonist), FGF19, or T-0901317 (LXR agonist) and Shp−/− mice. Tissue mRNA expression was determined by qRT-PCR. Amino acids were measured by HPLC. Results Mice supplemented with dietary cholate exhibited reduced hepatic CSAD mRNA expression while those receiving cholestyramine exhibited increased hepatic CSAD mRNA expression. Activation of FXR suppressed CSAD mRNA expression whereas hepatic CSAD mRNA expression was increased in Shp−/− mice. Hepatic hypotaurine concentration (the product of CSAD) was higher in Shp−/− mice with a corresponding increase in serum (but not hepatic) taurine-conjugated bile acids. FGF19 administration suppressed hepatic CYP7A1 mRNA but did not change CSAD mRNA expression. LXR activation induced CYP7A1 mRNA yet failed to induce CSAD mRNA expression. Conclusion CSAD mRNA expression is physiologically regulated by bile acids in a feedback fashion via mechanisms involving SHP and FXR but not FGF15/19 or LXR. These novel findings implicate bile acids as regulators of CSAD mRNA via mechanisms shared in part with CYP7A1. PMID:24033844

  20. Cytosol-nucleus traffic and colocalization with FXR of conjugated bile acids in rat hepatocytes.

    PubMed

    Monte, Maria J; Rosales, Ruben; Macias, Rocio I R; Iannota, Valeria; Martinez-Fernandez, Almudena; Romero, Marta R; Hofmann, Alan F; Marin, Jose J G

    2008-07-01

    Bile acids (BAs) are natural ligands of nuclear receptors, in particular farnesoid X receptor (FXR). Whether, in addition to protein-mediated cytosolic-nuclear BA translocation, other mechanisms are involved in the access of BAs to nuclear FXR was investigated. When rat hepatocytes were incubated with radiolabeled taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, and tauroursodeoxycholic acid, their nuclear accumulation was proportional to their intracellular levels. With the use of flow cytometry analysis, the accumulation by nuclei isolated from rat liver cells was found to differ for several fluorescent compounds of similar molecular weight and different charge, including fluorescein-tagged BAs [cholylglycyl amidofluorescein (CGamF), ursodeoxycholylglycyl amidofluorescein, or chenodeoxycholylglycyl amidofluorescein]. When we varied nuclear volume by incubation with different sucrose concentrations, a similar relationship between nuclear volume and content of FITC and 4-kDa FITC-dextran was found. In contrast, this relationship was markedly lower for CGamF. Confocal microscopy studies revealed that fluorescein-tagged BAs, but also FITC or 10-kDa FITC-dextran were found in the nuclear envelope and concentrated in regions where DNA was less densely packed. In contrast to the cytosolic subcellular localization of peroxisome proliferator-activated receptor-alpha, FXR and nucleolin (a marker of transcriptional active chromatin) were also localized by immunoreactivity in these intranuclear regions. In conclusion, although intranuclear levels of small organic molecules including conjugated BAs depend on their concentrations in the extranuclear space, the existence of certain molecular selectivity (not strictly dependent on molecular weight or charge) suggests that, in addition to simple diffusional exchange, other mechanisms may be also involved in determining their overall nuclear content in regions where these compounds coincide and may interact

  1. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach

    PubMed Central

    Lu, Weiqiang; Cheng, Feixiong; Jiang, Jing; Zhang, Chen; Deng, Xiaokang; Xu, Zhongyu; Zou, Shien; Shen, Xu; Tang, Yun; Huang, Jin

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are worldwide used drugs for analgesic, antipyretic, and anti-inflammatory therapeutics. However, NSAIDs often cause several serious liver injuries, such as drug-induced liver injury (DILI), and the molecular mechanisms of DILI have not been clearly elucidated. In this study, we developed a systems pharmacology approach to explore the mechanism-of-action of NSAIDs. We found that the Farnesoid X Receptor (FXR) antagonism of NSAIDs is a potential molecular mechanism of DILI through systematic network analysis and in vitro assays. Specially, the quantitative real-time PCR assay reveals that indomethacin and ibuprofen regulate FXR downstream target gene expression in HepG2 cells. Furthermore, the western blot shows that FXR antagonism by indomethacin induces the phosphorylation of STAT3 (signal transducer and activator of transcription 3), promotes the activation of caspase9, and finally causes DILI. In summary, our systems pharmacology approach provided novel insights into molecular mechanisms of DILI for NSAIDs, which may propel the ways toward the design of novel anti-inflammatory pharmacotherapeutics. PMID:25631039

  2. O-GlcNAcylation Links ChREBP and FXR to Glucose-Sensing

    PubMed Central

    Benhamed, Fadila; Filhoulaud, Gaelle; Caron, Sandrine; Lefebvre, Philippe; Staels, Bart; Postic, Catherine

    2015-01-01

    Accumulating evidence suggests that O-GlcNAc transferase, an enzyme responsible for O-GlcNAc post-translational modification acts as a nutrient sensor that links glucose and the hexosamine biosynthetic pathway to the regulation of transcriptional factors involved in energy homeostasis. In liver, glucose signaling is mediated by carbohydrate response element-binding protein (ChREBP), which stimulates glycolytic and lipogenic gene expression through its binding on a specific ChoRE DNA sequence. Modulation of ChREBP by O-GlcNAcylation increases its DNA binding affinity and its activity. ChREBP transcriptional activity also depends on the presence of several other co-factors and transcriptional factors. Among them, the nuclear Farnesoid X Receptor (FXR), a key transcription factor of bile acid metabolism involved in the gut–liver axis homeostasis was recently shown to directly interact with ChREBP, acting as a repressor on the ChoRE of glycolytic genes. Interestingly, similarly to ChREBP, FXR is O-GlcNAcylated in response to glucose. This review discusses the importance of ChREBP and FXR modifications through O-GlcNAcylation in liver and how glucose can modify their mutual affinity and transcriptional activity. PMID:25628602

  3. O-GlcNAcylation Links ChREBP and FXR to Glucose-Sensing.

    PubMed

    Benhamed, Fadila; Filhoulaud, Gaelle; Caron, Sandrine; Lefebvre, Philippe; Staels, Bart; Postic, Catherine

    2014-01-01

    Accumulating evidence suggests that O-GlcNAc transferase, an enzyme responsible for O-GlcNAc post-translational modification acts as a nutrient sensor that links glucose and the hexosamine biosynthetic pathway to the regulation of transcriptional factors involved in energy homeostasis. In liver, glucose signaling is mediated by carbohydrate response element-binding protein (ChREBP), which stimulates glycolytic and lipogenic gene expression through its binding on a specific ChoRE DNA sequence. Modulation of ChREBP by O-GlcNAcylation increases its DNA binding affinity and its activity. ChREBP transcriptional activity also depends on the presence of several other co-factors and transcriptional factors. Among them, the nuclear Farnesoid X Receptor (FXR), a key transcription factor of bile acid metabolism involved in the gut-liver axis homeostasis was recently shown to directly interact with ChREBP, acting as a repressor on the ChoRE of glycolytic genes. Interestingly, similarly to ChREBP, FXR is O-GlcNAcylated in response to glucose. This review discusses the importance of ChREBP and FXR modifications through O-GlcNAcylation in liver and how glucose can modify their mutual affinity and transcriptional activity. PMID:25628602

  4. Optimization of Electron Beam Transport for a 3-MeV DC Accelerator

    NASA Astrophysics Data System (ADS)

    Baruah, S.; Bhattacharjee, D.; Tiwari, R.; Sahu, G. K.; Thakur, K. B.; Mittal, K. C.; Gantayet, L. M.

    2012-11-01

    Transport of a low-current-density electron beam is simulated for an electrostatic accelerator system. Representative charged particles are uniformly assigned for emission from a circular indirectly-heated cathode of an axial electron gun. The beam is accelerated stepwise up to energy of 1 MeV electrostatically in a length-span of ~3 m using multiple accelerating electrodes in a column of ten tubes. The simulation is done under relativistic condition and the effect of the magnetic field induced by the cathode-heating filament current is taken into account. The beam diameter is tracked at different axial locations for various settings of the electrode potentials. Attempts have been made to examine and explain data on beam transport efficiency obtained from experimental observations.

  5. A quasi-Newton acceleration for high-dimensional optimization algorithms

    PubMed Central

    Alexander, David; Lange, Kenneth

    2010-01-01

    In many statistical problems, maximum likelihood estimation by an EM or MM algorithm suffers from excruciatingly slow convergence. This tendency limits the application of these algorithms to modern high-dimensional problems in data mining, genomics, and imaging. Unfortunately, most existing acceleration techniques are ill-suited to complicated models involving large numbers of parameters. The squared iterative methods (SQUAREM) recently proposed by Varadhan and Roland constitute one notable exception. This paper presents a new quasi-Newton acceleration scheme that requires only modest increments in computation per iteration and overall storage and rivals or surpasses the performance of SQUAREM on several representative test problems. PMID:21359052

  6. Optimization of Dose Distribution for the System of Linear Accelerator-Based Stereotactic Radiosurgery.

    NASA Astrophysics Data System (ADS)

    Suh, Tae-Suk

    The work suggested in this paper addresses a method for obtaining an optimal dose distribution for stereotactic radiosurgery. Since stereotactic radiosurgery utilizes multiple noncoplanar arcs and a three-dimensional dose evaluation technique, many beam parameters and complex optimization criteria are included in the dose optimization. Consequently, a lengthy computation time is required to optimize even the simplest case by a trial and error method. The basic approach presented here is to use both an analytical and an experimental optimization to minimize the dose to critical organs while maintaining a dose shaped to the target. The experimental approach is based on shaping the target volumes using multiple isocenters from dose experience, or on field shaping using a beam's eye view technique. The analytical approach is to adapt computer -aided design optimization to find optimum parameters automatically. Three-dimensional approximate dose models are developed to simulate the exact dose model using a spherical or cylindrical coordinate system. Optimum parameters are found much faster with the use of computer-aided design optimization techniques. The implementation of computer-aided design algorithms with the approximate dose model and the application of the algorithms to several cases are discussed. It is shown that the approximate dose model gives dose distributions similar to those of the exact dose model, which makes the approximate dose model an attractive alternative to the exact dose model, and much more efficient in terms of computer -aided design and visual optimization.

  7. Optimization of the accelerated curing process of concrete using a fibre Bragg grating-based control system and microwave technology

    NASA Astrophysics Data System (ADS)

    Fabian, Matthias; Jia, Yaodong; Shi, Shi; McCague, Colum; Bai, Yun; Sun, Tong; Grattan, Kenneth T. V.

    2016-05-01

    In this paper, an investigation into the suitability of using fibre Bragg gratings (FBGs) for monitoring the accelerated curing process of concrete in a microwave heating environment is presented. In this approach, the temperature data provided by the FBGs are used to regulate automatically the microwave power so that a pre-defined temperature profile is maintained to optimize the curing process, achieving early strength values comparable to those of conventional heat-curing techniques but with significantly reduced energy consumption. The immunity of the FBGs to interference from the microwave radiation used ensures stable readings in the targeted environment, unlike conventional electronic sensor probes.

  8. Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis.

    PubMed

    Anakk, Sayeepriyadarshini; Watanabe, Mitsuhiro; Ochsner, Scott A; McKenna, Neil J; Finegold, Milton J; Moore, David D

    2011-01-01

    Bile acid homeostasis is tightly regulated via a feedback loop operated by the nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP). Contrary to current models, which place FXR upstream of SHP in a linear regulatory pathway, here we show that the phenotypic consequences in mice of the combined loss of both receptors are much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. Fxr-/-Shp-/- mice exhibited cholestasis and liver injury as early as 3 weeks of age, and this was linked to the dysregulation of bile acid homeostatic genes, particularly cytochrome P450, family 7, subfamily a, polypeptide 1 (Cyp7a1). In addition, double-knockout mice showed misregulation of genes in the C21 steroid biosynthesis pathway, with strong induction of cytochrome P450, family 17, subfamily a, polypeptide 1 (Cyp17a1), resulting in elevated serum levels of its enzymatic product 17-hydroxyprogesterone (17-OHP). Treatment of WT mice with 17-OHP was sufficient to induce liver injury that reproduced many of the histopathological features observed in the double-knockout mice. Therefore, our data indicate a pathologic role for increased production of 17-hydroxy steroid metabolites in liver injury and suggest that Fxr-/-Shp-/- mice could provide a model for juvenile onset cholestasis. PMID:21123943

  9. Dissociation of intestinal and hepatic activities of FXR and LXRα supports metabolic effects of terminal ileum interposition in rodents.

    PubMed

    Mencarelli, Andrea; Renga, Barbara; D'Amore, Claudio; Santorelli, Chiara; Graziosi, Luigina; Bruno, Angela; Monti, Maria Chiara; Distrutti, Eleonora; Cipriani, Sabrina; Donini, Annibale; Fiorucci, Stefano

    2013-10-01

    The farnesoid X receptor (FXR) and the liver x receptors (LXRs) are bile acid-activated receptors that are highly expressed in the enterohepatic tissues. The mechanisms that support the beneficial effects of bariatric surgery are only partially defined. We have investigated the effects of ileal interposition (IT), a surgical relocation of the distal ileum into the proximal jejunum, on FXR and LXRs in rats. Seven months after surgery, blood concentrations of total bile acids, taurocholic acid, an FXR ligand, and taurohyocholic acid, an LXRα ligand, were significantly increased by IT (P < 0.05). In contrast, liver and intestinal concentrations of conjugated and nonconjugated bile acids were decreased (P < 0.05). These changes were associated with a robust induction of FXR and FXR-regulated genes in the intestine, including Fgf15, a negative regulator of bile acid synthesis. IT repressed the liver expression of glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase (Pepck), two gluconeogenetic genes, along with the expression of LXRα and its target genes sterol regulatory element-binding protein (Srebp) 1c and fatty acid synthase (Fas) in the liver. Treating IT rats with chenodeoxycholic acid ameliorated insulin signaling in the liver. Whether confirmed in human settings, these results support the association of pharmacological therapies with bariatric surgeries to exploit the selective activation of intestinal nuclear receptors. PMID:23835330

  10. Pharmacophore-based discovery of FXR-agonists. Part II: Identification of bioactive triterpenes from Ganoderma lucidum

    PubMed Central

    Grienke, Ulrike; Mihály-Bison, Judit; Schuster, Daniela; Afonyushkin, Taras; Binder, Markus; Guan, Shu-hong; Cheng, Chun-ru; Wolber, Gerhard; Stuppner, Hermann; Guo, De-an; Bochkov, Valery N.; Rollinger, Judith M.

    2011-01-01

    The farnesoid X receptor (FXR) belonging to the metabolic subfamily of nuclear receptors is a ligand-induced transcriptional activator. Its central function is the physiological maintenance of bile acid homeostasis including the regulation of glucose and lipid metabolism. Accessible structural information about its ligand-binding domain renders FXR an attractive target for in silico approaches. Integrated to natural product research these computational tools assist to find novel bioactive compounds showing beneficial effects in prevention and treatment of, for example, the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. Virtual screening experiments of our in-house Chinese Herbal Medicine database with structure-based pharmacophore models, previously generated and validated, revealed mainly lanostane-type triterpenes of the TCM fungus Ganoderma lucidum Karst. as putative FXR ligands. To verify the prediction of the in silico approach, two Ganoderma fruit body extracts and compounds isolated thereof were pharmacologically investigated. Pronounced FXR-inducing effects were observed for the extracts at a concentration of 100 μg/mL. Intriguingly, five lanostanes out of 25 secondary metabolites from G. lucidum, that is, ergosterol peroxide (2), lucidumol A (11), ganoderic acid TR (12), ganodermanontriol (13), and ganoderiol F (14), dose-dependently induced FXR in the low micromolar range in a reporter gene assay. To rationalize the binding interactions, additional pharmacophore profiling and molecular docking studies were performed, which allowed establishing a first structure–activity relationship of the investigated triterpenes. PMID:22014750

  11. RNA-Binding Protein FXR1 Regulates p21 and TERC RNA to Bypass p53-Mediated Cellular Senescence in OSCC.

    PubMed

    Majumder, Mrinmoyee; House, Reniqua; Palanisamy, Nallasivam; Qie, Shuo; Day, Terrence A; Neskey, David; Diehl, J Alan; Palanisamy, Viswanathan

    2016-09-01

    RNA-binding proteins (RBP) regulate numerous aspects of co- and post-transcriptional gene expression in cancer cells. Here, we demonstrate that RBP, fragile X-related protein 1 (FXR1), plays an essential role in cellular senescence by utilizing mRNA turnover pathway. We report that overexpressed FXR1 in head and neck squamous cell carcinoma targets (G-quadruplex (G4) RNA structure within) both mRNA encoding p21 (Cyclin-Dependent Kinase Inhibitor 1A (CDKN1A, Cip1) and the non-coding RNA Telomerase RNA Component (TERC), and regulates their turnover to avoid senescence. Silencing of FXR1 in cancer cells triggers the activation of Cyclin-Dependent Kinase Inhibitors, p53, increases DNA damage, and ultimately, cellular senescence. Overexpressed FXR1 binds and destabilizes p21 mRNA, subsequently reduces p21 protein expression in oral cancer cells. In addition, FXR1 also binds and stabilizes TERC RNA and suppresses the cellular senescence possibly through telomerase activity. Finally, we report that FXR1-regulated senescence is irreversible and FXR1-depleted cells fail to form colonies to re-enter cellular proliferation. Collectively, FXR1 displays a novel mechanism of controlling the expression of p21 through p53-dependent manner to bypass cellular senescence in oral cancer cells. PMID:27606879

  12. Optimal design of a standing-wave accelerating tube with a high shunt impedance based on a genetic algorithm

    NASA Astrophysics Data System (ADS)

    Tang, Zhenxing; Pei, Yuanji; Pang, Jian

    2015-08-01

    In this paper, we present an optimal design based on a genetic algorithm for a compact standing-wave (SW) accelerating tube with an operating frequency of 2998 MHz for industrial and medical applications. It consists of bi-periodic structures with a nose cone whose inter-cavity coupling is achieved through electric coupling rather than magnetic coupling. A mathematical model is established to optimize the arc at the cavity wall to reduce the microwave power loss and to optimize the nose cone to increase the electric field along the axis to achieve a high shunt impedance. The simulation results indicate that with the proper nose cone and arc, the shunt impedance of the cavity can be as high as 114 MΩ / m. Afterward, we present the tuning of the tube using SUPERFISH and the calculation of the beam dynamics using ASTRA and Parmela. The total length of the optimal tube is only 30.175 cm. Finally, a coupler is designed with a small-aperture coupling using CST MICROWAVE STUDIO.

  13. Electron cyclotron resonance 140 mA D(+) beam extraction optimization for IFMIF EVEDA accelerator.

    PubMed

    Delferrière, O; De Menezes, D; Gobin, R; Harrault, F; Tuske, O

    2008-02-01

    Based on the experience of the SILHI electron cyclotron resonance (ECR) ion source for the IPHI accelerator, which produces routinely 100-120 mA H(+) beam, the CEA-Saclay is in charge of the design and realization of the 140 mA cw deuteron source for the IFMIF project (International Fusion Materials Irradiation Facility). IFMIF is an accelerator-based neutron irradiation facility consisting of two accelerators of 125 mA D(+) beam at 40 MeV that hit in parallel a lithium target. IFMIF utilizes the deuteron-lithium (d-Li) neutron, producing a reaction to simulate the 14 MeV neutron environment in deuterium-tritium (D-T) fusion reactors. In the framework of the IFMIF EVEDA phase (Engineering Validation and Engineering Design Activities), we are studying a cw ECR ion source with a new extraction system to allow high current extraction while keeping a low divergence as well as a small emittance. Starting from SILHI five-electrode system with H(+) ions, the extracted beam characteristics as well as electric field conditions are compared with the cases of four- and three-electrode extraction systems. Experimental results made on the SILHI source with H(+) ions are briefly discussed. Extensive experimental results on the new source test bench BETSI are expected as soon as the design and fabrication of a dedicated extraction system with a new set of electrodes will be finished. PMID:18315214

  14. Novel substituted isoxazole FXR agonists with cyclopropyl, hydroxycyclobutyl and hydroxyazetidinyl linkers: Understanding and improving key determinants of pharmacological properties.

    PubMed

    Kinzel, Olaf; Steeneck, Christoph; Schlüter, Thomas; Schulz, Andreas; Gege, Christian; Hahn, Ulrike; Hambruch, Eva; Hornberger, Martin; Spalwisz, Adriana; Frick, Katharina; Perović-Ottstadt, Sanja; Deuschle, Ulrich; Burnet, Michael; Kremoser, Claus

    2016-08-01

    Several isoxazole-containing series of FXR agonists have been published over the last 15years, subsequent to the prototypical amphiphilic 'hammerhead'-type structure that was originally laid out by GW4064, the first potent synthetic FXR agonist. A set of novel compounds where the hammerhead is connected to the terminal carboxylic acid-bearing aryl or heteroaryl moiety by either a cyclopropyl, a hydroxycyclobutyl or a hydroxyazetidinyl linker was synthesized in order to improve upon the ADME properties of such isoxazoles. The resulting compounds all demonstrated high potencies at the target receptor FXR but with considerable differences in their physicochemical and in vivo profiles. The structure-activity relationships for key chemical features that have a major impact on the in vivo pharmacology of this series are discussed. PMID:27268696

  15. Insights on FXR selective modulation. Speculation on bile acid chemical space in the discovery of potent and selective agonists.

    PubMed

    Sepe, Valentina; Festa, Carmen; Renga, Barbara; Carino, Adriana; Cipriani, Sabrina; Finamore, Claudia; Masullo, Dario; Del Gaudio, Federica; Monti, Maria Chiara; Fiorucci, Stefano; Zampella, Angela

    2016-01-01

    Bile acids are the endogenous modulators of the nuclear receptor FXR and the membrane receptor GPBAR1. FXR represents a promising pharmacological target for the treatment of cholestatic liver disorders. Currently available semisynthetic bile acid derivatives cover the same chemical space of bile acids and therefore they are poorly selective toward BA receptors, increasing patient risk for adverse side effects. In this report, we have investigated around the structure of CDCA describing the synthesis and the in vitro and in vivo pharmacological characterization of a novel family of compounds modified on the steroidal tetracyclic core and on the side chain. Pharmacological characterization resulted in the identification of several potent and selective FXR agonists. These novel agents might add utility in the treatment of cholestatic disorders by potentially mitigating side effects linked to unwanted activation of GPBAR1. PMID:26740187

  16. Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei

    PubMed Central

    Sepe, Valentina; Ummarino, Raffaella; D’Auria, Maria Valeria; Taglialatela-Scafati, Orazio; Marino, Simona De; D’Amore, Claudio; Renga, Barbara; Chini, Maria Giovanna; Bifulco, Giuseppe; Nakao, Yoichi; Fusetani, Nobuhiro; Fiorucci, Stefano; Zampella, Angela

    2012-01-01

    Using theonellasterol as a novel FXR antagonist hit, we prepared a series of semi-synthetic derivatives in order to gain insight into the structural requirements for exhibiting antagonistic activity. These derivatives are characterized by modification at the exocyclic carbon-carbon double bond at C-4 and at the hydroxyl group at C-3 and were prepared from theonellasterol using simple reactions. Pharmacological investigation showed that the introduction of a hydroxyl group at C-4 as well as the oxidation at C-3 with or without concomitant modification at the exomethylene functionality preserve the ability of theonellasterol to inhibit FXR transactivation caused by CDCA. Docking analysis showed that the placement of these molecules in the FXR-LBD is well stabilized when on ring A functional groups, able to form hydrogen bonds and π interactions, are present. PMID:23203270

  17. Insights on FXR selective modulation. Speculation on bile acid chemical space in the discovery of potent and selective agonists

    PubMed Central

    Sepe, Valentina; Festa, Carmen; Renga, Barbara; Carino, Adriana; Cipriani, Sabrina; Finamore, Claudia; Masullo, Dario; del Gaudio, Federica; Monti, Maria Chiara; Fiorucci, Stefano; Zampella, Angela

    2016-01-01

    Bile acids are the endogenous modulators of the nuclear receptor FXR and the membrane receptor GPBAR1. FXR represents a promising pharmacological target for the treatment of cholestatic liver disorders. Currently available semisynthetic bile acid derivatives cover the same chemical space of bile acids and therefore they are poorly selective toward BA receptors, increasing patient risk for adverse side effects. In this report, we have investigated around the structure of CDCA describing the synthesis and the in vitro and in vivo pharmacological characterization of a novel family of compounds modified on the steroidal tetracyclic core and on the side chain. Pharmacological characterization resulted in the identification of several potent and selective FXR agonists. These novel agents might add utility in the treatment of cholestatic disorders by potentially mitigating side effects linked to unwanted activation of GPBAR1. PMID:26740187

  18. Accelerated optimization and automated discovery with covariance matrix adaptation for experimental quantum control

    NASA Astrophysics Data System (ADS)

    Roslund, Jonathan; Shir, Ofer M.; Bäck, Thomas; Rabitz, Herschel

    2009-10-01

    Optimization of quantum systems by closed-loop adaptive pulse shaping offers a rich domain for the development and application of specialized evolutionary algorithms. Derandomized evolution strategies (DESs) are presented here as a robust class of optimizers for experimental quantum control. The combination of stochastic and quasi-local search embodied by these algorithms is especially amenable to the inherent topology of quantum control landscapes. Implementation of DES in the laboratory results in efficiency gains of up to ˜9 times that of the standard genetic algorithm, and thus is a promising tool for optimization of unstable or fragile systems. The statistical learning upon which these algorithms are predicated also provide the means for obtaining a control problem’s Hessian matrix with no additional experimental overhead. The forced optimal covariance adaptive learning (FOCAL) method is introduced to enable retrieval of the Hessian matrix, which can reveal information about the landscape’s local structure and dynamic mechanism. Exploitation of such algorithms in quantum control experiments should enhance their efficiency and provide additional fundamental insights.

  19. Accelerated optimization and automated discovery with covariance matrix adaptation for experimental quantum control

    SciTech Connect

    Roslund, Jonathan; Shir, Ofer M.; Rabitz, Herschel; Baeck, Thomas

    2009-10-15

    Optimization of quantum systems by closed-loop adaptive pulse shaping offers a rich domain for the development and application of specialized evolutionary algorithms. Derandomized evolution strategies (DESs) are presented here as a robust class of optimizers for experimental quantum control. The combination of stochastic and quasi-local search embodied by these algorithms is especially amenable to the inherent topology of quantum control landscapes. Implementation of DES in the laboratory results in efficiency gains of up to {approx}9 times that of the standard genetic algorithm, and thus is a promising tool for optimization of unstable or fragile systems. The statistical learning upon which these algorithms are predicated also provide the means for obtaining a control problem's Hessian matrix with no additional experimental overhead. The forced optimal covariance adaptive learning (FOCAL) method is introduced to enable retrieval of the Hessian matrix, which can reveal information about the landscape's local structure and dynamic mechanism. Exploitation of such algorithms in quantum control experiments should enhance their efficiency and provide additional fundamental insights.

  20. A GPU-accelerated and Monte Carlo-based intensity modulated proton therapy optimization system

    SciTech Connect

    Ma, Jiasen Beltran, Chris; Seum Wan Chan Tseung, Hok; Herman, Michael G.

    2014-12-15

    Purpose: Conventional spot scanning intensity modulated proton therapy (IMPT) treatment planning systems (TPSs) optimize proton spot weights based on analytical dose calculations. These analytical dose calculations have been shown to have severe limitations in heterogeneous materials. Monte Carlo (MC) methods do not have these limitations; however, MC-based systems have been of limited clinical use due to the large number of beam spots in IMPT and the extremely long calculation time of traditional MC techniques. In this work, the authors present a clinically applicable IMPT TPS that utilizes a very fast MC calculation. Methods: An in-house graphics processing unit (GPU)-based MC dose calculation engine was employed to generate the dose influence map for each proton spot. With the MC generated influence map, a modified least-squares optimization method was used to achieve the desired dose volume histograms (DVHs). The intrinsic CT image resolution was adopted for voxelization in simulation and optimization to preserve spatial resolution. The optimizations were computed on a multi-GPU framework to mitigate the memory limitation issues for the large dose influence maps that resulted from maintaining the intrinsic CT resolution. The effects of tail cutoff and starting condition were studied and minimized in this work. Results: For relatively large and complex three-field head and neck cases, i.e., >100 000 spots with a target volume of ∼1000 cm{sup 3} and multiple surrounding critical structures, the optimization together with the initial MC dose influence map calculation was done in a clinically viable time frame (less than 30 min) on a GPU cluster consisting of 24 Nvidia GeForce GTX Titan cards. The in-house MC TPS plans were comparable to a commercial TPS plans based on DVH comparisons. Conclusions: A MC-based treatment planning system was developed. The treatment planning can be performed in a clinically viable time frame on a hardware system costing around 45

  1. Optimizing a microwave gas ion source for continuous-flow accelerator mass spectrometry

    SciTech Connect

    Reden, K. F. von; Roberts, M. L.; Burton, J. R.; Beaupre, S. R.

    2012-02-15

    A 2.45 GHz microwave ion source coupled with a magnesium charge exchange canal (C x C) has been successfully adapted to a large acceptance radiocarbon accelerator mass spectrometry system at the National Ocean Sciences Accelerator Mass Spectrometry (AMS) Facility, Woods Hole Oceanographic Institution. CO{sub 2} samples from various preparation sources are injected into the source through a glass capillary at 370 {mu}l/min. Routine system parameters are about 120-140 {mu}A of negative {sup 12}C current after the C x C, leading to about 400 {sup 14}C counts per second for a modern sample and implying a system efficiency of 0.2%. While these parameters already allow us to perform high-quality AMS analyses on large samples, we are working on ways to improve the output of the ion source regarding emittance and efficiency. Modeling calculations suggest modifications in the extraction triode geometry, shape, and size of the plasma chamber could improve emittance and, hence, ion transport efficiency. Results of experimental tests of these modifications are presented.

  2. Optimal resolution in maximum entropy image reconstruction from projections with multigrid acceleration

    NASA Technical Reports Server (NTRS)

    Limber, Mark A.; Manteuffel, Thomas A.; Mccormick, Stephen F.; Sholl, David S.

    1993-01-01

    We consider the problem of image reconstruction from a finite number of projections over the space L(sup 1)(Omega), where Omega is a compact subset of the set of Real numbers (exp 2). We prove that, given a discretization of the projection space, the function that generates the correct projection data and maximizes the Boltzmann-Shannon entropy is piecewise constant on a certain discretization of Omega, which we call the 'optimal grid'. It is on this grid that one obtains the maximum resolution given the problem setup. The size of this grid grows very quickly as the number of projections and number of cells per projection grow, indicating fast computational methods are essential to make its use feasible. We use a Fenchel duality formulation of the problem to keep the number of variables small while still using the optimal discretization, and propose a multilevel scheme to improve convergence of a simple cyclic maximization scheme applied to the dual problem.

  3. μMORE: A microfluidic magnetic oscillation reactor for accelerated parameter optimization in biocatalysis.

    PubMed

    Jussen, Daniel; Soltner, Helmut; Stute, Birgit; Wiechert, Wolfgang; von Lieres, Eric; Pohl, Martina

    2016-08-10

    Enzymatic parameter determination is an essential step in biocatalytic process development. Therefore higher throughput in miniaturized devices is urgently needed. An ideal microfluidic device should combine easy immobilization and retention of a minimal amount of biocatalyst with a well-mixed reaction volume. Together, all criteria are hardly met by current tools. Here we describe a microfluidic reactor (μMORE) which employs magnetic particles for both enzyme immobilization and efficient mixing using two permanent magnets placed in rotating cylinders next to the a glass chip reactor. The chip geometry and agitation speed was optimized by investigation of the mixing and retention characteristics using simulation and dye distribution analysis. Subsequently, the μMORE was successfully applied to determine critical biocatalytic process parameters in a parallelized manner for the carboligation of benzaldehyde and acetaldehyde to (S)-2-hydroxy-1-phenylpropan-1-one with less than 5μg of benzoylformate decarboxylase from Pseudomonas putida immobilized on magnetic beads. Here, one run of the device in six parallelized glass reactors took only 2-3h for an immobilized enzyme with very low activity (∼2U/mg). The optimized parameter set was finally tested in a 10mL enzyme membrane reactor, demonstrating that the μMORE provides a solid data base for biocatalytic process optimization. PMID:27288595

  4. Optimizing Laser-accelerated Ion Beams for a Collimated Neutron Source

    SciTech Connect

    C.L. Ellison and J. Fuchs

    2010-09-23

    High-flux neutrons for imaging and materials analysis applications have typically been provided by accelerator- and reactor-based neutron sources. A novel approach is to use ultraintense (>1018W/cm2) lasers to generate picosecond, collimated neutrons from a dual target configuration. In this article, the production capabilities of present and upcoming laser facilities are estimated while independently maximizing neutron yields and minimizing beam divergence. A Monte-Carlo code calculates angular and energy distributions of neutrons generated by D-D fusion events occurring within a deuterated target for a given incident beam of D+ ions. Tailoring of the incident distribution via laser parameters and microlens focusing modifies the emerging neutrons. Projected neutron yields and distributions are compared to conventional sources, yielding comparable on-target fluxes per discharge, shorter time resolution, larger neutron energies and greater collimation.

  5. Optimization of Fusion Pellet Launch Velocity in an Electrothermal Mass Accelerator

    NASA Astrophysics Data System (ADS)

    Gebhart, T. E.; Holladay, R. T.; Esmond, M. J.; Winfrey, A. L.

    2013-10-01

    Electrothermal mass accelerators, based on capillary discharges, that form a plasma propelling force from the ablation of a low-z liner material are candidates for fuelling magnetic fusion reactors. As lithium is considered a fusion fuel and not an impurity, lithium hydride and lithium deuteride can serve as good ablating liners for plasma formation in an electrothermal plasma source to propel fusion pellets. A comprehensive study of solid lithium hydride and deuteride as liner materials to generate a plasma to propel cryogenic fuel pellets is presented here. This study was conducted using the ETFLOW capillary discharge code. Relationships between propellants, source and barrel geometry, pellet volume and aspect ratio, and pellet velocity are determined for pellets ranging in volume from 5 to 100 mm3.

  6. Optimal extraction and fingerprinting of carotenoids by accelerated solvent extraction and liquid chromatography with tandem mass spectrometry.

    PubMed

    Saha, Supradip; Walia, Suresh; Kundu, Aditi; Sharma, Khushbu; Paul, Ranjit Kumar

    2015-06-15

    Accelerated solvent extraction (ASE) is applied for the extraction of carotenoids from orange carrot and the extraction parameters were optimized. Two carotenoids, lutein and β-carotene, are selected as the validation process. Hildebrand solubility parameters and dielectric constant of solvents were taken into consideration in selecting solvent mixture. The effects of various experimental parameters, such as temperature, static time, drying agent etc., on the ASE extraction efficiency are investigated systematically. Interactions among the variables were also studied. Furthermore, two carotenoids were analyzed and characterized by LC-ESI MS. The study concluded that Hildebrand solubility parameter approach may be applicable for less polar bioactive molecules like carotenoids. The properties of solvent and extraction temperature are found to be the most important parameters affecting the ASE extraction efficiency of thermolabile natural compounds. PMID:25660899

  7. Transcriptional Regulation of the Intestinal Nuclear Bile Acid Farnesoid X Receptor (FXR) by the caudal-related Homeobox 2 (CDX2)*

    PubMed Central

    Modica, Salvatore; Cariello, Marica; Morgano, Annalisa; Gross, Isabelle; Vegliante, Maria Carmela; Murzilli, Stefania; Salvatore, Lorena; Freund, Jean-Noel; Sabbà, Carlo; Moschetta, Antonio

    2014-01-01

    Farnesoid X receptor (FXR, NR1H4) is a bile acid-activated transcription factor that belongs to the nuclear receptor superfamily. It is highly expressed in the enterohepatic system, where it senses bile acid levels to consequently reduce their synthesis while inducing their detoxification. Bile acids are intestinal tumor promoters and their concentrations have to be tightly regulated. Indeed, reduced expression of FXR in the intestine increases colorectal cancer susceptibility in mice, whereas its activation can promote apoptosis in genetically modified cells. Notably, despite the broad knowledge of the FXR enterohepatic transcriptional activity, the molecular mechanisms regulating FXR expression in the intestine are still unknown. Herein, by combining both gain and loss of function approaches and FXR promoter activity studies, we identified caudal-related homeobox 2 (CDX2) transcription factor as a positive regulator of FXR expression in the enterocytes. Our results provide a putative novel tool for modulating FXR expression against bile acid-related colorectal cancer progression. PMID:25138215

  8. Chenodeoxycholic acid, an endogenous FXR ligand alters adipokines and reverses insulin resistance.

    PubMed

    Shihabudeen, Mohamed Sham; Roy, Debasish; James, Joel; Thirumurugan, Kavitha

    2015-10-15

    Adipose tissue secretes adipokines that regulate insulin sensitivity in adipocytes and other peripheral tissues critical to glucose metabolism. Insulin resistance is associated with severe alterations in adipokines characterized by release of increased pro-inflammatory cytokines and decreased anti-inflammatory cytokines from adipose tissue. The role of Farnesoid X receptor (FXR) activation on adipokines in relation to adipose tissue inflammation and insulin resistance is not completely explored. For the first time, we have evaluated the ability of Chenodeoxycholic acid (CDCA), an endogenous FXR ligand, in restoring the disturbance in adipokine secretion and insulin resistance in palmitate treated 3T3-L1 cells and adipose tissues of High fat diet (HFD) rats. CDCA suppressed several of the tested pro-inflammatory adipokines (TNF-α, MCP-1, IL-6, Chemerin, PAI, RBP4, resistin, vaspin), and enhanced the major anti-inflammatory and insulin sensitizing adipokines (adiponectin, leptin). CDCA suppressed the activation of critical inflammatory regulators such as NF-κB and IKKβ which are activated by palmitate treatment in differentiated cells and HFD in rats. We show the altered adipokines in insulin resistance, its association with inflammatory regulators, and the role of CDCA in amelioration of insulin resistance by modulation of adipokines. PMID:26188168

  9. Development and optimization of a beam shaper device for a mobile dedicated IOERT accelerator

    SciTech Connect

    Soriani, Antonella; Iaccarino, Giuseppe; Felici, Giuseppe; Ciccotelli, Alessia; Pinnaro, Paola; Giordano, Carolina; Benassi, Marcello; D'Andrea, Marco; Bellesi, Luca; Strigari, Lidia

    2012-10-15

    Purpose: The aim of this study was to design and build a prototype beam shaper to be used on a dedicated mobile accelerator that protects organs at risk within the radiation field and conforms the beam to the target geometry during intraoperative electron radiotherapy (IOERT). A dosimetric characterization of the beam shaper device was performed based on Monte Carlo (MC) simulations, as well as experimental data, at different energies, field sizes, and source to skin distances. Methods: A mobile light intraoperative accelerator (LIAC{sup Registered-Sign }, Sordina, Italy) was used. The design of the beam shaper prototype was based on MC simulations (BEAMnrc/OMEGA and DOSXYZnrc code) for a selection of materials and thicknesses, as well as for dosimetric characterization. Percentage depth dose (PDD) and profile measurements were performed using a p-type silicon diode and a commercial water phantom, while output factors were measured using a PinPoint ion chamber in a PMMA phantom. Planar doses in planes of interest were carried out using radiochromic films (Gafchromic{sup TM} EBT and EBT2) in PMMA and in a Solid Water{sup Registered-Sign} phantom. Several experimental set-ups were investigated with the beam shaper device fixed on the top of the phantom, varying both the short side of the rectangular field and the air gap between the device and the phantom surface, simulating the clinical situation. The output factors (OFs) were determined using different geometrical set-ups and energies. Results: The beam shaper prototype consists of four blades sliding alongside each other and mounted on a special support at the end of the 10 cm diameter PMMA circular applicator. Each blade is made of an upper layer of 2.6 cm of Teflon{sup Registered-Sign} and a lower layer of 8 mm of stainless steel. All rectangles inscribed in a 5 cm diameter can be achieved in addition to any 'squircle-shaped' field. When one side of the rectangular field is held constant and the second side is

  10. Enhanced docking with the mining minima optimizer: acceleration and side-chain flexibility.

    PubMed

    Kairys, Visvaldas; Gilson, Michael K

    2002-12-01

    The ligand-protein docking algorithm based on the Mining Minima method has been substantially enhanced. First, the basic algorithm is accelerated by: (1) adaptively determining the extent of each energy well to help avoid previously discovered energy minima; (2) biasing the search away from ligand positions at the surface of the receptor to prevent the ligand from staying at the surface when large sampling regions are used; (3) quickly testing multiple different ligand positions and orientations for each ligand conformation; and (4) tuning the source code to increase computational efficiency. These changes markedly shorten the time needed to discover an accurate result, especially when large sampling regions are used. The algorithm now also allows user-selected receptor sidechains to be treated as mobile during the docking procedure. The energies associated with the mobile side chains are computed as if they belonged to the ligand, except that atoms at the boundary between side chains and the rigid backbone are treated specially. This new capability is tested for several well-known ligand/protein systems, and preliminary application to an enzyme whose substrate is unknown--the recently solved hypothetical protein YecO (HI0319) from Haemophilus influenzae--indicates that side-chains relaxations allow candidate substrates of various sizes to be accommodated. PMID:12395431

  11. Design and high order optimization of the Accelerator Test Facility lattices

    NASA Astrophysics Data System (ADS)

    Marin, E.; Tomás, R.; Bambade, P.; Kubo, K.; Okugi, T.; Tauchi, T.; Terunuma, N.; Urakawa, J.; Seryi, A.; White, G. R.; Woodley, M.

    2014-02-01

    The Accelerator Test Facility 2 (ATF2) aims to test the novel chromaticity correction scheme which is implemented in the final focus systems of future linear colliders such as the International Linear Collider (ILC) and the Compact Linear Collider (CLIC). The ATF2 nominal and ultralow β* lattices are designed to vertically focus the beam at the focal point, or usually referred to as interaction point (IP), down to 37 and 23 nm, respectively. The vertical chromaticities of the nominal and ultralow β* lattices are comparable to those of ILC and CLIC, respectively. When the measured multipole components of the ATF2 magnets are considered in the simulations, the evaluated spot sizes at the IP are well above the design values. In this paper we describe the analysis of the high order aberrations that allows identifying the sources of the observed beam size growth. In order to recover the design spot sizes three solutions are considered, namely final doublet replacement, octupole insertion, and optics modification. Concerning the future linear collider projects, the consequences of magnetic field errors of the focusing quadrupole magnet of the final doublet are also addressed.

  12. Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy

    PubMed Central

    Giordano, Cinzia; Barone, Ines; Vircillo, Valentina; Panza, Salvatore; Malivindi, Rocco; Gelsomino, Luca; Pellegrino, Michele; Rago, Vittoria; Mauro, Loredana; Lanzino, Marilena; Panno, Maria Luisa; Bonofiglio, Daniela; Catalano, Stefania; Andò, Sebastiano

    2016-01-01

    Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment. PMID:26899873

  13. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice.

    PubMed

    Degirolamo, Chiara; Rainaldi, Stefania; Bovenga, Fabiola; Murzilli, Stefania; Moschetta, Antonio

    2014-04-10

    Gut microbiota influences host health status by providing trophic, protective, and metabolic functions, including bile acid (BA) biotransformation. Microbial imprinting on BA signature modifies pool size and hydrophobicity, thus contributing to BA enterohepatic circulation. Microbiota-targeted therapies are now emerging as effective strategies for preventing and/or treating gut-related diseases. Here, we show that gut microbiota modulation induced by VSL#3 probiotics enhances BA deconjugation and fecal excretion in mice. These events are associated with changes in ileal BA absorption, repression of the enterohepatic farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) axis, and increased hepatic BA neosynthesis. Treatment with a FXR agonist normalized fecal BA levels in probiotic-administered mice, whereas probiotic-induced alterations in BA metabolism are abolished upon FXR and FGF15 deficiency. Our data provide clear in vivo evidence that VSL#3 probiotics promote ileal BA deconjugation with subsequent fecal BA excretion and induce hepatic BA neosynthesis via downregulation of the gut-liver FXR-FGF15 axis. PMID:24656817

  14. Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy.

    PubMed

    Giordano, Cinzia; Barone, Ines; Vircillo, Valentina; Panza, Salvatore; Malivindi, Rocco; Gelsomino, Luca; Pellegrino, Michele; Rago, Vittoria; Mauro, Loredana; Lanzino, Marilena; Panno, Maria Luisa; Bonofiglio, Daniela; Catalano, Stefania; Andò, Sebastiano

    2016-01-01

    Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment. PMID:26899873

  15. Plakophilins 1 and 3 Bind to FXR1 and Thereby Influence the mRNA Stability of Desmosomal Proteins

    PubMed Central

    Fischer-Kešo, Regina; Breuninger, Sonja; Hofmann, Sarah; Henn, Manuela; Röhrig, Theresa; Ströbel, Philipp; Stoecklin, Georg

    2014-01-01

    Plakophilins 1 and 3 (PKP1/3) are members of the arm repeat family of catenin proteins and serve as structural components of desmosomes, which are important for cell-cell-adhesion. In addition, PKP1/3 occur as soluble proteins outside desmosomes, yet their role in the cytoplasm is not known. We found that cytoplasmic PKP1/3 coprecipitated with the RNA-binding proteins FXR1, G3BP, PABPC1, and UPF1, and these PKP1/3 complexes also comprised desmoplakin and PKP2 mRNAs. Moreover, we showed that the interaction of PKP1/3 with G3BP, PABPC1, and UPF1 but not with FXR1 was RNase sensitive. To address the cytoplasmic function of PKP1/3, we performed gain-and-loss-of-function studies. Both PKP1 and PKP3 knockdown cell lines showed reduced protein and mRNA levels for desmoplakin and PKP2. Whereas global rates of translation were unaffected, desmoplakin and PKP2 mRNA were destabilized. Furthermore, binding of PKP1/3 to FXR1 was RNA independent, and both PKP3 and FXR1 stabilized PKP2 mRNA. Our results demonstrate that cytoplasmic PKP1/3 are components of mRNA ribonucleoprotein particles and act as posttranscriptional regulators of gene expression. PMID:25225333

  16. Optimization of in-cell accelerated solvent extraction technique for the determination of organochlorine pesticides in river sediments.

    PubMed

    Duodu, Godfred Odame; Goonetilleke, Ashantha; Ayoko, Godwin A

    2016-04-01

    Organochlorine pesticides (OCPs) are ubiquitous environmental contaminants with adverse impacts on aquatic biota, wildlife and human health even at low concentrations. However, conventional methods for their determination in river sediments are resource intensive. This paper presents an approach that is rapid and also reliable for the detection of OCPs. Accelerated Solvent Extraction (ASE) with in-cell silica gel clean-up followed by Triple Quadrupole Gas Chromatograph Mass Spectrometry (GCMS/MS) was used to recover OCPs from sediment samples. Variables such as temperature, solvent ratio, adsorbent mass and extraction cycle were evaluated and optimized for the extraction. With the exception of Aldrin, which was unaffected by any of the variables evaluated, the recovery of OCPs from sediment samples was largely influenced by solvent ratio and adsorbent mass and, to some extent, the number of cycles and temperature. The optimized conditions for OCPs extraction in sediment with good recoveries were determined to be 4 cycles, 4.5 g of silica gel, 105 °C, and 4:3 v/v DCM: hexane mixture. With the exception of two compounds (α-BHC and Aldrin) whose recoveries were low (59.73 and 47.66% respectively), the recovery of the other pesticides were in the range 85.35-117.97% with precision <10% RSD. The method developed significantly reduces sample preparation time, the amount of solvent used, matrix interference, and is highly sensitive and selective. PMID:26838409

  17. Adaptive Particle Swarm Optimizer with Varying Acceleration Coefficients for Finding the Most Stable Conformer of Small Molecules.

    PubMed

    Agrawal, Shikha; Silakari, Sanjay; Agrawal, Jitendra

    2015-11-01

    A novel parameter automation strategy for Particle Swarm Optimization called APSO (Adaptive PSO) is proposed. The algorithm is designed to efficiently control the local search and convergence to the global optimum solution. Parameters c1 controls the impact of the cognitive component on the particle trajectory and c2 controls the impact of the social component. Instead of fixing the value of c1 and c2 , this paper updates the value of these acceleration coefficients by considering time variation of evaluation function along with varying inertia weight factor in PSO. Here the maximum and minimum value of evaluation function is use to gradually decrease and increase the value of c1 and c2 respectively. Molecular energy minimization is one of the most challenging unsolved problems and it can be formulated as a global optimization problem. The aim of the present paper is to investigate the effect of newly developed APSO on the highly complex molecular potential energy function and to check the efficiency of the proposed algorithm to find the global minimum of the function under consideration. The proposed algorithm APSO is therefore applied in two cases: Firstly, for the minimization of a potential energy of small molecules with up to 100 degrees of freedom and finally for finding the global minimum energy conformation of 1,2,3-trichloro-1-flouro-propane molecule based on a realistic potential energy function. The computational results of all the cases show that the proposed method performs significantly better than the other algorithms. PMID:27491033

  18. Semisynthetic bile acid FXR and TGR5 agonists: physicochemical properties, pharmacokinetics, and metabolism in the rat.

    PubMed

    Roda, Aldo; Pellicciari, Roberto; Gioiello, Antimo; Neri, Flavia; Camborata, Cecilia; Passeri, Daniela; De Franco, Francesca; Spinozzi, Silvia; Colliva, Carolina; Adorini, Luciano; Montagnani, Marco; Aldini, Rita

    2014-07-01

    We report on the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of semisynthetic bile acid analogs, including 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid (a selective farnesoid X receptor [FXR] receptor agonist), 6α-ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid (a specific Takeda G protein-coupled receptor 5 [TGR5] receptor agonist), and 6α-ethyl-3α,7α-dihydroxy-24-nor-5β-cholan-23-sulfate (a dual FXR/TGR5 agonist). We measured the main physicochemical properties of these molecules, including ionization constants, water solubility, lipophilicity, detergency, and protein binding. Biliary secretion and metabolism and plasma and hepatic concentrations were evaluated by high-pressure liquid chromatography-electrospray-mass spectrometry/mass spectrometry in bile fistula rat and compared with natural analogs chenodeoxycholic, cholic acid, and taurochenodexycholic acid and intestinal bacteria metabolism was evaluated in terms of 7α-dehydroxylase substrate-specificity in anaerobic human stool culture. The semisynthetic derivatives detergency, measured in terms of their critical micellar concentration, was quite similar to the natural analogs. They were slightly more lipophilic than the corresponding natural analogs, evaluated by their 1-octanol water partition coefficient (log P), because of the ethyl group in 6 position, which makes these molecules very stable toward bacterial 7-dehydroxylation. The hepatic metabolism and biliary secretion were different: 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid, as chenodeoxycholic acid, was efficiently conjugated with taurine in the liver and, only in this form, promptly and efficiently secreted in bile. 6α-Ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid was poorly conjugated with taurine because of the steric hindrance of the methyl at C23(S) position metabolized to the C23(R) isomer and partly conjugated with taurine. Conversely, 6

  19. Biological/biomedical accelerator mass spectrometry targets. 1. optimizing the CO2 reduction step using zinc dust.

    PubMed

    Kim, Seung-Hyun; Kelly, Peter B; Clifford, Andrew J

    2008-10-15

    Biological and biomedical applications of accelerator mass spectrometry (AMS) use isotope ratio mass spectrometry to quantify minute amounts of long-lived radioisotopes such as (14)C. AMS target preparation involves first the oxidation of carbon (in sample of interest) to CO 2 and second the reduction of CO 2 to filamentous, fluffy, fuzzy, or firm graphite-like substances that coat a -400-mesh spherical iron powder (-400MSIP) catalyst. Until now, the quality of AMS targets has been variable; consequently, they often failed to produce robust ion currents that are required for reliable, accurate, precise, and high-throughput AMS for biological/biomedical applications. Therefore, we described our optimized method for reduction of CO 2 to high-quality uniform AMS targets whose morphology we visualized using scanning electron microscope pictures. Key features of our optimized method were to reduce CO 2 (from a sample of interest that provided 1 mg of C) using 100 +/- 1.3 mg of Zn dust, 5 +/- 0.4 mg of -400MSIP, and a reduction temperature of 500 degrees C for 3 h. The thermodynamics of our optimized method were more favorable for production of graphite-coated iron powders (GCIP) than those of previous methods. All AMS targets from our optimized method were of 100% GCIP, the graphitization yield exceeded 90%, and delta (13)C was -17.9 +/- 0.3 per thousand. The GCIP reliably produced strong (12)C (-) currents and accurate and precise F m values. The observed F m value for oxalic acid II NIST SRM deviated from its accepted F m value of 1.3407 by only 0.0003 +/- 0.0027 (mean +/- SE, n = 32), limit of detection of (14)C was 0.04 amol, and limit of quantification was 0.07 amol, and a skilled analyst can prepare as many as 270 AMS targets per day. More information on the physical (hardness/color), morphological (SEMs), and structural (FT-IR, Raman, XRD spectra) characteristics of our AMS targets that determine accurate, precise, and high-hroughput AMS measurement are in the

  20. Design of a MeV, 4kA linear induction accelerator for flash radiography

    SciTech Connect

    Kulke, B.; Brier, R.; Chapin, W.

    1981-02-10

    For verifying the hydrodynamics of nuclear weapons design it is useful to have flash x-ray machines that can deliver a maximum dose in a minimum pulse length and with very high reliability. At LLNL, such a requirement was identified some years ago as 500 roentgens at one meter, in a 60 nsec pulse length. In response to this requirement, a linear induction accelerator was proposed to and funded by DOE in 1977. The design of this machine, called FXR, has now been completed and construction has begun. The FXR design extends the parameters of a similar machine that had been built and operated at LBL, Berkeley, some ten years ago. Using a cold cathode injector followed by 48 accelerator modules rated at 400 kV each, the FXR machine will accelerate a 4 kA electron beam pulse to 20 MeV final energy. Key design features are the generation and the stable transport of a low emittance (100 mr-cm) beam from a field emitter diode, the design of reliable, compact energy storage components such as Blumleins, feedlines and accelerator modules, and a computer-assisted control system.

  1. The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

    PubMed Central

    Qian, Jun; Hassanein, Mohamed; Hoeksema, Megan D.; Harris, Bradford K.; Zou, Yong; Chen, Heidi; Lu, Pengcheng; Eisenberg, Rosana; Wang, Jing; Espinosa, Allan; Ji, Xiangming; Harris, Fredrick T.; Rahman, S. M. Jamshedur; Massion, Pierre P.

    2015-01-01

    Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies. PMID:25733852

  2. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts.

    PubMed

    Hu, Li; Wang, Juan; Zhou, Xin; Xiong, Zehuan; Zhao, Jiajia; Yu, Ran; Huang, Fang; Zhang, Handong; Chen, Lili

    2016-01-01

    Prolonged healing and scar formation are two major challenges in the treatment of soft tissue trauma. Adipose mesenchymal stem cells (ASCs) play an important role in tissue regeneration, and recent studies have suggested that exosomes secreted by stem cells may contribute to paracrine signaling. In this study, we investigated the roles of ASCs-derived exosomes (ASCs-Exos) in cutaneous wound healing. We found that ASCs-Exos could be taken up and internalized by fibroblasts to stimulate cell migration, proliferation and collagen synthesis in a dose-dependent manner, with increased genes expression of N-cadherin, cyclin-1, PCNA and collagen I, III. In vivo tracing experiments demonstrated that ASCs-Exos can be recruited to soft tissue wound area in a mouse skin incision model and significantly accelerated cutaneous wound healing. Histological analysis showed increased collagen I and III production by systemic administration of exosomes in the early stage of wound healing, while in the late stage, exosomes might inhibit collagen expression to reduce scar formation. Collectively, our findings indicate that ASCs-Exos can facilitate cutaneous wound healing via optimizing the characteristics of fibroblasts. Our results provide a new perspective and therapeutic strategy for the use of ASCs-Exos in soft tissue repair. PMID:27615560

  3. Longitudinal laser ion acceleration in low density targets: experimental optimization on the Titan laser facility and numerical investigation of the ultra-high intensity limit

    NASA Astrophysics Data System (ADS)

    d'Humières, E.; Chen, S.; Lobet, Mathieu; Sciscio, M.; Antici, Patrizio; Bailly-Grandvaux, Mathieu; Gangolf, Thomas; Revet, Guilhem; Santos, Joao J.; Schroer, Anna-Marie; Willi, O.; Tikhonchuk, Vladimir T.; Pepin, Henri; Fuchs, Julien

    2015-05-01

    Recent theoretical and experimental studies suggest the possibility of enhancing the efficiency and ease of laser acceleration of protons and ions using underdense or near critical plasmas through electrostatic shocks. Very promising results were recently obtained in this regime. In these experiments, a first ns pulse was focused on a thin target to explode it and a second laser with a high intensity was focused on the exploded foil. The delay between two lasers allowed to control the density gradient seen by the second laser pulse. The transition between various laser ion acceleration regimes depending on the density gradient length was studied. With a laser energy of a few Joules, protons with energies close to the energies of TNSA accelerated protons were obtained for various exploded foils configurations. In the high energy regime (~180 J), protons with energies significantly higher than the ones of TNSA accelerated protons were obtained when exploding the foil while keeping a good beam quality. These results demonstrate that low-density targets are promising candidates for an efficient proton source that can be optimized by choosing appropriate plasma conditions. New experiments were also performed in this regime with gas jets. Scaling shock acceleration in the low density regime to ultra high intensities is a challenge as radiation losses and electron positron pair production change the optimization of the shock process. Using large-scale Particle-In-Cell simulations, the transition to this regime in which intense beams of relativistic ions can be produced is investigated.

  4. Identification of potential dual agonists of FXR and TGR5 using e-pharmacophore based virtual screening.

    PubMed

    Sindhu, Thangaraj; Srinivasan, Pappu

    2015-05-01

    Farnesoid X receptor and Takeda G-protein-coupled receptor-5 are well known bile acid receptors and act as promising targets for the drug development and treatment of diabetes. Agonists of both the bile acid receptors increase insulin sensitivity and control glucose, lipids and bile acid homeostasis. The current study deals with the identification of novel dual agonists using ligand and structure-based virtual screening. Initially, an experimentally proven well-known dual agonist of FXR and TGR5, namely INT-767, was docked into the binding sites of FXR and TGR5 to determine the protein residues important for ligand binding. The docked complexes FXRINT-767 and TGR5INT-767 were used to generate e-pharmacophore hypotheses. Ligand-based virtual screening was carried out using the hypothetical e-pharmacophore model against the ChemBridge database. Further, structure-based virtual screening was performed with screened hits to find potential agonists of FXR and TGR5. A total of four best agonists were identified based on their affinity and mode of interactions with the receptors. The binding mode of these compounds with both receptors was analyzed in detail. Furthermore, molecular dynamics, ADME toxicity prediction, density functional theory and binding free energy calculations were carried out to rank the compounds. Based on the above analyses, the most potent compound, ChemBridge_9149693, was selected for further in vitro studies. The results of in vitro assays suggested that ChemBridge_9149693 is a potent and promising drug for the treatment of type II diabetes. Thus, the compound could be used for further drug design and development of dual agonists of FXR and TGR5. PMID:25787676

  5. Combined modulated electron and photon beams planned by a Monte-Carlo-based optimization procedure for accelerated partial breast irradiation

    NASA Astrophysics Data System (ADS)

    Atriana Palma, Bianey; Ureba Sánchez, Ana; Salguero, Francisco Javier; Arráns, Rafael; Míguez Sánchez, Carlos; Walls Zurita, Amadeo; Romero Hermida, María Isabel; Leal, Antonio

    2012-03-01

    The purpose of this study was to present a Monte-Carlo (MC)-based optimization procedure to improve conventional treatment plans for accelerated partial breast irradiation (APBI) using modulated electron beams alone or combined with modulated photon beams, to be delivered by a single collimation device, i.e. a photon multi-leaf collimator (xMLC) already installed in a standard hospital. Five left-sided breast cases were retrospectively planned using modulated photon and/or electron beams with an in-house treatment planning system (TPS), called CARMEN, and based on MC simulations. For comparison, the same cases were also planned by a PINNACLE TPS using conventional inverse intensity modulated radiation therapy (IMRT). Normal tissue complication probability for pericarditis, pneumonitis and breast fibrosis was calculated. CARMEN plans showed similar acceptable planning target volume (PTV) coverage as conventional IMRT plans with 90% of PTV volume covered by the prescribed dose (Dp). Heart and ipsilateral lung receiving 5% Dp and 15% Dp, respectively, was 3.2-3.6 times lower for CARMEN plans. Ipsilateral breast receiving 50% Dp and 100% Dp was an average of 1.4-1.7 times lower for CARMEN plans. Skin and whole body low-dose volume was also reduced. Modulated photon and/or electron beams planned by the CARMEN TPS improve APBI treatments by increasing normal tissue sparing maintaining the same PTV coverage achieved by other techniques. The use of the xMLC, already installed in the linac, to collimate photon and electron beams favors the clinical implementation of APBI with the highest efficiency.

  6. Laser driven ion accelerator

    DOEpatents

    Tajima, Toshiki

    2006-04-18

    A system and method of accelerating ions in an accelerator to optimize the energy produced by a light source. Several parameters may be controlled in constructing a target used in the accelerator system to adjust performance of the accelerator system. These parameters include the material, thickness, geometry and surface of the target.

  7. Laser driven ion accelerator

    DOEpatents

    Tajima, Toshiki

    2005-06-14

    A system and method of accelerating ions in an accelerator to optimize the energy produced by a light source. Several parameters may be controlled in constructing a target used in the accelerator system to adjust performance of the accelerator system. These parameters include the material, thickness, geometry and surface of the target.

  8. Recent optimization of the beam-optical characteristics of the 6 MV van de Graaff accelerator for high brightness beams at the iThemba LABS NMP facility

    NASA Astrophysics Data System (ADS)

    Conradie, J. L.; Eisa, M. E. M.; Celliers, P. J.; Delsink, J. L. G.; Fourie, D. T.; de Villiers, J. G.; Maine, P. M.; Springhorn, K. A.; Pineda-Vargas, C. A.

    2005-04-01

    With the aim of improving the reliability and stability of the beams delivered to the nuclear microprobe at iThemba LABS, as well as optimization of the beam characteristics along the van de Graaff accelerator beamlines in general, relevant modifications were implemented since the beginning of 2003. The design and layout of the beamlines were revised. The beam-optical characteristics through the accelerator, from the ion source up to the analysing magnet directly after the accelerator, were calculated and the design optimised, using the computer codes TRANSPORT, IGUN and TOSCA. The ion source characteristics and optimal operating conditions were determined on an ion source test bench. The measured optimal emittance for 90% of the beam intensity was about 50π mm mrad for an extraction voltage of 6 kV. These changes allow operation of the Nuclear Microprobe at proton energies in the range 1 MeV-4 MeV with beam intensities of tenths of a pA at the target surface. The capabilities of the nuclear microprobe facility were evaluated in the improved beamline, with particular emphasis to bio-medical samples.

  9. The mechanism of action of FXR1P-related miR-19b-3p in SH-SY5Y.

    PubMed

    Ma, Yun; Tian, Shuai; He, Shuya; Chen, Qiong; Wang, Zongbao; Xiao, Xiao; Fu, Liang; Lei, Xiaoyong

    2016-08-15

    The biological effects of microRNAs (miRNAs) in the Fragile X Syndrome (FXS) have been widely studied. Dysregulation of miRNAs plays a critical role in the progression of nervous system diseases and in cell proliferation and differentiation. Our previous study validated that miR-19b-3p was associated with FXR1 (Fragile X related gene 1), one of homologous genes of FMR1 (Fragile X mental retardation 1). The purpose of this study was to investigate the relationship of FXR1 and miR-19b-3p, and the crucial role of miR-19b-3p in FXS and to validate whether miR-19b-3p could regulate the growth of SH-SY5Y cells. We determined that miR-19b-3p could regulate the expression of not only USP32, RAB18 and Dusp6 but also FXR1, and FXR1 could in turn regulate the expression of miR-19b-3p. What's more, the overexpression of miR-19b-3p significantly inhibited the proliferation, contributed the apoptosis and slowed down the cycle of SH-SY5Y cells. Taken together, our results indicate that miR-19b-3p plays a significant role in the molecular pathology of FXS by interacting with FXR1 and influencing the growth of SH-SY5Y cells. PMID:27138803

  10. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.

    PubMed

    Sayin, Sama I; Wahlström, Annika; Felin, Jenny; Jäntti, Sirkku; Marschall, Hanns-Ulrich; Bamberg, Krister; Angelin, Bo; Hyötyläinen, Tuulia; Orešič, Matej; Bäckhed, Fredrik

    2013-02-01

    Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum. PMID:23395169

  11. Self-Organizing Hierarchical Particle Swarm Optimization with Time-Varying Acceleration Coefficients for Economic Dispatch with Valve Point Effects and Multifuel Options

    NASA Astrophysics Data System (ADS)

    Polprasert, Jirawadee; Ongsakul, Weerakorn; Dieu, Vo Ngoc

    2011-06-01

    This paper proposes a self-organizing hierarchical particle swarm optimization (SPSO) with time-varying acceleration coefficients (TVAC) for solving economic dispatch (ED) problem with non-smooth functions including multiple fuel options (MFO) and valve-point loading effects (VPLE). The proposed SPSO with TVAC is the new approach optimizer and good performance for solving ED problems. It can handle the premature convergence of the problem by re-initialization of velocity whenever particles are stagnated in the search space. To properly control both local and global explorations of the swarm during the optimization process, the performance of TVAC is included. The proposed method is tested in different ED problems with non-smooth cost functions and the obtained results are compared to those from many other methods in the literature. The results have revealed that the proposed SPSO with TVAC is effective in finding higher quality solutions for non-smooth ED problems than many other methods.

  12. TH-A-19A-12: A GPU-Accelerated and Monte Carlo-Based Intensity Modulated Proton Therapy Optimization System

    SciTech Connect

    Ma, J; Wan Chan Tseung, H; Beltran, C

    2014-06-15

    Purpose: To develop a clinically applicable intensity modulated proton therapy (IMPT) optimization system that utilizes more accurate Monte Carlo (MC) dose calculation, rather than analytical dose calculation. Methods: A very fast in-house graphics processing unit (GPU) based MC dose calculation engine was employed to generate the dose influence map for each proton spot. With the MC generated influence map, a modified gradient based optimization method was used to achieve the desired dose volume histograms (DVH). The intrinsic CT image resolution was adopted for voxelization in simulation and optimization to preserve the spatial resolution. The optimizations were computed on a multi-GPU framework to mitigate the memory limitation issues for the large dose influence maps that Result from maintaining the intrinsic CT resolution and large number of proton spots. The dose effects were studied particularly in cases with heterogeneous materials in comparison with the commercial treatment planning system (TPS). Results: For a relatively large and complex three-field bi-lateral head and neck case (i.e. >100K spots with a target volume of ∼1000 cc and multiple surrounding critical structures), the optimization together with the initial MC dose influence map calculation can be done in a clinically viable time frame (i.e. less than 15 minutes) on a GPU cluster consisting of 24 Nvidia GeForce GTX Titan cards. The DVHs of the MC TPS plan compare favorably with those of a commercial treatment planning system. Conclusion: A GPU accelerated and MC-based IMPT optimization system was developed. The dose calculation and plan optimization can be performed in less than 15 minutes on a hardware system costing less than 45,000 dollars. The fast calculation and optimization makes the system easily expandable to robust and multi-criteria optimization. This work was funded in part by a grant from Varian Medical Systems, Inc.

  13. Bile acids and derivatives, their nuclear receptors FXR, PXR and ligands: role in health and disease and their therapeutic potential.

    PubMed

    Zimber, Amazia; Gespach, Christian

    2008-06-01

    Bile acids, their physiology and metabolism, their role in carcinogenesis and other major human diseases are recently undergoing significant progress. Starting in 1999 when the orphan nuclear receptor FXR was shown to be specifically activated by bile acids, these compounds became part of the arsenal of ligands of the steroid hormone superfamily of nuclear receptors, including receptors of Vitamin D3, retinoids (RAR, RXR), and thyroid hormone. Another decisive discovery pointed later that the pregnane X-receptor (PXR) is activated by the endogenous toxic lithocholic acid, as well as several xenobiotics and drugs. Bile acids have recently emerged as key regulators of their own metabolism, and of lipid and carbohydrate metabolism. They have important role as promoters of esophageal and colon cancers, cholangiocarcinoma, as well as new implications in breast cancer development and metastasis. This Review will emphasize novel aspects of bile acids, FXR and PXR as regulators of interfaces at cell proliferation and differentiation, cell death, survival, invasion, and metastasis during normal development and cancer progression. Signaling pathways controlled by bile acids will be presented and discussed in relation to their impact on gene expression. The biological and pharmacological significance of bile acids and their recently developed synthetic derivatives and conjugates, as well as new development in the design of FXR agonists and antagonists for clinical applications in cancer prevention and therapy, will be evaluated. This part includes advances in the utilization of bile acid transporters in drug resistance, therapeutic targeting and delivery of anticancer drugs, as well as therapeutic combinations using new bile acid derivatives, sequestrating agents and reabsorption inhibitors, and their limitations. PMID:18537536

  14. FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway

    PubMed Central

    Jung, Dongju; York, J. Philippe; Wang, Li; Yang, Chaofeng; Zhang, Aijun; Francis, Heather L.; Webb, Paul; McKeehan, Wallace L.; Alpini, Gianfranco; LeSage, Gene D.; Moore, David D.

    2014-01-01

    Cholangiocytes, bile duct lining cells, actively adjust the amount of cholesterol and bile acids in bile through expression of enzymes and channels involved in transportation and metabolism of the cholesterol and bile acids. Herein, we report molecular mechanisms regulating bile acid biosynthesis in cholangiocytes. Among the cytochrome p450 (Cyp) enzymes involved in bile acid biosynthesis, sterol 27-hydroxylase (Cyp27) that is the rate-limiting enzyme for the acidic pathway of bile acid biosynthesis expressed in cholangiocytes. Expression of other Cyp enzymes for the basic bile acid biosynthesis was hardly detected. The Cyp27 expression was negatively regulated by a hydrophobic bile acid through farnesoid X receptor (FXR), a nuclear receptor activated by bile acid ligands. Activated FXR exerted the negative effects by inducing an expression of fibroblast growth factor 15/19 (FGF15/19). Similar to its repressive function against cholesterol 7α-hydroxylase (Cyp7a1) expression in hepatocytes, secreted FGF15/19 triggered Cyp27 repression in cholangiocytes through interaction with its cognate receptor fibroblast growth factor receptor 4 (FGFR4). The involvements of FXR and FGFR4 for the bile acid-induced Cyp27 repression were confirmed in vivo using knockout mouse models. Different from the signaling in hepatocytes, wherein the FGF15/19-induced repression signaling is mediated by c-Jun N-terminal kinase (JNK), FGF15/19-induced Cyp27 repression in cholangiocytes was mediated by p38 kinase. Thus, the results collectively suggest that cholangiocytes may be able to actively regulate bile acid biosynthesis in cholangiocytes and even hepatocyte by secreting FGF15/19. We suggest the presence of cholangiocyte-mediated intrahepatic feedback loop in addition to the enterohepatic feedback loop against bile acid biosynthesis in the liver. PMID:24068255

  15. Pyrazinamide Induced Rat Cholestatic Liver Injury through Inhibition of FXR Regulatory Effect on Bile Acid Synthesis and Transport.

    PubMed

    Guo, Hong-Li; Hassan, Hozeifa M; Zhang, Yun; Dong, Si-Zhe; Ding, Ping-Ping; Wang, Tao; Sun, Li-Xin; Zhang, Lu-Yong; Jiang, Zhen-Zhou

    2016-08-01

    Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of tuberculosis which may cause serious hepatotoxicity; however, the mechanisms underlying these toxicities are poorly understood. Cholestasis plays an important role in drug-induced liver injury. Since there were no previous published works reported cholestasis and PZA hepatotoxicity relationship, this study aimed to identify whether PZA can induce liver injury with characterized evidences of cholestasis and to clarify expression changes of proteins related to both bile acid synthesis and transport in PZA-induced liver injury. PZA (2 g/kg) was administered for 7 consecutive days by oral gavage. Results showed there were 2-fold elevation in both ALT and AST serum levels in PZA-treated rats. In addition, a 10-fold increment in serum total bile acid was observed after PZA administration. The mRNA and protein expressions of bile acid synthesis and transport parameters were markedly altered, in which FXR, Bsep, Mrp2, Mdr2, Ostα/β, Oatp1a1, Oatp1b2, and Cyp8b1 were decreased (P < .05), while Mrp3, Ntcp, Oatp1a4, and Cyp7a1 were increased (P < .05). Moreover, treatment with the FXR agonist obeticholic acid (OCA) generated obvious reductions in serum ALT, AST, and TBA levels in PZA-treated rats. Those effects were due to transcriptional regulation of pre-mentioned target genes by OCA. Taken together, these results suggested that PZA-induced cholestatic liver injury was related to FXR inhibition, leading to the dysfunction in bile acid synthesis and transport. PMID:27255380

  16. Optimization of conditions for thermal treatment of rice bran using an accelerator including an organo-iron compound.

    PubMed

    Kanno, Hikari; Tachibana, Naoya; Fukushima, Masami

    2011-02-01

    A method for thermal conversion of raw organic waste (ROW) to a compost-like material (CLM) with higher levels of unsaturated carbohydrates, nitrogen- and oxygen-containing compounds was developed, in which rice bran and an organo-iron compound were employed as a model ROW and the accelerator, respectively. To evaluate the qualities of CLMs, organic substances of an acid insoluble fraction of alkaline extracts (AIAEs) from a CLM were structurally characterized by elemental analysis, pyrolysis-gas chromatography/mass spectrometry and FT-IR. The levels of unsaturated carbohydrates, and nitrogen- and oxygen-containing compounds in the CLM samples were increased by long-term treatment (60°C for 5 days, 170°C for 3 days). In particular, the high lipid content of the AIAEs, which was indicative of inadequate digestion of CLM components, was dramatically reduced in the presence of the accelerator. PMID:21044838

  17. Optimizing pulse shaping and zooming for acceleration to high velocities and fusion neutron production on the Nike laser

    NASA Astrophysics Data System (ADS)

    Karasik, Max; Weaver, J. L.; Aglitskiy, Y.; Zalesak, S. T.; Velikovich, A. L.; Oh, J.; Obenschain, S. P.; Arikawa, Y.; Watari, T.

    2010-11-01

    We will present results from follow-on experiments to the record-high velocities of 1000 km/s achieved on Nike [Karasik et al., Phys. Plasmas 17, 056317 (2010) ], in which highly accelerated planar foils of deuterated polystyrene were made to collide with a witness foil to produce extreme shock pressures and result in heating of matter to thermonuclear temperatures. Still higher velocities and higher target densities are required for impact fast ignition. The aim of these experiments is shaping the driving pulse to minimize shock heating of the accelerated target and using the focal zoom capability of Nike to achieve higher densities and velocities. Spectroscopic measurements of electron temperature achieved upon impact will complement the neutron time-of-flight ion temperature measurement. Work is supported by US DOE and Office of Naval Research.

  18. Optimal Model-Based Fault Estimation and Correction for Particle Accelerators and Industrial Plants Using Combined Support Vector Machines and First Principles Models

    SciTech Connect

    Sayyar-Rodsari, Bijan; Schweiger, Carl; /SLAC /Pavilion Technologies, Inc., Austin, TX

    2010-08-25

    parameters of the beam lifetime model) are physically meaningful. (3) Numerical Efficiency of the Training - We investigated the numerical efficiency of the SVM training. More specifically, for the primal formulation of the training, we have developed a problem formulation that avoids the linear increase in the number of the constraints as a function of the number of data points. (4) Flexibility of Software Architecture - The software framework for the training of the support vector machines was designed to enable experimentation with different solvers. We experimented with two commonly used nonlinear solvers for our simulations. The primary application of interest for this project has been the sustained optimal operation of particle accelerators at the Stanford Linear Accelerator Center (SLAC). Particle storage rings are used for a variety of applications ranging from 'colliding beam' systems for high-energy physics research to highly collimated x-ray generators for synchrotron radiation science. Linear accelerators are also used for collider research such as International Linear Collider (ILC), as well as for free electron lasers, such as the Linear Coherent Light Source (LCLS) at SLAC. One common theme in the operation of storage rings and linear accelerators is the need to precisely control the particle beams over long periods of time with minimum beam loss and stable, yet challenging, beam parameters. We strongly believe that beyond applications in particle accelerators, the high fidelity and cost benefits of a combined model-based fault estimation/correction system will attract customers from a wide variety of commercial and scientific industries. Even though the acquisition of Pavilion Technologies, Inc. by Rockwell Automation Inc. in 2007 has altered the small business status of the Pavilion and it no longer qualifies for a Phase II funding, our findings in the course of the Phase I research have convinced us that further research will render a workable model

  19. Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction.

    PubMed

    Liu, Xijun; Xue, Ruyi; Ji, Lingling; Zhang, Xingwang; Wu, Jian; Gu, Jianxin; Zhou, Meiling; Chen, She

    2014-07-18

    Fructose is a key dietary factor in the development of nonalcoholic fatty liver disease (NAFLD). Here we investigated whether WAY-362450 (WAY), a potent synthetic and orally active FXR agonist, protects against fructose-induced steatosis and the underlying mechanisms. C57BL/6J mice, fed 30% fructose for 8 weeks, were treated with or without WAY, 30 mg/kg, for 20 days. The elevation of serum and hepatic triglyceride in mice fed 30% fructose was reversed by WAY treatment. Histologically, WAY significantly reduced triglyceride accumulation in liver, attenuated microphage infiltration and protected the junction integrity in intestine. Moreover, WAY remarkably decreased portal endotoxin level, and lowered serum TNFα concentration. In lipopolysaccharide (LPS)-induced NAFLD model, WAY attenuated serum TNFα level. Moreover, WAY suppressed LPS-induced expression of hepatic lipid droplet protein adipose differentiation-related protein (ADRP), down-regulation of it in mice fed 30% fructose. Furthermore, WAY repressed lipid accumulation and ADRP expression in a dose-dependent manner in palmitic acid (PA)-treated HepG2 and Huh7 cells. WAY suppressed TNFα-induced ADRP up-regulation via competing with AP-1 for ADRP promoter binding region. Together, our findings suggest that WAY, an FXR agonist, attenuates liver steatosis through multiple mechanisms critically involved in the development of hepatosteatosis, and represents a candidate for NAFLD treatment. PMID:24875360

  20. A Specialized Mechanism of Translation Mediated by FXR1a-Associated MicroRNP in Cellular Quiescence.

    PubMed

    Bukhari, Syed I A; Truesdell, Samuel S; Lee, Sooncheol; Kollu, Swapna; Classon, Anthony; Boukhali, Myriam; Jain, Esha; Mortensen, Richard D; Yanagiya, Akiko; Sadreyev, Ruslan I; Haas, Wilhelm; Vasudevan, Shobha

    2016-03-01

    MicroRNAs predominantly decrease gene expression; however, specific mRNAs are translationally upregulated in quiescent (G0) mammalian cells and immature Xenopus laevis oocytes by an FXR1a-associated microRNA-protein complex (microRNP) that lacks the microRNP repressor, GW182. Their mechanism in these conditions of decreased mTOR signaling, and therefore reduced canonical (cap-and-poly(A)-tail-mediated) translation, remains undiscovered. Our data reveal that mTOR inhibition in human THP1 cells enables microRNA-mediated activation. Activation requires shortened/no poly(A)-tail targets; polyadenylated mRNAs are partially activated upon PAIP2 overexpression, which interferes with poly(A)-bound PABP, precluding PABP-enhanced microRNA-mediated inhibition and canonical translation. Consistently, inhibition of PARN deadenylase prevents activation. P97/DAP5, a homolog of canonical translation factor, eIF4G, which lacks PABP- and cap binding complex-interacting domains, is required for activation, and thereby for the oocyte immature state. P97 interacts with 3' UTR-binding FXR1a-associated microRNPs and with PARN, which binds mRNA 5' caps, forming a specialized complex to translate recruited mRNAs in these altered canonical translation conditions. PMID:26942679

  1. Curcumin protects ANIT-induced cholestasis through signaling pathway of FXR-regulated bile acid and inflammation.

    PubMed

    Yang, Fan; Tang, Xiaowen; Ding, Lili; Zhou, Yue; Yang, Qiaoling; Gong, Junting; Wang, Guangyun; Wang, Zhengtao; Yang, Li

    2016-01-01

    Cholestasis is a clinically significant symptom and widely associated with liver diseases, however, there are very few effective therapies for cholestasis. Danning tablet (DNT, a Chinese patent medicine preparation) has been clinically used to treat human liver and gallbladder diseases for more than 20 years in China. However, which ingredients of DNT contributed to this beneficial effect and their mechanistic underpinnings have been largely unknown. In the present study, we discovered that DNT not only demonstrated greater benefits for cholecystitis patients after cholecystectomy surgery in clinic but also showed protective effect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis model in rodent. Curcumin, one major compound derived from DNT, exerted the protective effect against cholestasis through farnesoid X receptor (FXR), which has been focused as potential therapeutic targets for treating cholestasis. The underlying mechanism of curcumin against cholestasis was restoring bile acid homeostasis and antagonizing inflammatory responses in a FXR-dependent manner and in turn contributed to overall cholestasis attenuation. Collectively, curcumin can be served as a potential treatment option for liver injury with cholestasis. PMID:27624003

  2. Dual Activation of the Bile Acid Nuclear Receptor FXR and G-Protein-Coupled Receptor TGR5 Protects Mice against Atherosclerosis

    PubMed Central

    Miyazaki-Anzai, Shinobu; Masuda, Masashi; Levi, Moshe; Keenan, Audrey L.; Miyazaki, Makoto

    2014-01-01

    Bile acid signaling is a critical regulator of glucose and energy metabolism, mainly through the nuclear receptor FXR and the G protein-coupled receptor TGR. The purpose of the present study was to investigate whether dual activation of FXR and TGR5 plays a significant role in the prevention of atherosclerosis progression. To evaluate the effects of bile acid signaling in atherogenesis, ApoE−/− mice and LDLR−/− mice were treated with an FXR/TGR5 dual agonist (INT-767). INT-767 treatment drastically reduced serum cholesterol levels. INT-767 treatment significantly reduced atherosclerotic plaque formation in both ApoE−/− and LDLR−/− mice. INT-767 decreased the expression of pro-inflammatory cytokines and chemokines in the aortas of ApoE−/− mice through the inactivation of NF-κB. In addition, J774 macrophages treated with INT-767 had significantly lower levels of active NF-κB, resulting in cytokine production in response to LPS through a PKA dependent mechanism. This study demonstrates that concurrent activation of FXR and TGR5 attenuates atherosclerosis by reducing both circulating lipids and inflammation. PMID:25237811

  3. Computer-aided design optimization with the use of a fast dose model for linear-accelerator-based stereotactic radiosurgery

    NASA Astrophysics Data System (ADS)

    Suh, Tae S.; Bova, Frank J.; Yoon, Sei C.; Choe, Bo Y.; Kim, Moon C.; Shinn, Kyung S.; Bahk, Yong W.; Ha, Sung W.; Park, Charn I.

    1996-04-01

    In order to efficiently plan non-spherical radiosurgical targets we have used computer-aided design optimization techniques with a fast dose model. A study of the spatial dose distribution for single or multiple non-coplanar arcs was carried out using a 18 cm diameter spherical head model. The dose distribution generated from the 3D dose computation algorithm can be represented by a simple analytic form. Two analytic dose models were developed to represent the dose for preset multiple non-coplanar arcs or a single arc: spherical and cylindrical. The spherical and cylindrical dose models compute dose quickly for each isocentre and single arc. Our approach then utilizes a computer-aided design optimization (CAD) with the use of two fast approximate dose models to determine the positions of isocentres and arcs. The implementation of CAD with fast dose models was demonstrated. While the fast dose models are only approximations of the true dose distribution, it is shown that this approximate model is sufficient to optimize isocentric position, collimator size and arc positions with CAD.

  4. Calculation for optimization of the experimental conditions for RBS analysis at the HUS 5SDH-2 tandem accelerator

    NASA Astrophysics Data System (ADS)

    Phong, Le Hong Khiem Ho, Vi; Nghia, Nguyen The

    2015-06-01

    The dependences of the depth and mass resolutions of analysis using Rutherford Backscattering Spectrometry (RBS) on some experimental conditions (such as the beam energy, the target tilting angle, etc.) have been investigated. A computer program for simulating the RBS spectra and for calculating the depth and mass resolution under different experimental conditions was developed. The results of calculation were experimentally checked by using some reference samples. The good agreements between calculated and experimental values have been found. The optimum analysis conditions over a wide range of RBS applications based on our calculation can be chosen. This investigation was conducted by using the RBS system at HUS 5SDH-2 Tandem accelerator at the Hanoi University of Science.

  5. Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia.

    PubMed

    Genin, Michael J; Bueno, Ana B; Agejas Francisco, Javier; Manninen, Peter R; Bocchinfuso, Wayne P; Montrose-Rafizadeh, Chahrzad; Cannady, Ellen A; Jones, Timothy M; Stille, John R; Raddad, Eyas; Reidy, Charles; Cox, Amy; Michael, M Dodson; Michael, Laura F

    2015-12-24

    The farnesoid X receptor (FXR) is a member of the "metabolic" subfamily of nuclear receptors. Several FXR agonists have been reported in the literature to have profound effects on plasma lipids in animal models. To discover novel and effective therapies for dyslipidemia and atherosclerosis, we have developed a series of potent FXR agonists that robustly lower plasma LDL and vLDL in LDLr-/- mice. To this end the novel piperidinylisoxazole system LY2562175 was discovered. This molecule is a potent and selective FXR agonist in vitro and has robust lipid modulating properties, lowering LDL and triglycerides while raising HDL in preclinical species. The preclinical ADME properties of LY2562175 were consistent with enabling once daily dosing in humans, and it was ultimately advanced to the clinic for evaluation in humans. The synthesis and biological profile of this molecule is discussed. PMID:26568144

  6. Coordinated Actions of FXR and LXR in Metabolism: From Pathogenesis to Pharmacological Targets for Type 2 Diabetes

    PubMed Central

    Ding, Lin; Pang, Shuguang; Sun, Yongmei; Tian, Yuling; Yu, Li; Dang, Ningning

    2014-01-01

    Type 2 diabetes (T2D) is the most prevalent metabolic disease, and many people are suffering from its complications driven by hyperglycaemia and dyslipidaemia. Nuclear receptors (NRs) are ligand-inducible transcription factors that mediate changes to metabolic pathways within the body. As metabolic regulators, the farnesoid X receptor (FXR) and the liver X receptor (LXR) play key roles in the pathogenesis of T2D, which remains to be clarified in detail. Here we review the recent progress concerning the physiological and pathophysiological roles of FXRs and LXRs in the regulation of bile acid, lipid and glucose metabolism and the implications in T2D, taking into account that these two nuclear receptors are potential pharmaceutical targets for the treatment of T2D and its complications. PMID:24872814

  7. Factors Associated With Optimal Long-Term Cosmetic Results in Patients Treated With Accelerated Partial Breast Irradiation Using Balloon-Based Brachytherapy

    SciTech Connect

    Vicini, Frank A.; Keisch, Martin; Shah, Chirag; Goyal, Sharad; Khan, Atif J.; Beitsch, Peter D.; Lyden, Maureen; Haffty, Bruce G.

    2012-06-01

    Purpose: To evaluate factors associated with optimal cosmetic results at 72 months for early-stage breast cancer patients treated with Mammosite balloon-based accelerated partial breast irradiation (APBI). Methods and Materials: A total of 1,440 patients (1,449 cases) with early-stage breast cancer undergoing breast-conserving therapy were treated with balloon-based brachytherapy to deliver APBI (34 Gy in 3.4-Gy fractions). Cosmetic outcome was evaluated at each follow-up visit and dichotomized as excellent/good (E/G) or fair/poor (F/P). Follow-up was evaluated at 36 and 72 months to establish long-term cosmesis, stability of cosmesis, and factors associated with optimal results. Results: The percentage of evaluable patients with excellent/good (E/G) cosmetic results at 36 months and more than 72 months were 93.3% (n = 708/759) and 90.4% (n = 235/260). Factors associated with optimal cosmetic results at 72 months included: larger skin spacing (p = 0.04) and T1 tumors (p = 0.02). Using multiple regression analysis, the only factors predictive of worse cosmetic outcome at 72 months were smaller skin spacing (odds ratio [OR], 0.89; confidence interval [CI], 0.80-0.99) and tumors greater than 2 cm (OR, 4.96, CI, 1.53-16.07). In all, 227 patients had both a 36-month and a 72-month cosmetic evaluation. The number of patients with E/G cosmetic results decreased only slightly from 93.4% at 3 years to 90.8% (p = 0.13) at 6 years, respectively. Conclusions: APBI delivered with balloon-based brachytherapy produced E/G cosmetic results in 90.4% of cases at 6 years. Larger tumors (T2) and smaller skin spacing were found to be the two most important independent predictors of cosmesis.

  8. Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis.

    PubMed

    Meng, Qiang; Chen, Xin-Li; Wang, Chang-Yuan; Liu, Qi; Sun, Hui-Jun; Sun, Peng-Yuan; Huo, Xiao-Kui; Liu, Zhi-Hao; Yao, Ji-Hong; Liu, Ke-Xin

    2015-03-15

    Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes. PMID:25655198

  9. Linear Accelerators

    SciTech Connect

    Sidorin, Anatoly

    2010-01-05

    In linear accelerators the particles are accelerated by either electrostatic fields or oscillating Radio Frequency (RF) fields. Accordingly the linear accelerators are divided in three large groups: electrostatic, induction and RF accelerators. Overview of the different types of accelerators is given. Stability of longitudinal and transverse motion in the RF linear accelerators is briefly discussed. The methods of beam focusing in linacs are described.

  10. Linear Accelerators

    NASA Astrophysics Data System (ADS)

    Sidorin, Anatoly

    2010-01-01

    In linear accelerators the particles are accelerated by either electrostatic fields or oscillating Radio Frequency (RF) fields. Accordingly the linear accelerators are divided in three large groups: electrostatic, induction and RF accelerators. Overview of the different types of accelerators is given. Stability of longitudinal and transverse motion in the RF linear accelerators is briefly discussed. The methods of beam focusing in linacs are described.

  11. H2 S inhibits apo(a) expression and secretion through PKCα/FXR and Akt/HNF4α pathways in HepG2 cells.

    PubMed

    Qu, Kai; Liu, Ya-Mi; He, Xing-Lan; Zhang, Hai; Zhang, Kai; Peng, Juan; Tang, Ya-Ling; Yu, Xiao-Hua; Zeng, Jun-Fa; Lei, Jian-Jun; Wei, Dang-Heng; Wang, Zuo

    2016-08-01

    Lipoprotein(a) [Lp(a)] is a strong genetic risk factor for coronary heart diseases. However, the metabolism of this protein remains poorly understood. Efficient and specific drugs that can decrease high plasma levels of Lp(a) have not been developed yet. Hydrogen sulfide (H2 S), a member of the gas transmitter family, performs important biological actions, including protection against cardiovascular diseases and maintenance of the lipid metabolism equilibrium in hepatocytes and adipocytes. In this study, we investigated the possible molecular mechanism of H2 S that influences apolipoprotein(a) [apo(a)] biosynthesis. We also determined the effects of H2 S on apo(a) expression and secretion in HepG2 cells as well as the underlying mechanisms. Results showed that H2 S significantly inhibited the expression and secretion levels of apo(a). These effects were attenuated by the PKCα inhibitor and FXR siRNA. H2 S also reduced HNF4α expression and enhanced FXR expression. The Akt inhibitor partially reversed H2 S-induced inhibition of apo(a) and HNF4α expression and apo(a) secretion. This study reveals that H2 S suppressed apo(a) expression and secretion via the PKCα-FXR and PI3K/Akt-HNF4α pathways. PMID:27298021

  12. Reduction in bile acid pool causes delayed liver regeneration accompanied by down-regulated expression of FXR and c-Jun mRNA in rats.

    PubMed

    Dong, Xiushan; Zhao, Haoliang; Ma, Xiaoming; Wang, Shiming

    2010-02-01

    The present study attempted to examine the effects of bile acid pool size on liver regeneration after hepatectomy. The rats were fed on 0.2% cholic acid (CA) or 2% cholestyramine for 7 days to induce a change in the bile acid size, and then a partial hepatectomy (PH) was performed. Rats fed on the normal diet served as the controls. Measurements were made on the rate of liver regeneration, the labeling indices of PCNA, the plasma total bile acids (TBA), and the mRNA expression of cholesterol 7alpha-hydroxylase (CYP7A1), farnesoid X receptor (FXR), and transcription factor c-Jun or c-fos. As compared with the normal and CA groups, the rate of liver regeneration was decreased on the day 3, and 7 after PH; the peak of the labeling indices of PCNA was delayed and the labeling indices were significantly reduced on the day 1; the TBA were also decreased on the day 1; the expression of FXR decreased but that of CYP7A1 increased at any given time; at the 1st, and 3rd h, the expression of c-Jun was declined in the cholestyramine group. The reduction in the bile acid pool size was found to delay the liver regeneration, which may be caused by the down-regulation of FXR and c-Jun expression. PMID:20155456

  13. Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis

    SciTech Connect

    Meng, Qiang; Chen, Xin-li; Wang, Chang-yuan; Liu, Qi; Sun, Hui-jun; Sun, Peng-yuan; Huo, Xiao-kui; Liu, Zhi-hao; Yao, Ji-hong; Liu, Ke-xin

    2015-03-15

    Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes. - Highlights: • AB23A has at least three roles in protection against ANIT-induced liver injury. • AB23A decreases Ntcp, and increases Bsep, Mrp2 and Mdr2 expression. • AB23A represses Cyp7a1 and Cyp8b1 through inducing Shp and Fgf15 expression. • AB23A increases bile acid metabolism through inducing Sult2a1 expression. • FXR activation is involved

  14. Simultaneous diastereo- and enantioseparation of farnesoid X receptor (FXR) agonists with a quinine carbamate-based chiral stationary phase.

    PubMed

    Sardella, Roccaldo; Marinozzi, Maura; Ianni, Federica; Lisanti, Antonella; Natalini, Benedetto

    2013-01-01

    In the frame of a project aimed at finding non-steroidal farnesoid X receptor (FXR) agonists, we identified 4-(2,4-dimethoxyphenyl)-3,6-dimethyl-1-(2-tolyl)-4,8-dihydro-1H-pyrazole[3,4-e][1,4]thiazepin-7-one (1) as a hit endowed with FXR activity. Most of the compounds synthesised during the hit-to-lead optimisation work were characterised by the presence of two chiral centres and were therefore obtained as mixtures of anti(±)- and syn(±)-diastereoisomers. A restricted sub-set of species harboured with a carboxylic acid group on the distal phenyl ring of the biphenyl (a(±)5 (A1) and s(±)5 (S1)) or the phenoxyphenyl (a(±)6 (A2) and s(±)6 (S2)) moiety at C-4 position of the pyrazole[3,4-e][1,4]thiazepin-7-one core, resulted in suitable diastereo- and enantioresolution with a quinine (QN) carbamate-derived chiral stationary phase (CSP). Differently from the compounds usually analysed with QN-based CSPs, the couples A1/S1 and A2/S2 were atypical selectands, in which the two chiral carbon atoms reside at a remote position with respect to the carboxylic function, the main "point of attack" to the CSP. We produced evidence that the scarcely employed normal-phase (NP) eluent systems represent the elective choice for achieving the simultaneous diastereo- and enantioseparation of this class of compounds over the usually preferred reversed-phase (RP) and polar-organic (PO) modes of elution. Indeed, after the optimisation of the eluent composition, NP conditions allowed to obtain profitable enantioselectivity profiles, along with excellent diastereoselectivity levels (α(A1) = 1.07, R (S)(A1) = 1.15; α(S1) = 1.09, R (S)(S1) = 1.47; α(A2) = 1.08, R (S)(A2) = 1.31; and α(S2) = 1.06, R (S)(S2) = 1.18). The optimised NP methods are suitable for simultaneously providing information on the diastereo- and enantiopurity of the investigated compounds. PMID:22932813

  15. Can Accelerators Accelerate Learning?

    NASA Astrophysics Data System (ADS)

    Santos, A. C. F.; Fonseca, P.; Coelho, L. F. S.

    2009-03-01

    The 'Young Talented' education program developed by the Brazilian State Funding Agency (FAPERJ) [1] makes it possible for high-schools students from public high schools to perform activities in scientific laboratories. In the Atomic and Molecular Physics Laboratory at Federal University of Rio de Janeiro (UFRJ), the students are confronted with modern research tools like the 1.7 MV ion accelerator. Being a user-friendly machine, the accelerator is easily manageable by the students, who can perform simple hands-on activities, stimulating interest in physics, and getting the students close to modern laboratory techniques.

  16. PARTICLE ACCELERATOR

    DOEpatents

    Teng, L.C.

    1960-01-19

    ABS>A combination of two accelerators, a cyclotron and a ring-shaped accelerator which has a portion disposed tangentially to the cyclotron, is described. Means are provided to transfer particles from the cyclotron to the ring accelerator including a magnetic deflector within the cyclotron, a magnetic shield between the ring accelerator and the cyclotron, and a magnetic inflector within the ring accelerator.

  17. Optimal moderator materials at various proton energies considering photon dose rate after irradiation for an accelerator-driven ⁹Be(p, n) boron neutron capture therapy neutron source.

    PubMed

    Hashimoto, Y; Hiraga, F; Kiyanagi, Y

    2015-12-01

    We evaluated the accelerator beam power and the neutron-induced radioactivity of (9)Be(p, n) boron neutron capture therapy (BNCT) neutron sources having a MgF2, CaF2, or AlF3 moderator and driven by protons with energy from 8 MeV to 30 MeV. The optimal moderator materials were found to be MgF2 for proton energies less than 10 MeV because of lower required accelerator beam power and CaF2 for higher proton energies because of lower photon dose rate at the treatment position after neutron irradiation. PMID:26272165

  18. Optimization and validation of an accelerated laboratory extraction method to estimate nitrogen release patterns of slow- and controlled-release fertilizers.

    PubMed

    Medina, L Carolina; Sartain, Jerry B; Obreza, Thomas A; Hall, William L; Thiex, Nancy J

    2014-01-01

    Several technologies have been proposed to characterize the nutrient release and availability patterns of enhanced-efficiency fertilizers (EEFs), especially slow-release fertilizers (SRFs) and controlled-release fertilizers (CRFs) during the last few decades. These technologies have been developed mainly by manufacturers and are product-specific based on the regulation and analysis of each EEF product. Despite previous efforts to characterize EEF materials, no validated method exists to assess their nutrient release patterns. However, the increased use of EEFs in specialty and nonspecialty markets requires an appropriate method to verify nutrient claims and material performance. A series of experiments were conducted to evaluate the effect of temperature, fertilizer test portion size, and extraction time on the performance of a 74 h accelerated laboratory extraction method to measure SRF and CRF nutrient release profiles. Temperature was the only factor that influenced nutrient release rate, with a highly marked effect for phosphorus and to a lesser extent for nitrogen (N) and potassium. Based on the results, the optimal extraction temperature set was: Extraction No. 1-2:00 h at 25 degrees C; Extraction No. 2-2:00 h at 50 degrees C; Extraction No. 3-20:00 h at 55 degrees C; and Extraction No. 4-50:00 h at 60 degrees C. Ruggedness of the method was tested by evaluating the effect of small changes in seven selected factors on method behavior using a fractional multifactorial design. Overall, the method showed ruggedness for measuring N release rates of coated CRFs. PMID:25051611

  19. Breakthrough: Fermilab Accelerator Technology

    ScienceCinema

    None

    2014-08-12

    There are more than 30,000 particle accelerators in operation around the world. At Fermilab, scientists are collaborating with other laboratories and industry to optimize the manufacturing processes for a new type of powerful accelerator that uses superconducting niobium cavities. Experimenting with unique polishing materials, a Fermilab team has now developed an efficient and environmentally friendly way of creating cavities that can propel particles with more than 30 million volts per meter.

  20. Breakthrough: Fermilab Accelerator Technology

    SciTech Connect

    2012-04-23

    There are more than 30,000 particle accelerators in operation around the world. At Fermilab, scientists are collaborating with other laboratories and industry to optimize the manufacturing processes for a new type of powerful accelerator that uses superconducting niobium cavities. Experimenting with unique polishing materials, a Fermilab team has now developed an efficient and environmentally friendly way of creating cavities that can propel particles with more than 30 million volts per meter.

  1. CEBAF accelerator achievements

    SciTech Connect

    Y.C. Chao, M. Drury, C. Hovater, A. Hutton, G.A. Krafft, M. Poelker, C. Reece, M. Tiefenback

    2011-06-01

    In the past decade, nuclear physics users of Jefferson Lab's Continuous Electron Beam Accelerator Facility (CEBAF) have benefited from accelerator physics advances and machine improvements. As of early 2011, CEBAF operates routinely at 6 GeV, with a 12 GeV upgrade underway. This article reports highlights of CEBAF's scientific and technological evolution in the areas of cryomodule refurbishment, RF control, polarized source development, beam transport for parity experiments, magnets and hysteresis handling, beam breakup, and helium refrigerator operational optimization.

  2. Comparison of effects of VDR versus PXR, FXR and GR ligands on the regulation of CYP3A isozymes in rat and human intestine and liver.

    PubMed

    Khan, Ansar A; Chow, Edwin C Y; van Loenen-Weemaes, Anne-miek M A; Porte, Robert J; Pang, K Sandy; Groothuis, Geny M M

    2009-05-12

    In this study, we compared the regulation of CYP3A isozymes by the vitamin D receptor (VDR) ligand 1 alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) against ligands of the pregnane X receptor (PXR), the glucocorticoid receptor (GR) and the farnesoid X receptor (FXR) in precision-cut tissue slices of the rat jejunum, ileum, colon and liver, and human ileum and liver. In the rat, 1,25(OH)(2)D(3) strongly induced CYP3A1 mRNA, quantified by qRT-PCR, along the entire length of the intestine, induced CYP3A2 only in ileum but had no effect on CYP3A9. In contrast, the PXR/GR ligand, dexamethasone (DEX), the PXR ligand, pregnenolone-16 alpha carbonitrile (PCN), and the FXR ligand, chenodeoxycholic acid (CDCA), but not the GR ligand, budesonide (BUD), induced CYP3A1 only in the ileum, none of them influenced CYP3A2 expression, and PCN, DEX and BUD but not CDCA induced CYP3A9 in jejunum, ileum and colon. In rat liver, CYP3A1, CYP3A2 and CYP3A9 mRNA expression was unaffected by 1,25(OH)(2)D(3), whereas CDCA decreased the mRNA of all CYP3A isozymes; PCN induced CYP3A1 and CYP3A9, BUD induced CYP3A9, and DEX induced all three CYP3A isozymes. In human ileum and liver, 1,25(OH)(2)D(3) and DEX induced CYP3A4 expression, whereas CDCA induced CYP3A4 expression in liver only. In conclusion, the regulation of rat CYP3A isozymes by VDR, PXR, FXR and GR ligands differed for different segments of the rat and human intestine and liver, and the changes did not parallel expression levels of the nuclear receptors. PMID:19429418

  3. Oleanolic acid attenuates obstructive cholestasis in bile duct-ligated mice, possibly via activation of NRF2-MRPs and FXR antagonism.

    PubMed

    Chen, Pan; Li, Jingjie; Fan, Xiaomei; Zeng, Hang; Deng, Rongrong; Li, Dongshun; Huang, Min; Bi, Huichang

    2015-10-15

    Obstructive cholestasis is characterized by impairment of hepatic canalicular bile efflux and there are no clinically effective drugs to cure except surgeries. Previously we revealed that oleanolic acid (OA) protected against lithocholic acid (LCA)-induced intrahepatic cholestasis in mice. Cholestasis caused by LCA is characterized by segmental bile duct obstruction, whether OA possesses the beneficial effect on completed obstructive cholestasis induced by bile duct ligation (BDL) remains unknown. In this study, we demonstrated that BDL-induced mice liver pathological change, and increase in serum levels of ALT, AST and ALP were all significantly reduced by OA (20 mg/kg, i.p.). Meanwhile, OA also lowered total bilirubin and total bile acids levels in serum, as well as total bile acids level in liver, in contrast, urinary total bile acids output was remarkably up-regulated by OA. Gene expression analysis showed that OA caused significant increased mRNA expression of MRP3 and MRP4 located at hepatic basolateral membrane, and restoration of MRP2 and BSEP located at hepatic cannalicular membrane. Furthermore, significant NRF2 protein accumulation in nucleus was also observed in OA treated mice. In mice primary cultured hepatocytes, the effects of OA on MRP2, MRP3 and MRP4 expression were directly proved to be mediated via NRF2 activation, and BSEP downregulation induced by OA was in part due to FXR antagonism. Luciferase assay performed in Hep G2 cells also illustrated that OA was a partial FXR antagonist. Taken together, we conclude that OA attenuates obstructive cholestasis in BDL mice, possibly via activation of NRF2-MRPs and FXR antagonism. PMID:26297978

  4. Research on computed tomography reconstructions from one or two radiographs: A report and the application to FXR radiography

    SciTech Connect

    Back, N.; Schneberk, D.; McMillan, C.; Azevedo, S.; Gorvad, M.

    1995-01-26

    This report documents some cooperative research into volumetric image reconstruction from single radiographs. Imaging dynamic events is the most important application for this type of work, but the techniques have possible extensions. Two general objectives guide this work. The first objective is to gain an understanding of the assumptions and limitations of single-view methods for representing internal features. Second, we endeavor to obtain and/or develop techniques for performing image reconstructions with FXR radiographs. If possible, we seek to obtain some quantitative measure of the accuracy of this class of image reconstructions in two respects: (i) in terms of the dimensional accuracy of feature boundaries, and (ii) as pertains to the accuracy of the voxel intensities. Dynamic events are not always self-calibrating, and it is important to establish the reconstruction accuracy of single-view methods for placing bounds on the kinds of conclusions which can be advanced from single-view reconstructed images. Computed tomographic image reconstructions provide dimensional detail of internal structures of objects and provide a measure of the per-voxel attenuation of material in the object. When assumptions behind a reconstruction algorithm are not satisfied, or are satisfied in a limited way, the accuracy of the reconstructed image is compromised. It is the goal of Cr analysis to discern the {open_quotes}real{close_quotes} features of the internals of an object in the midst of a certain level of artifactual content in the image. By understanding the ways in which CT reconstructions from a single radiograph can produce misleading results we hope to develop some measure of the benefits and limitations of single view techniques. 31 refs., 20 figs.

  5. Plasma accelerators

    SciTech Connect

    Ruth, R.D.; Chen, P.

    1986-03-01

    In this paper we discuss plasma accelerators which might provide high gradient accelerating fields suitable for TeV linear colliders. In particular we discuss two types of plasma accelerators which have been proposed, the Plasma Beat Wave Accelerator and the Plasma Wake Field Accelerator. We show that the electric fields in the plasma for both schemes are very similar, and thus the dynamics of the driven beams are very similar. The differences appear in the parameters associated with the driving beams. In particular to obtain a given accelerating gradient, the Plasma Wake Field Accelerator has a higher efficiency and a lower total energy for the driving beam. Finally, we show for the Plasma Wake Field Accelerator that one can accelerate high quality low emittance beams and, in principle, obtain efficiencies and energy spreads comparable to those obtained with conventional techniques.

  6. A comparison of ALPHAScreen, TR-FRET, and TRF as assay methods for FXR nuclear receptors.

    PubMed

    Glickman, J Fraser; Wu, Xiang; Mercuri, Robert; Illy, Chantal; Bowen, Benjamin R; He, Yang; Sills, Matthew

    2002-02-01

    New developments in detection technologies are providing a variety of biomolecular screening strategies from which to choose. Consequently, we performed a detailed analysis of both separation-based and non-separation-based formats for screening nuclear receptor ligands. In this study, time-resolved fluorescence resonance energy transfer (TR-FRET), ALPHAScreen, and time-resolved fluorescence (TRF) assays were optimized and compared with respect to sensitivity, reproducibility, and miniaturization capability. The results showed that the ALPHAScreen system had the best sensitivity and dynamic range. The TRF assay was more time consuming because of the number of wash steps necessary. The TR-FRET assay had less interwell variation, most likely because of ratiometric measurement. Both the ALPHAScreen and the TR-FRET assays were miniaturized to 8-microl volumes. Of the photomultiplier tube-based readers, the ALPHAScreen reader (ALPHAQuest) presented the advantage of faster reading times through simultaneous reading with four photomultiplier tubes. PMID:11897050

  7. Shaping of pulses in optical grating-based laser systems for optimal control of electrons in laser plasma wake-field accelerator

    SciTech Connect

    Toth, Cs.; Faure, J.; Geddes, C.G.R.; van Tilborg, J.; Leemans, W.P.

    2003-05-01

    In typical chirped pulse amplification (CPA) laser systems, scanning the grating separation in the optical compressor causes the well know generation of linear chirp of frequency vs. time in a laser pulse, as well as a modification of all the higher order phase terms. By setting the compressor angle slightly different from the optimum value to generate the shortest pulse, a typical scan around this value will produce significant changes to the pulse shape. Such pulse shape changes can lead to significant differences in the interaction with plasmas such as used in laser wake-field accelerators. Strong electron yield dependence on laser pulse shape in laser plasma wake-field electron acceleration experiments have been observed in the L'OASIS Lab of LBNL [1]. These experiments show the importance of pulse skewness parameter, S, defined here on the basis of the ratio of the ''head-width-half-max'' (HWHM) and the ''tail-width-halfmax'' (TWHM), respectively.

  8. Optimization of an accelerated solvent extraction dispersive liquid-liquid microextraction method for the separation and determination of essential oil from Ligusticum chuanxiong Hort by gas chromatography with mass spectrometry.

    PubMed

    Yang, Guang; Sun, Qiushi; Hu, Zhiyan; Liu, Hua; Zhou, Tingting; Fan, Guorong

    2015-10-01

    In this study, an accelerated solvent extraction dispersive liquid-liquid microextraction coupled with gas chromatography and mass spectrometry was established and employed for the extraction, concentration and analysis of essential oil constituents from Ligusticum chuanxiong Hort. Response surface methodology was performed to optimize the key parameters in accelerated solvent extraction on the extraction efficiency, and key parameters in dispersive liquid-liquid microextraction were discussed as well. Two representative constituents in Ligusticum chuanxiong Hort, (Z)-ligustilide and n-butylphthalide, were quantitatively analyzed. It was shown that the qualitative result of the accelerated solvent extraction dispersive liquid-liquid microextraction approach was in good agreement with that of hydro-distillation, whereas the proposed approach took far less extraction time (30 min), consumed less plant material (usually <1 g, 0.01 g for this study) and solvent (<20 mL) than the conventional system. To sum up, the proposed method could be recommended as a new approach in the extraction and analysis of essential oil. PMID:26304788

  9. Spallator - accelerator breeder

    SciTech Connect

    Steinberg, M.

    1985-01-01

    The concept involves the use of spallation neutrons produced by interaction of a high energy proton (1 to 2 GeV) from a linear accelerator (LINAC) with a heavy metal target (uranium). The principal spallator concept is based on generating fissile fuel for use in LWR nuclear power plants. The spallator functions in conjunction with a reprocessing plant to regenerate and produce the Pu-239 or U-233 for fabrication into fresh LWR reactor fuel elements. Advances in proton accelerator technology has provided a solid base for predicting performance and optimizing the design of a reliable, continuous wave, high-current LINAC required by a fissile fuel production machine.

  10. 'Light Sail' Acceleration Reexamined

    SciTech Connect

    Macchi, Andrea; Veghini, Silvia; Pegoraro, Francesco

    2009-08-21

    The dynamics of the acceleration of ultrathin foil targets by the radiation pressure of superintense, circularly polarized laser pulses is investigated by analytical modeling and particle-in-cell simulations. By addressing self-induced transparency and charge separation effects, it is shown that for 'optimal' values of the foil thickness only a thin layer at the rear side is accelerated by radiation pressure. The simple 'light sail' model gives a good estimate of the energy per nucleon, but overestimates the conversion efficiency of laser energy into monoenergetic ions.